Diagnostic Considerations
Gene defects other than those found in Pelizaeus-Merzbacher disease can cause a Pelizaeus-Merzbacher disease–like syndrome. In particular, these include mutations that affect the GJA12 gene on chromosome 1. [12] SOX10 mutations cause severe peripheral and central dysmyelination and dysmorphic facial abnormalities.
Salla disease, caused by defects in a lysosomal transporter protein for sialic acid (N -acetyl neuraminic acid), may manifest with nystagmus in the first months of life, as well as hypotonia and cognitive impairment. Children with severe impairment do not ambulate or acquire language but do typically learn to walk and speak and can have a normal life expectancy. MRI reveals arrested or delayed myelination.
Lazzarini described a Pelizaeus-Merzbacher disease–like disorder, observed in a single family, in which the condition was linked to Xq28. [13] However, MRI data have not been obtained on members of this family.
Other leukodystrophies, such as metachromatic leukodystrophy, adrenoleukodystrophy, Krabbe disease, Cockayne disease, and Canavan disease, do not typically cause nystagmus. MRI scans in these diseases usually reveal a disease-based regional predilection for associated abnormalities (eg, occipital white matter in adrenoleukodystrophy, frontal white matter in metachromatic leukodystrophy). Peripheral nerve conduction and evoked potential test results are usually abnormal.
Infants with merosin deficiency have a dramatically increased T2 signal in the cerebral white matter, but the presence of severe weakness and hypotonia and the absence of nystagmus should direct the clinician toward consideration of myopathy. A fatal X-linked syndrome of ataxia, blindness, deafness, and mental retardation has been described and is linked to Xq21-24, but MRI does not reveal a pattern of leukodystrophy. Mutations in the PLP1 coding regions have been excluded in this disorder.
Mutations in the cell adhesion molecule gene L1CAM at Xq28 cause X-linked spastic paraplegia type 1 (SPG1). This disorder is associated with mental retardation and adducted thumbs and is allelic to mental retardation, aphasia, shuffling gait, and adducted thumbs (MASA) syndrome and X-linked hydrocephalus. MRI scans of these disorders may reveal enlarged ventricles or agenesis of the corpus callosum but do not reveal leukodystrophy.
Conditions to consider in the differential diagnosis of Pelizaeus-Merzbacher disease include the following:
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Alexander disease – Reportedly caused by mutations in glial fibrillary acid protein
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Adrenoleukodystrophy
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Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
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Canavan disease
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Cockayne disease
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Congenital muscular dystrophy due to merosin deficiency
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Congenital nystagmus
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Familial spastic paraplegia
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Krabbe disease (globoid cell leukodystrophy)
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Metachromatic leukodystrophy
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Pelizaeus-Merzbacher–like disease
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Salla disease (sialic aciduria)
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Sjögren-Larsson syndrome
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SOX10 mutation syndrome
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Spastic paraplegia type 1
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X-linked ataxia, deafness, blindness, and mental retardation
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Multiple sclerosis
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Parkinson disease
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Parkinson-plus syndromes
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Peroxisomal disorders
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Progressive supranuclear palsy
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Striatonigral degeneration
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Temporal lobe epilepsy
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Tonic-clonic seizures
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Wilson disease
Differential Diagnoses
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T2-weighted magnetic resonance imaging (MRI) scan of a child aged 10 months with duplication of the proteolipid protein (PLP) gene; note the high-intensity signal throughout the cerebral white matter.
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T2-weighted magnetic resonance imaging (MRI) scan of a man aged 41 years with duplication of the proteolipid protein (PLP) gene; note the increased white matter signal, as well as diffuse atrophy.
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T2-weighted magnetic resonance imaging (MRI) scan of a man aged 20 years with connatal Pelizaeus-Merzbacher disease due to a Pro14Leu mutation; note the severe reduction in white matter volume, as well as the increased white matter signal.
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T2-weighted magnetic resonance imaging (MRI) scan of a boy aged 17 years with null mutation of the proteolipid protein (PLP) gene; note the more subtle increase in signal intensity relative to that seen in the previous images, and observe that the volume of white matter is normal.
