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 the 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 beyond.
Patients who are more severely affected (ie, those with connatal Pelizaeus-Merzbacher disease) have nystagmus present beginning within the first week or 2 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, persons with this form of Pelizaeus-Merzbacher disease who learn to walk begin to lose ambulatory abilities during adolescence; in some cases, however, loss of ambulation can be delayed until adulthood.
Physical Examination
The physical signs of Pelizaeus-Merzbacher disease depend on the age of the patient, the severity of the mutation, and, probably, on modifier genes, as well as, perhaps, on environmental factors.
Infants with connatal Pelizaeus-Merzbacher disease invariably have nystagmus within the first week or 2 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 in the 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.
Patients 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 and impacts 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. Numata et al conducted a nationwide epidemiological survey in Japan. PLP1 gene abnormalities were observed in 62%. Patients with PLP1 mutations showed a higher proportion of nystagmus and hypotonia, both of which tend to disappear over time. [11]
Clinical signs and symptoms are as follows:
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Usually, nystagmus is of a pendular nature; it can often have horizontal and rotatory components
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Over 95% patients have nystagmus; this sign may disappear later during childhood
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The patient's age at onset of nystagmus alone does not predict clinical severity
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Ataxia is evident once voluntary movements are acquired and occurs in virtually all patients
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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
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Most patients who are severely affected have neonatal hypotonia that may mimic spinal muscular atrophy
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Titubation is an early characteristic sign; frequency of head bobbing is typically synchronous with or follows eye movements
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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
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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.
