17 -Inherited Metabolic ,WHITE MATTER, and DEGENERATIVEDISEASES of THE BRAIN

C H A P T E R Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain “Things should be made as simple as possible But no simpler.” - Albert Einstein Normal Myelination Birth (Term Infant) Three Postnatal Months Six Postnatal Months Eight Postnatal Months Three Years of Age Disorders that Primarily Affect White Matter (Leukodystrophies) Metachromatic Leukodystrophy Krabbe Disease Adrenoleukodystrophy (X-linked) Pelizaeus-Merzbacher Disease Alexander Disease Canavan Disease Phenylketonuria and Amino Acid Disorders Disorders that Primarily Affect Gray Matter Tay-Sachs Disease and Other Lipidoses Hurler Syndrome and Other Mucopolysaccharidoses Mucolipidoses and Fucosidosis Glycogen Storage Diseases Disorders that Affect Both Gray and White Matter Leigh Disease and Other Mitochondrial Encephalopathies Zellweger Syndrome and Other Peroxisomal Disorders Basal Ganglia Disorders Huntington Disease Hallervorden-Spatz Disease Fahr Disease Wilson Disease The inherited metabolic and degenerative diseases are complex, heterogeneous brain disorders that defy easy categorization Dividing white matter pathology into dysmyelinating diseases (disorders with defective formation or maintenance of myelin) and demyelinating diseases (destruction of otherwise normally formed myelin) is a time-h system Recent classifications have focussed role of enzyme defects and organelle pathology pathogenesis of many metabolic disorders that a the CNS In this system the various neurodegenerative disorders are subdivided into 1yosomal, peroxisomal, and mitochondrial diseases.1 Recognizing that simple is generally bett6r m,' that no system yet devised is without flaws, we will discuss inherited metabolic brain disorders according to their pathologic-radiologic manifestations We first briefly review normal myelination patterns in the developing brain, then turn our attention to the inherited metabolic disorders themselves The first group of disorders mainly or exclusively involves the white-matter, the so-called leukoencephalopathies Other inherited diseases predominately affect gray matter A few diseases affect both We close this chapter by considering neurodegen- erative disorders in a special area, i.e., the basal ganglia Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain 717 Normal Myelination Birth (full term) Medulla Dorsal midbrain Inferior and superior cerebellar peduncles Posterior limb of internal capsule Ventrolateral thalamus One month Deep cerebellar white matter Corticospinal tracts Pre/postcentral gyri Optic nerves, tracts Three months Brachium pontis, cerebellar folia Ventral brainstem Optic radiations Anterior limb of internal capsule Occipital subcortical U fibers Corpus callosurn splenium Six months Corpus callosurn genu Paracentral subcortical U fibers Centrum semiovale (partial) Eight months Centrum semiovale (complete except for some frontotemporal areas) Subcortical U fibers (complete except for most rostral frontal areas) Eighteen months Essentially like adult NORMAL MYELINATION Normal brain myelination is a dynamic process that begins during the fifth fetal month and continues throughout life.2 Myelination usually occurs in highly predictable, very orderly patterns Delays in, or departures from, the expected patterns can be detected and exquisitely delineated with MR imaging.2a In general, myelination progresses from caudal to cephalad, from dorsal to ventral, and from central to peripheral.3 Sensory tracts also generally myelinate earlier than fiber systems that correlate sensory data into movement.1 Myelination takes place rapidly during the first years, by which time it is nearly completed Some association tracts remain unmyelinated until age 20 to 30 years (see box.) The MR imaging appearance of normal brain changes substantially as the pulse sequences are var- Table 17-1 MR Myelination/Developmental Markers Structure High signal (T1Wl) Low signal (T2Wl) first appears at: first appears at: Posterior fossa Dorsal medulla/ Birth midbrain Inferior/superior Birth cerebellar peduncles Middle cerebellar month peduncle Cerebellar white to months matter (deep to peripheral) Birth Birth months to 18 months Supratentorial Internal capsule Posterior limb Birth Birth Anterior limb months to months Thalamus Birth Birth (ventro-lateral nuclei) Pre/postcentral month to 12 months gyri Corpus callosum Splenium to months months Genu months months Centrum semiov- Birth to month months ale (deep) Optic radiations months months Subcortical U fibers (poste- to months to 18 months rior to ante(occipital first) (frontal last) rior) Modified from Byrd SE, Darling CR, Wilczynski NA: Whitematter of the brain: maturation and myelination on magnetic resonance in infants and children, Neuroimaging Clin N Amer 3:247-266, 1993; Bird CR, Hedberg M, Drayer BP et al: MR assessment of myelination in infants and children: usefulness of marker sites, AJNR 10:731-740, 1989; Barkovich AJ, Pediatric Neuroimaging, pp 13-24, New York, Raven Press, 1990; Barkovich AJ, Lyon G, Evrard P: Formation, maturation and disorders of white matter, AJNR 13:447-461, 1992; and Barkovich AJ: Brain development: normal and abnormal In SW Atlas, editor, Magnetic resonance imaging of the brain and spine, p 139, New York, Raven Press, 1991 ied Brain maturation occurs at different rates and times on T1-compared to T2-weighted images4 (Table 17-1) We will therefore discuss the normal appearance of the developing brain on both T1- and T2weighted sequences Whereas the standard “T2-weighted" spin-echo sequences throughout this text used TRs between 2500 and 3000 msec and TEs of 70 to 90 msecs, to image the infant brain we typically use TRs of up to 3500 to 4000 msec and TEs between 80 and 120 msec 718 PART FOUR Infection, White Matter Abnormalities, and Degenerative Diseases Birth (Term Infant) At birth, much of the brain is unmyelinated and there is relatively poor differentiation between gray and white matter, especially on T1-and proton density-weighted sequences.5 The relative signal intensities of cortex and white matter are reversed compared to the pattern normally seen in older children and adults.6 T1-weighted scans The following areas are myehlinated at birth and therefore exhibit high signal intensity: Medulla Dorsal midbrain Inferior and superior cerebellar peduncles Posterior limb of the internal capsule Small areas of myelinated white matter may extend a short distance from the posterior limb superioly into the corona radiata The ventrolateral thalamus of normal term infants also appears hyperintense on T1WI.6,7 T2-weighted scans Unmyelinated white matter appears very hyperintense relative to the low signal cortex Structures that are myelinated, and also therefore low signal on T2WI, include the dorsal midbrain' inferior and superior cerebellar peduncles, and parts of the posterior limb of the internal capsule (Fig 17-1, A to C) The ventrolateral thalamus and perirolandic gyri are also low signal (Fig 17-1, D).7 Three Postnatal Months Myelination proceeds rapidly during the first few postnatal months Tl-weighted scans High signal can now be seen in the deep cerebellar white matter, folia, and middle cerebellar peduncles, the ventral brainstem, and corticospinal tracts, as well as the optic nerves, tracts, and optic radiations The anterior limb of the internal capsule is now myelinated The subcortical white matter in the occipital pole is also high signal T2-weighted scans At month there is little change from the appearance at birth However, by months low signal can be seen throughout the cerebellar white matter, anterior limb of the internal ca, sule, the optic radiations, and some parts of the centrum semiovale (Fig 17-2) Six Postnatal Months T1-weighted scans By months, high signal seen in the corpus callosurn splenium; by months, the genu also normally appears hyperintense Myelination has proceeded further into the centrum semiovale and toward the more rostral subcortical white matter T2-weighted scans There is little change at months from the pattern seen at months, However, by months after birth the centrum semiovale begins to show decreased signal Eight Postnatal Months By the eighth postnatal month the infant brain it largely myelinated and the appearance on MR imaging approaches the adult pattern T1-weighted scans High signal is now-'present in virtually all white matter except in the most anterior frontal subcortical areas (Fig 17-3) T2-weighted scans The centrum semiovale all but the most rostral subcortical U fibers are hypointense relative to cortex Three Years of Age T2-weighted scans Very heavily myelinateld, compact white matter fiber pathways such as the anterior commissure, internal capsule, corpus callosum, and uncinate fasciculus normally show very low signal intensity, whereas association fiber tracts around the ventricular trigones are still unmyelinated ml therefore remain hyperintense (Fig 17-3, C) These tracts often not myelinate until age 30 Other areas that also normally appear hyperintense on T2WI are adjacent to the frontal horns There are relatively fewer white matter fibers here, and therefore a "Cap" of high signal intensity on T2WI is normal (Fig 17, B) Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain Fig 17-1 Axial anatomic diagrams illustrate brain myelination (dark patterned areas: arrows) present at birth A, Posterior fossa myelinated areas include the dorsal midbrain (arrows), as well as the medulla and inferior and superior cerebellar peduncles B, The posterior limb of the internal capsule is myelinated; some myelination also extends superiorly into the deep centrum semiovale (C, arrows) D, No myelination is present in the subcortical U (arcuate) fibers but the pre- and postcentral gyri (arrows) often appear low signal on T2-weighted MR scans by the first postnatal month 719 720 PART FOUR Infection, White Matter Abnormalities, and Degenerative Diseases Fig 17-2 Brain myelination at about to months A, The deep cerebellar white matter and corticospinal tracts are myelinated B, The anterior limb of the internal capsule (large arrows) and corpus callosurn splenium are now at least partially myelinated Occipital radiations and subcortical arcuate fibers are beginning to myelinate (B and C, small arrows) C, Myelination also extends further into the centrum semiovale (large arrows) D, Some arcuate fiber and centrum semiovale myelination around the pre- and postcentral gyri is present (arrows) Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain 721 Fig 17-3 Normal myelination between and months A, Myelination of the cerebellar white matter is nearly completed and extends peripherally to the folia (small arrows) Temporal lobe myelination (large arrows) is present B, The corpus callosum genu is also myelinated C and D, Myelination extends through the centrum semiovale into the subcortical U fibers and is virtually complete except for some frontotemporal areas The peritrigonal white matter may not myelinate completely until age 20 to 30 years 722 PART FOUR Infection, White Matter Abnormalities, and Degenerative Diseases DISORDERS THAT PRIMARILY AFFECT WHITE MATTER (LEUKODYSTROPHIES) The leukodystrophies, also known as dysmyelinating diseases, are a heterogeneous group of disorders characterized by enzyme deficiencies that result in abnormal formation, destruction, or turnover of myelin.8,9 In some diseases such as metachromatic leukodystrophy the specific biochemical abnormalities have been identified; in others (e.g., Alexander disease), the enzyme defect has not been determined Some leukodystrophies have distinctive imaging features (see box); many others have nonspecific findings There are many different leukodystrophies In this chapter we focus on the more common and important of these disorders The first two, metachromatic leukodystrophy and Krabbe disease, are lysosomal enzyme disorders (Table 17-2) The next, adrenoleukodystrophy, is caused by a single peroxisomal enzyme defect Pelizaeus-Merzbacher disease is caused by defective biosynthesis of proteolipid protein, Leukodystrophies Distinctive features Complete/near complete lack of myelination Canavan disease Pelizaeus-Merzbacher disease Frontal white matter most involved Alexander disease Occipital white matter most involved Adrenoleukodystrophy (also callosal splenium) whereas a cytosolic enzyme defect has been implicated in another striking leukodystrophy, Canavan disease Leukodystrophies with unknown etiologies include Alexander disease, Cockayne disease, sudanophilic leukodystrophy.9 We close our discussion of inherited white matter diseases by considering the amino acid disorders Metachromatic Leukodystrophy Etiology, inheritance, and pathology Etiology and inheritance metachromatic leukodystrophy (MLD) is a lysosomal disorder caused by a deficiency of the catabolic enzyme arylsulfatase A Inheritance is autosomal recessive.10 Pathology Symmetric demyelination that spares the subcortical U fibers is characteristic (Fig 17-4, A and B).9 The cerebellum is often atrophic Microscopic findings include axonal loss with astrogliosis.9 A metchromatic lipid material, galactosy1cerarnide sulfatide, accumulates in the peripheral and central nervous system white matter.11 Incidence and age MLD is the most common hereditary leukodystrophy, with a prevalence of in 100,000 newborns.11 Three different types of MLD are recognized according to age at onset These are Table 17-2 Lysosomal Disorders Disorder Sphingolipidoses Metachromatic leukodystrophy Krabbe disease Enzyme Deficiency Arylsulfatase A Galactocerebroside beta-galactosidase Sphingomyelinase Alpha-galactosidase A Beta-galactosidase Macrocephaly Alexander disease Canavan disease Mucopolysacchariclosis type I (Hurler) Mucopolysaccharidosrs type II (Hunter) Niemann-Pick disease Fabry disease GM1 gangliosidosis (pseudo-Hurler) GM2 ganghosidosis (Tay-Sachs, Sandhoff disease) Thick meninges Hurler syndrome Mucolipidoses (e.g., fucosidosis) Varies (alphafucosidase with fucosidosis) High density basal ganglia Krabbe disease Canavan disease Aspartoacylase Enhancement following contrast administration Alexander disease ALD Mucopolysaccharidoses (e.g., Hurler, Hunter) Varies (alpha-Liduronidase with Hurler) Strokes Leigh syndrome MELAS MERRF Homocystinuria Ceroid lipofuscinoses (e.g., Batten disease) Varies (ATP synthesase with Batten disease) Beta-hexosaninidase A/B Data from Kendall BE: Disorders of lysosomes, peroxisomes mitochondria, AJNR 13:621-653, 1992 Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain Fig 17-4 A, Metachromatic leukodystrophy (MLD) is illustrated on this coronal autopsy specimen Note extensive white matter demyelination (arrows) that spares the subcortical U fibers Volume loss has caused moderate ventricular enlargement B, Axial anatomic diagram depicts MLD Extensive, confluent periventricular demyelination is present (arrows) Note sparing of the subcortical U fibers C, Axial NECT scan in a 22-year-old man with MLD Note bilateral symmetric low density areas in the centrum semiovale (arrows) Involvement is more severe anteriorly and there is some arcuate fiber tract sparing, particularly in the occipital lobes D and E, Axial T2-weighted MR scans in a 9-year-old boy with MLD Note periventricular and deep white matter high signal areas (white arrows) The thalami are abnormally hypointense (E, black arrows) (A, Courtesy E Ross.) Continued 723 724 PART FOUR Infection, White Matter Abnormalities, and Degenerative Diseases Fig 17-4, cont'd F and G, Axial T2-weighted scans in a 40-year-old man with adult-onset MLD Note confluent white matter demyelination (arrows) and moderately severe cortical atrophy Arcuate fiber involvement, present in this case, usually is not seen until late in the disease course the late infantile, juvenile, and adult forms Approximately 80% of cases occur in childhood with onset typically between I and years of age.9,11 Location MLD involves the deep periventricular white matter and typically spares the arcuate fibers until late in the disease process (Fig 17-4, B) The anterior white matter is more severely affected.10 Clinical presentation and natural history In its most common form, late infantile MLD, motor signs of peripheral -neuropathy are followed by deterioration in intellect, speech, and coordination Within years of onset, gait disorders, quadriplegia, blindness, and decerebrate posturing can be seen.9 Disease progress is inexorable, and death occurs within months to years following symptom onset.11 Imaging CT NECT scans show moderate ventricular enlargement Low density lesions are present, progressing anteriorly to posteriorly within the white matter (Fig 17-4, C).11 CT scans show no enhancement following contrast administration.10 MR Diffuse confluent high signal is present in the periventricular white matter on T2WI (Fig 17-4, D) Initially the arcuate fibers are spared A striking feature in many cases is increased signal in the cerebellar white matter.12 The thalami may appear mildly to extremely hypointense (Fig 17-4, E) Corticosubcortical atrophy often occurs in later stages of the disease, particularly when myelin loss extends into the subcortical arcuate fibers (Fig 17-4, F and G).10 Krabbe Disease Krabbe disease is also known as globoid cell leukodystrophy (GLD) Etiology, inheritance, and pathology Etiology and inheritance GLD is a lysosomal disorder that is caused by deficiency of the lysosomal hydrolase galactocerebroside beta-galactosidase.13 inheritance is autosomal recessive Pathology The brain is small and atrophic Extensive symmetric dysmyelination of the centrum semiovale and corona radiata with subcortical arcuate fiber sparing is seen The cerebellar white matter is affected but to a lesser degree.9 Microscopically, there is myelin loss with astrogliosis Perivascular clusters of large multinucleated "globoid" and mononuclear epitheloid cells are present in the demyelinated zones.11 Incidence and age There is a reported prevalence of 1:50,000 in Sweden but the incidence is much lower elsewhere.11 Infantile, late infantile, and adultonset Krabbe disease are recognized The infantile form is the most common.12,12a Location The centrum semiovale and periventricular white matter are most severely affected; the subcortical U fibers are relatively spared Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain 725 Fig 17-5 Krabbe disease (globoid cell leukodystrophy) A and B, Anatomic diagrams demonstrate periventricular white matter demyelination (white areas: large arrows) and hyperdense basal ganglia and thalami (vertical lines: curved arrows) C, Axial T2-weighted MR scan in a 10-month-old child with Krabbe disease The periventricular demyelination (arrows) is typical but not pathognomonic for Krabbe disease Note early involvement of parietoocciptal white matter periventricular white matter No enhancement occurs following contrast administration MR Nonspecific confluent, symmetric periventricular white matter hyperintensities are present on T2-weighted studies (Fig 17-5, C) Late-onset disease may show changes limited to the posterior hemispheric white matter Severe progressive atrophy occurs in the infantile form of GLD.12,12a A) The parietooccipital lobes may be selectively involved early in the disease course (Fig 17-5, C).12b Clinical presentation and natural history Psychomotor deterioration, irritability, optic atrophy, and cortical blindness are seen Seizures may occur in later stages Krabbe disease typically is rapidly progressive and fatal.11 Imaging CT The thalami and basal ganglia often appear hyperdense on NECT scans (Fig 17-5, B).13 The corona radiata and cerebellum may show similar changes.14 Diffuse low density is present in the Adrenoleukodystrophy (X-linked) Peroxisomes are small intracellular organelles that are involved in the oxidation of very long-chain and monounsaturated fatty acids.15 Peroxisomal enzymes are also involved in gluconeogenesis, lysine metabolism, and glutaric acid catabolism.1 Peroxisomal disorders are inborn errors of cellular metabolism caused by the deficiency of one or more of these enzymes X-linked adrenoleukodystrophy is a leukodystrophy caused by a single peroxisomal enzyme deficiency, whereas Zellweger syndrome and neonatal adrenoleukodystrophy affect both the gray and white matter and are caused by multiple enzyme defects (see box, p 727) (see subsequent section).1 Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain Fig 17-9 Canavan disease (CD) A and B, Axial anatomic drawings depict CD Note virtual complete lack of myelination except for the internal capsule (A, dark pattern: large arrows) The basal ganglia and thalami can appear very hypointense (A, vertical pattern: curved arrows) B, The near-total lack of myelination also involves the subcortical arcuate fibers The appearance resembles that of a newborn infant (compare with Fig 17-1, D) Axial T1- (C and D) and T2-weighted (E) MR scans in a 7-month-old with CD show nearly complete lack of myelination Only parts of the internal capsule appear myelinated The subcortical arcuate fibers are also involved The appearance resembles that of a newborn infant (C to E, Courtesy L Tan and S Lin.) 733 734 PART FOUR Infection, White Matter Abnormalities, and Degenerative Diseases Fig 17-10 Aminoaciduria Axial anatomic drawing (A), axial NECT scan (B), and coronal T2-weighted MR scan (C) depict the extensive but nonspecific periventricular demyelination (arrows) seen in most aminoacidurias PKU patients are normal at birth but if untreated will develop mental retardation and other abnormalities such as autism, seizures, lack of coordination, hyperactive behavior, and hyperreflexia.32 Recognition of this disorder is important because appropriately restricted- diets should be instituted immediately Cessation of dietary restrictions can cause neurologic deterioration within months.31 With some exceptions, imaging studies in most aminoacidurias, including PKU, are generally nonspecific Varying degrees of demyelination occur, usually involving the periventricular white matter with relative sparing of the subcortical U fibers (Fig 17-10, A) Periventricular hypodensity is seen on NECT scans (Fig 17-10, B) Increased signal in the periventricular deep cerebral white matter can be identified on T2-weighted MR scans (Fig 1710, C).33 The changes are most prominent posteriorly, particularly in the optic radiations.32 Although MR imaging is not specifically diagnostic of PKU, it is a valuable tool in assessing the efficacy of dietary treatment and patient compliance.34 Amino Acid Disorders Phenylketonuria Maple syrup urine disease Homocystinuria Glutaric acidemia type I Methylmalonic acidemia Nonketotic hyperglycinemia Oculocerebralrenal syndrome Maple syrup urine disease Maple syrup urine disease (MSUD) is caused by failure to catabolize branched-chain amino acids (leucine, isoleucine, and valine) The corresponding ketoacids accumulate and result in urinary excretion of a metabolite with a characteristic odor that resembles maple syrup.35 Inheritance is autosomal recessive, and its estimated incidence is 1: 224, 000.35 MSUD typically presents within to days after birth with severe, rapidly progressive neurologic de- Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain 735 Fig 17-11 Axial T1- (A) and T2-weighted (B) MR scans in a 3-month-old child with glutaric acidemia type I Note the enlarged sylvian fissures with “bat wing” appearance (A, large black arrows) The caudate and lenticular nuclei have diffuse high signal (curved arrows) fects Without treatment, death occurs within year.12 Milder intermediate or even intermittent forms of MSUD have been described.35 Sequential imaging studies follow the natural disease course CT scans typically are negative during the first few postnatal days A marked, generalized diffuse edema appears and remains for to weeks in untreated infants It then decreases and is transformed into better-demarcated periventricular white matter disease.35 A characteristic, more intense local edema (MSUD edema) involves the deep cerebellar white matter, dorsal brainstem, cerebral peduncles, and posterior limb of the internal capsule.35 Low densities in the globus pallidus and thalami may also occur.11 T2-weighted MR scans show high signal intensities in these areas Homocystinuria Homocystinuria is an inborn error of methionine metabolism with autosomal recessive inheritance Pathologically, homocytinuria is characterized by abnormalities in collagen and elastin formation The intracranial vessels are often affected Multiple small arterial thromboembolic infarcts, sagittal sinus thrombosis, and deep cerebral venous occlusion with infarction occur.11 Glutaric aciduria type I Glutaric aciduria type I (GA-I) is an autosomal recessive metabolic disorder caused by a deficiency of glutaryl-CoA dehydrogenase, the coenzyme responsible for breakdown of lysine to tryptophan.12,36 GA-I adversely affects mitochondrial activity and preferentially involves the basal ganglia.12 Clinically, GA-I is characterized by progressive dystonia and dyskinesia Imaging studies show frontotemporal atrophy and "batwing" dilatation of the sylvian fissures (Figs 17-11, A and B).34,37 High signal changes in the basal ganglia and caudate nuclei are seen in some cases on T2-weighted MR scans (Fig 17-11, C) Methylmalonic acidemia Methylmalonic acidemia (MMA) is an aminoacidopathy that also adversely affects mitochondrial activity A block in the conversion of methylmalonyl-CoA to succinyl-CoA is present Methylmalonate accumulates in the blood and urine, resulting in secondary hyperammonemia and severe ketoacidosis.38 CT scans show bilateral low density lesions in the globus pallidi T1-weighted MR studies show decreased signal in the corresponding areas with symmetric hyperintensities on T2WI (Fig 17-12).38 Nonketotic hyperglycinemia Nonketotic hyperglycinemia (NKH) is a disorder of glycine metabolism characterized by elevated glycine levels in the plasma, CSF, and urine.39 Inheritance is autosomal recessive Two forms of NKH occur: a neonatal and a late- 736 PART FOUR Infection, White Matter Abnormalities, and Degenerative Diseases Fig 17-12 Methylmalonic acidemia (MMA) Axial Tl- (A) and T2-weighted (B) MR scans show the focal globus pallidus lesions (arrows) typically seen in MMA (Courtesy M Gado.) onset type In the more common neonatal type, disease onset occurs in early infancy Clinical manifestations include seizures, hypotonia, severe developmental delay, lethargy, and coma.39 Death usually occurs before years of age.40 Autopsy studies show severe white matter vacuolation Imaging studies show decreased or absent myelination of the supratentorial white matter tracts.40 The corpus callosurn appears abnormally thin Progressive supra- and infratentorial atrophy occur Oculocerebral renal syndrome Oculocerebral renal syndrome (OCRS), also known as Lowe syndrome, is an example of defective amino acid transport.12 OCRS is an X-linked recessive disorder that is characterized by congenital ocular abnormalities (cataracts), mental retardation, renal tubular disease (Fanconi syndrome), and metabolic bone disease (hypophosphatemic rickets).41 Excessive excretion of multiple amino acids occurs MR studies in patients with OCRS show diffuse supratentorial white matter abnormalities Two distinct lesions occur Multiple small CSF-like spherical foci in the deep and subcortical white matter are identified These discrete lesions are surrounded by confluent areas of diffuse white matter signal abnormality that appear slightly hypointense on T1- and hyperintense on T2-weighted sequences.41 DISORDERS THAT PRIMARILY AFFECT GRAY MATTER The disorders that primarily affect gray matter are largely- but by no means exclusively- due to lysosomal enzyme defects (see Table 17-2) These enzymes are synthesized in the cytoplasm, then transported to the endoplasmic reticulum, where the Golgi apparatus packages them into primary lysosomes.9 Microglia and phagocytic cells such as leukocytes and tissue macrophages have abundant lysosomes.1 Lysosomes aid in the digestion of phagocytosed material The eminent pediatric neuropathologist L.E Becker has termed these organelles the "Darth Vaders" of cells When the activity of a specific lysosomal catabolic enzyme is deficient, undigested material accumulates within the affected cells A lysosomal storage disorder is the result.1 These disorders are often classified according to the abnormal material that accumulates, viz., lipid (lipidoses), mucopolysaccharide (mucopolysaccharidoses), or both (mucolipidoses) Enzyme deficiencies involved in carbohydrate (mainly glycogen) storage, synthesis, and degradation are termed “glycogen storage diseases.” In this section we will consider some examples of each of the major lysosomal storage disorders that produce their most devastating effects on the cerebral gray matter Tay-Sachs Disease and Other Lipidoses Lipid storage diseases are rare.9 Two important lipidoses with gray matter manifestations include TaySachs disease and neuronal ceroid-lipofuscinosis.1 Tay-Sachs disease Tay-Sachs disease (TSD) is classified as a GM2 gangliosiclosis.1 Sandhoff disease is a related but rarer related GM2 disorder Although Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain 737 Fig 17-13 Neuronal ceroid lipofuscinosis, Batten type Sagittal T1- (A) and axial T2-weighted (B) MR scans in this young adult with long-standing neurodegenerative disease show strikingly enlarged sulci and ventricles The T2WI shows the cortex is extremely atrophic but the underlying white matter is preserved genetically different, these two disorders are phenotypically indistinguishable.42 TSD is an inherited sphingomyelin lipidosis caused by deficiency of hexosaminidase A As the abnormal GM2-ganglioside accumulates and interferes with intracellular function, neuronal deterioration and cell death ensue Neuronal death also causes axonal deterioration and secondary demyelination The latter can become prominent and be confused with diseases that produce primary demyelination, the leukodystrophies.9 TSD is diagnosed definitively by hexosaminidase leukocyte assay Early in the disease process the caudate nuclei appear enlarged and protrude into the lateral ventricles.43 CT scans typically show symmetrically, homogeneously hyperdense thalami.42 MR scans in these patients show high signal intensity in the, caudate nuclei, thalamus, and putamen on T2-weighted studies.44 Progression is typically rapid, and severe cortical atrophy with widened sulci, shrunken gyri, and large ventricles is characteristically present later in the disease course Neuronal ceroid-lipofuscinosis Neuronal ceroidhpofuscinosis (NCL) is a clinically heterogeneous group of inherited neurodegenerative disorders that is subdivided into the following four groups, based on age at onset:45 Infantile Late infantile juvenile (Batten disease) Adult (Kufs disease) The gene for infantile NCL is on chromosome 1, whereas juvenile NCL is located on chromosome 16.44a Because no specific enzyme defect has been identified in NCL,9 diagnosis is currently established by electron microscopic examination of leukocytes or skin biopsies NCL patients have characteristic curvilinear or "fingerprint" inclusions of an autofluorescent lipopigment (lipofuscin) within cytosomes.9,45 Imaging studies in these patients show mild to moderate cortical atrophy Patients with infantile NCL may also have hyperintense white matter and low signal in the thalami and striatum on T2-weighted MR scans.44a No white matter changes are seen in Batten disease (Fig 17-13).9 Positron emission tomography (PET) studies of brain metabolism have shown decreased glucose utilization in all gray matter structures, most marked at the thalamus and posterior association cortex.45 Hurler Syndrome and the Mucopolysaccharidoses The mucopolysaccharidoses (MPS) are lysosomal storage diseases that are marked by failure to degrade glycosaminoglycans (mucopolysaccharides).46 Mucopolysaccharide accumulation due to specific catabolic enzyme defects produces 13 syndromes or variants; six are well recognized (Table 17-3, p 739) Storage of undegraded mucopolysaccharides occurs in the cells of most organs, producing the typical gargoyle 738 PART FOUR Infection, White Matter Abnormalities, and Degenerative Diseases Fig 17-14 A, Sagittal transcranial ultrasound in this 2-week-old infant with dysmorphic facies shows striking perivascular echogenicities in the basal ganglia (arrows) Probable mucopolysaccharidosis The differential diagnosis includes toxoplasmosis, cytomegalovirus infection, trisomy 13, and lysosomal storage diseases B to C, Axial T1- (B) and T2-weighted (C) MR scans in a 2-year-old child with mucopolysaccharidosis (MPS IH) show very prominent dilated Virchow-Robin spaces (arrows) in the peritrigonal areas Margins of the enlarged perivascular spaces are obscured on the T2-weighted scan by surrounding demyelination or edema (A, Courtesy K Murray B and C, Courtesy S Blaser.) features.1 Hurler syndrome (MPS 1) is the prototypical mucopolysaccharide storage disease.9 Hurler syndrome Hurler syndrome, also known as MPS I, is an autosomal recessive mucopolysaccharidosis that results from deficiency of alpha-Liduronidase.46 Cortical and cerebellar neurons are ballooned from large intralysosomal accumulations of ganglioside, forming the so-called meganeurites The perivascular spaces are grossly enlarged by accumulation of mucopolysaccharide-containing histiocytes (gargoyle cells) that surround the penetrating blood vessels.9 Gross meningeal thickening is common Death occurs between and 10 years of age and is usually secondary to respiratory failure or cardiac involvement.46 Clinical features include gargoyle-like facies dwarfism, progressive kyphosis, protuberant abdomen, hepatosplenomegaly, and severe psychomotor retardation.9 Cerebral sonography in neonates with some lysosomal storage disorders shows stripelike perivascular echogenicities (Fig 17-14, A).46A MR Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain 739 Fig 17-15 MPS III (Sanfilipo syndrome) Coronal T1- (A) and axial T2-weighted (B) MR scans show large lateral ventricles and sulci with markedly thinned gray matter (open arrows) Secondary white matter changes are also present (B, arrowheads) Table 17-3 Mucopolysaccharidoses Number Eponym MPS IH Hurler MPS II Hunter MPS III Sanfilippo MPS IV Morquio Distinctive imaging features Macrocrania, thick dura, perivascular "pits," concave or "hooked" thoracolumbar vertebrae with gibbus/ kyphoscoliosis Thick dura, perivascular "pits" Cortical atrophy Atlantoaxial subluxation, cord injury MPS V Not used MPS VI Maroteaux-Lamy Thick dura, ligamentous instability, subluxations, white matter lesions MPS VII Sly Odontoid hypoplasia MPS VIII Not used studies typically disclose thickened dura, cortical atrophy, and perivascular "pits," seen as low and high signal cystic foci on T1- and T2WI, respectively (Fig 17-14, B and C).46 Communicating hydrocephalus is common.46 Spinal cord compression secondary to the thickened dura may be present in some cases.47 Other mucopolysaccharidoses Other MPS storage diseases that may have striking imaging findings include severe Hunter (MPS IIA) and Sanfilippo syndrome (MPS IIIB) T1-weighted MR scans show cortical atrophy; reduced gray-white matter contrast on T2WI is common (Fig 17-15) Hyperintense white matter foci may also be present Mucolipidoses and Fucosidosis The mucolipidoses are disorders associated with accumulation of mucopolysaccharide and lipids resulting from a single enzyme defect that affects both catabolic pathways Examples of mucolipidoses include I-cell disease, fucosidosis, and mannosidosis.9 Neuronal destruction with myelin loss, gliosis, and atrophy occur Imaging studies show thin cortex with nonspecific white matter changes (Fig 17-16) Glycogen Storage Diseases Glycogen storage diseases are a heterogeneous group of disorders resulting from deficiencies of enzymes involved in glycogen storage, synthesis, and degradation Multisystem manifestations are common Pompe disease is one disorder that has both CNS and peripheral lesions Glycogen accumulates within neurons of the dorsal root ganglia, anterior horn cells, and motor nuclei of the brain stem.9 Mild nonspecific cortical atrophy may be present 740 PART FOUR Infection, White Matter Abnormalities, and Degenerative Diseases Mitochondrial Encephalopathies Leigh disease (subacute necrotizing encephalomyelopathy) MELAS (mitochondrial encephalomyelopathy, lactic acidosis, and strokelike episodes) MERRF (myoclonic epilepsy with ragged red fibers) Kearns-Sayre syndrome Others (Alpers disease, Menkes disease) Fig 17-16 Mucolipidosis (fucosidosis) Axial T2-weighted MR scan shows confluent periventricular demyelinated areas (large arrows) The cortex (open arrows) is thinned secondary to myelin loss DISORDERS THAT AFFECT BOTH GRAY AND WHITE MATTER A few inherited metabolic disorders affect gray and white matter to approximately the same extent These are mostly diseases with mitochondrial or peroxisomal enzyme defects.9 Leigh Disease and Other Mitochondrial Encephalopathies Mitochondria are threadlike cytoplasmic organelles that contain the DNA coding for production of numerous enzymes involved in the oxidative respiratory cycle Krebs cycle enzymes and the cytochrome-electron transfer system required for adenosine triphosphate (ATP) formation are located in the mitochondria.1,9 Other than Leigh encephalopathy and focal cerebral ischemic lesions, the patterns of pathology associated with mitochondrial enzyme disorders have not been firmly established.9 There is also considerable overlap with other entities For example, certain aminoacidemias (e.g., glutaric acidemia type I and methylmalonic acidemia) are also involved with mitochondrial protein formation and result in basal ganglia abnormalities similar to those of primary mitochondrial defects.12 Despite these conceptual difficulties, three syn- dromes of mitochondrial dysfunction have emerged as follows (see box): Myoclonic epilepsy with ragged-red fibers (MERRF) Mitochondrial encephalopathy, lactic acidosis, and strokelike syndromes (MELAS) Kearns-Sayre syndrome (KSS) A subacute necrotizing encephalomyelopathy, Leigh disease, represents end stage mitochondrial dysfunction and can occur from virtually any mitochondrial enzyme defect.9 We will begin our discussion by considering Leigh disease, then turn our attention to MERRF, MELAS and KSS Leigh disease Leigh disease, also known as acute necrotizing encephalopathy, is a rare disorder that has been associated with several mitochondrial enzyme deficiencies: pyruvate dehydrogenase complex, pyruvate carboxylase, defects in the electron transport chain, and cytochrome c oxidase, among others.11,48 Inheritance is autosomal recessive Leigh disease is characterized by spongiosis, myelination, astrogliosis, and capillary proliferation.9 Necrosis and capillary proliferation occur in the basal ganglia, spinal cord, and brainstem (Fig 17-17, A) The periaqueductal, subependymal, and tegmental gray matter are commonly involved.11 Three clinical subtypes are recognized 49: An infantile form with symptom onset during the first years of life A juvenile form with disease manifestations in early childhood An adult form with onset during the fifth or sixth decade The infantile form of Leigh disease occurs with hypotonia, vomiting, seizures, and loss of head control Slow progression with death from respiratory failure is typical NECT scans usually show low density areas in the putamina and caudate nuclei The lesions typically not enhance following contrast administration.48 T2-weighted MR scans show striking symmetric hyper Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain 741 Fig 17-17 Leigh disease is illustrated on the anatomic drawing (A) and axial T2-weighted MR scan (B) Note the bilaterally symmetric lesions in the caudate nuclei and basal ganglia (large arrows) Mild white matter disease is present (small arrows) intense foci in the globus pallidus, putamen, and caudate (Fig 17-17, B) The periventricular white matter.50 and periaqueductal gray matter are often affected MERRF syndrome MERRF syndrome (for myoclonic epilepsy with ragged red fibers) is a mitochonal encephalomyopathy that causes myoclonic epileps, muscle weakness, and progressive external ophthalmoplegia Short stature, cardiac conduction defects, and endocrine deficiencies are common.1 The definitive diagnosis is established by muscle biopsy that shows ragged red fibers with Gomori's modified trichrome stain.54 Imaging findings are similar to those in MELAS syndrome, i.e., multiple infarcts in the cortex, subjacent white matter, and, sometimes, the basal ganglia.12 MELAS syndrome MELAS syndrome (for mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes) is a familial disease that may have maternal inheritance.51 A specific mutation in mitochondrial tRNA is associated with MELAS syndrome.52 The patterns of brain damage with MELAS are related to cerebral infarcts Although any part of the brain can be affected, the occipital lobes are the most common site.1 Both large and multifocal small vessel occlusions occur (Fig 17-18, A) Angiographic, Fig 17-18 A, Anatomic diagram depicts pathologic changes seen in MELAS syndrome Multiple small vessel infarcts (large arrows) and major vessel occlusions (vertical lines: small arrows) occur The occipital lobes are the most common site of large infarcts Continued 742 PART FOUR Infection, White Matter Abnormalities, and Degenerative Diseases Fig 17-18, cont'd B and C, This 5-year-old boy with developmental delay and lactic acidosis has two siblings with known mitochondrial encephalopathy Axial T2-weighted MR scans show ventriculomegaly and multifocal white matter lesions (arrows) (B and C, Courtesy P.D Barnes.) Fig 17-19 A, Coronal gross autopsy specimen of Zellweger's syndrome shows hypomyelination with scanty white matter The cortex is thickened and has foci of polymicrogyria B and C, A 3-month-old girl with dysmorphic features, hypotonia, and seizures had these axial T2-weighted MR scans Hypomyelination is seen as markedly diminished white matter volume (large arrows) Note polymicrogyria (small arrows) The diagnosis of Zellweger syndrome was confirmed at autopsy (A, Courtesy Rubinstein Collection, Armed Forces Institute of Pathology B and C, Courtesy P.D Barnes.) Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain CT, and MR findings are those of nonspecific cerebral infarction (Fig 17-18, B).53 Keams-Sayre syndrome Kearns-Sayre syndrome GS) is an autosomal dominant mitochondrial encephalopathy with elevated serum pyruvate Pathologic and imaging findings are similar to Leigh disease (see previous discussion).12 Zellweger Syndrome and Other Peroxisomal Disorder Peroxisomes are cell organelles responsible for mebolism of long-chain fatty acids Their role in some inherited neurodegenerative disorders has been recently elucidated Two major groups of peroxisomal disorders are 1w recognized The first group is caused by multiple enzyme defects with failure of peroxisomal development or maintenance This category includes Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease The second group consists of disorders in which the peroxisomes appear structurally normal and only a single enzyme defect occurs 11is class includes X-linked adrenoleukodys-trophy.55 We have already discussed one of these important peroxisomal disorders that primarily affects white matter, i.e., X-linked adrenoleukodystrophy In this section we discuss peroxisomal enzyme deficiencies that affect both gray and white matter approximately equally The prototype disorder is Zellweger syndrome (see box, p 727) Zellweger Syndrome Zellweger syndrome, also known as cerebrohepatorenal syndrome, is an autosomal recessive neurodegenerative disorder that is 743 associated with deficiency of multiple peroxisomal enzymes.1 Numerous organs are affected In the brain, there is an unusual combination of abnormalities: neuronal migration disorders with heterotopic gray matter, pachygyria, and polymicrogyria occur, with a general decrease in white matter volume.9,12 T2-weighted MR scans show pachygyria, periventricular heterotopias, cerebral white matter hypomyelination, and cortical neuronal loss (Fig 17-19).12,56 BASAL GANGLIA DISORDERS Numerous congenital and acquired metabolic disorders affect the basal ganglia In this section we discuss inherited diseases whose primary or sole imaging manifestations are found in this location Huntington Disease Huntington disease (HD) is a fully penetrant, autosomal dominant, inherited neurodegenerative disorder that is characterized clinically by movement, mentation, and behavioral disturbances.57 Disease prevalence in North America is estimated at 10 cases per 100,000 Onset is typically in the fourth or fifth decade, although 5% of patients are under 14 years of age.11,58 Disease duration averages between 15 and 30 years The most conspicuous neuropathologic finding is striking basal ganglia atrophy, although atrophy of other structures such as the cerebellum and brainstem are also common.57 Imaging studies show both cortical and subcortical atrophy Caudate nucleus volume loss causes focal enlargement of the frontal horns of the lateral ventricles (Fig 17-20) Both increased and decreased putaminal signal intensity on T2-weighted scans have been reported in HD.59 Fig 17-20 A, Coronal gross pathology of Huntington disease shows striking caudate atrophy B, Coronal CECT scan in a patient with known Huntington disease demonstrates caudate nucleus atrophy, shown by the laterally convex margin of the frontal horns (arrows) (A, Courtesy J Townsend.) 744 PART FOUR Infection, White Matter Abnormalities, and Degenerative Diseases Fig 17-21 Axial T2-weighted MR scans in this patient with Hallervorden-Spatz disease show characteristic low signal changes in the basal ganglia and substantia nigra (arrows) Fig 17-22 Axial NECT scans in a patient with head trauma A small right subdural hematoma is present (large arrows) Incidentally noted are extensive calcifications in the caudate, lenticular and dentate nuclei, the thalamus, and the subcortical white matter (small arrows) "Fahr's disease." (Courtesy M Fruin.) Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain 745 Fig 17-23 Axial NECT scans show extensive idiopathic calcifications in the basal ganglia and centruM semiovale (arrows) The deep white matter calcifications appear to follow the perivascular spaces No metabolic abnormalities were present Bilateral Basal Ganglia Lucencies Common Normal (dilated perivascular spaces) Arterial infarct (lacunar) Hypoxic/ischemic encephalopathy (e.g., perinatal hypoxia, cardiac arrest, drowning) Toxic encephalopathy (e.g., carbon monoxide, methanol, hydrogen sulfide, cyanide) Uncommon Metabolic (severe hypoglycemia, osmotic myelinolysis) Infection (especially toxoplasmosis, cryptococcosis in AIDS; some encephalitides); postinfectious acute striatal necrosis Inherited disorders (e.g., Leigh disease, Wilson disease, methylmalonic acidemia, juvenile Huntington disease; Alexander, Canavan and MLD) Venous infarct (internal cerebral vein thrombosis) Hemolytic-uremic syndrome Hallervorden-Spatz Disease Hallervorden-Spatz disease (HSD) is a rare neurodegenerative disease with no known biologic marker to date Both familial and sporadic cases have been reported.60 Characteristic pathologic findings are iron deposits in the globus pallidus and substantia nigra NECT scans show bilateral low densities in these areas The differential diagnosis of congenital and acquired basal ganglia low densities is extensive, and summarized in the box, above Bilateral Basal Ganglia Calcifications Common Idiopathic (no endocrine abnormality) "Fahr disease" (familial cerebrovascular ferrocalcinosis Postinflammatory (TB, CID, toxoplasmosis, cystic ercosis, congenital HIV) Uncommon congenital (tuberous sclerosis, Down syndrome, MELAS/MERRF, Cockayne syndrome, neurofibromatosis, methemoglobinopathy) Post-anoxic/toxic (e.g., carbon monoxide, chemotherapy and radiation therapy, lead intoxication) Typical findings of HSD on T2-weighted MR scans include pallidonigral low signal intensity (Fig 1721).61 Sometimes smaller anteromedial high signal intensities are also present (eye-of-the-tiger sign).61, 62 Fahr Disease So-called Fahr disease is not a single entity but a diverse group of disorders that have striking basal ganglia calcifications in common.11 Some cases also have prominent calcifications in the dentate nuclei, centrum seMiovale, and subcortical white matter (Figs 17-22 and 17-23) The differential diagnosis of inherited and acquired basal ganglia calcifications is extensive, and summarized in the box, above 746 PART FOUR Infection, White Matter Abnormalities, and Degenerative Diseases Wilson Disease Wilson disease (hepatolenticular degeneration) is an autosomal recessive inherited disorder of copper metabolism caused by a deficiency of ceruloplasmin, the serum transport protein for copper Abnormal copper deposition occurs in various tissues, especially the liver, brain, cornea, bones, and kidneys.63 Wilson disease (WD) is associated with cirrhosis of the liver 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Neuroradiol 34:222-224, 1992 66.Ho VB, Fitz CR, Chuang SH, Geyer CA: Bilateral basal ganglia lesions: pediatric differential considerations, RadioGraphics 13:269-292, 1993 ... fibers here, and therefore a "Cap" of high signal intensity on T2WI is normal (Fig 17, B) Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain Fig 17- 1 Axial anatomic... Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain 741 Fig 17- 17 Leigh disease is illustrated on the anatomic drawing (A) and axial T2-weighted MR scan (B) Note the. .. around the pre- and postcentral gyri is present (arrows) Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain 721 Fig 17- 3 Normal myelination between and months