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Selected References

Alcohol and Related Disorders

Juhás M et al: Deep grey matter iron accumulation in alcohol use disorder. Neuroimage. 148:115-122, 2017

Volkow ND et al: Neurochemical and metabolic effects of acute and chronic alcohol in the human brain: studies with positron emission tomography. Neuropharmacology. 122:175-188, 2017

Logan C et al: Neuroimaging of chronic alcohol misuse. J Med Imaging Radiat Oncol. ePub, 2016

Wernicke Encephalopathy

Chamorro AJ et al: Differences between alcoholic and nonalcoholic patients with Wernicke encephalopathy: a multicenter observational study. Mayo Clin Proc. 92(6):899-907, 2017

Ashraf VV et al: Wernicke's encephalopathy due to hyperemesis gravidarum: clinical and magnetic resonance imaging characteristics. J Postgrad Med. 62(4):260-263, 2016

Hattingen E et al: Wernicke encephalopathy: SWI detects petechial hemorrhages in mammillary bodies in vivo. Neurology. 87(18):1956-1957, 2016

Liong CC et al: Nonalcoholic Wernicke encephalopathy: an entity not to be missed! Can J Neurol Sci. 43(5):719-20, 2016

Methanol Intoxication

Zakharov S et al: Acute methanol poisoning: prevalence and predisposing factors of haemorrhagic and non-haemorrhagic brain lesions. Basic Clin Pharmacol Toxicol. 119(2):228-38, 2016

Vaneckova M et al: Imaging findings after methanol intoxication (cohort of 46 patients). Neuro Endocrinol Lett. 36(8):737-44, 2015

Amphetamines and Derivatives

Montoya-Filardi A et al: The addicted brain: imaging neurological complications of recreational drug abuse. Radiologia. 59(1):17-30, 2017

Methamphetamine

Kish SJ et al: Brain dopamine neurone 'damage': methamphetamine users vs. Parkinson's disease - a critical assessment of the evidence. Eur J Neurosci. 45(1):58-66, 2017

Prakash MD et al: Methamphetamine: effects on the brain, gut and immune system. Pharmacol Res. 120:60-67, 2017

Wang TY et al: Pattern and related factors of cognitive impairment among chronic methamphetamine users. Am J Addict. 26(2):145151, 2017

London ED et al: Chronic methamphetamine abuse and corticostriatal deficits revealed by neuroimaging. Brain Res. 1628(Pt A):174-85, 2015

MDMA ("Ecstasy")

Mueller F et al: Neuroimaging in moderate MDMA use: a systematic review. Neurosci Biobehav Rev. 62:21-34, 2016

Cocaine

Shrot S et al: Acute brain injury following illicit drug abuse in adolescent and young adult patients: spectrum of neuroimaging findings. Neuroradiol J. 30(2):144-150, 2017

Opioids and Derivatives

Morgan DJ et al: 2016 Update on medical overuse: a systematic review. JAMA Intern Med. 176(11):1687-1692, 2016

Warner M et al: Drugs most frequently involved in drug overdose deaths: United States, 2010-2014. Natl Vital Stat Rep. 65(10):1-15, 2016

Heroin

Lefaucheur R et al: Leucoencephalopathy following abuse of sniffed heroin. J Clin Neurosci. 35:70-72, 2017

Inhaled Gases and Toxins

Carbon Monoxide Poisoning

Kim DM et al: Acute carbon monoxide poisoning: MR imaging findings with clinical correlation. Diagn Interv Imaging. 98(4):29930, 2017

Rose JJ et al: Carbon monoxide poisoning: pathogenesis, management and future directions of therapy. Am J Respir Crit Care Med. 195(5):596-606, 2017

Tsai PH et al: Early white matter injuries in patients with acute carbon monoxide intoxication: a tract-specific diffusion kurtosis imaging study and STROBE compliant article. Medicine (Baltimore). 96(5):e5982, 2017

Nitrous Oxide

Sellers WF: Misuse of anaesthetic gases. Anaesthesia. 71(10):1140- 3, 2016

Toluene Abuse

Jayanth SH et al: Glue sniffing. Med Leg J. 85(1):38-42, 2017

Treatment-Related Disorders

Radiation Injury

Lumniczky K et al: Ionizing radiation-induced immune and inflammatory reactions in the brain. Front Immunol. 8:517, 2017

Balentova S et al: Molecular, cellular and functional effects of radiation-induced brain injury: a review. Int J Mol Sci. 16(11):27796815, 2015

Chemotherapy Effects

Rossi Espagnet MC et al: Magnetic resonance imaging patterns of treatment-related toxicity in the pediatric brain: an update and review of the literature. Pediatr Radiol. 47(6):633-648, 2017

Effects of Surgery

Ashayeri K et al: Syndrome of the trephined: a systematic review. Neurosurgery. 79(4):525-34, 2016

Kleinschmidt-DeMasters BK: Textiloma (Muslinoma, Gauzoma, Gossypiboma). In: Diagnostic Pathology: Neuropathology, 2e, edited by Burger P et al. Salt Lake City, UT: Elsevier, 2016, pp 716721

Vasung L et al: Radiological signs of the syndrome of the trephined. Neuroradiology. 58(6):557-68, 2016

Inherited metabolic disorders (IMDs)—also known as inborn errors of metabolism—represent conditions in which a genetic defect leads to a deficiency of a protein (e.g., enzyme or non-enzyme protein) that subsequently affects mechanisms of synthesis, degradation, transport, and/or storage of molecules in the body. IMDs are relatively uncommon diseases that pose diagnostic dilemmas for clinicians and radiologists alike. IMDs can present at virtually any age from infancy well into the fifth and sixth decades, although infantile and childhood presentation is most common.

Symptoms vary among the various disorders and within the degree of severity in patients with the same disorder. As radiologists, in the process of constructing an ordered, differential diagnosis, keeping the category of IMD in mind will serve our patients well. IMDs may mimic hypoxic ischemic injury (HII), sepsis, and CNS abnormalities attributed to underlying vascular (e.g., stroke) and congenital heart diseases. The most immediate impact on patient well-being of making a timely diagnosis of IMD is that many of these conditions can be treated effectively. Rapid therapeutic intervention can avoid irreversible brain injury. Additionally, if the IMD diagnosis is associated with a defined pattern of inheritance, this information is essential to parents who may be considering having other children. Our focus here will be on disorders most often presenting in the newborn, infant, and child.

Family history often provides clues to the diagnosis of IMDs. These clues include (1) families that are known to have members with IMD, (2) neonatal deaths that have occurred without cause, and (3) unexplained severe and progressive illness in childhood. When history is strongly suggestive of IMD in advance of childbirth, a rapid diagnostic and treatment plan can be established prior to parturition.

In utero, the placenta serves the function of an effective dialysis unit, removing toxic metabolites. Therefore, the newborn and young infant with some inherited metabolic disorders may initially appear clinically sound. The specific metabolic disorder will dictate, in large part, the pace of clinical presentation. The expression of this dysfunction may range between sudden neonatal death in the first few weeks of life to gradual deterioration after a symptom-free intmoyaerval of months to years. Interestingly, IMDs are rarely associated with premature birth.

The neonatal and young infant repertoire of physiologic responses to severe illness is limited. Respiratory distress, lethargy, weak suck, poor feeding, weight loss, vomiting, diarrhea, and dehydration are individually and in aggregate nonspecific symptoms and signs that may herald an underlying

IMD. Older affected children and adolescents may exhibit seizures, movement disorders, hypotonia, ataxia, autism, or delayed achievement of developmental milestones. Some IMDs will present with developmental delay including features of autism. Thus, there is a broad range of phenotypes among those affected.

In conceptualizing IMDs, consider these broad categories: (1) disorders that give rise to intoxication symptoms —accumulation of toxic compounds (e.g., maple syrup urine disease); (2) disorders involving energy metabolism—symptoms arising from a deficiency in energy production or utilization (e.g., mitochondrial defects, creatine deficiency states); (3) disorders involving large or complex molecules—abnormalities arising from disordered synthesis and/or catabolism of molecules that accumulate in cellular organelles (e.g., lysosomal—Gaucher disease or peroxisomal—Zellweger disease); (4) disorders involving neurotransmitters (e.g., glycine, serine, and pterin metabolism); and (5) other inherited disorders.

Neuroimaging has great potential to improve diagnostic accuracy (e.g., in some cases clinching the diagnosis—MRS and creatine deficiency states), follow therapeutic interventions, and monitor disease progression in patients afflicted with

IMDs. The informed radiologist can merge his or her understanding of the pathogenetic and pathomorphologic underpinnings of the various IMDs with imaging observations. Specifically, we observe what part of the brain is involved (e.g., GM vs. WM), what kind of involvement is present (e.g., cortex, basal ganglia, white matter—subcortical, deep, or periventricular), and what locations are most affected (e.g., frontal lobes). Additional information such as the presence of cysts, calcifications, diffusion restriction, and pathologic enhancement aids in crystallizing the imaging differential diagnosis.

MR is routinely obtained in newborns, infants, and children with delayed neurologic development and when they present with neurologic disorders. Familiarization with the normal progression of white matter myelination is a prerequisite for detecting and understanding IMDs, as many of the metabolic derangements to be discussed exhibit early disturbance in the anticipated progression of myelination. We therefore begin this chapter with a review of how normal myelination progresses from birth through 2 years of life. DWI/DTI and MRS have become important adjunctive MR sequences to the comprehensive MR examination.

Once we have reviewed the patterns of normal myelination as assessed with MR, we continue with an overview and introduction of the IMDs. A discussion of classification systems is a recommended and practical approach to analyzing imaging. Selected discussion of the leukodystrophies and nonleukodystrophic white matter disorders focuses on abnormal myelin development, myelin degeneration, and hypomyelination. Those IMDs most often clinically encountered will be emphasized.

Normal Myelination and

White Matter

Development

General Considerations

Myelination

Myelination is an orderly, highly regulated, multistep process that begins during the fifth fetal month and is largely complete by 18-24 postnatal months. Some structures (e.g., cranial nerves) myelinate relatively early in fetal development, whereas others (e.g., optic radiations and fibers to/from association areas) often do not completely myelinate until the third or even the fourth decade of life. CNS myelin is produced by oligodendrocytes. The myelin sheath consists of multiple double membranes wrapped radially around axons. Myelin is rich in lipids, including cholesterol, glycolipids, and phospholipids.

Importantly, because white matter abnormalities form a constant part of many if not most inborn metabolic diseases, it is imperative that the radiologist have a firm grasp on normal patterns of myelination.

Brain myelination is an event involving more than oligodendrocytes; it is an interaction between oligodendrocytes, axons, astrocytes, and many soluble factors. Normal myelination follows a typical topographical pattern, progressing from inferior to superior, central to peripheral, and posterior to anterior. For example, the brainstem myelinates before the peripheral cerebellar hemispheres, the posterior limbs of the internal capsules myelinate before the anterior limbs, and the deep periventricular white matter (WM) myelinates before the subcortical U-fibers. The dorsal brainstem myelinates before the anterior brainstem, and—with the exception of the parietooccipital association tracts—occipital WM myelinates earlier than WM in the anterior temporal and frontal lobes.

CT

The hemispheres of normal term infants at birth appear well formed. The gyral pattern is mature with distinctly defined cortex and surface sulci. The lateral cerebral (sylvian) fissures may be slightly prominent but generally resemble those seen in older children. The frontal subarachnoid spaces and basal cisterns often appear prominent up to 1 year of age.

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At birth, the WM is largely unmyelinated, so it appears quite hypoattenuating compared with regional gray matter due to the comparatively high water content of WM. There is a symmetry to the peripheral, deep, and periventricular pattern of normal neonatal and early infantile unmyelinated WM.

MR

MR allows visualization of the process of myelination. The appearance of WM maturation varies with two important factors, i.e., patient age and the imaging sequence employed. MR remains the imaging gold standard when it comes to in vivo assessment of brain formation, organization, and myelin maturation.

Unmyelinated WM is hypointense relative to gray matter on T1WI and hyperintense to gray matter on T2WI. As the WM matures, it becomes more hyperintense (T1 shortening) on T1WI. T1 shortening is related to water molecules within the myelin sheath that are tightly bound to macromolecules and the high myelin content of cholesterol and galactocerebroside. In fact, there are several properties of maturing WM that can be studied on clinical MR scanners and used in the clinical care arena. The normal progressive T2 shortening (hypointensity) that occurs in the first 2 years of life is due mainly to decreasing proton density within maturing myelin.

Consider these normal WM MR findings within the first 2 years of life: T1 and T2 shortening, decreasing mean diffusivity, decreased radial diffusivity, increased fractional anisotropy (FA), increased magnetization transfer, and increased bound water fraction of WM. In aggregate, during the normal myelin maturational period, the increasingly complex intracellular and extracellular structures that transiently bind water molecules exhibit dynamic T1/T2 relaxivity and diffusivity characteristics that affect T1 and T2 prolongation. Simply put, normal myelin maturation results in progressively reduced water content with MR demonstrating T1 hyperintensity and T2 hypointensity.

During the first 6-8 months of life, T1 shortening occurs earlier and is more conspicuous than T2 shortening. Therefore,T1weighted sequences are best both to evaluate WM maturation and brain morphology. Partially myelinated structures will have high signal on T1 and T2 sequences (T1 and T2 shortening). Heavily weighted T2 sequences are sensitive to follow WM maturation between 6 and 18 months and to help characterize cortical organization and to assess other gray matter structures.

Therefore, fully myelinated WM has high T1 signal and low T2 signal. Normal myelin maturation results in progressively reduced WM water content with concomitant T2 hypointensity. The radiologist makes a mental note when interpreting MR examinations in the first 6 months of life that T1 shortening normally occurs before T2 shortening and is more prominent and that normal myelin T1 and T2 signal intensities vary during the process of myelination.

In the clinical neuroimaging arena, at a minimum, accurate evaluation of myelination status requires both T1 and T2 sequences with orthogonal planes advised. More advanced

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techniques such as DTI, magnetization transfer imaging (MTI), and T1/T2 relaxometry may provide additional information but do not supplant the utility of spin magnitude imaging. When in doubt about the pediatric patient's myelination status, particularly if a pathologic state of myelination is suspected, repeat MR in 6 months, and make sure that at least one of the MR examinations has been performed at or after the first year of life.

DWI/DTI. DWI/DTI is an important MR adjunct. Acute demyelination is often associated with restricted diffusion. Certain diffusion patterns are strongly suggestive of specific inborn errors of metabolism [e.g., crenulated ribbon of restricted diffusion at the depth of cerebral hemispheric sulci in urea cycle disorders, juxta-ventricular diffusion restriction in phenylketonuria (PKU), cerebellar WM and four bright dots of pontine diffusion restriction in maple syrup urine disease, and "worst case ever of hypoxic-ischemic encephalopathy-like DWI abnormalities" in isolated sulfite oxidase deficiency].

Magnetic Resonance Spectroscopy. A lactate doublet at 1.3 ppm is a nonspecific indicator of disturbed oxidative metabolism and may be seen in several inherited metabolic disorders. A prominent resonant peak at 3.55 ppm on long TE proton spectroscopy aquisitions is characteristic of nonketotic hyperglycinemia (myoinositol at 3.6 ppm is seen only at short TES). The PKU peak at 7.4 ppm is out of range of the standard clinical x-axis display.

Imaging of Normal Myelination

Selected major milestones of normal myelination on T1and T2-weighted images are summarized earlier in the chapter (Table 31-1) and discussed in greater detail here. The radiologist who has committed these normal MR milestones to memory will be well suited to detect early pathologic states of myelination. Although a nonspecific finding, disordered myelination is common among many inborn metabolic errors or inborn errors of metabolism.

throughout the third month of life. The entire PLIC becomes hyperintense by the end of the second month and the entire anterior limb of internal capsule by the third month of life. As an aside, the presence of the normal T1 hyperintense myelin marker in the PLIC in the newborn is an important marker when profound hypoxic ischemic injury (HII) to the deep nuclei is suspected.

T2WI. On T2WI, the WM of a term newborn infant resembles that of a T1 image in an adult, i.e. it has higher signal relative to gray matter. Hypointensity can be seen in corticospinal tract and dorsal brainstem, PLIC, and ventrolateral thalamus. The dentate nuclei of the cerebellum consist of gray matter and thus also appear hypointense. Normal T2 hypointensity is seen at birth within the brainstem cranial nerve nuclei and within the inferior and superior cerebellar peduncles. Always check for the presence of the normal newborn linear T2 hypointensity (myelin marker) within the PLIC when profound HII is suspected.

At birth, the rolandic and perirolandic gyri of the cortex appear quite hypointense. This corresponds to known early myelination of the WM within these gyri. An ill-defined "smudgy" hypointensity in the WM underlying the rolandic/perirolandic gyri is a normal finding shortly after birth.

Three to Six Months

T1WI. The anterior limb of the internal capsule and the proximal, most central WM of the cerebellar folia become hyperintense by three postnatal months (31-1). High signal appears in the splenium of the corpus callosum (CC) by 4 months and can be identified in the genu at 6 months (31-2). Remember, the CC myelinates from back to front.

T2WI. Focal linear low signal appears in the PLIC at the location of the corticospinal tracts normally at birth and represents an important landmark in assessing neonatal health. The entire PLIC and splenium of the CC show hypointensity at 6 months.

Birth to Three Months

T1WI. Compared with the timing of neuronal migration and sulcation, normal myelination lags in the fetus. However, during the early third trimester, the dorsal brainstem myelination is advancing.

On T1-weighted sequences, the brain of a full-term newborn resembles an adult's on T2WI, i.e., most of the cerebral WM has lower signal than gray matter. The dorsal brainstem (medial longitudinal fasciculus, medial and lateral lemnisci), decussation of the superior cerebellar peduncles, central cerebellar WM, posterior limb of the internal capsule (PLIC), ventrolateral thalami, corticospinal tracts, and the deep corona radiata adjacent to the lateral ventricles exhibit T1 hyperintensity (myelinated) in the normal term newborn. In the newborn posterior fossa, look for T1 hyperintensity within the brachium of the inferior colliculus and within the inferior and superior cerebellar peduncles.

At birth and throughout the first month of life, there is progressive hyperintensity within the central cerebellar hemispheres. This normal myelination proceeds peripherally

The last normal regions of T2 hypointensity are the orbital region of the frontal lobes and the most anterior temporal lobes. This normal progression of T2 hypointensity may not be complete until 28-30 months. WM in the deep corona radiata extending from the motor cortex toward the lateral ventricle body myelinates early, appearing "smudgy" and slightly hypointense (31-2).

Potential diagnostic pitfall: normal tiny foci of T2 hypointensity may be seen immediately anterior to the frontal horn tips in preterm and term newborns. These represent small aggregates of germinal matrix and typically vanish by 44 postconceptual weeks. These should not be misdiagnosed as gray matter heterotopia.

Six Months to One Year

T1WI. The WM assumes a near-adult appearance by 8 months with hyperintensity extending throughout most of the cerebellum and hemispheric WM. The corona radiata is almost completely hyperintense except for its most anterior and peripheral fibers.

Continued normal progression of T1 hyperintensity within the subcortical white matter is seen through the seventh month of life in the occipital white matter and through 8-11 months in the frontal and temporal white matter. Only minimal T1 hyperintensity changes are normally seen after 11 months. By 11-12 months, the WM resembles that of an adult with hyperintensity extending into most of the subcortical U-fibers. Only the anterior temporal and most peripheral frontal lobe WM remain unmyelinated, appearing isointense with the overlying cortex (31-3).

T2WI. Hypointensity appears throughout the CC genu by 8 months and in the anterior limb of the internal capsule by 11 months. The basal ganglia demonstrate diminishing T2 signal compared with subcortical WM by 5-7 months of life. Most of the deep WM tracts of the cerebral hemispheres show progressive hypointensity between 6 and 12 months of life. The subcortical WM with the exception of the perirolandic and calcarine regions (which demonstrate early T2 hypointensity) continues (from posterior to anterior) to demonstrate T2 hypointensity. Within the cerebral hemispheric WM, occipital hypointensity is seen by 12 months, and frontal subcortical WM hypointensity is seen by 20 months.

Historically, it has been said that subcortical WM myelination (T2 hypointensity) was complete by 24 months of life. However, with improvements in MR hardware and software, we know that peripheral myelin T2 hypointensity is complete closer to 30 months, at which time the WM assumes a nearadult appearance. The caveat or pitfall is the persistence of T2 hyperintensity that is seen in the normal terminal zones (see below).

Two Years to Adulthood

T1WI. Although little discernible T1 hyperintensity change is appreciated by most radiologists after 11 months of patient age, the anterior temporal lobe WM does not become completely hyperintense on T1 scans until 24-30 months. Although WM myelination is visually complete at this age, functional MR studies demonstrate that some active myelination continues well into adolescence.

T2WI. It is common to see symmetric brush-border-like high signal intensity regions in the WM, both lateral and dorsal to the atria of the lateral ventricles. These parietal and parietal occipital regions of association fibers (terminal zones) of incompletely myelinated WM are considered a normal finding. Terminal zones are isointense to surrounding WM on proton density, show an interposed zone or collar of normally myelinated WM between the ventricular ependyma and the terminal zones, and are not affiliated with signs of volume loss. Terminal zones may remain hyperintense on T2WI well into the second or even third decade (31-3D) (31-3F) (314D).

The term terminal zones was coined due to the fact that some axons in these association regions may not stain for myelin until the fourth decade of life.

Scattered punctate and linear T2 hyperintense WM foci that suppress completely on FLAIR are also common. These are

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normal perivascular (Virchow-Robin) spaces and occur at all ages.

Classification of Inherited

Metabolic Disorders

Overview

The sheer number and variety of inherited metabolic disorders (IMDs) are overwhelming. New entities together with their MR findings are constantly added to the evergrowing list of these disorders. Moreover, identifying one of these elusive diseases is a multidisciplinary endeavor requiring, not only correct interpretation of imaging features, but also appreciation at times of the subtle and nonspecific clinical derangements, pathogenetics, and biochemical defect(s) of IMDs. In some cases, brain, skin, or muscle biopsy may be necessary to establish a definitive diagnosis. Adding to these diagnostic challenges for clinician and radiologist alike are the facts that these disorders are rare and that the accumulated individual experience that a physician has in diagnosing and treating IMDs throughout a lifetime practice is often limited.

An exhaustive discussion of IMDs is far beyond the scope of this book. The interested reader is referred to the superb definitive texts by A. James Barkovich. In this chapter, we consider the major and some of the less common but important inherited neurometabolic diseases, summarizing the pathoetiology, genetics, demographics, clinical presentation, and key imaging findings of each.

CLASSIFICATION OF IMDs RESULTING FROM

ACCUMULATION OR DEFICIENCY OF SPECIFIC

METABOLITES

•Disorders of intermediary metabolism

•Amino acid metabolism

•Fatty acid oxidation and ketogenesis

•Carbohydrate metabolism

•Vitamin-related disorders

•Mitochondrial energy metabolism

•Mineral and peptide metabolism

•Disorders of biosynthesis and breakdown of complex molecules

•Peroxisomes

•Lysosomes

•Purine and pyrimidine metabolism

•Glycosylation

•Lipoprotein metabolism

•Bile acid and Heme metabolism

•Disorders of neurotransmitter metabolism

•Glycine and serine metabolism

•Pterin and biogenic amine metabolism

•γ-Aminobutyrate metabolism

We begin by considering several approaches to classifying these unusual but fascinating disorders. There are several strategies that can be used to conceptually frame IMDs. One way is to divide IMDs according to which cellular organelle

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(e.g., mitochondria, lysosomes) is predominantly affected. Another characterizes them by defects in a specific metabolic pathway (e.g., disorders of carbohydrate metabolism). Although intellectually sound, these methods lack the kind of pragmatic approach needed by the radiologist to be a contributing member of the clinical care team. To this end, we will emphasize—and advocate the use of—an approach to imaging analysis pioneered by A. James Barkovich that is primarily based on anatomic location and specific imaging features with an emphasis on MR—the imaging-based approach.

Organelle-Based Approach

Three cellular organelles are primarily affected in IMDs, i.e., the lysosomes, peroxisomes, and mitochondria. Classifying IMDs according to the affected organelle has the benefit of conceptual simplicity. However, many IMDs do not arise from disordered organelle formation or function, making this classification scheme less than comprehensive.

Lysosomal Diseases

Lysosomal disorders are characterized by abnormal lysosomes and disordered carbohydrate metabolism. The frequency of lysosomal disorders varies widely with geographic distribution. Some are far more frequent in certain locations because of the high prevalence of founder mutations.

The mucopolysaccharidoses are the classic lysosomal storage disorders. They result from deficiencies of enzymes involved in the degradation of mucopolysaccharides (glycosaminoglycans). Incompletely degraded mucopolysaccharides accumulate in the lysosomes, which often become enlarged and vacuolated. Prototypical mucopolysaccharidoses include Hurler, Hunter, Sanfilippo, and Morquio syndromes.

The gangliosidoses are rare lysosomal storage disorders characterized by deficient β-galactosidase. Abnormal oligosaccharides accumulate in the brain and viscera. Typical disorders are GM1 and GM2 gangliosidoses (Tay-Sachs and Sandhoff diseases, respectively).

Peroxisomal Disorders

Peroxisomes contain multiple enzymes essential for normal growth and development. Inherited peroxisomal disorders can result in lack of organelle development or normally formed peroxisomes that nonetheless have disordered or deficient function of a single enzyme.

Deficiencies in peroxisomal formation result in syndromes such as Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease. Disorders in which the peroxisomes are formed but function improperly include X-linked adrenoleukodystrophy and classic Refsum disease.

Mitochondrial Disorders

Mitochondrial disorders, also called respiratory chain disorders, are characterized by abnormal mitochondrial

function. The result is impaired ATP (energy) production in affected cells.

Some mitochondrial disorders predominantly or exclusively affect striated muscle and therefore are not discussed in this text. Important mitochondrial encephalopathies include Leigh syndrome, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), Kearns-Sayre syndrome (KSS), and glutaric aciduria types 1 and 2.

ORGANELLE-BASED CLASSIFICATION OF IMDs

Lysosomal Disorders

•Mucopolysaccharidoses

•Gangliosidoses

•Metachromatic leukodystrophy

•Krabbe disease

•Fabry disease

Peroxisomal Disorders

•Abnormal peroxisomal formation

○Zellweger syndrome

○Neonatal adrenoleukodystrophy

○Infantile Refsum disease

•Abnormal peroxisomal function

○X-linked adrenoleukodystrophy

○Classic Refsum disease

Mitochondrial Disorders

•Leigh syndrome

•MELAS

•MERRF

•Kearns-Sayre

•Glutaric aciduria types 1 and 2

Metabolic Approach

Many IMDs result in accumulation of one or more abnormal metabolites such as ammonia, copper, or iron degradation products. These IMDs are summarized below and discussed in more detail later in the chapter.

Organic/Aminoacidopathies and Urea Cycle

Disorders

The aminoacidopathies and urea cycle disorders result from disrupted nitrogen elimination and are characterized by hyperammonemia and elevated glutamine levels. Typical urea cycle disorders include maple syrup urine disease, methylmalonic acidemia, ornithine transcarbamylase deficiency, and citrullinemia.

Canavan disease is characterized by N-acetyl-L-aspartate (NAA) aciduria and NAA accumulation in the brain, which causes striking spongy degeneration.

Alexander disease results from mutations in the gene that encodes glial fibrillary acidic protein. Massive accumulation of Rosenthal fibers in astrocytes results in macrocephaly and a paucity of myelin in the frontal white matter.

Disorders of Copper Metabolism

Copper is an essential trace element required by all living organisms. However, excessive amounts of copper damage cells. Disruptions to normal copper homeostasis are the hallmarks of three genetic disorders: Wilson disease, Menkes disease, and occipital horn disease.

Brain Iron Accumulation Disorders

Iron accumulates within the basal ganglia and dentate nuclei during normal aging. A group of genetic disorders termed neurodegeneration with brain iron accumulation (NBIA) are characterized by brain iron deposition in abnormal amounts and in abnormal locations. Neuronal death results.

SELECTED DISORDERS OF INTERMEDIARY

METABOLISM

•Amino acid disorders

•Phenylketonuria

•Maple syrup urine disease

•Homocystinuria

•Galactosemia

•Tyrosinemia

•Disorders of glycogenesis (glycogen storage diseases, GSD)

•Glucose-6-phosphatase deficiency (GSD1, von Gierke disease)

•Lysosomal acid maltase deficiency (GSD2, Pompe disease)

•Disorders of gluconeogenesis

•Pyruvate carboxylase deficiency

•Pyruvate dehydrogenase deficiency

•Fatty acid oxidation disorders

•Organic acidurias (propionic, methylmalonic, isovaleric)

•Very-long-chain acyl-coenzyme A dehydrogenase deficiency

•Selected mitochondrial disorders

•Glutaric acidemia type 1

•Leigh syndrome

•Mitochondrial encephalopathy lactic acidosis and stroke (MELAS)

•Myoclonic epilepsy, ragged red fiber disease (MERRF)

•Kearns-Sayre

Imaging-Based Approach

Barkovich et al. have elaborated a practical imaging-based approach to the diagnosis of IMDs derived from the seminal work of van der Knaap and Valk. This approach is based on determining whether the disease involves primarily or exclusively (1) WM, (2) mostly GM, or (3) both. Furthermore, a heightened awareness of the region of the brain most heavily involved (e.g., periventricular WM vs. subcortical white matter or frontal lobe vs. parietal occipital lobes) and the presence of miscellaneous findings (e.g., cysts and/or calcifications) leads to greater specificity in the radiologist's differential diagnosis. In some cases, the aggregate of imaging findings leads to a specific unequivocal diagnosis (e.g., the MR and MRS findings in creatine transporter deficiency states).

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In this text, we follow the imaging-based approach, the clinically practical classification based on the three abovementioned categories of predominant imaging features (e.g., WM, GM, or both being involved). General findings for each individual category are delineated at the beginning of each section. We then discuss the major diagnostic entities in each imaging-based group. It is important to recognize that early imaging assessment with any IMD is of paramount importance, as the end-stage MR findings of these disorders may significantly overlap.

IMDs Predominantly

Affecting White Matter

Historically, nearly all abnormalities of the white matter (WM) have been described as "leukodystrophies." The term leukodystrophy unfortunately is often loosely applied to all heritable disorders with WM changes on MR. "Leukodystrophies" have been further divided into three categories: (1) dysmyelinating disorders (i.e., normal myelination does not occur), (2) demyelinating disease (i.e., myelin forms normally, is deposited around axons, but later breaks down or is destroyed), and (3) hypomyelinating diseases (i.e., here the WM may partially myelinate but never myelinates completely). Hypomyelinating leukoencephalopathies represent an important yet uncommon group of genetic disorders that cause delayed myelin maturation or undermyelination.

Updating our understanding and usage of terminology leads to greater understanding of the pathomorphology, genetics, and imaging characteristics of many disorders affecting WM, often becoming clinically evident in infants and children.

Leukodystrophies are inherited disorders caused by an inborn metabolic defect. Leukodystrophies are characterized histopathologically by demyelination and clinically by progressive neurologic deterioration, often leading to death. Well-recognized leukodystrophies include metachromatic leukodystrophy, globoid cell leukodystrophy (Krabbe disease), and X-linked adrenoleukodystrophy. Key leukodystrophy elements include heritable inborn metabolic error and demyelination and inexorable clinical progression.

Of equal importance in the discussion of inherited WM abnormalities is the category of nonleukodystrophic white matter changes (NLWMC). Here, the histopathology may show arrested or highly delayed myelination, abnormal and irregular myelination, gliosis, spongiosis of the WM without demyelination, small WM infarctions, or enlarged VirchowRobin spaces. Unlike many leukodystrophies, NLWMCs demonstrate a more indolent clinical picture and greater variability in the spectrum of MR abnormalities. Key NLWMC elements include disorders that are typically inherited, varied histopathology (i.e., demyelination not principle), and more indolent clinical progression.

From an imaging perspective, it can be difficult to determine whether a disorder is dysmyelinating, demyelinating, or hypomyelinating. In structuring a differential diagnosis, it is

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(31-5A) Axial NECT in 6y boy with MLD shows periventricular WM hypoattenuation . The subcortical U-fibers are spared .

(31-5B) Axial T2WI shows WM demyelination (hyperintensity) . Note "granular" hypointense frontal perivenular myelin sparing .

(31-5C) Axial FLAIR shows the "butterfly" pattern of MLD. U-fibers appear normal . CC and PLIC are involved.

important to determine whether the disorder primarily affects deep (periventricular) WM or the subcortical short association WM fibers (U-fibers). In a few diseases, both the deep and peripheral WM are affected.

Examples of leukodystrophies that exhibit early deep WM predominance include metachromatic leukodystrophy and X-linked adrenoleukodystrophy. Leukodystrophies that involve the subcortical U-fibers early in the disease course include megaloencephalic leukoencephalopathy with cysts and infantile Alexander disease. The latter two diagnoses also present with a large head.

Diseases in which virtually all the WM (both periventricular and subcortical) remains unmyelinated are rare. The imaging appearance in these disorders resembles that of a normal newborn brain with immature, almost completely unmyelinated WM. Here the entire WM—including the subcortical U-fibers—appears uniformly hyperintense on T2WI.

A good imaging rule of thumb, when interpretation of the MR in a newborn or infant suggests a disorder of the WM, is to repeat the MR in 6 months. Ideally, one of the MR examinations should follow the child's first birthday. This is particularly helpful in the hypomyelinating disorders in which there will be no discernible interval improvement in myelin milestones as assessed by MR.

Periventricular White Matter Predominance

The prototypical disorder that typically begins with symmetric deep WM involvement and spares the subcortical U-fibers until late in the disease course is metachromatic leukodystrophy (MLD). Others with a similar pattern of periventricular predominance include Krabbe disease (globoid cell leukodystrophy), X-linked adrenoleukodystrophy, and vanishing WM disease (VWMD).

MAJOR IMDs WITH PERIVENTRICULAR WM PREDOMINANCE

Common

•Metachromatic leukodystrophy

•Classic X-linked adrenoleukodystrophy

Less Common

•Globoid cell leukodystrophy (Krabbe disease)

•Vanishing WM disease

Rare But Important

•Phenylketonuria

•Maple syrup urine disease

•Merosin-deficient congenital muscular dystrophy

Metachromatic Leukodystrophy

Terminology. MLD, also known as sulfatide lipoidosis, is a devastating lysosomal storage disease caused by a reduction in or complete absence of arylsulfatase A (ARSA), resulting in the intralysosomal accumulation of sphingolipid sulfatide in tissues including the CNS and peripheral nervous system (PNS).

Etiology. MLD is caused by reduction of or complete absence of ARSA with failure of myelin breakdown and reutilization. It affects the CNS, PNS, and other tissues. Reduced or absent ARSA leads to increased lysosomal storage of sulfatide and eventually lethal demyelination. The late stage of disease is associated with progressive demyelination and diffuse cerebral atrophy.

ARSA gene is located at 22q13.31-qter. Over 110 mutations have been reported. Earlier onset is associated with greater reduction in ARSA.

Pathology. Grossly, a brain affected by MLD may be normal or demonstrate mild volume loss. Initially, the periventricular WM shows a grayish discoloration (e.g., "tigroid" or "leopard " pattern) with relatively normal-appearing subcortical U-fibers.

Demyelination is the main histopathologic feature and affects both the CNS and PNS. Characteristic PAS + material, reflecting brownish metachromasia (for which the disorder is named), is seen with acidic cresyl violet stain and represents intracellular deposits of cholesterol, phospholipids, and sulfatides. Deposition occurs within glial cells, plasma membranes, inner layer of myelin sheath, neurons, Schwann cells, and macrophages. Tissue assays for ARSA are positive. There is a distinctive lack of inflammation in the regions that demonstrate demyelination.

Clinical Issues. MLD is one of the most common of all inherited WM disorders with a prevalence of 1:100,000 live births. MLD is more common among Habbani Jews and Navajo American Indians. Prognosis is variable based on the

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clinical form of disease. The initial signs of MLD may appear at any age.

Three distinct clinical forms are currently recognized, late infantile (onset earlier than 3 years), juvenile (onset earlier than 16 years), and adult MLD. The late infantile form is the most common and typically presents in the second year of life with visuomotor impairment, gait disorder, and abdominal pain. Progressive decline and death within 4 years are expected. The juvenile form presents between 5-10 years, often with deteriorating school performance. Survival beyond 20 years is rare. The adult form may present with early-onset dementia, MS-like symptoms, and progressive cerebellar signs.

Established treatment options include hematopoietic stem cell transplantation. Therapies such as enzyme replacement and gene therapy with oligodendroglial or neural progenitor cells are still experimental.

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Imaging. The early imaging hallmark of MLD is a confluent butterfly-shaped pattern of deep cerebral hemispheric altered CT attenuation and MR signal intensity. Depending on the clinical form of disease, the imaging changes may be rapidly progressive.

CT Findings. Early NECT shows symmetric diminished attenuation involving the central cerebral hemispheric white matter (31-6). CECT shows no enhancement, and CT perfusion demonstrates reduced perfusion to the hemispheric WM. Cerebral atrophy is an expected nonspecific late finding.

MR Findings. The typical MR features of early MLD are confluent, symmetric, butterfly-shaped hyperintensities (i.e., T2/FLAIR) involving the periventricular WM. The subcortical U- fibers and cerebellum are typically spared until late in the disease. Serial MR shows a centrifugal spread of confluent T2/FLAIR hyperintensity. With disease progression, demyelination involves the corpus callosum (i.e., splenium), parietooccipital WM, and the frontal and then the temporal WM. Eventually, the progressive subcortical demyelination involves the subcortical U-fibers. Additional sites of late involvement include the corpus callosum, pyramidal tracts, and internal capsules. Islands of normal myelin around medullary veins in the WM may produce a striking "tiger," "tigroid," or "leopard" pattern with linear hypointensities in a sea of confluent hyperintensity (31-7). This tigroid pattern reflects early sparing of perivenular myelin. No enhancement is seen on T1 C+. A few cases of MLD have been reported with enlarged, enhancing cranial nerves and/or cauda equina nerve roots.

DWI/DTI. Reduction of diffusivity in zones of active demyelination is seen. Regions of "burnt-out," aging, or chronic demyelination demonstrate increased diffusivity.

MRS. Nonspecific elevation of choline and myoinositol may be seen in early and active disease (31-6) (31-8).

Differential Diagnosis. The major differential diagnosis of MLD includes other IMDs that primarily affect the periventricular WM. Globoid cell leukoencephalopathy (Krabbe disease) shows bithalamic hyperattenuation on NECT, involves the cerebellum early, and often demonstrates enlarged optic nerves and optic chiasm.

Pelizaeus-Merzbacher disease usually presents in neonates and shows almost total lack of myelination that does not show interval improvement on serial MRs. The cerebellum may be markedly atrophic.

Periventricular white matter injury (PVL) is associated with a history of low birthweight/preterm deliveries and clinical static spastic dior quadriparesis and shows nonprogressive periventricular volume loss and T2/FLAIR hyperintensity.

Pseudo-TORCH demonstrates progressive cerebral and cerebellar demyelination and Ca++ involving brainstem, basal ganglia, and cerebral parenchyma. If the severity of WM involvement appears at first blush to represent the "worst case ever of MLD," consider pseudo-TORCH. The presence of

elevated CSF neurotransmitters is noteworthy in pseudoTORCH.

METACHROMATIC LEUKODYSTROPHY (MLD)

Etiology and Pathology

•Lysosomal storage disorder

•Decreased ARSA → sphingolipid accumulation

•Periventricular demyelination

Clinical Issues

•Most common inherited leukodystrophy

•Three forms

○Late infantile (most common)

○Juvenile

○Adult (late onset)

Imaging

•Centrifugal spread of demyelination

○Starts in corpus callosum splenium, deep parietooccipital WM

○Frontal, temporal WM affected later

○Spares subcortical U-fibers, cerebellum

•Classic = butterfly pattern

○Symmetric hyperintensities around frontal horns, atria

•Tiger pattern

○"Stripes" of perivenular myelin sparing in WM

Differential Diagnosis

•Other disorders that predominantly affect periventricular WM

○Globoid cell leukodystrophy (Krabbe disease)

○Pelizaeus-Merzbacher disease

○Vanishing white matter disease

•Destructive disorders

○Periventricular leukomalacia

TORCH including Zika virus infection is nonprogressive and often associated with micrencephaly and polymicrogyria. Variable WM changes (representing gliosis and demyelination) and varied patterns of Ca++ may be present.

Vanishing white matter disease (VWMD) begins in the periventricular WM but eventually involves all the hemispheric white matter. VWMD often cavitates and does not enhance.

Megalencephaly with leukoencephalopathy and cysts represents a slowly progressive disorder, associated with macrocephaly, spared cognition, demyelination with "swollen" WM, and eventual development of subcortical cysts (frontal, parietal, and temporal).

Sneddon syndrome also known as ARSA pseudodeficiency represents demyelination that may be triggered by a hypoxic event. The diagnosis can be confirmed by skin biopsy.

Ischemic white matter disease [e.g., moyamoya syndrome, as seen in Down syndrome, sickle cell disease, neurofibromatosis type 1 (NF1), and ACTA2 gene mutation (31-8)] is a differential diagnosis of MLD. (Moyamoya disease is more common among children in Japan.) Deep white matter gliosis and demyelination, diminished size of circle of Willis, lateral

cerebral fissure "candelabra" vessels, and hypertrophy of lenticulostriate vessels are seen (31-8).

SELECTED WELL-KNOWN LEUKODYSTROPHIES

•Metachromatic leukodystrophy

•Globoid cell leukodystrophy (Krabbe disease)

•X-linked adrenoleukodystrophy

•Adrenomyeloneuropathy

•Canavan disease

•Alexander disease

•Refsum disease

•Cerebrotendinous xanthomatosis

SELECTED INHERITED DISEASES WITH NONLEUKODYSTROPHIC WM CHANGES

Arrested or Highly Delayed Myelination

•Pelizaeus-Merzbacher disease

•Infantile-onset neuronal degenerative disorders

○Infantile GM1 and GM2 gangliosidosis

○Infantile neuronal ceroid lipofuscinosis

○Alpers disease

○Menkes disease

Abnormal and Irregular Myelination

•Amino organic acidopathies

○Phenylketonuria

○Propionic acidemia

○Maple syrup urine disease

○Nonketotic hyperglycemia

•Chromosomal abnormalities (e.g., 18q syndrome)

Widespread White Matter Gliosis

• Lowe syndrome and galactosemia

Large Virchow-Robin Spaces

• Mucopolysaccharidoses

Small White Matter Infarctions

• Fabry disease and hyperhomocysteinemia

Status Spongiosis of Cerebral White Matter

Megalencephaly With Leukoencephalopathy and Cysts

X-Linked Adrenoleukodystrophy

Terminology. X-linked adrenoleukodystrophy (X-ALD) is also known as childhood cerebral X-ALD (CCALD). It was historically known as "bronze" Schilder disease and "melanodermic type leukodystrophy" before its adrenal involvement was recognized. At least five variants other than CCALD have been described, including presymptomatic X-ALD, adolescent (AdolCALD), adult (ACALD), adrenomyeloneuropathy (AMN), and Addison-only symptomatic female carriers.

Etiology. ALD is an inherited disorder of peroxisomal metabolism. Peroxisomes are ubiquitous organelles involved in catabolic pathways. Altered peroxisome metabolism in ALD results from absent or deficient acylCoA synthetase leading to impaired β-oxidation of very-long-chain fatty acids (VLCFAs). VLCFAs accumulate in the WM, causing a severe inflammatory demyelination ("brittle" myelin). Axonal degeneration in the posterior fossa and spinal cord are also typical of the disease.

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(31-7A) Axial T1MR shows MLD in a 2y boy with sparing of U-fibers , preserved striate myelin surrounding venules (tigroid pattern) .

(31-7B) Axial FLAIR shows hyperintense demyelination , preserved perivenule myelin (tigroid pattern), sparing of U-fibers .

(31-7C) Sagittal FLAIR shows hypointense dots (leopard pattern) of preserved myelin within demyelinated WM sparing U-fibers.

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Genetics. ALD is an X-linked recessive disorder caused by mutations of the gene ABCD1, which has been mapped to Xq28. More than 500 mutations of the ABCD1 gene have been described. The Xq28 chromosome normally codes for a peroxisomal membrane protein also known as an ATPase transporter protein, "traffic" ATPase.

Pathology. There are two distinctive active pathophysiologic processes in ALD. The first is axonal degeneration that predominates in the posterior fossa and spinal cord, and the second is a severe inflammatory demyelination.

Three distinct zones of myelin loss are seen in ALD (31-11). The innermost zone consists of a necrotic core of demyelination with astrogliosis, ± Ca++. An intermediate zone of active demyelination and perivascular inflammation lies just outside the necrotic, "burned out" core of the lesion. The most peripheral zone consists of ongoing demyelination without inflammatory changes (31-12).

Clinical Issues. X-ALD is the most common single protein or enzyme deficiency disease to present in childhood. The incidence is 1:20,000-50,000.

Several clinical forms of ALD and related disorders have been described. Phenotypes are unpredictable (even intrafamilial ALD). Classic X-linked ALD is the most common form (45%) and is seen almost exclusively in boys 5-12 years of age. Behavioral difficulties and deteriorating school performance are common. Hearing loss and skin bronzing may be seen. Approximately 10% of affected patients present acutely with seizures, adrenal crisis, acute encephalopathy, or coma.

Adrenomyeloneuropathy (AMN) is the second most common type (35%). It is another X-linked disorder that occurs primarily in male patients. It presents between 14 and 60 years, thus presenting later than classic X-ALD. AMN is characterized by axonal degeneration in the spinal cord more than the brain and peripheral nerves.

(31-9) Classic X-ALD shows periatrial WM hypoattenuation and calcifications on NECT. There is periatrial T2 hyperintensity and diffusion restriction in the actively demyelinating, inflammatory regions.

ADRENOLEUKODYSTROPHY (ALD): ETIOLOGY, PATHOLOGY, AND CLINICAL ISSUES

Etiology

•Peroxisomal disorder

•Impaired oxidation of VLCFAs

Pathology

•Severe inflammatory demyelination

•Three zones

○Necrotic "burned out" core

○Intermediate zone of active demyelination + inflammation

○Peripheral demyelination without inflammation

Clinical Issues

•Classic X-linked ALD

○Most common form (45%)

○Preteen boys

○Deteriorating cognition, school performance

•Adrenomyeloneuropathy (AMN)

○Second most common form (35%)

○Most common in male patients

•Addison disease without CNS involvement (20%)

Approximately 20% of X-ALD patients exhibit isolated adrenal insufficiency (Addison disease). Neurologic involvement is absent. Other less common forms of ALD include adolescent and adult-onset ALD and mild symptomatic disease in female carriers.

Untreated X-ALD carries a dismal prognosis. Relentless progression with spastic quadriparesis, blindness, deafness, and vegetative state is typical. Dietary intake of Lorenzo oil (a mixture of triolein and trierucin) has helped mitigate

(31-10) FLAIR (upper left) in a 5y boy with early ALD shows a small hyperintense focus in the splenium . Six months later, T1WI (upper right), FLAIR (lower left) show the increasing size of the lesion . T1 C+ (lower right) shows enhancement .

symptoms in some patients. Early bone marrow transplantation or hematopoietic stem cell gene therapy has improved clinical outcome for others.

Imaging. The definitive diagnosis of X-ALD is established by tissue assays for increased amounts of VLCFAs. When typical, imaging findings can be strongly suggestive of the diagnosis. Although CT scans are sometimes obtained as an initial screening study in children with encephalopathy of unknown origin, MR without and with IV contrast is the procedure of choice.

ALD: IMAGING AND DIFFERENTIAL DIAGNOSIS

Imaging

•X-linked ALD posterior predominance in 80%

○Earliest finding: corpus callosum splenium hyperintensity

○Spreads posterior to anterior, center to periphery

○Intermediate zone often enhances, restricts

•Variant patterns

○X-linked ALD with anterior predominance (10-15%)

○AMN involves corticospinal tracts, cerebellum, cord more than hemispheric WM

Differential Diagnosis

•X-linked ALD pathognomonic if sex, age, imaging findings classic

CT Findings. NECT scans demonstrate hypoattenuation involving the corpus callosum splenium and WM around the atria and occipital horns. Calcification in the affected WM may be seen (31-9). CECT typically shows enhancement around the central hypoattenuating WM.

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MR Findings. A posterior-predominant pattern is seen in 80% of patients with X-ALD (31-13). The earliest spin magnitude finding is T2/FLAIR hyperintensity in the middle of the corpus callosum splenium (31-10). As the disease progresses, hyperintensity spreads from posterior to anterior and from the center to the periphery. The peritrigonal WM, corticospinal tracts, fornix, commissural fibers, plus the visual and auditory pathways can all eventually become involved.

The leading edge of demyelination appears hyperintense on T1WI but does not enhance (31-14). The intermediate zone of active inflammatory demyelination typically enhances T1 C+. Thus, always include T1 C+ when imaging suspected leukodystrophy.

The Loes MR scoring system is a severity score based on the location, extent of disease, and atrophy. It divides the brain into nine regions with 23 subregions. Each region is scored for the presence (1) or absence (0) of atrophy, and every

subregion is assessed as normal (0), unilateral abnormality (0.5), or bilateral abnormalities (1) in signal intensity.

Variant imaging patterns of X-ALDs are common. Approximately 10-15% of all patients with classic X-ALD have an anterior predominant demyelination; T2WI/FLAIR hyperintensity initially appears in the corpus callosum genu (not the splenium) and spreads into the frontal lobe WM (3115). Other atypical reported patterns include unilateral disease, disease with both bioccipital and bifrontal WM abnormality. Another variant involves only the internal capsules. In summary, X-ALD may present at an atypical age, demonstrate atypical sites of involvement, and lack enhancement. X-ALD may present with "mild" peritrigonal T2/FLAIR signal changes (31-17). Rarely, the patient with X- ALD presents with Guillain-Barré-like acute demyelinating radiculopathy of the cauda equina nerve roots.

Imaging findings in patients with adrenomyeloneuropathy vary from those of patients with classic X-ALD. The cerebral

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hemispheres are relatively spared with predominant involvement of the cerebellum, corticospinal tracts, and spinal cord (31-16). Enhancement is typically absent.

DWI/DTI shows reduced diffusivity in active zones of demyelination and increased diffusivity in regions of "burntout" demyelination. DTI shows reduced connectivity (i.e., loss of fractional anisotropy) in WM that MR demonstrates as abnormal and in "normal" WM (31-14).

MRS shows, at TE of 35 ms, peaks at 0.8-1.4 (i.e., cytosolic amino acids and VLCFA macromolecules). Reduced NAA may be detected prior to observed MR abnormality and predicts progression. Increased myoinositol, CHO, and lactate doublet are typical findings.

Differential Diagnosis. When X-ALD presents in patients of classic age and sex (i.e., 5- to 12-year-old boys) and with typical posterior predominance on imaging studies, the differential diagnosis is very limited.

Leukoencephalopathy with brainstem/spinal cord involvement and high lactate may resemble ALD but has a different clinical presentation and is caused by homozygous mutation in the DARS2 gene. Hypoglycemia in neonates and young infants may involve the parietal and occipital WM and GM, CC splenium, calcar avis, peritrigonal WM with T2WI/FLAIR hyperintensity, and restricted diffusion. There is a lack of WM enhancement. Alexander disease is associated with macrocephaly and involves frontal WM (not peritrigonal as in typical X-ALD). WM enhances. Metachromatic leukodystrophy demonstrates symmetric nonenhancing periventricular T2/FLAIR hyperintensity.

Globoid Cell Leukodystrophy (Krabbe

Disease)

Terminology. Globoid cell leukodystrophy (GLD) is also commonly known as Krabbe disease. GLD is characterized by the presence of unique "globoid" cells in the demyelinating

lesions. It is a progressive degenerative leukodystrophy of the CNS and peripheral nervous system.

Etiology and Pathology. GLD is an autosomal-recessive lysosomal storage disease caused by deficiency of the enzyme galactocerebroside β-galactosidase. Faulty galactose cleavage results in progressive psychosine accumulation in large ("globoid") multinucleated epithelioid cells. Psychosine (accumulations to ~ 100 times normal in Krabbe disease) is especially toxic to oligodendrocytes; the result is severe oligodendrocyte destruction with resultant demyelination. Psychosine upregulates AP-1 (a proapoptotic pathway) and downregulates NF-κB (antiapoptotic).

The brain demonstrates progressive volume loss with WM thinning, dilated ventricles, and enlarged sulci. The periventricular WM shows "grayish" discoloration. The subcortical U-fibers are typically spared. The optic and peripheral nerves can appear enlarged and fibrotic.

Typical histopathologic findings are extensive WM demyelination and gliosis with numerous conspicuous PASpositive multinucleated macrophages ("globoid" cells). Electron microscopy shows dense crystalloid inclusions of galactocerebroside.

GLOBOID CELL LEUKODYSTROPHY (KRABBE DISEASE)

Etiology and Pathology

•Lysosomal storage disease

•Galactocerebroside β-galactosidase deficiency

•Psychosine accumulation in "globoid" cells

•Highly toxic to oligodendrocytes

Clinical Issues

•Female (80%)

•Three forms

○Infantile (majority)

○Juvenile

○Adult (rare)

Imaging

•NECT: basal ganglia, thalamic Ca++

•MR

○Periventricular WM, corticospinal hyperintensity

○Subcortical U-fibers spared

○Alternating "halos" around dentate nuclei

○Optic nerve/chiasm enlarged ± other cranial nerves

Differential Diagnosis

•Other disorders with periventricular WM predominance

○Metachromatic leukodystrophy

○Vanishing WM disease

•Other lysosomal storage diseases

○Neuronal ceroid lipofuscinosis

○GM2 gangliosidosis

Genetics. GLD is an an autosomal-recessive lysosomal disorder. Gene mapping to Ch 14 (14q24.3 to 14q32.1) is needed to confirm the diagnosis.

Clinical Issues. GLD is a panethnic disease with an 80% female prevalence. Infantile, juvenile, and adult forms are recognized.

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The infantile form is the most common, typically presenting between 3 and 6 months with extreme irritability and feeding difficulties. Neonatal GLD is rapidly progressive and almost invariably fatal.

Hematopoietic stem cell transplantation halts progression in mild cases. Clinical and imaging manifestations may mitigate or reverse the disease.

Imaging

NECT Findings. Scans can be helpful in the diagnosis of GLD, unlike most other leukodystrophies. Bilaterally symmetric increased attenuation (i.e., globoid accumulation + calcification) in the thalami, basal ganglia, internal capsule, corticospinal tracts, and dentate nuclei of the cerebellum can sometimes be identified even prior to the development of visible abnormalities on standard MR sequences. Deep periventricular hypoattenuation is seen, and atrophy becomes apparent as CNS degeneration progresses.

MR Findings. Classic MR findings in GLD are corticospinal tract hyperintensity on T2/FLAIR with confluent symmetric demyelination in the deep periventricular WM. The subcortical U-fibers are typically spared. Bithalamic hypointensity on T2WI is common. The presence of globoid and Ca++ accumulation in the thalami and basal ganglia may lead to T1 shortening or hyperintensity.

Krabbe disease is one of the few leukodystrophies in which cerebellar findings appear early in the disease course. Alternating "halo" or ring-like hypointensities on T1WI and hyperintensities on T2WI can be identified in the cerebellar WM surrounding the dentate nuclei (31-19).

Another distinctive feature of GLD is enlargement of the intracranial optic nerves and chiasm (31-20C). Diffusely enlarged, enhancing cranial nerves and cauda equina nerve roots have also been reported in GLD.

Diffusion tensor imaging (DTI) may demonstrate reduced fractional anisotropy in the corticospinal tracts before other abnormalities appear. Relative anisotropy (RA) differences in thalami, basal ganglia, middle cerebellar peduncles, internal capsule, corpus callosum, and periventricular WM are seen. RA values can be followed after stem cell transplant (RA of untreated patients less than treated cohort).

MRS. Findings vary with age, including increased choline, myoinositol, and lactate and reduced NAA in affected areas; these are common yet nonspecific.

Differential Diagnosis. Although the histopathology of GLD is unique and virtually pathognomonic of the disease, the imaging differential diagnosis of GLD includes other leukodystrophies with periventricular WM predominance. The WM changes in metachromatic leukodystrophy and vanishing white matter disease may initially appear quite similar, but these disorders lack the basal ganglia/thalamic deposits typical of GLD.

Other lysosomal storage disorders that can mimic GLD include neuronal ceroid lipofuscinosis and the GM2 gangliosidoses.

Neuronal ceroid lipofuscinosis (i.e., Batten disease) can have

hyperattenuating thalami on NECT. "Classic" infantile GM2 gangliosidosis (i.e., Tay-Sachs disease) shows similar thalamic hypointensity on T2WI. Late-onset GM2 shows progressive cerebellar atrophy. NF1 demonstrates optic nerve enlargement in 15% of patients (i.e., optic nerve glioma) and shows characteristic T2WI/FLAIR hyperintensities in zones of myelin vacuolization or focal areas of signal intensity (FASI). Distinctive cutaneous phenotypic features are present.

Vanishing White Matter Disease

Terminology. Vanishing white matter disease (VWMD) has become recognized as one of the most prevalent inherited leukoencephalopathies. VWMD, formerly termed childhood ataxia with CNS hypomyelination, is an unusual leukoencephalopathy characterized by diffusely abnormal cerebral WM that literally "vanishes" over time. Cree leukoencephalopathy (i.e., a rare and severely progressive form of VWMD)—once considered a separate entity—is now considered an early-onset, especially severe form of VWMD. Other terms for VWMD that have been used include vanishing WM leukodystrophy and ovarian failure.

Etiology

Genetics. VWMD is an autosomal-recessive disorder caused by point mutation of genes responsible for encoding any of the five subunits of the eukaryotic translation inhibiting factor 2B (EIF2B). Mutation plays an essential role in the faulty initiation of mRNA translation to protein, particularly following exposure to physiologic stressors (e.g., heat, trauma, infection). This results in deficient protein recycling and intracellular accumulation of denatured proteins. This represents a fatal disorder.

Pathology. VWMD is also previously described as an orthochromatic sudanophilic leukodystrophy. This slowly progressive eventually cavitating WM disease involves the deep frontoparietal regions most severely affected with lesser involvement of the temporal lobes (31-21). The basal ganglia, corpus callosum, anterior commissure, and internal capsules are characteristically spared. The gross appearance of the affected WM varies from grayish gelatinous discoloration to areas of cystic degeneration with frank cavitation. The cortex appears spared.

VWMD predominantly affects oligodendrocytes and astrocytes with relative sparing of neurons. Microscopic findings include myelin pallor, thinned myelin sheaths, vacuolation, a limited number of reactive astrocytes with atypical features, and cystic changes. There is no inflammatory component of the leukodystrophy. Paradoxical increase in oligodendrocytes can be seen in some areas with marked loss in others. The cerebellar WM is usually affected, and atrophy evolves. The cortex and gray matter structures appear normal. At autopsy, a cystic leukoencephalopathy is observed with both axons and myelin sheaths absent.

Clinical Issues. Classic VWMD presents in children 2-5 years of age. Development is initially normal, but progressive motor and cognitive impairment with cerebellar and pyramidal signs follows. Episodic deterioration is often associated with

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systemic illness, trauma, or emotional stress. Progression is typically slow. Death by adolescence is typical.

Cree leukoencephalopathy is an especially severe, rapidly progressive form of VWMD that affects infants between the ages of 3 and 9 months and is invariably fatal by 21 months of age (31-22).

Approximately 15% of VWMD cases occur in adolescents and adults. Mean age of late-onset VWMD is 30 years. Learning disabilities with insidious, protracted cognitive impairment are typical. Stress-induced rapid neurologic deterioration with death is common.

Imaging

NECT Findings. Involved areas exhibit hypoattenuation. Calcifications are not typical. Eventually profound WM volume loss is seen.

MR Findings. Extensive confluent WM T1 hypointensity with T2/FLAIR hyperintensity is typical. The disease is initially periventricular but later spreads to involve the subcortical arcuate fibers. Over time, the affected WM undergoes rarefaction. Cavitary foci of CSF-like signal intensity develop (31-21). Diffuse volume loss with enlarged ventricles and sulci is seen on serial studies. VWMD does not enhance.

DWI/DTI. Early reduced diffusivity in normal-appearing WM reflects brain degeneration. Anisotropy progressively decreases as disease progresses.

MRS. In time, reduced NAA, Cho, and Cr with normal myoinositol are seen on MRS and reflect early WM degeneration without reactive gliosis. Lactate may be present as disease progresses.

Differential Diagnosis. VWMD is not the only leukoencephalopathy that causes "melting away" or "vanishing" of the cerebral WM. Alexander disease and mitochondrial encephalopathies can be associated with WM rarefaction and cystic degeneration. Alexander disease presents with macrocephaly and is not associated with the episodic neurologic deterioration characteristic of VWMD; it demonstrates a frontoparietal gradient of disease. Frontal WM cysts can occur in end-stage disease. Approximately 10% of mitochondrial encephalopathies predominantly affect the WM and may form cavitations.

Globoid cell leukodystrophy (or Krabbe disease) may resemble severe VWMD clinically, but the imaging findings of basal ganglia/thalamic globoid material and calcifications and cerebellar "halos" help distinguish GLD from VWMD.

Phenylketonuria

Phenylketonuria (PKU) is the most common inborn error of amino acid metabolism, caused by mutations in the phenylalanine (Phe) hydroxylase (PAH) gene, which is mapped to chromosome 12q24.1. Elevated levels of Phe are toxic to the developing brain.

Neonates are often asymptomatic. Fair skin and blue eyes (reflecting difficulty in forming melanin) are common

(31-21) Images show vanishing white matter disease in a 5y boy, originally diagnosed with MLD. Note the symmetric periventricular disease, spared U-fibers, and early cyst formation. (Courtesy S. Harder, MD.)

phenotypes. Nonspecific signs and symptoms including eczema, developmental delay, seizures, and hyperactivity may herald the disease. Severe mental retardation and profound global developmental delay result if the disease remains untreated or if dietary protein restriction is not followed.

In the past, PKU was diagnosed by the presence of hyperphenylalaninemia and "musty-smelling" urine. Most PKU cases are now diagnosed through state health departmentsponsored newborn metabolic disease-screening programs. With adherence to dietary protein restriction, mitigation of the ravages of this disease occurs. Early treatment is key to minimizing cognitive impairment.

Imaging. The MR in PKU can appear normal! When abnormality is detected, T2/FLAIR imaging shows hyperintensity in the periventricular WM, particularly frontal and peritrigonal regions (31-23) (31-24). The subcortical arcuate fibers are spared. There is no enhancement following contrast administration (31-24). Diffusion can be present and, when followed serially, may reflect a progression of disease or poor dietary control (31-23). A centrifugal progression of PKU eventually leads to end-stage disease. MRS shows a Phe peak resonating at 7.37 ppm (which is missed on routine clinical MRS that only displays to 4 ppm).

Differential Diagnosis. Periventricular WM injury (PVL) (atrisk population of low birth weight, premature neonates who, when affected, eventually manifest signs and symptoms of cerebral palsy, a nonprogressive neurologic disorder), metachromatic leukodystrophy (demonstrating more confluent zones of deep WM T2/FLAIR hyperintensity), and Krabbe disease (optic and cranial nerve enlargement, thalamic hyperattenuation on NECT, MR showing T2/FLAIR hyperintensity in corticospinal tracts, deep cerebral WM, and

(31-22) Cree leukoencephalopathy (now recognized as a severe variant of vanishing white matter disease) in an 8m infant shows nearly complete lack of myelination.

early cerebellar involvement) are differential diagnoses for PKU.

Maple Syrup Urine Disease

Maple syrup urine disease (MSUD), also known as leucine encephalopathy, is an autosomal-recessive disorder of branched-chain amino acid (leucine, isoleucine, valine) metabolism. More than 50 different gene mutations governing enzyme components of BCKDK have been identified. Decreased activity of the branched chain α-keto acid dehydrogenase complex disrupts the Krebs cycle and results in elevated brain levels of leucine and other leukotoxic metabolites. In turn, these induce cytotoxic or intramyelinic edema and spongiform degeneration.

The overall prevalence is 1:850,000 live births with a greater frequency among Mennonites, people of Middle Eastern descent, and Ashkenazi Jews.

Infants with classic MSUD are initially normal. Breastfeeding delays onset of symptoms. Within days after birth, poor feeding, lethargy, vomiting, seizures, and encephalopathy may occur. In severe cases, the urine smells of maple syrup or burnt sugar. If the family history is positive for MSUD, immediate postparturition testing is necessary, and, if positive, start therapy within hours to assure excellent outcome.

Imaging. Transcranial US during the acute stage of MSUD edema shows hyperechogenicity reflecting edema within the thalami and basal ganglia, periventricular WM, brainstem, and cerebellum. In fact, unexplained cerebral hemispheric, basal ganglia, thalamic, brainstem, and cerebellar edema in the newborn should provoke a consideration of MSUD in the differential diagnosis.

NECT scans show profound hypoattenuation within the myelinated WM as well as within the dorsal brainstem, cerebellum, cerebral peduncles, and posterior limb of the internal capsule (31-25).

MR shows striking T2/FLAIR hyperintensity involving the cerebellar WM, dorsal brainstem, cerebral peduncles, thalami, globi pallidi, posterior limbs of internal capsule, internal medullary lamina, and pyramidal and tegmental tracts (3126). Margins of parenchymal hyperintensity tend to become sharp during the subacute phase of disease. Imaging abnormalities are much more conspicuous infratentorially than supratentorially.

DWI/DTI shows restricted diffusion (e.g., low ADC values) in the T2/FLAIR hyperintense regions; look for four-dot brainstem sign (31-26D)!

MRS shows a peak at 0.9 ppm caused by accumulation of branched-chain α-keto amino acids (31-26F). This peak is

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present at short (35 ms), intermediate (144 ms), and long (288 ms) PRESS MRS aquisitions, distinguishing them from the broad cytosolic amino acid peaks that only resonate at a short TE (35 ms).

Differential Diagnosis. Sepsis (brain MR expected to be normal), Alexander disease (T2 hyperintensity of the frontal WM and enhancement), hypoxic ischemic injury (with history of periparturitional distress, no significant symptom-free period), and mitochondrial cytopathy (episodic stroke-like clinical events of varied severity depending on the genotype of the disorder) should all be considered.

Nonketotic Hyperglycinemia

Nonketotic hyperglycinemia (NKH) is an autosomal-recessive disorder in glycine metabolism. It is the second most common inherited disorder of amino acid metabolism, PKU being first. Glycine is normally metabolized to the final end-products of ammonia and carbon dioxide. The estimated incidence is

(31-24) Axial MRs show a 13y girl with PKU and mild cognitive impairment. Findings are subtle with periventricular WM hyperintensity (top L) showing no enhancement (top R) and restricting on DWI (bottom L and R).

1:60,000 live births. Eighty percent of affected newborns exhibit mutation of the GLDC gene, and 10% exhibit mutation of the AMT gene.

The affected newborn with NKH presents with lethargy, hypotonia, apnea, seizures, and often myoclonic jerks. When the diagnosis of NKH has been made, the oral administration of sodium benzoate has been shown to lower plasma levels of glycine although the CSF levels remain high. Such treatment may mitigate the severity of neurologic deterioration.

Imaging. Restricted diffusion and T2/FLAIR hyperintensity within the corticospinal tracts and flocculus of the cerebellum are common. One may appreciate a lack of expected normal myelin signal in the PLIC (T1WI hyperand T2WI hypointensity) (31-27A). Importantly, in the neonate with NKH, who presents with seizure, the initial MR may appear normal. MRS with glycine peak at 3.55 ppm on short and long TE proton spectroscopy (31-27) is characteristic. Normal myoinositol resonance at 3.6 ppm is detected on short, not long, TE MRS acquisitions (31-27C). The initial MR may appear completely normal; thus, adjunctive MRS in the evaluation of newborn seizures is critical.

Differential Diagnosis. Hypoxic ischemic injury has a relevant health history and characteristic striatal, thalamic, and corticospinal tract involvement.

Hyperhomocysteinemia

Hyperhomocysteinemia (HHcy)—formerly known as homocystinuria—is a heterogeneous group of IMDs exhibiting autosomal-recessive inheritance that affects methionine metabolism, resulting in elevated plasma homocysteine.

(31-25) Axial NECT in a 13d boy with MSUD shows edema (low attenuation) in the dorsal midbrain and central cerebellar WM , cerebral peduncles (upper R), internal capsules (lower L), and centrum semiovale.

HHcy patients are normal at birth but develop multisystem abnormalities involving the eye, skeleton, spinal dural dysplasia, vascular system, and CNS. Upward dislocation of the lens develops early and affects the majority of patients. Osteoporosis and kyphoscoliosis are common. Endothelial damage and hypercoagulability result in a high incidence of both arterial and venous occlusions, which occur at all ages.

Imaging. The major imaging manifestations of HHcy in the brain are vascular. Stenoocclusive disease in both the arterial and venous systems is typical. Microangiopathy from premature atherosclerosis, thrombolic arterial strokes, lacunar infarcts, sinovenous occlusion, and generalized volume loss are common. An increased number of T2/FLAIR WM hyperintensities is seen in patients with even mildly elevated plasma homocysteine levels (31-28).

Differential Diagnosis. Mitochondrial disorders (episodic stroke events, lack of systemic HHcy phenotype) and moyamoya disease (obliterative vasculopathy in circle of Willis and other manifestations, like NF1) should be considered.

Congenital Muscular Dystrophy

The congenital muscular dystrophies (CMDs) have varied clinical manifestations. They are a heterogeneous group of myopathies of broad phenotypes and genotypes. They are autosomal-recessively inherited. Some infants and children present with hypotonia (i.e., floppy newborn) and muscle weakness without CNS symptoms. Others present with developmental delay, seizures, and blindness. Their MRs often show WM T2/FLAIR hyperintensities (e.g., watery WM). See Chapter 37 for discussion of CMDs and cobblestone abnormalities.

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(31-27A) Axial T2WI shows a term newborn with nonketotic hyperglycinemia, seizures. Note lack of expected myelin hypointensity in the PLICs .

(31-27B) MRS short TE (35 ms) shows glycine peak at 3.55 ppm . There is diminished NAA . Glycine is not a normal MRS resonance!

(31-27C) MRS long TE (288 ms) shows glycine peak (3.55 ppm) , ↓ NAA . Normal myoinositol (3.6 ppm) won't resonate at long TEs.

Most of the CMDs characterized by abnormal myelination are merosindeficient CMDs. Muscle biopsy shows dystrophic changes with negative expression of merosin (laminin α2).

Imaging. These patients are usually hypotonic at birth ("floppy infant") and exhibit severely delayed motor milestones. MR shows diffuse confluent T2/FLAIR hyperintensity in the periventricular WM. The corpus callosum, internal capsule, and subcortical U-fibers are typically spared (31-29).

Differential Diagnosis. States of hypomyelination (i.e., 4H, PMD in which myelination never progresses vs. CMD, with progressive neurologic decline), MLD (central cerebral hemispheric butterfly pattern of WM hyperintensity and tigroid pattern on T2/FLAIR), and VWMD (begins in the periventricular WM, relentlessly progresses, and may cavitate) should be considered.

Subcortical White Matter Predominance

IMDs that initially or predominantly affect the subcortical WM are much less common than those that begin with deep periventricular involvement. The most striking IMD with preferential involvement of the subcortical WM is megaloencephalic leukoencephaly with subcortical cysts (MLC), formally known as van der Knapp disease or van der Knapp leukoencephalopathy.

Megaloencephalic Leukodystrophy With Subcortical

Cysts

Terminology. MLC is also known as vacuolating megaloencephalic leukoencephalopathy, formally called van der Knaap disease or vacuolating megaloencephalic leukoencephalopathy with benign slowly progressive course. MLC is a rare autosomal-recessive disorder with characteristic MR features and a variable but mild clinical course.

Etiology. MLC is a genetically heterogeneous disorder. Approximately 75% of cases are caused by mutations in the MLC1 gene located on Chr. 22q(tel). MLC1 is an oligomeric membrane protein located in astrocyte-astrocyte junctions. A newly described mutation in the HEPACAM gene that encodes for the GlialCAM protein, an IgG-like hepatic and glial cell adhesion molecule, may account for the remaining cases. Both defects lead to abnormal cell junction trafficking with associated disturbed water homeostasis and osmotic balance and functional disturbance in volume-regulated anion channels (i.e., impaired osmoregulation). Patients with HEPACAM mutations develop a spectrum of abnormalities ranging from benign familial macrocephaly to MLC that is indistinguishable from that caused by MLC1 mutation.

Pathology. Gross pathology shows a swollen cerebral hemispheric WM, relative occipital sparing, variable involvement of the subcortical arcuate fibers, frequent involvement of the external capsules, and sparing of the internal capsules with multiple variably sized subcortical cysts often initially involving the temporal lobes (31-31) (31-32). The basal ganglia are spared. In the few reported cases of MLC with histopathology, extensive vacuolation is seen in the outer layers of myelin sheaths, accounting for the characteristic swollen appearance of the WM on MR.

Clinical Issues. MLC is distinguished clinically from other leukoencephalopathies by its remarkably slow course of neurologic deterioration. Infantile-onset macrocephaly is characteristic, but neurologic deterioration is often delayed. Age at symptom onset varies widely, ranging from birth to 25 years; median age of onset of prominent clinical symptoms is 6 months.

Pyramidal and cerebellar signs are common. Therefore, early motor developmental delay, gait ataxia, and hypotonia may be observed.

Eventually, progression to spastic tetraparesis occurs. Seizures are variable. Intellectual skills are typically preserved early in the disease, but slow cognitive decline is observed as the disease progresses. Although the geographical distribution of MLC is global, increased population isolates of MLC have been reported among Libyan Jewish, Turkish, and Agrawal Indian communities.

Imaging. Cranial US in symptomatic infants shows unexplained hyperechogenicity of affected WM. NECT will demonstrate hypoattenuation of the cerebral hemispheric WM.

The diagnosis of MLC is typically established by MR. Commonly, the magnitude of MR abnormalities appears much worse than the clinical appearance of the child. Macrocephaly with diffuse confluent WM T2/FLAIR hyperintensity in the subcortical WM is typical. The affected subcortical WM appears "watery" and swollen. The overlying gyri seemingly stretch over the swollen WM. The optic radiations, occipital

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subcortical WM, and basal ganglia are typically spared. The corpus callosum and internal capsule are usually normal. Variable involvement of the cerebellar WM is generally normal or only mildly affected. Characteristic CSF-like subcortical cysts develop in the anterior temporal lobes followed in frequency by fronto-parietal cysts. Unlike the "watery" WM, which exhibits T2/FLAIR hyperintensity, the cysts approximate the signal intensity of CSF on FLAIR. The number and size of the cysts may increase over time. The abnormal WM and cysts do not enhance on T1 C+.

On DWI/DTI, the increased water content within the interstitial spaces leads to reduced anisotropy and increased ADC values.

MRS shows mild to moderate reduced NAA and NAA:Cr ratio. Myoinositol is normal, with or without lactate. Cystic regions show reduction of all neurometabolites.

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(31-30A) Axial T2WI in a 4y boy with merosindeficient muscular dystrophy shows central and peripheral hyperintensities.

(31-30B) Axial T2WI in same patient shows confluent subcortical and centrum semiovaleWM T2 hyperintensity.

(31-30C) Axial ADC map through the cerebral convexities in the same patient shows WM increased diffusivity (ADC hyperintensity) .

Differential Diagnosis. MLC must be distinguished from other IMDs with macrocrania. The two major considerations are Canavan disease and Alexander disease, both of which are characterized by much greater clinical disability.

Canavan disease almost always involves the basal ganglia, lacks the development of subcortical cysts, and demonstrates a large NAA peak on MRS. Canavan disease also shows very early involvement of the subcortical U-fibers, which may appear uninvolved in the early presentation of MLC.

Alexander disease demonstrates a frontal WM gradient, involves the basal ganglia, and often enhances following contrast administration.

Hypomyelinating Disorders

Hypomyelination refers to a permanent, substantial deficit in myelin deposition within the brain. Hypomyelinating leukoencephalopathies have been observed in the context of a number of genetic disorders that may share some clinical characteristics. These heterogeneous disorders exhibit reduced or absent myelination. Hypomyelination often reflects a deficiency of mature oligodendrocytes. Immature oligodendrocytes do not produce myelin; myelin is essential to axonal nourishment. Hypomyelination may be a primary hypomyelination syndrome or may be secondary to other pathologies. Hypomyelinating disorders differ from other WM diseases that are characterized by abnormal myelin formation (dysmyelinating diseases) or myelin destruction (demyelinating diseases).

Some hypomyelinating disorders may be differentiated by their MR characteristics. These include 4H syndrome (hypomyelination with hypogonadotropic hypogonadism and hypodontia), Pelizaeus-Merzbacher disease (PMD), Pelizaeus-Merzbacher-like disease (PMLD), hypomyelination with atrophy of the BG and cerebellum (HABC), hypomyelination with congenital cataract (HCC), and PMD-like diseases (GM1, GM2, Salla disease, and fucosidosis). These represent only a small number of hypomyelinating disorders that have been described.

HYPOMYELINATING DISORDERS

Most Common

•Hypomyelination of unknown cause

•4H syndrome

•Pelizaeus-Merzbacher disease

•Pelizaeus-Merzbacher-like disease

Less Common

•Hypomyelination with congenital cataract

•GM2 gangliosidosis

•Salla disease (sialuria)

•Fucosidosis

•Cockayne syndrome

•GM1 gangliosidosis

•Hypomyelination with atrophy of the basal ganglia and cerebellum

Rare

•18q-syndrome

•Cockayne syndrome

•Trichothiodystrophies (brittle, sulfur-deficient hair)

Most of the hypomyelinating leukoencephalopathies are lysosomal storage diseases. Although some have been identified and characterized, hypomyelinating disorders of unknown origin constitute the largest single category of these leukoencephalopathies.

The generally accepted imaging criterion for the diagnosis of hypomyelination is an unchanged pattern of deficient myelination on two successive MR scans obtained at least 6 months apart, with one of these MR studies being performed after 12 months of age (31-35). For the interpreting radiologist, it is very helpful in the interpretation to assess and estimate the maturity pattern of myelination prior to reviewing the chronological age of the patient. Doing so will avoid predetermination bias. The most common MR finding is mild T2 hyperintensity in much or most of the cerebral hemispheric WM. In some cases, signal intensity on T1WI can appear deceptively normal. Remember to always adjust chronological age for degree of prematurity when interpreting infant brain MRs.

After hypomyelination of unknown etiology, the next most commonly diagnosed inherited hypomyelinating disorder is 4H syndrome. The bestknown hypomyelination syndrome is Pelizaeus-Merzbacher disease. 4H syndrome, PMD, and spastic paraplegia type 2 (SPG2) are caused by a mutation in the gene that encodes myelin proteolipid protein 1 (PLP1). 18qsyndrome (another hypomyelinating disorder) causes a hemizygous deletion (one copy of gene missing) of the MBP gene. Some experts consider PMD and 18q-syndrome to represent the prototypes of hypomyelination.

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(31-31) MLC autopsy shows multiple subcortical cysts and WM rarefaction in frontal subcortical WM. (Courtesy R. Hewlett, MD.)

4H Syndrome

The diagnosis of 4H syndrome is based on the combination of hypomyelination on MR, hypogonadotropic hypogonadism, and hypodontia. The hypomyelination in 4H syndrome is distinctive. T2 hypointensity of the optic radiations, pyramidal tracts in the posterior limb of the internal capsule, and anterolateral thalami together with cerebellar atrophy and mild cerebellar WM hyperintensity are characteristic (31-34).

Pelizaeus-Merzbacher Disease

Terminology and Etiology. PMD is an X-linked disorder that results in nearly complete lack of myelination. Some (10-30%) of PMD patients exhibit defects in the PLP1 gene located at Xq21-q22. The PMD brain looks like a much less mature brain than expected for the patient's chronological age.

PMD is a hypomyelinating disorder caused by variations in PLP1. Two forms of PMD are recognized: type 1 (classic) and type 2 (connatal). Classic PMD is an X-linked recessive disorder, whereas patients with the connatal form show either autosomal or X-linked recessive inheritance.

Most patients with PMD have homogeneous hyperintensity of the entire cerebral WM. The hyperintense WM in PMD is more muted than the striking T2 prolongation (hyperintensity) of the WM in demyelinating disorders. Cerebellar atrophy is common in PMD and very common in 4H syndrome.

Pathology. With advanced disease, the brain appears atrophic with normal cortex and shrunken, grayish, or gelatinous-appearing WM. Both the central and subcortical WM are affected. The cerebellar WM, brainstem, and spinal cord are also shrunken and gray. The optic nerves (which are brain tracts) are usually involved, but other cranial nerves (which are ensheathed with a different myelin protein called PMP 22) are normally myelinated.

Histopathology shows markedly reduced or absent oligodendrocytes with variable myelin staining. Cases of connatal PMD show almost complete lack of myelin staining, whereas more slowly progressive cases demonstrate preservation of myelin islets around blood vessels in a classic "tiger" or discontinuous pattern. Absent or deficient myelin sheaths contribute to what the pathologist describes as redundant myelin balls.

Clinical Issues. Although it is one of the most common hypomyelinating disorders, PMD causes only 5-7% of all the inherited leukodystrophies.

(31-32A) Axial FLAIR in a 22m child with MLC shows swollen, hyperintense, "watery" WM and CSF-like temporal subcortical cysts .

(31-32B) Axial FLAIR scan in a 2y child with MLC shows swollen, hyperintense subcortical WM . Note fluid-filled subcortical hypointense cysts .

(31-34A) Axial T2WI in a 3y girl with 4H syndrome shows that most of the hemispheric WM is hyperintense. The T2 hypointensity in the optic tracts and posterior limb of the internal capsules are characteristic.

Nearly 100% of classic PMD cases occur in male patients. Connatal PMD can affect either sex.

Mean age at diagnosis is helpful when interpreting MR studies and ordering the DDx in hypomyelinating disorders. PMD exhibits a broad age range of presentation (i.e., 1-30 years and a mean age of initial MR diagnosis of 4.7 years). Therefore, the diagnosis of PMD is often entertained in the mid-first decade. Common clinical features include hypotonia, developmental delay, inability to sit, and head titubation, with progression, nystagmus, and spasticity. The long-term prognosis is poor, and death often occurs in early childhood.

Imaging

MR Findings. The typical imaging appearance of PMD is nearly complete lack of myelination. The entire cerebral WM appears diffusely and homogeneously hyperintense on T2WI (yet not as hyperintense as demyelinating leukodystrophies). In some cases, preserved myelin around perivascular spaces gives the WM a "tigroid" pattern. Hyperintensity of the pyramidal tracts or entire pons is typically present. Progressive WM and cerebellar volume loss are common. Cavitary WM changes are typically absent.

DTI/DWI. ADC values predate T1and T2-weighted signal changes. ADC values and radial diffusivity decrease with myelin maturation (31-36A).

MRS. Relative increases in myoinositol, choline, and cytosolic (lipid) resonances with hypomyelination are common yet nonspecific. Choline is normally reduced with normal myelination (31-36C).

(31-34B) Coronal T2WI in the same patient shows that the absent myelination also involves the subcortical U-fibers . The striking early cerebellar atrophy is characteristic of 4H syndrome.

Differential Diagnosis. The major differential diagnosis of PMD is other hypomyelinating disorders. Pyramidal tract and pontine hyperintensity are helpful distinguishing features. Patients with 4H syndrome and PMD-like disease typically present clinically a bit later than PMD (i.e., in the late first decade). The MR in 4H syndrome shows early cerebellar atrophy, relative T2 hypointensity within the anterior lateral thalami, and pyramidal tracts at the level of the PLICs. MR in PMLD patients shows T2 hyperintensity either within pontine pyramidal tracts alone or T2 hyperintensity throughout the pons. Patients with fucosidosis show T2 hypointensity of the globus pallidus and substantia nigra. Patients with GM1/GM2 gangliosidosis show early T2 hyperintensity within the basal ganglia. Also consider mucopolysaccharidoses and mitochondrial encephalopathies in the differential diagnosis.

IMDs Predominantly

Affecting Gray Matter

Inherited metabolic disorders (IMDs) that involve the gray matter (GM) without affecting the white matter (WM) are also known as poliodystrophies. They can be subdivided into those that involve the cortex and those that mostly affect the deep gray nuclei. Inherited GM disorders that involve the deep gray nuclei are significantly more common than those that primarily affect the cortex.

(31-35A) Axial T2WI in a 6m boy with PMD, delayed motor development, and normal head circumference shows almost complete absence of myelination, including the subcortical U- fibers. At this age, the internal capsules should be myelinated.

IMDs Primarily Affecting Deep Gray

Nuclei

A number of inherited disorders affect mostly the basal ganglia and thalami. Three inborn errors of metabolism with specific predilection for the deep gray nuclei include (1) pantothenate kinase-associated neurodegeneration (PKAN), (2) creatine deficiency syndromes, and (3) a cytosine-adenine- guanine (CAG) repeat disorder called Huntington disease.

We begin this section with an overview of brain iron accumulation disorders before turning our attention specifically to PKAN, creatine deficiency syndromes, and Huntington disease. We close the section with a discussion of two inherited disorders with abnormal copper metabolism,

Wilson disease and Menkes disease.

Brain Iron Accumulation Disorders

Some iron accumulation within the basal ganglia and dentate nuclei occurs as part of normal aging (see Chapter 33). Neurodegeneration with brain iron accumulation (NBIA) represents a clinically and genetically heterogeneous group of conditions characterized by progressive neurodegeneration and abnormally elevated brain iron.

Four major NBIA subtypes have been defined at the molecular genetic level: (1) PKAN (or NBIA type 1), (2) neuroferritinopathy (NBIA type 2), (3) infantile neuroaxonal dystrophy, and (4) aceruloplasminemia.

We focus our discussion on PKAN, the most common type of NBIA. We then briefly discuss the other three types.

(31-35B) Axial T2WI in the same patient at age 3 years shows no interval progression of myelination. Genetic analysis showed PLP1 mutation, diagnostic for PMD. Serial MR is warranted when hypomyelination is suspected.

PKAN

Terminology. PKAN was formerly known as HallervordenSpatz disease.

Etiology. PKAN is a rare familial autosomal-recessive disorder characterized by excessive iron deposition in the globus pallidus (GP) and substantia nigra (SN). It is caused by mutations in the pantothenate kinase gene (PANK2) localized to chromosome 20p12.2-13p13. More than 100 individual PANK2 mutations have been described. It is estimated that approximately 50% of the cases occur sporadically.

Pathology. Grossly, PKAN is characterized by shrinkage and rust-brown discoloration of the medial GP, the reticular zone of the SN (31-41), and sometimes the dentate nuclei. The red nuclei are generally spared. Granular pigment consisting of iron, lipofuscin, and neuromelanin accumulates in axonal "spheroids" (swollen distended axons), neurons, astrocytes, and microglia, which in turn causes neuronal loss and gliosis. Immunostaining for hyperphosphorylated tau reveals numerous neurofibrillary tangles. Microscopically, increased iron content is found in the GP interna and pars reticulata SN. Iron deposition is found within astrocytes, microglial cells, neurons, and around vessels. The "eye of the tiger" corresponds to regions of reactive astrocytes, dystrophic axons, and vacuoles in the anteromedial GP.

Clinical Issues. PKAN or NBIA type 1 can develop at any age. Four clinical forms are recognized: infantile (onset in the first year of life), late-infantile (onset between 2 and 5 years), juvenile or "classic" (onset between 7 and 15 years), and adultonset NBIA type 1.

Most cases are diagnosed late in the first decade or during early adolescence. The disorder classically begins with slowly

progressive gait disturbances and delayed psychomotor development. Choreoathetosis, dysarthria, and dystonia are observed. Hyperkinesia occurs in about 50% of cases. Progressive mental deterioration finally leads to dementia. In the later stages of the disease, the dyskinesias are replaced by rigid stiffness. An atypical clinical presentation is behavioral and psychiatric disorders, speech delay, and pyramidal and extrapyramidal disturbance.

PANK2 mutations are associated with younger age at onset, more rapid progression, and higher frequency of dystonia, dysarthria, intellectual impairment, and gait disturbances. Parkinsonism is seen predominantly in patients with adult-onset disease.

Imaging. Imaging findings reflect the anatomic distribution of the excessive iron accumulation. T2WI demonstrates marked hypointensity in the GP and SN. A small focus of central hyperintensity in the medial aspect of the very hypointense GP (the classic "eye of the tiger" sign) is caused by tissue gliosis and vacuolization (31-37).

It is important to note that not all cases of PKAN demonstrate the "eye of the tiger" (31-38). Additionally, detection of the T2/FLAIR hyperintense eye of the tiger may antedate the T2 hypointense border. T1WI may show GP T1 shortening reflecting the presence of ferritin-bound iron. T2WI shows diffuse pallidal hypointensity with a medial focus of T2 hyperintensity (eye of the tiger). In time, as the disease progresses, the "eye of the tiger" T2 hyperintensity "shrinks" and becomes less conspicuous. Striking, severe T2 shortening in the GP with hypointense "blooming" on T2* (GRE, SWI) (31-39) in a child or young adult should strongly suggest the diagnosis of an NBIA—either PKAN or infantile neuroaxonal dystrophy—even in the absence of an "eye of the tiger" sign (31-38).

NECT shows variable features with pallidus showing either hypoattenuation, hyperattenuation, or normalcy.

PKAN does not enhance on T1 C+, nor does it demonstrate restricted diffusion although DTI demonstrates significantly increased fractional anisotropy in both the GP and SN. MRS shows decreased NAA peak and reduced NAA:Cr ratio consistent with neuraxonal loss. Increased myoinositol peak (at 3.6 ppm) and increased mI:Cr ratio at short TE are present, suggesting reactive glial proliferation.

Differential Diagnosis. Abnormal iron deposition in the basal ganglia occurs with PKAN as well as other NBIAs. Aceruloplasminemia and neuroferritinopathy are both adult-onset disorders. Both involve the cortex, which is spared in PKAN.

Disorders with increased T2 signal within the GP can be grouped within metabolic derangements and toxic/ischemic insults. These entities lack pallidal GRE and SWI "blooming."

Inherited metabolic disorders to consider in the differential diagnosis of BG T2 hyperintensity include methylmalonic acidemia (increased T2 signal in GP + WM T2 prolongation), Canavan disease (GP and other deep nuclei showing increased T2 signal, subcortical WM T2 hyperintensity, and significantly increased NAA:Cr), guanidinoacetate methyltransferase deficiency (GAMT) (with or without GP T2 hyperintensity, absent or severely reduced Cr on MRS), neuroferritinopathy (variable GP T2 hyperintensity),

Wilson disease, Leigh syndrome, infantile bilateral striatal necrosis, and mitochondrial encephalopathies, which show striatal hyperintensity (not hypointensity or blooming). Additionally, they also predominantly involve the caudate and putamen, not the medial GP. Toxic/ischemic insults include hypoxic ischemic injury (positive health history, T2 hyperintensity involving striatum, GP, thalami, corticospinal tracts, with or without cortical involvement), CO poisoning (increased T2 signal involving GP, other deep

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(31-36A) Axial DWI in a 3y hypotonic boy with PMD shows similar diffusivity of cortical GM and hemispheric WM.

(31-36B) Axial T2WI in the same patient shows a lack of normal hypointense myelinated WM aside from the PLICs and corpus callosum .

(31-36C) MRS short TE (35 ms) in the same patient elevated cytosolic amino acids in the 0.8- to 1.4-ppm range .

(31-37) T2WI (top), GRE (bottom) in a patient with PKAN show classic "eye of the tiger" sign with bilateral hyperintense central foci in the medial globi pallidi surrounded by striking hypointensity .

nuclei, cortex, and WM), cyanide toxicity (T2 increased within basal ganglia with or without hemorrhagic necrosis), and kernicterus (neonate) (increased T1/T2 GP).

Neuroferritinopathy. Mutations in the carboxy terminus of the ferritin light chain gene (FTL) interfere with the transport of iron. Redox active iron is deposited in neurons, causing oxidative stress with neuronal loss and gliosis. The result is neuroferritinopathy, an adult autosomal-dominant disorder, mean age of 39 years at onset.

The predominant clinical neuroferritinopathy phenotype is an extrapyramidal disorder with choreiform movements and focal dystonia. Early cognitive and psychiatric disturbances are absent, thus distinguishing neuroferritinopathy from Huntington disease.

Imaging. The earliest detectable imaging findings in neuroferritinopathy are T2* GRE and SWI hypointensity ("blooming") in the GP and SN. T2 hypointensity in the GP and SN, red nuclei, caudate, putamen, thalamus, and cerebral cortex typically follow. In later stages, gliosis and cystic degeneration in the medial GP may produce foci of T2 hyperintensity that causes an "eye of the tiger" appearance similar to that seen in PKAN (see above).

Infantile Neuroaxonal Dystrophy. Mutations in phospholipase A2 (PLA2G6) cause infantile neuroaxonal dystrophy (INAD), a severe psychomotor disorder showing progressive hypotonia, hyperreflexia, and tetraparesis. Median age at onset is 14 months. Rapid progression with a mean age of death of 9 years is typical.

Imaging. Children with INAD show striking cerebellar atrophy in over 95% of cases. T2/FLAIR hyperintensity in the cerebellum secondary to demyelination and gliosis is also

(31-38) Multiplanar MR shows a 19y woman with documented PKAN. Note the profound hypointensity in the GP , SN , red nuclei , and the lack of an "eye of the tiger" sign. DWI is normal (bottom right).

common. Almost 50% of cases demonstrate abnormal iron deposition with T2 hypointensity in the GP and SN.

NBIA T2* HYPOINTENSITY

PKAN

•GP, SN, dentate nuclei

•"Eye of tiger" sign variable

•Spares cortex

Infantile Neuroaxonal Dystrophy

•Cerebellar atrophy (95%)

•T2* hypointensity in GP, SN (50%)

•Spares cortex

Neuroferritinopathy

•T2* hypointensity in GP, SN

•Then dentate/caudate nuclei, thalami

•Affects cortex

Aceruloplasminemia

•GP, caudate nuclei, putamen, thalamus

•Red nucleus, SN, dentate nuclei

•Affects cerebral, cerebellar cortices

Aceruloplasminemia. Homozygous mutations in the ceruloplasmin gene cause aceruloplasminemia, also known as hereditary ceruloplasmin deficiency. Ceruloplasmin carries over 95% of all plasma copper and acts as a ferroxidase, thus playing an important role in mobilizing tissue iron.

Aceruloplasminemia is a disease of middle-aged adults characterized by the clinical triad of diabetes, retinopathy, and neurologic symptoms (primarily dementia, craniofacial dyskinesia, and cerebellar ataxia). T2 and T2* (GRE, SWI) demonstrate striking hypointensity in the cerebral and

cerebellar cortex, GP, caudate nucleus, putamen, thalamus, red nucleus, SN, and dentate nuclei (31-40).

Imaging. MR is especially useful in diagnosing NBIAs. All feature iron deposition in the GP but differ in other associated findings. The distribution of T2 or T2* hypointensity can help distinguish between the different NBIA subtypes (see box below).

Creatine Deficiency Syndromes

Creatine (kreas in Greek) is required for the utilization of ATPderived energy at sites of high energy utilization (i.e., muscle, brain, and heart). Specifically, creatine and creatine phosphate are essential for the storage and transmission of phosphatebound energy in both muscle and brain. About half of our bodies' needs come from our diet, and the remainder is synthesized in the kidney and liver. Brain creatine deficiency syndromes are a group of rare disorders that include guanidinoacetate methyltransferase (GAMT) deficiency,

Inherited Metabolic Disorders

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arginine:glycine amidinotransferase (AGAT) deficiency, and creatine transporter defect (SLC6A8) (CRTR). The first two are inherited in an autosomal-recessive pattern, and the third is an X-linked recessive disorder. Dietary supplementation can partially or completely reverse the symptoms and imaging abnormalities, so making the diagnosis is crucial to patient management.

Imaging. MR may show variably conspicuous bilaterally symmetric T2/FLAIR hyperintensity and/or restricted diffusion within the globi pallidi (31-42). MRS is often key to making this challenging diagnosis, showing a diminished or absent creatine peak on short and long TE studies at 2.0 ppm (31-42) (31-43). Also, in GAMT deficiency, a guanidinoacetate peak will be detected at 3.8 ppm. MRS may be abnormal when MR appears normal (31-43). This emphasizes the importance of always supplementing MR with MRS in infants and children with unexplained hypotonia and/or unexplained basal ganglia DWI and/or T2/FLAIR hyperintensity.

Differential Diagnosis. Differential diagnoses include other disorders with increased T2/FLAIR signal within the GP. This includes metabolic disorders such as methylmalonic acidemia (increased GP T2 signal and WM T2 hyperintensity), neuroferritinopathy (eye of the tiger and SWI GP blooming), Canavan disease (macrocephaly, subcortical WM T2 hyperintensity, GP increased T2 signal). Toxic/ischemic insults include HII (health history, striatal and thalamic DWI hyperintensity, with or without watershed ischemia), CO poisoning (increased GP, other deep nuclei, and WM T2/FLAIR hyperintensities), and cyanide poisoning (hemorrhagic necrosis and basal ganglia increased T2 signal).

Huntington Disease

Until recently, Huntington disease (HD) was thought to be regionally selective, affecting only GM (most specifically the caudate nuclei and putamina). Although advanced imaging techniques such as DTI have demonstrated that WM is also affected, the dominant imaging features are abnormalities of the deep gray nuclei. Therefore, we include HD in this section with the other IMDs that preferentially involve the striatum, manifesting with profound caudate nucleus atrophy.

Terminology and Etiology. HD is also known as Huntington chorea. HD is an autosomal-dominant chronic hereditary neurodegenerative disorder with complete penetrance. The responsible genetic defect occurs on the short arm of chromosome 4 (4p16.3) and codes for the protein huntingtin. The huntingtin gene includes a repeating CAG trinucleotide segment of variable length. It is more common in a paternally transmitted mutated allele. The presence of more than 38 repeats confirms the diagnosis of HD. There is a progressive increase in the length of the CAG repeat sequences with successive generations.

Pathology. Aggregates of huntingtin protein accumulate in axonal terminals, which eventually leads to the death of medium spiny neurons. Autopsy shows generalized cerebral atrophy with an average of 30% reduction in brain weight. Both the cortex and hemispheric WM are affected. The most characteristic gross abnormality is volume loss with rarefaction of the caudate nucleus, putamen, and globus pallidus (31-44) (31-45).

Microscopically, HD features neuronal loss with huntingtin nuclear inclusions, astrocytic gliosis, and iron accumulation. The changes are most severe in the basal ganglia but can also be seen in other regions of the brain, including the cerebellum (which is less commonly involved in the adult).

Clinical Issues. The incidence of HD is 4-7:100,000 in most populations. Mean age at symptom onset is 35-45 years. Only 5-10% of patients present before the age of 20 years (juvenile-onset HD). In the juvenile-onset form, look for cerebellar atrophy in addition to caudate atrophy There is no sex predilection.

CAG repeat length and age influence both the expression and the progression of HD. Adult-onset HD is characterized by progressive loss of normal motor function, development of stereotypic choreiform movements, and deteriorating cognition. Once symptoms appear, the disease progresses relentlessly and results in death within 10-20 years.

Juvenile-onset HD is initially characterized by rigidity and dystonia, much more than by chorea. Cerebellar signs are also common.

Imaging. Standard imaging studies (CT, MR) are normal early in the disease course. As symptoms develop and progress, NECT scans show caudate atrophy with enlarged, outwardly convex frontal horns and variable generalized diffuse atrophy (31-46) with or without cerebellar atrophy.

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(31-43A) Axial FLAIR in a 10m hypotonic girl with creatine deficiency (GAMT deficiency) shows subtle GP hyperintensity .

(31-43B) Axial FLAIR in the same patient shows BG MRS voxel placement.

(31-43C) MRS short TE (35 ppm) shows diminished creatine peak at 2.0 ppm .

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MR shows diffuse cerebral volume loss with T2/FLAIR hyperintensity in shrunken caudate heads. Putaminal hyperintensity is also common (31-47). The pattern of cerebral volume loss may show predilection for the frontal lobes. There is no enhancement of involved structures.

MR volumetric studies can demonstrate decreased basal ganglia volumes years before the onset of motor disturbances. Voxel-based morphometry, DTI, and PET have also demonstrated abnormalities in the hemispheric WM and cortex of both asymptomatic carriers and patients with "premanifest" HD.

Magnetization transfer imaging (MTI) demonstrates peak height reduction proportionate to CAG repeat length in normal-appearing GM and WM. Disturbances in MTI are apparent in early HD and are homogeneous across both GM and WM.

Differential Diagnosis. Some acquired neurodegenerative disorders can mimic adult HD. These include multiple system atrophy (MSA), corticobasal degeneration, and frontotemporal lobar dementia. All these acquired disorders are often accompanied by basal ganglia atrophy, although, unlike in HD, the caudate nuclei are not disproportionately affected.

The differential diagnosis of juvenile HD includes Leigh syndrome (DWI hyperintensity and increased T2/FLAIR in the putamen, caudate, and tegmentum), late-stage Wilson disease (caudate and brainstem atrophy, increased symmetric signal in the caudate nucleus, putamen, midbrain, and pons and regions of caudate and putaminal irregular T2 hypointensities), and PKAN with choreoathetosis and dementia, which can mimic the symptoms of HD. The "eye of the tiger" sign in the medial GP distinguishes PKAN from HD.

HUNTINGTON DISEASE

Etiology

•Autosomal-dominant, complete penetrance

•CAG trinucleotide repeat disorder

Pathology

•Caudate nuclei, putamina, GP

○Huntingtin protein nuclear inclusions

○Neuronal loss, gliosis, iron accumulation

Clinical

•Adult onset (35-45 years) = 90%

•Juvenile onset HD (< 20 years) = 10%

Imaging

•Caudate nuclei, putamina T2/FLAIR hyperintense

•Frontal horns outwardly convex

Disorders of Copper Metabolism

Copper is essential for normal brain development. Copper-containing proteins are a critical element in a number of enzymatic systems, including iron homeostasis. Copper homeostasis is a delicate balance that requires both adequate dietary intake and proper excretion. Excess copper is neurotoxic. Two disorders of copper metabolism—Wilson disease (WD) and Menkes disease—have striking CNS manifestations.

The major manifestations of WD are found in the basal ganglia, midbrain, and dentate nucleus of the cerebellum. Therefore, WD is discussed in this section with IMDs that predominantly affect the gray matter. A brief consideration of Menkes disease follows.

Wilson Disease

Etiology. WD is an uncommon autosomal-recessive disorder of copper trafficking caused by mutations in the ATP7B gene, which is found on chromosome 13q14.3q21.1. The mutation causes defective incorporation of cooper into ceruloplasmin and impaired biliary copper excretion. There is excessive accumulation of Cu in hepatocytes, which later spills into the circulation. Copper deposition in Golgi complexes and the mitochondria results in oxidative damage primarily to the liver, brain, kidney, skeletal system, and eye.

Pathology. Selective vulnerability of the corpus striatum to mitochondrial dysfunction accounts for the predominant basal ganglia volume loss seen in WD (31-49). Gross pathologic features are nonspecific, with ventricular enlargement and widened sulci seen at autopsy in severe cases. Microscopic features include edema, necrosis, and spongiform changes in the basal ganglia. Variable gliosis and demyelination are present in the cerebral and cerebellar WM.

Clinical Issues. WD most commonly affects children and young adults. The reported incidence of symptomatic WD is 1:30,000-40,000, but the frequency of asymptomatic carriers is 1:90. There is no sex predilection.

Symptoms of early-onset WD (8-16 years of age) are usually related to liver failure. Later-onset WD symptoms are primarily neurologic and are generally recognized in the second or third decade. Dysarthria, dystonia, tremors, ataxia, Parkinson-like symptoms, and behavioral disturbances are common. Copper deposition in the cornea causes the characteristic greenish yellow Kayser-Fleischer rings seen on slit-lamp examination (31-48).

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(31-48) Wilson disease (WD) is shown with classic peripheral greenish-yellow Kayser-Fleischer ring. (Courtesy AFIP Archives.)

(31-49) Autopsy in WD shows atrophic putamina, caudate , and basal ganglia characteristic of WD. (Courtesy R. Hewlett, MD.)

(31-50) Acute WD shows hyperintensity on T1 and T2WI , DWI restriction , and no enhancement . (Courtesy M. Ayadi, MD.)

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Clinical symptoms generally improve, and signal abnormalities on MR may diminish with appropriate treatment. Treatments include restriction of foods rich in Cu (i.e., nuts, mushrooms, chocolate), chelating drugs (i.e., Trientene), and liver transplantation. Untreated WD is always fatal.

WILSON DISEASE

Etiology

•Abnormal copper metabolism

•Autosomal recessive

•ATP7B gene mutations

Pathology

•Copper accumulates in hepatocytes, brain, eye

•Mitochondrial dysfunction damages basal ganglia

Clinical Issues

•Childhood WD: liver disease

•Young adults: Parkinson-like

•Kayser-Fleischer rings

Imaging

•T2/FLAIR hyperintensity

○Putamina, caudate, thalami, midbrain

•T2* "blooming"

Differential Diagnosis

•Leigh syndrome

•PKAN

Imaging. NECT scans may be normal, especially early in the disease course. CT grossly underestimates WD pathology. Diffuse brain atrophy, widening of the frontal horns of the lateral ventricles, and striatal or thalamic hypoattenuation may be seen in advanced cases.

Signal intensity on T1WI is variable. Some cases demonstrate subtle hypointensity in the affected areas, whereas others show T1 shortening similar to that seen in chronic hepatic encephalopathy (see Chapter 32). BG T2 signal reflects paramagnetic effects of Cu.

The most common imaging finding of WD on MR is bilaterally symmetric T2/FLAIR hyperintensity (sometimes heterogeneous) in the putamina (70%), caudate nuclei (60%), ventrolateral thalami (55-60%), and midbrain (50%) (31-50). Initially, swelling of the basal ganglia then atrophy are seen. Hyperintensity can sometimes be seen in the pons (20%), medulla (10-15%), and cerebellum (10%). The cerebral (25%) and cerebellar WM (10%) can show focal or diffuse confluent hyperintensities.

In 10-12% of cases, diffuse tegmental (midbrain) hyperintensity with sparing of the red nuclei gives an appearance that has been termed the "face of a giant panda."

T2* (GRE, SWI) sequences show blooming in the putamina, caudate nuclei, ventrolateral thalami, and often the dentate nuclei. Contrast enhancement is typically absent although mild enhancement can occur in the acute stages.

Restricted diffusion in the corpus striatum can be seen in the early stages of WD. Elevated ADC values consistent with

necrosis and spongiform degeneration are seen in chronic longstanding WD. MRS shows reduced NAA and Cho and reduced myoinositol:creatine ratio in affected areas. PET shows markedly reduced glucose metabolism and diminished dopa-decarboxylase activity indicative of striatonigral dopaminergic pathway dysfunction.

Differential Diagnosis. The differential diagnoses of WD includes other inherited metabolic disorders that affect the basal ganglia, such as Leigh syndrome, NBIAs, the organic acidurias, and Japanese encephalitis (JE). Leigh syndrome (subacute necrotizing encephalomyelopathy) shows bilateral, symmetric, spongiform, and hyperintense lesions particularly in the putamen and brainstem. The WM is often affected in Leigh syndrome, whereas the caudate and thalamus are less commonly involved. MRS demonstrates elevated lactate levels in the basal ganglia. Organic aciduria (widened CSF spaces, symmetric WM T2/FLAIR hyperintensities, basal ganglial increased T2 signal) and JE (mosquito-borne illness showing characteristic homogeneous T2/FLAIR hyperintensities in the basal ganglia and posteromedial thalami) should be considered.

Likewise, PKAN can resemble WD. WD predominantly affects the putamina and caudate nuclei rather than the medial GP and lacks the "eye of the tiger" sign often seen in PKAN.

Menkes Disease. Menkes disease—also known as kinky hair syndrome—is an X-linked, multisystemic, lethal disorder of copper metabolism caused by ATP7A gene mutations. Severe classic Menkes disease is characterized by progressive neurodegeneration, connective tissue abnormalities, pili torti ("kinky" hair), and death in early childhood. It accounts for 9095% of cases. A milder phenotype, occipital horn syndrome, also called Ehlers-Danlos type 9, is characterized by skeletal abnormalities and longer survival.

Imaging. Menkes disease shows severe brain atrophy with subdural fluid collections and excessive tortuosity and prominence of the intracranial arteries (remember: "kinky hair, kinky vessels") (31-51A) (31-51B). Wormian bones, although nonspecific, are also seen (31-51C). With progression in neurodegeneration and brain atrophy, development of subdural hemorrhage is common.

Differential Diagnosis. Differential diagnoses include glutaric aciduria type I (widened lateral cerebral fissures, GP increased DWI and T2/FLAIR signal), hypoxic ischemic encephalopathy (HII) (positive health history, nonprogressive neurologic features), urea cycle defects (initial diffuse cerebral edema, looks like "worst case ever" of HII), TORCH infections (microcephaly, Ca++, nonprogressive), and Loeys-Dietz syndrome (characterized by aneurysms of the aorta and other vessels, including intracranial, similar to Marfan syndrome).

IMDs Primarily Affecting Cortex

Compared with IMDs that affect the deep gray nuclei, disorders that exclusively or primarily affect the cortical GM are rare. Two prototypical IMDs that involve the cortex are briefly discussed here. These are neuronal ceroid lipofuscinoses (NCLs) and Rett syndrome (RTT).

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Neuronal Ceroid Lipofuscinosis

The NCLs are a heterogeneous family of inherited neurodegenerative disorders characterized by accumulation of ceroid-lipopigment inclusions in neurons. A number of different types have been described. Previously, the NCLs were classified according to age at onset with infantile, lateinfantile, juvenile (i.e., Batten disease), and adult forms (e.g., Kufs disease). The specific gene mutations that cause most forms have been identified, and the NCLs are now classified according to the eight affected genes (CLN1-8).

NCL is predominantly a childhood disease with an estimated incidence of 1:12,500. The diagnosis is established through clinicopathologic findings, enzymatic assay, and molecular genetic testing. Ultrastructural studies—usually from skin biopsy specimens—are used to confirm the presence and nature of lysosomal storage material (i.e., specific lipopigments).

anterior temporal cortex (31-53). DTI shows reduced fractional anisotropy (FA) in the corpus callosum, internal capsule, frontal WM, and anterior cingulate gyrus with preservation or increased FA in the posterior corona radiata. MRS shows decreased NAA.

Differential Diagnosis. The clinical differential diagnosis of RTT includes NCL and autism. Cortical thinning in NCL is generalized and does not exhibit the frontotemporal pattern seen in RTT. Autism is excluded if the patient is MECP2 mutation positive. Hypoxic ischemic encephalopathy to include watershed infarction is nonprogressive and associated with positive health history.

Disorders Affecting Both

Gray and White Matter

Gross pathologic findings in the childhood NCLs are striking global atrophy with no specific lobar predominance. All NCLs demonstrate similar histopathologic features, i.e., abnormal accumulation of PASand Sudan black-positive inclusions in ballooned neurons. Cortical layers III, V, and VI are most severely affected. Progressive and selective neuronal loss and gliosis with secondary WM degeneration are universally present.

Imaging. The NCLs share common but nonspecific imaging features. Thalami and GP are hyperattenuating on NECT and hypointense on T2WI. Serial MR shows progressive atrophy with thinned cortex, enlarged ventricles, periventricular T2/FLAIR hyperintense rims, and prominent sulci.

Differential Diagnosis. Differential diagnoses include HIIstatus marmoratus (positive health history of perinatal hypoxic ischemic insult, nonprogressive hyperattenuating GP and thalami, striatal increased T2 signal, perirolandic atrophy), Krabbe disease (hyperattenuating on NECT thalami, caudate, and dentate nuclei, increased T2 signal cerebral WM), and juvenile GM1 gangliosidoses (hyperattenuating thalami on NECT, T2 hypointensity of ventral thalami, hypointense dorsal thalami).

Rett Syndrome

RTT is a progressive neurodevelopmental disorder that almost always affects girls. The majority of cases are sporadic, and no risk factors have been identified. A mutation in the methyl- CpG-binding protein-2 gene (MECP2) is identified in 80% of cases.

RTT occurs in 1:20,000 girls. Affected individuals are usually normal at birth with no obvious abnormalities. Head growth gradually decelerates after the first few months, and severe psychomotor retardation develops. Intellectual impairment, mood and behavioral changes, speech difficulty, truncal apraxia, and stereotypical hand waving develop.

Imaging. Imaging shows microcephaly with mild but diffuse reduction in both cortical and hemispheric WM volume (3153). The most prominent loss is seen in the frontal and

In the last section of this chapter, we discuss inherited metabolic disorders (IMDs) that affect both gray and white matter. The pathoetiologies are quite variable and range from abnormal organelles to specific enzymatic dysfunctions.

Selected for discussion are the mucopolysaccharidoses (MPSs), Canavan disease, Alexander disease, peroxisomal spectrum disorders, and mitochondrial disorders.

Mucopolysaccharidoses

Terminology and Etiology

The MPSs are lysosomal storage disorders characterized by incomplete degradation and progressive accumulation of toxic glycosaminoglycan (GAG) in various organs. In the brain, this accumulation includes GAG deposits in the Virchow-Robin spaces, leptomeninges, and craniocervical junction ligamentous structures. GAG represents a CNS toxin. The MPSs were once grouped into a single entity and termed "gargoylism" for their supposedly characteristic facies.

The MPSs have a classification of 1-9. Each has a specific enzyme deficiency and gene defect that leads to the inability to break down GAG.

MPS 1H (Hurler) and MPS 1HS (Hurler-Scheie disease) have deficiency of α-L-iduronidase (4p16.3). MPS 2 (Hunter disease) is characterized by iduronate 2-sulfatase deficiency (Xq28). Other MPSs include MPS 3A (Sanfilippo disease), a deficiency of heparin N-sulfatase (17q25.3), MPS 4A (Morquio disease), a deficiency in galactose 6-sulfatase (16q24.3), and MPS 6 (Maroteaux-Lamy disease) associated with a deficiency in arylsulfatase B (5q11-q13).

Pathology

Autophagy is a highly regulated process in the lysosomal pathway that degrades proteins and damaged cellular organelles. Abnormal autophagy combined with the incomplete degradation and progressive accumulation of GAGs is the pathology that underlies the MPSs.

(31-55) T1WI in a toddler with MPS 1H (Hurler disease) shows markedly enlarged WM PVSs, including the corpus callosum.

(31-56) MPS 1HS (Hurler-Scheie) myelin stain shows large PVSspacked with undegraded mucopolysaccharides. (Courtesy P. Shannon, MD.)

The two distinctive gross features of the MPSs are thickened meninges and dilated perivascular spaces (PVSs). The enlarged PVSs give a cribriform appearance to the brain on both pathology and imaging (31-52) (31-55).

Microscopically, the MPSs are characterized by dilated PVSs packed with undegraded GAG (31-56). GAG infiltrates the leptomeninges and ligaments as well.

Clinical Issues

Each MPS subtype has different clinical phenotypes. Clinical observations include macrocrania, coarse facies, bushy eyebrows, macroglossia, flat nasal bridge, hepatosplenomegaly, and skeletal dysostoses. Age at presentation varies, as do sex predilection and prognosis based on the inherited MPS type.

Hurler (MPS 1H) and Hunter (MPS 2) diseases are two of the most common "prototypical" MPSs. Hurler patients appear normal at birth but soon develop CNS symptoms, including delayed development and mental retardation. Untreated Hurler disease typically results in death by age 10.

MPS 2 (Hunter disease) is an X-linked disorder and is seen only in male patients. Hunter disease is characterized by progressive multisystem involvement in the CNS, joints, bones, heart, skin, liver, eyes, and other organs. Patients often survive into their mid teens but usually expire from cardiac disease.

Therapy for MPS includes bone marrow transplant and IV recombinant enzyme replacement therapies (i.e., α-L- iduronidase for MPS 1H).

Imaging

The prototypical imaging findings in MPSs are illustrated by Hurler (MPS 1H) and Hunter (MPS 2) diseases. The major features of these disorders are macrocephaly, frontal calvarial bossing, J-shaped sella, enlarged PVSs, WM abnormalities, pachymeningopathy, rosette formation of impacted teeth, broad ribs, dysostosis multiplex, and trident hands.

Macrocephaly. NECT and MR scans show an enlarged head, often with metopic "beaking" and scaphocephalic configuration (31-57). Reduced attenuation of WM, progressive hydrocephalus, and atrophy of Virchow-Robin spaces are rarely seen on NECT. Sagittal MR scans also demonstrate a large head with craniofacial disproportion. Pannus of ligaments at craniocervical junction can be seen.

Enlarged Perivascular Spaces and WM Abnormalities. A striking sieve-like cribriform appearance in the posterior cerebral WM and corpus callosum is characteristic and is caused by numerous dilated PVSs (31-55) (31-57) (31-58) (31-59) (31-61). Although sometimes called "Hurler holes," these enlarged PVSs are typical of both Hurler and Hunter diseases. They are much less common in the other MPSs.

NECT scans may show decreased attenuation with multifocal CSF-like regions in the WM and basal ganglia (31-57).

T2 scans show CSF-like hyperintensity in the enlarged PVSs. The surrounding WM may show patchy or confluent hyperintensity. The PVSs themselves suppress completely on FLAIR (31-58) (31-59C). A faint "halo" of hyperintensity often surrounds the lesions. Some MPS types (MPS 3A) demonstrate subtle enlargement of the PVSs.

(31-57) NECT of Hunter disease shows WM and focal BG hypoattenuating lesions . T2WI shows enlarged PVSs in corpus callosum and confluent WM disease . PVSs suppress on FLAIR ; the WM disease remains hyperintense. This is MPS 2.

The enlarged PVSs do not "bloom" on T2* and do not enhance following contrast administration. These may be subtle in MPS 3A (31-59) (31-61).

There is a linear correlation between the severity of WM abnormality and the cognitive impairment and developmental delay.

Pachymeningopathy. The meninges, especially around the craniovertebral junction, are often thickened and appear very hypointense on T2-weighted images (31-60). In severe cases, the thickened meninges can compress the medulla or upper cervical cord. Odontoid dysplasia and a short C1 posterior arch—common in the MPSs—can exacerbate the craniovertebral junction stenosis, causing progressive myelopathy. A lumbar gibbus with a "beaked" L1 vertebral body is common in Hurler disease. The practical consideration here is to always assess the craniocervical junction for level and degree of compression and to image infants under an anesthesiologist's supervision to avoid sudden death.

Differential Diagnosis

The differential diagnosis of MPS is limited. Prominent PVSs can be normal findings in patients of any age. Although they can be seen in children and even infants, prominent PVSs are more common in middle-aged and older patients. No macrocephaly is present with this normal variant.

Dilated PVSs with a frontal predominance are a feature of velocardiofacial syndrome. Deviated carotid arteries in the pharynx are present, a finding not associated with the MPSs. Hypomelanosis of Ito may show dilated PVSs. Cutaneous hypopigmented zones with irregular borders are seen; seizures usually develop in the first year of life.

(31-58) Sagittal, coronal, axial T2 scans in a 2y boy with Hunter disease show multiple enlarged PVSs . Note the posterior predominance and corpus callosum involvement. The lesions suppress on FLAIR . This is MPS 2.

Canavan Disease

Canavan disease (CD) is a fatal autosomal-recessive neurodegenerative disorder for which there is currently no effective treatment. CD is the only identified genetic disorder caused by a defect in a metabolite—N-acetyl-L-aspartate (NAA)—that is produced exclusively in the brain.

Terminology

CD is also known as spongiform leukodystrophy, spongy degeneration of the CNS, aspartoacylase deficiency, aminoacylase 2 deficiency, and Canavan-van Bogaert-Bertrand disease.

Etiology

NAA is the second most abundant amino acid in the mammalian brain. NAA levels in the brain are normally maintained within a tightly regulated range. Aspartoacylase—the enzyme responsible for metabolizing NAA—is a signature marker of mature oligodendrocytes. Mutations in the ASPA gene, located on the long arm of chromosome 17, cause abnormal NAA accumulation in the brain and result in CD.

The how and why of excessive NAA, causing intramyelinic edema and myelin damage associated with CD, are unknown.

Pathology

The brain in CD appears grossly swollen. Microscopic analysis shows spongiform WM degeneration with swollen astrocytes in the globi pallidi and thalami.

CD is most common in Ashkenazi Jews and rare in other nonJewish populations. One in 40 Ashkenazi Jews carries the mutated ASPA gene. There is no sex predilection.

Three clinical variants of CD are recognized. The congenital form presents within the first few days of life and leads to profound hypotonia with poor head control. Death rapidly ensues. The most common form by far is infantile CD. Infantile CD presents between 3 and 6 months and is characterized by hypotonia, macrocephaly, and seizures. Death between 1 and 2 years is typical. Juvenile-onset CD begins between 4 and 5 years of age and is the most slowly progressive form.

Imaging

NECT shows a large head with diffuse WM hypoattenuation in the cerebral hemispheres and cerebellum. The globi pallidi also appear hypoattenuating. CD does not enhance.

MR eventually shows virtually complete absence of myelination with confluent T2/FLAIR hyperintensity throughout the WM and globi pallidi. These involved regions show T1 prolongation. Early in the disease course, the subcortical arcuate fibers are initially affected, and the gyri may appear swollen (31-62). Early occipital WM T2/FLAIR hyperintensity is observed. As the disease progresses, diffuse volume loss with ventricular and sulcal enlargement ensues. The hemispheric and cerebellar WM, basal ganglia, and cortex are all extensively affected. DWI reveals bright DWI signal with normal to reduced ADC values in the involved areas.

MRS is the key to the definitive imaging diagnosis of CD. Markedly elevated NAA is seen in virtually all cases (31-63). Cr is reduced. An elevated myoinositol peak is sometimes present. The choline/creatine (Ch/Cr) ratio is reduced.

Differential Diagnosis

The major differential diagnosis of CD is Alexander disease. Both CD and Alexander disease cause macrocephaly, but an elevated NAA peak on MRS distinguishes the two disorders. Furthermore, Alexander disease exhibits a frontal WM predilection and enhancement; CD does neither.

Megalencephaly with leukoencephalopathy and cysts involves the subcortical arcuate fibers, as does CD; however, the basal ganglia are not affected. Pelizaeus-Merzbacher disease demonstrates virtually complete lack of myelination but does not cause macrocephaly and does not affect the basal ganglia. ADC values are increased. Merosin-deficient congenital muscular dystrophy spares involvement of the GP and thalami and demonstrates increased ADC values.

Alexander Disease

Terminology

Alexander disease (AxD) is also known as fibrinoid leukodystrophy, a misnomer given that it involves both white and gray matter.

AxD patients have de novo heterozygous dominant mutations in the GFAP gene (17q21) in more than 95% of cases. GFAP encodes for glial fibrillary acidic protein, an intermediate filament protein that is expressed only in astrocytes. The parents of patients with infantileor childhood-onset AxD are neurologically normal.

GFAP mutations cause precipitation and accumulation of mutant GFAP aggregates, which begins during fetal development.

Pathology

The brains of infants with AxD have markedly increased astrocytic density and are grossly enlarged. Dramatic myelin loss in the hemispheres, brainstem, cerebellum, and spinal cord makes the WM—especially in the frontal lobes—appear very pale. In severe cases, the WM appears partially or almost entirely cystic. The subcortical arcuate fibers are relatively spared. Cortical thinning with basal ganglia and thalamic atrophy is common.

The hallmark histopathologic feature of AxD is the presence of enormous numbers of Rosenthal fibers (RFs) in astrocytes. RFs are ovoid or rod-shaped eosinophilic cytoplasmic inclusion bodies. The striking lack of nearly all myelin in AxD is considered a secondary phenomenon that arises from severely disrupted astrocyte-derived myelination signaling.

Clinical Issues

AxD is rare, accounting for just 1-2% of childhood inherited leukodystrophies.

Three clinical forms are recognized: infantile, juvenile, and adult. In the infantile form, which is the most common, patients younger than 2 years present with megalencephaly, progressive psychomotor retardation, and seizures. Spasticity and eventually quadriplegia often develop. All forms eventually lead to death. Care is supportive.

Juvenile AxD presents between ages 2-12 years and is characterized by bulbar and cerebellar signs. Patients over the age of 12 years present with a variety of signs and symptoms, including ataxia, bulbar signs, and cognitive decline. Palatal myoclonus occurs in 40% of adult AxD cases.

Disease progression is variable. Patients with adult-onset AxD have a slower, more protracted course. Although imaging findings can be suggestive of the disease, the diagnosis of AxD is confirmed by increased GFAP CSF levels or GFAP gene analysis.

Imaging

NECT scans of infants with AxD show a large head with symmetric WM hypoattenuation in the frontal lobes that extends posteriorly into the caudate nuclei and internal/external capsules (31-64A). AxD is one of the few IMDs that demonstrates enhancement following contrast. The other is X-ALD. Intense bifrontal periventricular

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enhancement can be seen on CECT scans early in the disease course.

MR shows macrocephaly, T1 hypointensity, and T2/FLAIR hyperintensity involving the frontal WM, caudate nuclei, and anterior putamina. Although infantile AxD involves the subcortical U-fibers early in the disease course, the periventricular WM is more severely affected in the juvenile and adults forms. A classic finding is a T1 hypointense, T2 hyperintense rim around the frontal horns. FLAIR scans may demonstrate cystic encephalomalacia in the frontal WM in more severe, protracted cases (31-64).

A unique finding in AxD is enlargement of the caudate heads and fornices, which appear swollen and hyperintense. The thalami, globi pallidi, brainstem, and cerebellum are less commonly affected (31-64B).

Unlike most IMDs, AxD can demonstrate moderate to striking enhancement on T1 C+. Rims of intense enhancement can be

seen around the surfaces of the swollen caudate nuclei and affected frontal lobe WM (31-64A). In the juvenile and adult forms, brainstem and cerebellar involvement can be striking and may even mimic a neoplasm.

MRS shows decreased NAA, elevated myoinositol, with variable choline and lactate. DWI shows normal to increased diffusivity in the affected WM.

Differential Diagnosis

The major differential diagnoses of AxD are other inherited leukodystrophies with macrocephaly. These primarily include

Canavan disease and the mucopolysaccharidoses. Although both AxD and Canavan disease show almost complete lack of myelination with T2/FLAIR WM hyperintensity, the predilection of AxD for the frontal lobes, caudate heads, and enhancement helps distinguish it from Canavan disease.

DIFFERENTIAL DIAGNOSIS: CHILD WITH A LARGE HEAD

Common

•Normal variant

•Benign familial macrocrania

•Benign macrocrania of infancy

Less Common

• Nonaccidental trauma with subdural hematomas

Rare But Important

•Inherited metabolic disorder

○Canavan disease

○Alexander disease

○Mucopolysaccharidoses

○Megalencephaly with leukoencephalopathy and cysts

○Glutaric aciduria type 1

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The mucopolysaccharidoses, especially Hurler and Hunter diseases, display a striking "cribriform" appearance of the WM and corpus callosum caused by enlarged perivascular spaces. Deep gray involvement is absent, and the lesions do not enhance. Some of the MPSs—especially MPS-1—cause dural thickening, which is absent in AxD.

Megalencephaly with leukoencephalopathy and cysts has striking subcortical arcuate involvement early in the disease course, does not involve the basal ganglia, and does not enhance. Glutaric aciduria type 1 shows characteristic widening of the lateral cerebral fissures, symmetric BG involvement, no enhancement, and periventricular WM involvement in severe cases.

Peroxisomal Biogenesis Disorders

Peroxisomes are small single-membrane-bound organelles that contain over 50 enzymes required for normal growth, development, and cellular metabolism. Biosynthesis of

(31-63A) Sagittal T1WI in a 2y boy with Canavan disease shows macrocephaly. Volume loss involves the cerebral hemispheres and cerebellum. Note the swollen lower brainstem. (31-63B) Axial T2WI shows diffuse WM hyperintensity throughout the WM, indicating complete absence of myelination. The globi pallidi are hyperintense and shrunken.

(31-63C) T2WI through the corona radiata in the same patient shows the virtually complete absence of myelination (hyperintense WM) . The cortex appears thinned, and the sulci are enlarged. (31-63D) Multivoxel MRS of the WM with TE = 135 ms shows a markedly elevated NAA peak resonating at 2.0 ppm . Cr is significantly reduced. A small myoinositol peak is present.

plasmalogens and β-oxidation of very-long-chain fatty acids (VLCFAs) are among the essential functions of peroxisomes. Genetic defects that affect either peroxisomal formation or enzymatic function cause a group of diseases called peroxisomal disorders.

Terminology

Synonyms are cerebrohepatorenal syndrome and Zellweger syndrome spectrum (ZSS). There are two main types of peroxisomal disorders. The most common type is caused by single protein deficiencies within intact (morphologically normal) peroxisomes. This group includes, among others, X-linked adrenoleukodystrophy (ALD), adrenomyeloneuropathy (AMN), and classic (adult) Refsum disease. ALD and AMN affect periventricular WM and were discussed earlier in the chapter.

The second less common group of peroxisomal disorders caused by abnormal formation of peroxisomes is discussed below. Disorders in which the peroxisomal organelles themselves fail to form normally are called peroxisomal biogenesis disorders (PBDs). PBDs are typically characterized by multiple (not single) enzymatic defects.

Four major PBDs are recognized: Zellweger syndrome (ZS, also called cerebrohepatorenal syndrome), neonatal adrenoleukodystrophy, infantile Refsum disease, and classic rhizomelic chondrodysplasia punctata. The first three disorders are grouped together and referred to as Zellweger syndrome spectrum (ZSS).

Etiology

PBDs are autosomal-recessive disorders caused by mutations in one of 13 peroxisomal assembly (PEX) genes. The most severe form is ZSS, which accounts for 80% of all cases and is characterized by nearly complete absence of peroxisomes.

Pathology

PBDs are characterized pathologically by germinal matrix injury, subependymal germinolytic cysts, disordered neuronal migration, and hypomyelination.

The most common gross findings are cerebral neocortical and cerebellar abnormalities. Brain atrophy and abnormal gyration—most often pachygyria or polymicrogyria—are common in patients with severe ZSS (31-65). Defective peroxisomes in oligodendroglial cells also cause abnormal WM formation and maintenance.

Clinical Issues

PBDs are less common than many other inherited metabolic disorders. The estimated incidence is 1:20,000-100,000 live births. In contrast to ALD, there is no sex predilection.

The PBDs are clinically diverse, but frequent features include dysmorphic facies with large fontanelle and sutures, high forehead, and broad nasal bridge. Hepatointestinal dysfunction, hypotonia ("floppy infant"), seizures, retinitis pigmentosa, and psychomotor retardation are common.

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The disease course of different PBDs varies considerably. The most severely affected neonates with ZS typically die by 6 months of age, whereas those with milder forms of the disease may survive more than 20 years.

Imaging

Imaging in PBDs is variable, but the most common features are disordered neuronal migration and abnormal myelination. ZSS is known by microgyria and pachygyria, often with bilaterally symmetric parasylvian lesions. Hypomyelinated WM is seen as confluent T2/FLAIR WM hyperintensity. Subependymal (caudothalamic) germinolytic cysts are common findings (31-66). Hyperbilirubinemia may cause increased T1 signal intensity in the globi pallidi of older patients. T1WI C+ may show enhancement within the corticospinal tracts of the brainstem. MRS demonstrates lipid peaks on short TE sequences (i.e., TE 35 ms) between 0.80 and 1.33 ppm, reduced NAA, and increased Cho.

Differential Diagnosis

The major differential diagnosis of ZSS is congenital cytomegalovirus (CMV). Both ZSS and congenital CMV exhibit hypomyelination and cortical malformations. Calcifications are a more prominent feature of CMV, particularly along the caudostriatal groove, and the periventricular cysts (particularly anterior temporal) are strongly suggestive of CMV. Isolated neuronal migration disorders (e.g., bilateral perisylvian polymicrogyria) occur without other clinical and imaging stigmata of ZSS. Pseudo-TORCH shows basal ganglia, brainstem, thalamic, and periventricular Ca++. In pseudoTORCH, the clinical course is that of progressive neurologic deterioration.

Mitochondrial Diseases (Respiratory

Chain Disorders)

The mitochondria are cellular organelles that are the "power plants" responsible for energy production. Five complexes are embedded in the inner mitochondrial membrane and are responsible for oxidative phosphorylation (OXPHOS); defects in any one result in defective OXPHOS and deficient ATP production.

Mitochondrial disorders are caused by mitochondrial DNA (mtDNA) mutations and are among the most common of all IMDs. Although virtually every organ or tissue of the body can be affected, the nervous system and skeletal muscle are especially vulnerable because of their high energy demands.

Four major encephalomyopathic syndromes have been described and are considered here: Leigh syndrome, KearnsSayre syndrome, MELAS, and MERRF. We then discuss glutaric aciduria types 1 and 2, also caused by mtDNA-mediated enzyme abnormalities. Other mitochondrial disorders—including Alpers syndrome, infantile mitochondrial myopathy, and Leber hereditary optic neuropathy (LHON)—are very rare and not examined further in this text.

Mitochondrial disorders have significant clinical and imaging overlap and are challenging to distinguish from each other.

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(31-65) Coronal autopsy specimen of ZSS shows abnormal gyration with pachy-, polymicrogyria, poor sulcation. (Courtesy AFIP Archives.)

(31-66A) Coronal T2WI in newborn with ZSS shows a germinolytic cyst and several areas of polymicrogyria .

Leigh Syndrome

Terminology and Etiology. Leigh syndrome (LS) is also known as subacute necrotizing encephalopathy. LS is caused by mutations that encode for OXPHOS enzymes, a group of disorders caused by defective terminal oxidative metabolism.

Pathology. LS demonstrates brownish gray gelatinous or cavitary foci within the basal ganglia, brainstem, dentate nuclei, thalami, and spinal cord with variable WM spongiform degeneration and demyelination.

Clinical Issues. Clinical manifestations of LS are variable. Most patients with LS present in infancy or childhood with failure to thrive, central hypotonia, developmental regression, ataxia, bulbar dysfunction, and ophthalmoplegia. Serum and/or CSF lactate levels are increased.

Imaging. MR in LS shows bilaterally symmetric areas of T2/FLAIR hyperintensity (often speckled) in the basal ganglia (31-67). The putamina (especially the posterior segments) are consistently affected, as are the caudate heads. The dorsomedial thalami can also be involved, whereas the globi pallidi are less commonly affected. Acute lesions show swelling of the basal ganglia.

Mid and lower brainstem (pons/medulla) lesions are typical in LS and in a few cases can be the only finding. Symmetric lesions in the cerebral peduncles are common, and the periaqueductal gray matter is frequently affected. Brainstem lesions are especially common in cytochrome-C oxidase deficiency.

Acute lesions restrict on DWI but do not enhance. MRS of the brain and CSF typically shows a lactate doublet at 1.3 ppm. Lactate resonates above baseline at short (35 ms) and long (288 ms) TEs and inverts at an intermediate TE (144 ms).

Differential Diagnosis. As their imaging findings often overlap, the differential diagnosis of LS includes the other mitochondrial encephalomyopathies. MELAS typically shows stroke-like abnormalities in the cortical gray matter in a nonvascular distribution in the hemispheres, peripheral in location and often crossing vascular territories and sparing underlying white matter.

Metabolic and hypoxic-ischemic disease can mimic some findings of LS. Wilson disease (WD) shows T2/FLAIR hyperintensity in the putamina, midbrain, and thalami. The globi pallidi in WD often show T1 shortening secondary to hepatic failure. Perinatal asphyxia (HII) can affect the basal ganglia and mimic LS, and the corticospinal tracts and perirolandic cortex are commonly affected.

MELAS

(31-66B) Axial T2WI in the same patient shows diffuse microgyria and foci of abnormal WM hyperintensity .

Terminology and Etiology. Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) is caused by several different point mutations. A mitochondrial tRNA mutation at nucleotide 3.243 is found in most patients with MELAS.

Clinical Issues. The clinical triad of lactic acidosis, seizures, and stroke-like episodes is the classic presentation, but other common symptoms include progressive sensorineural hearing loss, migraines, episodic vomiting, alternating hemiplegia, and progressive brain injury. Cardiac abnormalities, renal dysfunction, GI motility disorders, and generalized muscle weakness are also common. The diagnosis of MELAS should always be considered when encountering an atypical stroke and encephalitis of seizure presentation with diffusion and DWI.

Abnormal mitochondria have been found in the arterial walls of MELAS patients, implicating a vasculogenic etiology. MELAS is an uncommon but important cause of childhood stroke. The prevalence is approximately 1.2-13.0 cases/100,000 live births. Mean age at symptom onset is 15 years, although some patients may not become symptomatic until 40-50 years of age.

Imaging. Imaging findings vary with disease acuity (31-68). Acute MELAS often shows swollen T2/FLAIR hyperintense gyri. The underlying WM is normal, and the cortical abnormalities cross vascular distribution territories, distinguishing MELAS from acute cerebral infarction (31-69). The parietal and occipital lobes are most commonly affected (31-70C). The appearance of strokes of differing ages is often a clue to the diagnosis of MELAS. Gyral enhancement on T1 C+ is typical. Abnormal cortical vein T2/FLAIR signal hyperintensity has been reported in MELAS patients, perhaps representing vessel

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wall thickening and/or sluggish flow. MRA in MELAS shows no evidence of major vessel occlusion.

Chronic MELAS shows multifocal lacunar-type infarcts, symmetric basal ganglia calcifications, WM volume loss, and progressive atrophy of the parietooccipital cortex.

MRS is extremely helpful in the diagnosis of most mitochondrial encephalopathies. Nearly two-thirds of cases with MELAS show a prominent lactate "doublet" at 1.3 ppm in otherwise normal-appearing brain (31-70D). Caution: onethird of cases show no evidence for elevated lactate levels in the brain parenchyma but may demonstrate a lactate peak in the ventricular CSF.

Differential Diagnosis. The differential diagnosis of MELAS includes major territorial cerebral infarction. MELAS spares the subcortical and deep WM and crosses vascular territories (often the middle and posterior cerebral distributions).

Prolonged seizures can cause gyral swelling, hyperintensity,

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and enhancement that appears identical to MELAS. MRS shows no evidence of elevated lactate levels in the CSF and normal-appearing brain.

LS often involves the brainstem, which is less commonly involved in MELAS. MERRF shows a propensity to involve the basal ganglia, caudate nuclei, and vascular watershed zones. Certain vitamin deficiencies (congenital folate deficiency) may simulate LS (31-72).

Kearns-Sayre Syndrome

Terminology and Etiology. Kearns-Sayre syndrome (KSS), also known as Kearns-Sayre ophthalmoplegic syndrome, is another mtDNA disorder. A number of different gene deletions have been identified in KSS patients.

Pathology. The most typical and consistent pathologic finding of KSS is spongiform WM vacuolation. The cerebral hemispheres and midbrain are most commonly affected. The

cerebellum, brainstem, and spinal cord are also frequently involved, whereas the corpus callosum and internal capsules are usually spared.

Clinical Issues. KSS typically presents in older children or young adults and is characterized by short stature, progressive external ophthalmoplegia, retinitis pigmentosa, sensorineural hearing loss, and ataxia.

Other organs are frequently involved in KSS. Heart block and proximal muscle weakness are common. Ragged red fibers are present on muscle biopsy.

Imaging. CT scans show variable symmetric basal ganglia calcifications. Mild cortical and cerebellar volume loss is common.

MR shows increased signal intensity in the basal ganglia, WM, and cerebellum on T2/FLAIR. The subcortical arcuate fibers, corticospinal tracts, cerebellum, and posterior brainstem are

involved early in the disease course, whereas the periventricular WM remains relatively spared (31-71).

DWI shows reduced diffusivity in the brainstem and subcortical WM. MRS demonstrates elevated lactate.

Differential Diagnosis. There is significant overlap between imaging findings in KSS and other mitochondrial disorders such as MELAS. Early involvement of the cortex in a nonvascular distribution—particularly the parietal and occipital lobes—is characteristic of MELAS but uncommon in KSS.

MERRF

Myoclonus epilepsy with ragged red fibers (MERRF) is another syndrome with mtDNA mutations that result in defective mitochondrial OXPHOS. MERRF is a multisystem disorder characterized by myoclonus (often the first symptom)

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followed by epilepsy, ataxia, weakness, cardiomyopathy, and dementia. Childhood onset is typical.

MERRF is typified pathologically by systemic degeneration involving the globus pallidus, substantia nigra, red nuclei, dentate nuclei, inferior olivary nuclei, cortex, and spinocerebellar tracts.

Imaging studies show watershed and basal ganglia infarcts. The major imaging differential diagnosis of MERRF is MELAS; the two disorders often overlap. Pathologically, the major differential diagnosis is KSS, as both can demonstrate the presence of ragged red fibers on muscle biopsy.

Glutaric Aciduria Type 1

Terminology. Glutaric aciduria type 1 (GA1), glutaric acidemia type 1, and mitochondrial glutaryl-coenzyme A dehydrogenase (GCDH) deficiency are synonyms.

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Etiology. GA1 is an autosomal-recessive IMD caused by deficiency of the mitochondrial enzyme GCDH. GCDH missense mutations (Chr 19p13.2) result in amino acid substitutions. GCDH is required for metabolism of lysine, hydroxylysine, and tryptophan. GCDH deficiency induces imbalances in neurotransmission. The accumulation of glutaric acid impedes operculization during the third trimester and postnatally leads to globi pallidi, dentate nuclei, and WM degeneration.

Pathology. Excess glutaric acid is neurotoxic. Cells in the basal ganglia and WM are especially vulnerable. Spongiform changes with neuronal loss, myelin splitting and vacuolation, and intramyelinic fluid accumulation are typical microscopic features of GA1.

Clinical Issues. The prevalence of GA1 is approximately 1:100,000 live births. There is a higher case rate among the old order Amish. The majority of infants with GA1 exhibit macrocephaly at birth. Most GA1 patients (85%) present

during the first year of life, usually around the time of their first birthday with acute encephalopathy, seizures, dystonia, choreoathetosis, vomiting, and/or opisthotonus. These episodic crises are often triggered by febrile illness, immunization, or surgery. Approximately 25% present insidiously with dystonia without crisis. Disease progression is characterized by permanent motor and mental disability.

Patients may develop an acute Reye-like encephalopathy with ketoacidosis and vomiting. Hypoglycemia accompanied by elevated urinary organic acids is typical. Serum and urine metabolites may be completely normal between metabolic crises.

Therapy for GA1 requires limitation of lysine and tryptophan and administration or oral carnitine.

Imaging. The three "signature" imaging findings of classic GA1 are (1) macrocrania, (2) bilateral widened ("open") lateral cerebral or sylvian fissures (i.e., widened operculum), and (3)

bilaterally symmetric basal ganglia lesions (31-73). Severe GA1 may also cause diffuse hemispheric WM abnormalities (i.e., central and periventricular) (31-75) (31-76A). Cerebellar dentate nuclei T2/FLAIR hyperintensity is common. T2/FLAIR hyperintensity may also involve the corpus striatum, substantia nigra, thalamus, and dentate nuclei.

GA1 infants in metabolic crisis often present with acute striatal necrosis. Bilateral diffusely swollen basal ganglia that are T2/FLAIR hyperintense and that restrict on DWI are typical (31-74) (31-75). In between crises, GP and dentate findings "normalize" (31-76).

Chronic GA1 causes enlarged CSF spaces and cerebral atrophy (31-75). Volume loss leads to tearing of cortical dural bridging veins that cross from the brain surface to the superior sagittal venous sinus, resulting in recurrent subdural hematomas (31-77).

GA1 does not enhance on T1 C+ scans. DWI in the acute phase or during crises shows restricted diffusion within the globi pallidi. MRS is nonspecific with reduced NAA, increased lipids, increased Cho:Cr ratio, and (during crisis) elevated lactate level (31-76D).

Differential Diagnosis. The major differential diagnosis of GA1 is subdural hemorrhage occurring in the setting of abusive head trauma. However, GA1 is not associated with fractures, and the subdural hematomas associated with GA1 do not occur in the absence of enlarged CSF spaces and characteristic globi pallidi and other parenchymal T2/FLAIR and/or DWI changes.

Other causes of macrocephaly and conditions with middle cranial fossa cystlike spaces in infants and children should be considered in the differential diagnosis. These include hydrocephalus, benign expansion of the subarachnoid spaces (BESS) of infancy (enlarged subarachnoid spaces) in the first year of life, benign familial macrocephaly (a normal variant), middle cranial fossa arachnoid cysts (i.e., usually unilateral), and other IMDs, such as the mucopolysaccharidoses (CSF-like mucopolysaccharide pachymeningeal deposition in all but Morquio type 4 MPS), Canavan disease, and Alexander disease.

Glutaric Aciduria Type 2

Glutaric aciduria type 2 (GA2) results from a defect in the mitochondrial electron transport chain at coenzyme Q.

Clinical Issues. Three phenotypes are reported, including neonatal onset with multiple associated congenital anomalies, neonatal onset without anomalies, and late-onset form. The neonatal onset form presents with overwhelming illness, including metastatic acidosis and severe hypoglycemia. The late-onset form presents with vomiting, hypoglycemia, and unexplained acidosis.

Imaging Findings. MR demonstrates symmetric T2/FLAIR hyperintensity involving the corpus striatum, caudate nucleus, putamen, middle cerebral peduncles, splenium of the corpus callosum, and hemispheric WM. The "open" sylvian fissures characteristic of GA1 are absent in GA2.

Differential Diagnosis. Diabetic ketoacidosis can be a clinical and imaging mimic of GA2; MR may show central herniation with resultant diencephalic ischemia and infarction. Profound hypoxic ischemic injury (HII) targets the striatum and thalami. A positive health history is typically present.

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(31-72A) Axial DWI in a newborn with congenital folate deficiency shows midbrain and epithalamus restriction, confirmed on ADC.

(31-72B) Axial FLAIR shows red nucleus hyperintensity . Mild diffuse volume loss is noted.

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Urea Cycle/Ammonia Disorders

Ammonia is an important source of nitrogen and is required for amino acid synthesis as well as normal acid-base balance. When present in high concentrations, ammonia is toxic.

The urea cycle normally prevents excess accumulation of toxic nitrogen products by incorporating nitrogen into urea, which is then excreted in the urine. Interruption of the urea cycle results in elevated serum ammonia, which readily crosses the blood-brain barrier and causes diffuse cerebral edema. In chronic disease, atrophy with resultant ulegyria is seen.

Six disorders of the urea cycle have clinical importance. These include ornithine transcarbamylase deficiency (OTCD), carbamoyl phosphate synthetase 1 deficiency, citrullinemia or argininosuccinate synthetase deficiency, argininosuccinate aciduria or argininosuccinate lyase deficiency, argininemia or arginase deficiency (AD), and N-acetylglutamate synthase deficiency. The two classic and most common disorders are

(31-73) Axial graphic depicts typical findings of glutaric aciduria type 1. Note the symmetrically enlarged basal ganglia and the bilateral "open" sylvian or lateral cerebral fissures . The thalamiappear normal. (31-74) Axial DWI in an infant in acute metabolic crisis with acute striatal necrosis shows restricted diffusion in the basal ganglia . Note the "open" sylvian fissures and sparing of the thalami.

(31-75A) Axial T2WI in a

7m child with GA1 shows enlarged, hyperintense caudate nuclei, putamina, and globi pallidi with thalamic sparing. The sylvian fissures are enlarged. The hemispheric WM myelination is grossly delayed. (31-75B) Coronal T2WI in the same patient shows generalized brain volume loss , swollen basal ganglia , and delayed myelination. The sylvian fissures appear underoperculized and "open."

OTCD and citrullinemia. Both are characterized by diffuse brain swelling (which does not spare the basal ganglia) on NECT and MR scans.

Imaging

MR shows basal ganglia and cortical swelling with T2/FLAIR hyperintensity (31-78). The peri-insular cortex is usually affected first (i.e., linear T2 prolongation and restricted diffusion between the globi pallidi and putamina), with involvement then extending into the frontal, parietal, temporal, and (finally) the occipital lobes (31-78) (31-79). The globi pallidi, putamina, and thalami are affected with prolonged hyperammonemia and may show restricted diffusion (31-78D) (31-78E). A characteristic pattern of "crenulated" subcortical diffusion restriction and T2 prolongation strongly suggests urea cycle disorder (31-78E). MRS demonstrates increased lactate and glutamineglutamate and eventually reduced NAA (31-78).

Differential Diagnosis

The major imaging differential diagnosis of acute hyperammonemia caused by urea cycle disorders is hypoxicischemic encephalopathy (HIE). Infants with HIE typically have more thalamic and perirolandic cortical abnormalities.

Neonatal herpes simplex encephalitis (i.e., usually HSV type 2) is often associated with hepatitis and diffuse pulmonary involvement. HSV2 is nonpatterned and may present with diffuse edema.

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show microcephaly, movement and psychomotor disorders, mental retardation, and ketoacidosis. Central hypotonia with pyramidal tract signs and symptoms at the time of clinical crisis is seen. Dystonia and choreoathetosis are common sequelae of basal ganglia involvement. Respective acids (methylmalonic/propionic) are detected in the urine. Methylmalonic acidemia is caused by mutation of the MUT gene located at 6p21, which encodes methylmalonic CoA mutase. Propionic acidemia is caused by mutations in the gene encoding propionyl-CoA carboxylase, PCCA.

Methylmalonic and Propionic

Acidemias

Both methylmalonic acidemia (MMA) and propionic acidemia (PPA) are autosomal-recessive disorders that both present early in life with episodic ketoacidosis, lethargy, tachypnea, nausea, vomiting, progressive hypotonia, and seizures, eventually progressing to coma and death. Survivors

Imaging

MR findings in both disorders are nonspecific yet reflective of increased water within involved tissues (therefore, reduced attenuation on NECT and T1 and T2 prolongation on MR). Neuroimaging findings vary based on the specific acidemia and the stage of brain maturation at the time of presentation. Ventricular enlargement, cortical atrophy, cerebellar volume

(31-76A) Coronal T2WI in a 14m girl with GA1 "between crises" shows diffuse delay in WM maturation . Note the normal appearance of the BG. (31-76B) Axial T1WI in the same patient demonstrates open lateral cerebral (sylvian) fissuresand subtle T1 shortening within the globi pallidi (GP) .

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loss, and T2/FLAIR hyperintensity involving the periventricular WM and globi pallidi are the most common abnormalities in MMA. Bilateral basal ganglia calcifications are present in 5- 10% of cases of MMA. PPA involves the putamina and caudate nuclei and causes reduced myelination in the hemispheric WM (31-80). MRS can not distinguish MMA from PPA. Both show reduced NAA and myoinositol and increased glutamate/glutamine.

Differential Diagnosis

Hypoxic ischemic injury (HII) of the profound type involves striatum and thalami as well as corticospinal tracts and hippocampi. Carbon monoxide poisoning targets the BG and is associated with often deep GM structures showing T2 prolongation.

Patients with juvenileor adult-onset disease may show only cerebellar atrophy.

MR scans in infantile-onset gangliosidosis may demonstrate T1 hyperand hypointensity of the thalami. Variable T1 signal of the striatum and hypointense cerebral WM may be seen (31-80). With disease progression, the globi pallidi and ventral thalami often appear profoundly shrunken and hypointense on T2WI. In TS, on T2WI, the ventral thalami are hypointense, and the dorsal thalami are hyperintense. In SD, the thalami are diffusely hypointense on T2WI (31-80B). With the exception of the corpus callosum (which is often spared), the WM appears variably T2/FLAIR hyperintense. There is no enhancement, and DWI shows variable reduced diffusivity in the ventral thalami (TS). MRS shows reduced NAA and increased choline and myoinositol.

Gangliosidoses

Clinically important forms of gangliosidoses include GM1 and GM2 [Tay-Sachs (TS), Sandhoff disease (SD), and GM2 variant AB]. They are biochemically distinct but clinically indistinguishable.

GM1 is a rare lysosomal storage disease. Deficiency of the lysosomal enzyme β-galactosidase results in accumulation of GM1 ganglioside in the brain (especially the basal ganglia) and oligosaccharide in the abdominal viscera. Three forms of the disease have been described, all being the result of mutations of the GLB1 gene located on chromosome 3p21.33.

GM2 is an autosomal-recessive disorder of sphingolipid storage caused by a deficiency of hexosaminidase. Deficiency of isoenzyme A, coded by the HEXA gene at Chr 15q23-24, causes TS. β-Subunit deficiencies of both isoenzymes A and B coded by the HEXB gene at Chr 5q13 cause SD. The GM2 AB variant is caused by deficiency of the GM2 activator protein. All three forms are associated with an abnormal accumulation of GM2 ganglioside in the cytoplasm of neurons. This results in extensive neuronal loss and WM degeneration, leading to atrophy. Atrophy may be more cerebellar than cerebral.

GM1 and GM2, as well as GM2 AB variant (rare), exist in infantile, juvenile, and adult forms. Patients with infantile GM1 present between birth and 6 months with coarse facial features, skeletal dysostosis, and hepatosplenomegaly. There is clinical overlap with Morquio type B disease. Juvenile-onset GM1 presents with psychomotor retardation. Adult-onset disease is characterized by slowly progressive dystonia and ataxia, as well as extrapyramidal signs. The three forms of GM2 disease (TS, SD, and GM2 AB variant) share similar clinical and imaging features. In the most common infantile form, initial psychomotor retardation and hypotonia are followed by neurologic deterioration. Progressive weakness, choreiform movements, dystonia, and ataxia occur.

Imaging

In both GM1 and GM2, imaging findings are quite similar. Patients with infantile-onset gangliosidoses show preferential involvement of the thalami, small and hyperattenuating on NECT scans. The basal ganglia (striatum) and sometimes the cerebral and cerebellar WM are hypoattenuating on NECT.

Differential Diagnosis

HII (status marmoratus) demonstrates atrophic hyperattenuating thalami, atrophic striatum, and perirolandic cortex. Nonprogressive neurologic deficits and positive health history are common. Krabbe disease demonstrates hyperattenuating thalami, caudate, and dentate nuclei. T2 prolongation involves the cerebral and cerebellar WM.

Fabry Disease

Fabry disease causes 1.5-5.0% of unexplained strokes in young patients and is present in 4-5% of men with unexplained left ventricular hypertrophy or cryptogenic stroke. As enzyme replacement therapy is now widely available, it is key to find Fabry disease before irreversible organ damage occurs.

Etiology and Pathology

Fabry disease is an X-linked lysosomal storage disorder of glycosphingolipid metabolism. Mutation in α-galactosidase leads to abnormal accumulation of glycosphingolipids in various tissues, especially in the vascular endothelium and smooth muscle cells. Impaired endothelial function results in progressive multisystem vasculopathy. The renal, cardiac, and cerebral vessels are severely affected. Cardiac emboli, large vessel arteriopathy, and microvascular disease all occur.

Clinical Issues

Infants with Fabry disease typically present with diffuse angiokeratomas, but late-onset Fabry disease is much more difficult to diagnose. Fabry-induced stroke often occurs before the definitive diagnosis has been established. Although mean onset of first stroke is 39 years in men and 45 years in women, nearly 22% of patients are younger than 30 years at initial presentation. Over 85% of strokes in Fabry disease are ischemic strokes. Hemorrhagic strokes are less common and usually occur secondary to renovascular hypertension.

Imaging

NECT scans show bilateral, often symmetric calcifications in the basal ganglia and thalami. Multifocal deep WM hypodensities consistent with lacunar infarcts can be

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identified in some cases. Patients with long-standing Fabry disease show volume loss with enlarged ventricles and sulci.

MR may show T1 shortening in the basal ganglia and thalami. The "pulvinar" sign (T1 hyperintensity in the posterior thalamus) is highly suggestive of Fabry disease. Between 45 and 50% of adult patients with Fabry disease have patchy multifocal T2/FLAIR hyperintensities in the basal ganglia, thalami, and cerebral WM. With time, the lesions increase in number and may become coalescent. Ten percent of patients demonstrate "blooming" hypointensities on T2* (GRE, SWI) due to microbleeds. Dolichoectasias is less common.

Differential Diagnosis

Look for other disorders marked by BG calcifications. Fahr disease causes bilateral, dense, thick calcifications in the BG and thalami. The cerebellum and GM-WM interfaces are frequently affected but generally not involved in Fabry disease. Endocrinologic disorders like hyperparathyroidism,

hypoparathyroidism, pseudohypoparathyroidism, and hypothyroidism may have similar calcifications but lack the multifocal infarcts typical of Fabry disease.

Congenital Glycosylation Disorders

Etiology and Pathology

Carbohydrate-deficient glycoprotein (CDG) syndrome is a disorder in glycosylation of N-linked oligosaccharides. Genetically heterogeneous, autosomal recessive in inheritance, CDG1a is caused by mutation in the gene encoding PMM2 (most common). Asparagine-N-linked oligosaccharide transfer deficiency is suspected. At autopsy, marked atrophy of the cerebellum is seen, especially the anterior vermis, pontine nuclei, and inferior olive. There are a complete loss of Purkinje cells and subtotal loss of cerebellar granular cells.

Clinical Issues

CDG ranges from severe infantile multisystem involvement to mild late-onset forms, with hypotonia, developmental delay, failure to thrive, stroke-like episodes, strabismus, ataxia, abnormal subcutaneous fat distribution, and nipple retraction.

Inherited Metabolic Disorders

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telangiectasias, scattered WM foci of T2 hyperintensity and SWI hypointensity, GM2 gangliosidosis showing characteristic T1WI and T2WI findings of the thalami, and Wilson disease showing tortuous intracranial vessels (corkscrew) and cerebral and cerebellar atrophy and wormian bones.