Metabolic Disorders Affecting Primarily White Matter
Bernadette L. Koch, MD
DIFFERENTIAL DIAGNOSIS
Common
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Leukodystrophies
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X-Linked Adrenoleukodystrophy (X-ALD)
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Canavan Disease
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Metachromatic Leukodystrophy (MLD)
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Krabbe Disease (GLD)
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Hypomyelination
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Alexander Disease
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Vanishing White Matter Disease
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Less Common
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Mucopolysaccharidoses
Rare but Important
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Megaloencephalic Leukoencephalopathy with Cysts (MLC)
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Merosin Deficient Congenital Muscular Dystrophy
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Maple Syrup Urine Disease
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Nonketotic Hyperglycinemia
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Urea Cycle Disorders
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Giant Axonal Neuropathy
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Trichothiodystrophies
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Oculocerebrorenal (Lowe) Syndrome
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Hyperhomocysteinemia (Homocystinuria)
ESSENTIAL INFORMATION
Key Differential Diagnosis Issues
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Leukodystrophy
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Inborn errors of metabolism → abnormal growth or development of myelin sheath → progressive degeneration of WM
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Symmetric subcortical or deep WM ± GM
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Macrocephaly: Canavan, Alexander, & MLC
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Initial PVWM involvement: MLD, Globoid-cell leukodystrophy (GLD), X-linked ALD
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Initial subcortical WM involvement: MLC, vanishing white matter
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Many → diffuse WM disease and atrophy
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MRS: Majority → ↓ NAA; Canavan → ↑ NAA
Helpful Clues for Common Diagnoses
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X-Linked Adrenoleukodystrophy (X-ALD)
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Most common in males 5-12 years old
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Immune-mediated inflammation at active zones of demyelination → enhancement
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80% splenium
peritrigonal WM 
corticospinal tracts/fornix/commisural fibers/visual and auditory pathways -
15% frontal pattern, genu, anterior/genu internal capsule ± cerebellar (CB) WM
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Spares subcortical U-fibers
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± Ca++
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Canavan Disease
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Macrocephaly
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↑ T2 subcortical U-fibers, thalami, and globi pallidi
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MRS: ↑ NAA
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Metachromatic Leukodystrophy (MLD)
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Most common form is late infantile variant; presents in 2nd year of life
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Frontal and posterior WM
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Symmetric, confluent, nonenhancing ↑ T2 PVWM in “butterfly” pattern
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± radial stripes (relative sparing of myelin in perivenular regions)
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Atrophy, subcortical U-fibers involved late
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Krabbe Disease (GLD)
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Globoid-cell leukodystrophy (GLD)
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CT: Symmetric, bilateral high attenuation in thalami on early CT (3-6 months old)
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↑ T2: Thalami, basal ganglia, CB nuclei, PVWM, corticospinal and pyramidal tracts
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± optic nerve enlargement
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± enhancement at junction of normal and abnormal WM
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± lumbar nerve root enhancement
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Hypomyelination
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T2 hypointensity of myelin normally lags behind T1 hyperintensity by 4-8 months
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Myelination on T2WI should be complete by 3 years, usually by 2 years of age
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Primary hypomyelination syndromes 2° to chromosome deletions and mutations
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Pelizaeus-Merzbacher disease (PMD)
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Spastic paraplegia type 2 (SPG2)
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Hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC)
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18q-syndrome
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Jacobsen syndrome (11q-)
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Hypomyelination with congenital cataracts (DRCTNNB1A)
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Hypomyelination + trichothiodystrophy
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Alexander disease
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Macrocephaly
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Infantile form most common
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↑ T2 in bifrontal WM; caudate heads > putamina, thalami
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Enhancement in periventricular frontal lobe white matter in infantile form
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Enhancement in cerebellum and medulla in juvenile form
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± enhancement in thalami, brainstem, dentate nuclei, cerebellar cortex, optic chiasm, fornix
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± obstructive hydrocephalus 2° to periaqueductal disease
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Vanishing White Matter Disease
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Childhood ataxia with diffuse CNS hypomyelination, childhood ataxia with central hypomyelination (CASH)
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WM ultimately becomes isointense to CSF, begins in central cerebral WM
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Helpful Clues for Less Common Diagnoses
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Mucopolysaccharidoses
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Hunter & Hurler syndrome most common
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Enlarged Virchow-Robin spaces, filled with glycosaminoglycans
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Mild PVWM disease
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Helpful Clues for Rare Diagnoses
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Megaloencephalic Leukoencephalopathy with Cysts (MLC)
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a.k.a. van der Knaap disease
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Macrocephaly
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Peripheral WM swollen with enlarged gyri
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Less severe involvement of CB WM
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Subcortical cysts in posterior frontal and anterior temporal lobes
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Merosin Deficient Congenital Muscular Dystrophy
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Hypomyelination of central cerebral WM
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± CB vermis and pontine hypoplasia
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Maple Syrup Urine Disease
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Acute phase: Edema and restricted diffusion in areas where normal neonatal WM should be myelinated
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Deep CB and perirolandic WM, dorsal brainstem, cerebral peduncles, posterior limb internal capsule ± globi pallidi
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Nonketotic Hyperglycinemia
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Delayed myelination and edema in frontal cortex and subcortical WM
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Long-echo MRS: Abnormal peak at 3.56 ppm probably represents glycine
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Urea Cycle Disorders
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Multiple different enzyme deficiencies
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Severe edema in cortex, subcortical WM, and basal ganglia
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Giant Axonal Neuropathy
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↑ T2 in cerebral and cerebellar WM, spares subcortical U-fibers
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Trichothiodystrophies
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Galactosemia: Delayed myelination in subcortical WM on T2WI, normal on T1WI; ± cerebral and CB atrophy
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Cockayne syndrome: ↑ T2 periventricular WM, basal ganglia, CB dentate nuclei
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Oculocerebrorenal (Lowe) Syndrome
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