eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases

Pelizaeus-Merzbacher Disease

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

Introduction

Background

Although Pelizaeus-Merzbacher disease (PMD) and X-linked spastic paraplegia type 2 (SPG2) are nosologically distinguished, they are at opposite ends of a clinical spectrum of X-linked diseases caused by mutations of the same gene, the proteolipid protein 1 (PLP1) gene, and result in defective CNS myelination. Clinical signs usually include some combination of nystagmus, stridor, spastic quadriparesis, hypotonia, cognitive impairment, ataxia, tremor, and diffuse leukoencephalopathy on MRI. Seizures and perinatal stridor are rare signs and are typically seen only in the most severe cases.

Severe clinical syndromes (sometimes referred to as the connatal form) are typically caused by missense and other small mutations that affect critical positions in PLP1, whereas the milder spastic paraplegia syndrome is caused by mutations that presumably affect less critical regions of the protein. The most common mutations that cause Pelizaeus-Merzbacher disease are duplications of a region of the X chromosome that includes the entire PLP1 gene.

Pathophysiology

In most cases, Pelizaeus-Merzbacher diseaseis caused by mutations of PLP1 on the X chromosome. Of note, the gene was previously termed PLP but is now designated as PLP1. PLP1 encodes 2 major products, PLP1 and a smaller protein, DM20, that results from alternative splicing. These proteins constitute about 50% of the mass of CNS white matter and are believed to serve an important structural function in compact myelin.

Approximately 60-70% of cases of Pelizaeus-Merzbacher disease result from duplications of the region of the X chromosome that contains PLP1. Extent and breakpoints of duplications vary among different families. Inclusion of other genes in the duplicated region, or inclusion of aberrations of genes at the duplication endpoints, may potentially affect the phenotype. Most individuals with PLP1 duplications present with classic Pelizaeus-Merzbacher disease, typified by nystagmus that begins in the first year of life, delayed motor and cognitive milestones, and ataxia. Most of these patients acquire some language function, which can be quite good (although slow). Recently, some patients with Pelizaeus-Merzbacher disease have been found to have 3 or more copies of the PLP1 gene.¹ These individuals have a more severe phenotype than most individuals with duplications.

Transgenic mice that have extra copies of PLP1 develop a syndrome that effectively models the PLP1 duplication form of Pelizaeus-Merzbacher disease; this provides strong experimental support for the hypothesis that overexpression of PLP1 is deleterious to oligodendrocytes.^2,3 Approximately 15-20% of mutations in Pelizaeus-Merzbacher disease are point mutations or other small mutations that result in base substitutions, insertions, or deletions. Base substitutions usually result in missense mutations, but nonsense mutations (ie, substitution of an amino acid codon by a stop codon) and splicing mutations also occur. Splicing mutations are now recognized as quite common and may account for almost 20% of point mutations in the PLP1 gene.

The most severe form of Pelizaeus-Merzbacher disease, the so-called connatal form, usually results from missense substitutions. These severe mutations are believed to result in misfolding of the newly synthesized protein, which then accumulates in the endoplasmic reticulum and triggers apoptosis, or programmed cell death. Thus, oligodendrocyte numbers are severely reduced, and little (if any) myelin is made.

Mutations that prevent any PLP1 from being made result in a syndrome (PLP1 null syndrome) that is usually more mild than classic Pelizaeus-Merzbacher disease; however, these mutations appear to cause a demyelinating peripheral neuropathy. Moreover, these null mutations do not result in oligodendrocyte cell death. Interestingly, mice that have been genetically engineered to prevent PLP1 expression develop a similar pathologic syndrome characterized by severe late-onset axonal degeneration. Mutations that result in spastic paraplegia type 2 are generally missense mutations that do not prevent processing of DM20, although they may interfere with the processing of PLP itself. These mutations do not appear to cause oligodendrocyte cell death.

Because females are mosaic with respect to X chromosome gene expression due to X inactivation, heterozygous females begin life with roughly equal proportions of oligodendrocytes that use the normal or mutated X chromosome. Females heterozygous for severe mutations are neurologically normal as adults, probably because the defective oligodendrocytes die as described above, and are replaced by healthy ones. These females may have transient neurologic abnormalities during childhood. However, females heterozygous for mutations that do not result in oligodendrocyte apoptosis (programmed cell death) continue to have oligodendrocytes that use the defective PLP1 and, therefore, are more likely to have detectable neurologic signs.

Frequency

United States

Frequency is not known with certainty, but the estimated prevalence is at least 1 case per 500,000 population; however, this is a conservative estimate.

International

Frequency is estimated to be 1 case per 100,000-1,000,000 population.

Mortality/Morbidity

• Severe Pelizaeus-Merzbacher disease is often fatal during the first decade of life, typically due to respiratory complications.
• Patients with classic Pelizaeus-Merzbacher disease (such as that caused by PLP1 gene duplications) may survive into the sixth decade of life.
• Patients with spastic paraplegia type 2 generally have a normal life span.

Race

Pelizaeus-Merzbacher disease and spastic paraplegia type 2 are global syndromes and affect all major ethnic groups.

• So far, no case reports of patients of African descent have been published; however, the author is aware of African Americans with Pelizaeus-Merzbacher disease.
• Pelizaeus-Merzbacher disease has been reported in people of Asian, Middle Eastern, and European descent.

Sex

• Pelizaeus-Merzbacher disease typically affects males, but female heterozygotes can be clinically affected, especially those who carry alleles that are relatively mild in males. In heterozygous females with alleles that are severe in males, the defective oligodendrocytes die and are replaced by healthy oligodendrocytes, and neurologic function is maintained or improves with maturation. Females heterozygous for the less severe alleles of PLP1 that are not believed to cause oligodendrocyte cell death or apoptosis may develop a more progressive and nonremitting syndrome that usually begins during adulthood.
• Some females with Pelizaeus-Merzbacher disease (such as the original Pelizaeus-Merzbacher disease family) probably have a clinical course much like that of affected males, in which the symptoms do not remit and may be the result of skewed X inactivation (ie, most oligodendrocytes have inactivated the normal X chromosome, and insufficient healthy oligodendrocytes are available to effectively myelinate the CNS.)

Age

• Pelizaeus-Merzbacher disease typically begins during infancy, but milder syndromes may not be recognized until early childhood. Although most heterozygous (ie, carrier) females are asymptomatic, young girls in families with severe-to-classic Pelizaeus-Merzbacher disease have reportedly developed classic Pelizaeus-Merzbacher disease that regresses as the child matures, followed by completely normal neurologic health. This transient phase most likely reflects the defective myelination brought about by those oligodendrocytes that have inactivated the normal X chromosome. As these defective oligodendrocytes die and are replaced by healthy oligodendrocytes, neurologic function improves.
• Females heterozygous for the less severe alleles of PLP1 that are not believed to cause oligodendrocyte cell death or apoptosis may develop a more progressive and nonremitting syndrome that usually begins during adulthood. See Sex.

Clinical

History

The clinical severity of Pelizaeus-Merzbacher disease (PMD) widely varies, primarily depending on the precise nature of the causative mutation and, probably to a certain extent, on other genetic and environmental influences.

• The presentation of classic Pelizaeus-Merzbacher disease involves infantile-onset (typically within the first 2 months of life) nystagmus, titubation, and weakness, followed by development of ataxia, cognitive delay, and spasticity. Most patients never ambulate. Most do acquire some degree of language skills, which may approach normal levels, but the speed of language output is usually slow and may suggest a more severe degree of mental retardation than is present. These patients may survive to the sixth decade of life or longer.
• Patients who are more severely affected (ie, those with so-called connatal Pelizaeus-Merzbacher disease) have nystagmus present beginning within the first week or two of life, often have stridor and respiratory difficulty and hypotonia, and may even have seizures. These patients typically have limited language skills, never ambulate, and develop severe spasticity with little voluntary movement. These individuals usually die before the third decade of life.
• Individuals with the least severe form of Pelizaeus-Merzbacher disease, which overlaps with spastic paraplegia type 2, present with childhood-onset spastic paraplegia, mild cognitive impairment, ataxia, and athetosis. Survival to the sixth decade of life or later is characteristic. Typically, neurologic signs progress but at a gradual rate with reported periods of relative stability. Generally, those who learn to walk begin to lose ambulatory abilities during adolescence; however, in some cases, this can be delayed until adulthood.

Physical

Physical signs depend on the age of the patient, severity of mutation, and probably on modifier genes and perhaps environmental factors.

• Infants with connatal Pelizaeus-Merzbacher disease invariably have nystagmus within the first week or two of life and typically have stridor and hypotonia. The latter may be severe enough to suggest spinal muscular atrophy. As these children age, limb spasticity usually replaces the hypotonia, but the child has poor head control and does not learn to sit unsupported, much less walk. Seizures can occur in this severe form. Growth is poor; developmental milestones are significantly delayed or never achieved. Patients may comprehend spoken words, but verbal output is typically limited or absent. Motor function is severely limited.
• Children with the classic form of Pelizaeus-Merzbacher disease generally have nystagmus present in the first few weeks of life or at least in the first year of life. Early hypotonia is succeeded by limb spasticity, which is worse in the legs than arms. Ataxia of truncal and limb movements is prominent; dystonic posturing and movements can occur as well. Occasionally, a child can walk, although movement is impaired by weakness and spasticity. Walking ability is usually lost by adolescence or earlier. Language ability can be mildly to moderately impaired, and some cognitive delay is usual. Diffuse hyperreflexia and Babinski signs are seen.
• Those with milder mutations may not ever have nystagmus; they have delayed sitting and walking but usually learn to walk. They have limb spasticity, which is worse in the legs, and ataxia that affects speech as well as limb movements. Patients are hyperreflexic and have Babinski signs.
• Patients with PLP1 null mutations can have mild distal sensory loss and relative hyporeflexia in addition to spastic paraparesis, but they have Babinski signs. These individuals have mild-to-moderate cognitive impairment.
• Clinical signs and symptoms include the following:
  • Usually, nystagmus is of a pendular nature; it can often have horizontal and rotatory components. Over 95% patients have nystagmus. This sign may disappear later during childhood. The patient's age at onset of nystagmus alone does not predict clinical severity.
  • Ataxia is evident once voluntary movements are acquired and occurs in virtually all patients.
  • Spasticity develops in most patients (>90%) but may not be apparent until the second year of life or even later. Hyperreflexia and Babinski signs are present. Most patients who are severely affected have neonatal hypotonia that may mimic spinal muscular atrophy.
  • Titubation is an early characteristic sign. Frequency of head bobbing is typically synchronous with or follows eye movements.
  • Seizures and stridor are reported only in patients who are most severely affected, who tend to have missense or frameshift mutations of the PLP1 gene.

Causes

• Pelizaeus-Merzbacher disease is caused by mutations of the PLP1 gene located on the long arm of the X chromosome (Xq22). The most common mutation, duplication of the PLP1 gene, has been proposed to be caused by defective DNA replication. See the discussion in Pathophysiology of mutation types and molecular mechanisms believed to be important in the disease.
• Other gene defects can also cause a Pelizaeus-Merzbacher disease–like syndrome, in particular mutations that affect the GJA12 gene on chromosome 1. SOX10 mutations cause both 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.
• Other diagnostic considerations include the following:
  • Lazzarini has described a Pelizaeus-Merzbacher disease–like disease;⁴ unfortunately, MRI data have not been obtained on members of this single family whose disorder is linked to Xq28.
  • Other leukodystrophies, such as metachromatic leukodystrophy, adrenoleukodystrophy, Krabbe disease, Cockayne disease, and Canavan disease, do not typically cause nystagmus, and MRI scans in these diseases usually reveal a regional predilection of abnormality (eg, occipital white matter in adrenoleukodystrophy, frontal white matter in metachromatic leukodystrophy). Peripheral nerve conduction test results and evoked potentials test results are usually abnormal.
  • Infants with merosin deficiency have 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 the MRI does not reveal a pattern of leukodystrophy. Mutations in the PLP1 coding regions have been excluded for 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 the 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.

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