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At a glance

A very rare, slowly progressive dysmyelinating leukodystrophy affecting, in a diffuse pattern, the cerebrum, cerebellum, brain stem, and spinal cord. Clinical features also include stridor, muscle spasticity, and nystagmus. Often fatal in the first year of life from respiratory complications.

Synonyms

Perinatal Sudanophilic Leukodystrophy Acute Infantile Form; Connatal Pelizaeus-Merzbacher Syndrome; Seitelberger Type of Pelizaeus-Merzbacher Syndrome.

History

Described in 1908 by F. Pelizaeus, a German neurologist, and L. Merzbacher, a German psychiatrist.

Incidence

Estimated to be about 1:100,000 to 1:500,000. There are no reports of African descent published; however, African American cases do exist. Also present in Asia and Europe.

Genetic inheritance

X-linked recessive (infantile form) affects boys. Female heterozygotes can be clinically affected. Autosomal dominant (preadulthood form). Caused by a mutation of PLP1 (proteolipid protein 1) on Xq22.2. PLP1 encodes two products—PLP and a smaller protein DM20. Clinical severity is related to the type of PLP1 gene mutation (point mutation, duplication, or null mutation). Approximately 60 to 70% of cases result from duplication.

Pathophysiology

There is a loss of myelin with intact axons because of an anomaly in the gene for proteolipid protein located on chromosome Xq22.2; this makes oligodendrocytes unable to produce myelin. Severe Pelizaeus-Merzbacher disease is often fatal in the first year of life, typically from respiratory complications. Patients with classic Pelizaeus-Merzbacher disease may survive until the sixth decade. Patients affected with the Spastic Paraplegia Type II (SPG II) generally have a normal life span.

Diagnosis

Only men are affected. Diagnosis is based on the clinical constellation. CT scan and MRI are normal in the early stages, but may show ventricular enlargement. Evoked potentials are usually normal but may show delayed latencies.

Clinical aspects

Group of diseases characterized by progressive mental retardation and abnormal movements; there are three forms of clinical presentation.

  • Infantile Form (Fast Progression): Also called the connatal Pelizaeus-Merzbacher disease. During the first 2 weeks of life the infant presents with severe head shaking with nystagmus and roving eye movements. Poor airway tone with stridor and respiratory complications, severe hypotonia. Motor function is very severely limited. Choreoathetotic movements and spasticity. Developmental milestones are delayed. Acquired microcephaly. Optic atrophy and facial weakness develop later. Seizures are possible. Death usually occurs before 5 to 7 years of age.

  • Infantile Form (Slow Progression): The signs of the disease appear later and the evolution is slower. The nystagmus is weaker but stridor, dystonia, and pyramidal signs are present. Seizures and cerebellar ataxia are possible. Dysarthria and difficult swallowing develop later. Acquired microcephaly. These children never walk and are unable to sit without support. Death usually occurs in the second to third decade.

  • Preadulthood Form: Nystagmus may not be ...

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