Table 3.

Genes of Interest in the Differential Diagnosis of Pelizaeus-Merzbacher Disease (PMD)

Gene(s) 1Disorder 2MOIFeatures of Differential Diagnosis Disorder
Overlapping w/PMDDistinguishing from PMD
AIFM1 Hypomyelination w/spondyloepiphyseal dysplasia 3XLHypomyelinationSpondyloepiphyseal dysplasia
DARS1 Hypomyelination w/brain stem & spinal cord involvement & severe leg spasticity (OMIM 615281)ARSpasticity/ataxia; nystagmus; hypomyelinationCharacteristic involvement of brain stem & spinal cord structures on MRI
EPRS1 Hypomyelinating leukodystrophy 15 (OMIM 617951)ARSpasticity/ataxia; nystagmus; hypomyelinationPosterior columns may be affected on MRI
GJA1 Oculodentodigital dysplasia (OMIM 164200)ADHypomyelinationMild symptoms, sometimes diagnosis only in adulthood; syndactyly; ocular abnormalities; dysmorphic signs; prominent spastic bladder
GJC2 Pelizaeus-Merzbacher-like disease 1 ARSpasticity/ataxia; nystagmus; hypomyelinationEpilepsy is frequent. More pronounced hypomyelination in subcortical white matter; prominent brain stem involvement
HSPD1 Hypomyelinating leukodystrophy 4 (OMIM 612233)ARResembles severe PMD 4; hypomyelinationAcquired microcephaly; severe epilepsy
HYCC1 (FAM126A) Hypomyelination & congenital cataract ARSpasticity/ataxia; nystagmus; demyelinating peripheral neuropathy; hypomyelinationCongenital cataract; areas w/both T2-weighted hyperintensity & T1-weighted hypointensity
NKX6-2 NKX6-2 disorder ARSpasticity/ataxia; nystagmus; hypotonia; hypomyelinationSevere early dystonia, early-onset (transitory) respiratory failure
POLR3A
POLR3B
POLR3K
POLR1C 		4H leukodystrophy (hypomyelination, hypodontia, & hypogonadotropic hypogonadism)ARAtaxia; hypomyelinationMyopia (no nystagmus); hypodontia; hypogonadotropic hypogonadism; early cerebellar atrophy; better myelination of posterior limb of the internal capsule, ventrolateral thalamus & optic radiation
RARS1 Hypomyelinating leukodystrophy 9 (OMIM 616140)ARSpasticity/ataxia; nystagmus; hypomyelinationNo specific distinguishing features; in severe cases, microcephaly & early epileptic encephalopathy
SLC16A2 Allan-Hernon-Dudley syndrome (MCT8-specific thyroid hormone cell-membrane transporter deficiency)XLNeonatal hypotonia, nystagmus, severe DDHigh serum T3 concentration; low serum reverse T3 concentration; MRI shows (severely) delayed myelination, but not hypomyelination
SLC17A5 Salla disease (See Free Sialic Acid Storage Disorders.)AR± hypotonia, nystagmus, DD; in severely affected children, diffusely abnormal myelination w/uniformly hyperintense white matter on T2-weighted images; in less severely affected children, delayed myelination, occurring mainly in periventricular regionsSeizures are more common than in PMD, but children w/Salla disease are more likely to show improvement; MRI shows thin corpus callosum early on.
SOX10 PCWH syndrome (OMIM 609136)ADHypomyelinationPeripheral congenital hypomyelinating neuropathy; Waardenburg-Hirschsprung syndrome
TMEM106B Hypomyelinating leukodystrophy 16 (OMIM 617964)ADNystagmus; hypomyelinationMild clinical presentation (mild ataxia, mild cognitive impairment)
TMEM63A Transient hypomyelination 5ADInitially indistinguishable from PMD (congenital nystagmus, hypotonia, hypomyelination)Positive evolution w/normalization of development & MRI findings
TUBB4A Hypomyelination w/atrophy of basal ganglia & cerebellum (See TUBB4A-Related Leukodystrophy.)ADSpasticity, nystagmus (not invariable); hypomyelinationUsually atrophy of basal ganglia & cerebellum

AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; PCWH = peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease; XL = X-linked

1.

Genes are listed alphabetically.

2.

Other leukodystrophies should also be considered.

3.
4.

Described in an Israeli Bedouin family

5.

From: PLP1 Disorders

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