eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Pelizaeus-Merzbacher Disease: Differential Diagnoses & Workup

Author: James Y Garbern, MD, PhD, Clinical Director of Neurogenetics Clinic, Associate Professor, Department of Neurology and Center for Molecular Medicine and Genetics, Detroit Medical Center, Wayne State University School of Medicine
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Updated: Aug 22, 2008

Differential Diagnoses

Other Problems to Be Considered

Alexander disease
Adrenoleukodystrophy
Ataxias with identified biochemical defects 
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)
Canavan disease
Cockayne disease
Congenital muscular dystrophy due to merosin deficiency
Congenital nystagmus
Familial spastic paraplegia
Krabbe disease (globoid cell leukodystrophy)
Metachromatic leukodystrophy
Pelizaeus-Merzbacher–like disease
Salla disease (sialic aciduria)
Sjögren-Larsson syndrome
SOX10 mutation syndrome
Spastic paraplegia type 1
X-linked ataxia, deafness, blindness, and mental retardation

Workup

Imaging Studies

MRI is the most useful imaging study and demonstrates symmetric and widespread abnormality of the white matter of cerebrum, brain stem, and cerebellum.

• White matter has increased signal intensity on T2-weighted and inversion recovery images (see Media files 1-2) and is hypointense on T1 images. These changes may not be readily evident or as confidently detected until after age 1 year because the newborn brain is not well myelinated at birth. The normal differentiation of white from gray matter is most easily observed after age 1 year, by which time myelination is normally actively proceeding. However, the brainstem and cerebellum are partially myelinated at birth, and the posterior limbs of the internal capsule, splenium, and genu are normally myelinated at age 3 months; therefore, absence of the normal myelin MRI signals in these areas should raise suspicion of Pelizaeus-Merzbacher disease (PMD) in an appropriate clinical setting.
• In addition to the diffuse increased T2 signal intensity, the absolute volume of white matter is often reduced, most severely in patients with connatal Pelizaeus-Merzbacher disease (see Media file 3). Patients with spastic paraplegia type 2 may have only patchy areas of increased T2 signal. Patients with the null mutation may have a more subtle increase in signal intensity relative to that seen in other patients with Pelizaeus-Merzbacher disease, and the volume of white matter may be normal (see Media file 4).

Other Tests

• Auditory evoked potential testing shows normal latency of wave 1, and possibly of wave 2 as well, but with prolongation or abolition of central waves 3-5. Caution should be used when interpreting this test because functional hearing is often present, even in the absence of undetectable evoked responses.
• Visual evoked potential testing reveals increased latency of P100.
• Somatosensory evoked potential testing reveals normal peripheral latencies with prolonged or absent central latencies.
• Evoked potentials of other leukodystrophies typically have delayed peripheral as well as central components.
• Nerve conduction test results are usually normal, but patients with null mutations (ie, those that prevent any PLP1 expression) have a mild, multifocal, demyelinating peripheral neuropathy. In contrast, other leukodystrophies, such as Krabbe disease, Cockayne disease, metachromatic leukodystrophy, and adrenoleukodystrophy, have diffusely slow nerve conduction velocities.
• Molecular diagnostic testing is the definitive method to diagnose Pelizaeus-Merzbacher disease, by detecting mutations of the PLP1 gene. Most patients (about 70%) have duplications (or rarely triplication or quintuplication) of the gene, which can usually be identified by fluorescent in situ hybridization (FISH) testing on interphase leukocytes. Other cells, such as buccal epithelia, chorionic villus cells, and amniocytes, can be tested as well. Duplications can also be identified by Southern blot and quantitative polymerase chain reaction (Q-PCR) testing. Chromosomal microarray analysis (CMA) or comparative genomic hybridization (CGH) testing also can identify duplications or other changes in dosage of the PLP1 gene. FISH testing of metaphase chromosomes can be helpful in identifying rare cases when the duplicated PLP1 gene is inserted in anomalous sites, such as distant loci of the X chromosome or the Y chromosome or autosomes.
  • About 15-20% of patients have small, typically single, nucleotide mutations that result in missense substitutions. Since FISH testing, CMA, and CGH testing do not identify these mutations, patients suspected of having Pelizaeus-Merzbacher disease who do not have PLP1 duplications should have PLP1 sequence analysis performed.
  • Mutations have been described that cause nonsense, frameshift, and splicing changes, in addition to complete gene duplications and deletions.
  • The remaining 5-10% of patients without duplication or other mutations may have mutations in PLP1 remote from those regions that are routinely examined in testing laboratories.
  • Locus heterogeneity (ie, additional genes that can also cause a Pelizaeus-Merzbacher disease–like syndrome) is also observed. Mutations that affect a gap junction protein, GJA12 (also known as connexin 46.6), cause a syndrome virtually identical to Pelizaeus-Merzbacher disease. Patients with this autosomal recessive syndrome have nystagmus, motor and cognitive impairment, and diffuse leukodystrophy on MRI scans. Peripheral neuropathy and seizures are more prevalent in this Pelizaeus-Merzbacher disease–like syndrome.
• Testing for lysosomal storage diseases (particularly for arylsulfatase A, galactosylceramide beta-galactosidase, and hexosaminidase), Salla disease (urine sialic acid), and adrenoleukodystrophy (very long chain fatty acids) should be done to exclude these diseases. Children with Canavan disease have elevated cerebral, serum, and urine N -acetyl aspartate (NAA) levels. If prominent peripheral as well as central dysmyelination is present along with facial features of Waardenburg-Hirschsprung syndrome, then screening for mutations of the SOX10 gene should be considered. Individuals with typical clinical history and signs of Pelizaeus-Merzbacher disease, but for whom results of routine mutation testing for PLP1 mutations is negative, should be referred to a research laboratory for possible research testing and additional mutation screening.
• Alexander disease has been reported to be caused by mutations of the glial fibrillary acidic protein (GFAP). Canavan disease is caused by mutations in the aspartoacylase gene and is characterized by elevations in the levels of NAA in the brain, urine, and blood. Magnetic resonance spectroscopy reveals elevation in the N -acetylaspartate resonance in patients with Salla disease or Canavan disease.

Histologic Findings

White matter areas classically show a tigroid or patchy pattern of staining with myelin stains, but individuals who are more severely affected may have uniform and total loss of myelin staining. Oligodendrocyte numbers are reduced in most patients, but patients with null or other relatively mild mutations have normal to near-normal oligodendrocyte numbers and are able to make normal amounts of myelin, although it stains poorly with conventional histochemical myelin stains, such as Luxol fast blue. Some patients have loss of axons, especially of the longer tracts. Patients with null mutations of PLP1 develop patchy demyelination of the peripheral nerves, typically at sites prone to compression, such as the elbow and wrist.

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