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

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

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

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

Encepha-lopathies

Zellweger Syndrome and Other Peroxisomal Disorders

Basal Ganglia Disorders

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

C H A P T E R

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

Anterior limb of internal capsule

Occipital subcortical U fibers

Corpus callosurn splenium

Six months

Corpus callosurn genu

Paracentral subcortical U fibers

Centrum semiovale (partial)

Essentially like adult

Table 17-1 MR Myelination/Developmental Markers

High signal (T1Wl) Low signal (T2Wl) Structure first appears at: first appears at: Posterior fossa

Dorsal medulla/ Birth Birth midbrain

Inferior/superior Birth Birth cerebellar pe-

duncles Middle cerebellar 1 month 3 months peduncle

Cerebellar white 1 to 3 months 8 to 18 months matter (deep

to peripheral) Supratentorial

Internal capsule Posterior limb Birth Birth Anterior limb 3 months 3 to 6 months Thalamus Birth Birth

(ventro-lateral nuclei)

Pre/postcentral 1 month 8 to 12 months gyri

Corpus callo- sum Splenium 3 to 4 months 6 months Genu 6 months 8 months Centrum semiov- Birth to 1 month 3 months ale (deep)

Optic radiations 3 months 3 months Subcortical U

fibers (poste- 3 to 8 months 8 to 18 months rior to ante- (occipital first) (frontal last) rior)

Modified from Byrd SE, Darling CR, Wilczynski NA: White- matter 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

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

dur-ing the first 2 years, by which time it is nearly

com-pleted 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-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,

relative signal intensities of cortex and white matter are reversed

compared to the pattern normally seen in older children and

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 1 month there is little change

from the appearance at birth However, by 3

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 4 months, high signal seen

in the corpus callosurn splenium; by 6 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 4

months from the pattern seen at 3 months, However, by

6 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 imag- ing 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 terior 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

an-do 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 719

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

720 PART FOUR Infection, White Matter Abnormalities, and Degenerative Diseases

Fig 17-2 Brain myelination at about 3 to 4 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 6 and 8 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

leukodys-trophy 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,

adrenoleu-kodystrophy, is caused by a single peroxisomal enzyme

defect Pelizaeus-Merzbacher disease is caused by

defective biosynthesis of proteolipid protein,

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 1 in 100,000 newborns.11 Three different types of MLD are recognized according to age at onset These are

Table 17-2 Lysosomal Disorders

GM2 ganghosidosis Beta-hexosaninidase (Tay-Sachs, Sandhoff A/B

disease)

Mucolipidoses (e.g., Varies (alpha-

fucosidosis) fucosidase with

fucosidosis)

Canavan disease Aspartoacylase

Mucopolysacchari- Varies (alpha-L-

doses (e.g., Hurler, iduronidase with

Ceroid lipofuscinoses Varies (ATP synthe- (e.g., Batten disease) sase with Batten dis-

ease) Data from Kendall BE: Disorders of lysosomes, peroxisomes

Occipital white matter most involved

Adrenoleukodystrophy (also callosal splenium)

Macrocephaly

Alexander disease

Canavan disease

Mucopolysacchariclosis type I (Hurler)

Mucopolysaccharidosrs type II (Hunter)

Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain 723

Fig 17-4 A, Metachromatic leukodystrophy (MLD) is

il-lustrated 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

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

Approx-imately 80% of cases occur in childhood with onset

typically between I and 2 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 2 years of

onset, gait disorders, quadriplegia, blindness, and

decerebrate posturing can be seen.9 Disease progress is

inexorable, and death occurs within 6 months to 4 years

following symptom onset.11

Imaging

CT NECT scans show moderate ventricular

en-largement 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 leu- kodystrophy (GLD)

Etiology, inheritance, and pathology

Etiology and inheritance GLD is a lysosomal

dis-order that is caused by deficiency of the lysosomal hydrolase galactocerebroside beta-galactosidase.13 in-heritance 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 af-fected 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 adult-onset 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

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

A) The parietooccipital lobes may be selectively

in-volved early in the disease course (Fig 17-5, C).12b

Clinical presentation and natural history

Psy-chomotor 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

726 PART FOUR Infection, White Matter Abnormalities, and Degenerative Diseases

Fig 17-6 X-linked adrenoleukodystrophy (ALD) A, Axial autopsy specimen demonstrates

gross pathologic changes of ALD Note striking bilateral demyelination in the peritrigonal

areas and corpus callosurn splenium B, Anatomic diagram illustrates the three zones typical

of ALD The central necrotic zone is indicated by the horizontal lines and small black arrows The intermediate zone of active demyelination that enhances following contrast administration is indicated by the solid black line and curved arrows, The peripheral demyelinating area without inflammatory change is shown in white and indicated by the

large white arrows C to E, Pre- (C) and postcontrast (D and E) axial CT scans in a

6-year-old boy with 1-month history of progressive ataxia and dysarthria The precontrast

study shows bilaterally symmetric low density areas in both periatrial regions (C, arrows)

The anterolateral margins enhance strongly following contrast administration (D and E,

arrows) Note small focus of calcification (E, open arrows) Adrenoleukodystrophy F and

G, Axial postcontrast T1- (F) and T2-weighted (G) MR scans in another patient with ALD

show striking bilateral periatrial enhancement (F, arrows) and active demyelination (G,

arrows) (A, From Okazaki H, Scheithauer B, Slide Atlas of Neuropathology, Gower

Medical Publishing F and G, Courtesy C Sutton.)

Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain 727

Fig 17-6 cont'd For legend see p 726.

Peroxisomal Disorders Peroxisomes absent

Peroxisomes present with multiple enzyme defects

Rhizomelic chondrodysplasia punctata

Data from Naidu SB, Moser H: Infantile Refsum

disease, AJNR 12:1161-1163,1991

Etiology, inheritance, and pathology

Etiology and inheritance

Adrenoleukodystrophy-adrenomyeloneuropathy complex is a group of three

closely related peroxisomal disorders, as follows:

1 Adrenoleukodystrophy (ALD)

2 Adrenomyeloneuropathy (AMN)

3 Adrenoleukomyeloneuropathy (ALMN)

Classic ALD is caused by deficiency of a single enzyme,

acyl-CoA synthesase This prevents breakdown of very

long-chain fatty acids (VLFAs) VLFAs then accumulate

in numerous tissues and plasma.16 Inheritance is X-linked

recessive

A rare form of ALD, neonatal adrenoleukodystrophy,

is an autosomal recessive disorder with multiple enzyme deficiencies

Gross pathology Autopsy specimens of ALD show

enlarged ventricles and cerebral atrophy due to white matter volume loss The cortex is normal Demyelination classically first involves the occipital lobes and corpus callosum splenium in a bilaterally symmetric pattern (Fig 17-6, A) Atypical ALD patterns include unilateral

or predominately frontal disease (see subsequent discussion)

Microscopic appearance The affected cerebral white

matter typically has three zones,1 as follows:

1 An innermost central and posterior zone with necrosis, gliosis, and, sometimes, calcification

2 An intermediate zone of active demyelination and inflammatory changes

3 A peripheral zone of demyelination without in flammatory reaction

Incidence, gender, and age X-linked ALD is seen in

males Symptom onset typically occurs between 3 and 10 years of age This childhood type of ALD represents 40%

of all ALD-AMN cases.17 AMN is the second most common form Symptom onset is typical in young adulthood in members of families affected by childhood ALD.18 AMN represents approximately 20% of ALD-AMN cases.17

Location In the early stages of classical ALD,

symmetric white matter demyelination occurs in the peritrigonal regions and extends across the corpus

callosurn splenium (Fig 17-6, A and B).1 Demyelination then spreads outward and forward as a confluent lesion until most of the cerebral white matter is

728 PART FOUR Infection, White Matter Abnormalities, and Degenerative Diseases

affected Auditory pathway involvement is common.19

The subcortical white matter is relatively spared early

but is often involved in later stages.20,21

Atypical cases with unilateral or predominately

frontal lobe involvement occur.16,22 Secondary

de-generative changes in the posterior limb of the internal

capsule, cerebral peduncles, pons, pyramid, and

cerebellum are common.9

Adrenomyeloneuropathy typically involves the

spinal cord and peripheral nerves.12 The most common

imaging manifestation is spinal cord atrophy, seen in

approximately 30% of AMN patients The thoracic cord

is most commonly involved.18

Clinical presentation and natural history The

various ALD-AMN phenotypes involve the central and

peripheral nervous systems and the endocrine systems

differently.18 In childhood ALD, neurologic

abnormalities recede adrenal insufficiency in over 80%

of cases.17 Visual and behavioral disturbances are the

most frequent initial symptoms.9,19 Seizures, hearing

loss, corticospinal tract involvement, and spastic

quadraparesis occur The interval between the first

neurologic symptoms and vegetative state is

ap-proximately 2 years.17

Symptom onset in AMN is typically later, usually

between the ages of 20 and 30 years.18 Paraparesis is

seen in virtually all cases, and adrenal dysfunction

occurs in 87% Cerebral involvement is seen in only

10% of cases.17 Female heterozygotes are usually

asymptoMatic but approximately 12% have spastic

paraparesis.18

Imaging The definitive diagnosis of ALD is made

by plasma, erythrocyte, or cultured skin fibroblast assay

for the presence of increased VLFAs.2 Imaging findings

in most cases are characteristic

CT NECT scans typically show large, symmetric

low density lesions in the parietooccipital (peritrigonal)

regions (Fig 17-6, C) Calcifications occasionally can

be identified (Fig 17-6, E) CECT scans show

en-hancement in the advancing rim, surrounded by a more

peripheral nonenhancing edematous zone (Figs 17-6, D

and E).17

MR The three histopathologic zones described in

ALD can be delineated on MR (Fig 17-6, F and G) The

central necrotic zone is seen as a low signal region on

T1WI and a homogeneously very hyperintense region

on T2-weighted sequences The intermediate zone of

active demyelination and inflammation enhances

following contrast administration It is interposed

between the central necrotic zone and the more

peripheral, nonenhancing edematous area that is

slightly hypointense on T1- and hyperintense on

T2-weighted images.20 Abnormal signal is usually

present in the lateral geniculate bodies and auditory

pathways, as well as the corpus callosurn splenium and corticospinal tracts.19

Findings in AMN are symmetric hyperintensities in the posterior limb of the internal capsule on T2WI The frontal, parietal, occipital, and temporal lobe white matter is spared.21

Pelizaeus-Merzbacher Disease Etiology, inheritance, and pathology

Etiology and inheritance Pehzaeus-Merzbacher

disease (PMD) has been linked to a severe deficiency of myelin-specific lipids caused by a lack of proteolipid apoprotein (lipophilin).9 The myelin-specific proteolipid protein is necessary for oligodendrocyte differentiation and survival.11

Two main forms of PMD are recognized: the classical form, type I, is X-linked recessive in inheritance The connatal form, type II, is either X-linked or autosomal recessive.23 A transitional form has also been described.24

Gross pathology The brain and cerebellum are

atrophic The ventricles are large and there is patchy white matter demyelination The cortex is normal (Fig 17-7, A).9

Microscopic appearance Patchy demyelination with

characteristic sparing of perivascular white matter creates

a "tigroid" or "leopard-skin" pattern Lipid-laden macrophages are often present.9

Incidence, gender, and age PMD is a rare

neurodegenerative disorder that typically occurs in you boys, although rare cases in females have been reported Symptom onset in type I PMD occurs during infancy or early childhood, whereas the connatal form, type II, is clinically more severe and symptoms begin in the neonatal period.23

Location In the connatal type there is ma e paucity to

complete absence of myelin in all parts of the brain Some residual myelin may be present in the diencephalon, brainstem, and cerebellum, as well as in the subcortical white matter.24 Less pronounced changes are seen in the classical type I PMD The internal capsule and subcortical U fibers are preserved and residual islands of perivascular white matter myelination are present (Fig

17-7, B)

Clinical presentation and natural history he classic

PMD (type I) has its onset during infancy Early symptoms are poor head control, nystagmus, and cerebellar ataxia.21 The disease progresses slowly; death occurs in late adolescence or young adulthood

The connatal type of PMD is a more severe variant Abnormal eye movements are present in the neonatal period, and psychomotor development is severely

Chapter 17 Inherited Metabolic, White Matter, and Degenerative Diseases of the Brain 729

Fig 17-7 Pelizaeus-Merzbacher disease (PMD) A, Coronal gross pathology

specimen from an infant with connatal PMD shows marked white matter

hypomyelination (arrows) B, Axial anatomic drawing of PMD shows extensive

periventricular demyelination Note islands of residual myelin around penetrating

vessels, giving the "tigroid" appearance sometimes noted in PMD C and D, Axial

T2-weighted MR scans in an 8-year-old boy with PMD who was normal at birth

At age 3 years he developed progressive gait disturbance, limb ataxia, and

nystagmus Note extensive high signal throughout the white matter (arrows)

Some residual myelination is present in the internal capsule and subcortical U

fibers (A, Courtesy Rubinstein Collection, University of Virginia C and D,

Courtesy D

retarded Progression is comparatively rapid, and

death typically occurs during the first decade.21

Imaging

CT NECT scans show mild nonspecific cerebral

and cerebellar atrophy The white matter may appear

normal, nearly normal, or show diffuse low density

changes The cortex is intact.23,25

MR In contrast to CT, MR shows widespread

white matter abnormality (Fig 17-7, C) Severe cases show near-total lack of normal myelination with dif-fuse high signal on T2-weighted scans that extends per2ipherally to involve the arcuate fibers (Fig 17-7, D).26

Some cases show heterogeneous high signal in the white matter with small scattered foci of more nor-

730 PART FOUR Infection, White Matter Abnormalities, and Degenerative Diseases

Fig 17-7, cont'd E to H, MR scans in another patient with probable PMD show

a "tigroid" pattern of perivascular myelin preservation (open arrows) within the extensive confluent demyelinated area (solid arrows) The subcortical U fibers are

spared Note low signal in thalami (F), possibly reflecting abnormal iron

deposition Sagittal T1WI (E), axial (F and G), and coronal (H) T2WI are shown

mal areas that may be the imaging manifestation of the

"tigroid" pattern identified histopathologically (Fig

17-7, E and H).23,25 The brainstem, diencephalon,

cerebellum, and subcortical white matter may

demonstrate myelin preservation.11 The basal ganglia

and thalamus may appear unusually hypointense on

T2WI, possibly re- presenting abnormal iron deposition

(Fig 17-7, F).26

Alexander Disease

Etiology, inheritance, and pathology

Etiology and inheritance Alexander disease (AD) is a

sporadic leukoencephalopathy of unknown etiology

There is no definitive biochemical test for AD and the

diagnosis is usually made by brain biopsy.27

Pathology Grossly, the brain is increased in size

and weight with massive deposition of Rosenthal fibers These are dense eosinophilic rodlike cystoplasmic inclusions that are found in astrocytes.27 Rosenthal fibers accumulate around blood vessels, in the subependymal region, and under the pia.9 Extensive demyelination occurs in infantile-onset AD The cortex is not involved

Incidence, gender, and age AD is a rare disorder that

typically presents in infants, although juvenile and adult forms are recognized (see subsequent

discussion) There is no gender predilection

Location AD has a predilection for the frontal lobe

white matter early in its course (Fig 17-8, A) Rosenthal fibers are also found in the basal ganglia, thalamus, and hypothalamus

Fig 17-8 Alexander disease (AD) A, Axial anatomic

drawing shows the frontal lobe demyelination (small

arrows) that is characteristic of early AD The basal

ganglia are also involved (large arrows) B, Axial

NECT scan in a 14-monthold boy who was healthy at birth but now has seizures and macrocephaly The

frontal white matter (solid arrows), caudate nuclei

(open arrows), and external capsule show symmetric

low density changes C, Following contrast

admin-istration there is some enhancement in the deep frontal

lobe white matter and caudate nuclei (arrows) D and

E, Axial T2-weighted MR scans show the extensive

demyelination in the frontal white matter and external

capsules (arrows) Note sparing of the internal

capsules, corpus callosum genu, and posterior white matter in this patient with AD