Pelizaeus-Merzbacher disease

Pelizaeus-Merzbacher disease (PMD) is a rare central nervous system disorder in which coordination, motor abilities, and intellectual function are delayed to variable extents.

Overview
The disease is one of a group of genetic disorders called the leukodystrophies that affect growth of the myelin sheath, the fatty covering--which acts as an insulator--on nerve fibers in the brain. It is caused by a usually recessive mutation of the gene on the long arm of the X-chromosome that codes for a myelin protein called proteolipid protein 1 or PLP1. There are several forms of Pelizaeus-Merzbacher disease including classic, connatal, transitional, adult variants. Milder mutations of the PLP1 gene that mainly cause leg weakness and spasticity, with little or no cerebral involvement, are classified as spastic paraplegia 2 (SPG2).

The onset of Pelizaeus-Merzbacher disease is usually in early infancy. The most characteristic early signs are nystagmus (rapid, involuntary, rhythmic motion of the eyes) and hypotonia (low muscle tone). Motor abilities are delayed or never acquired, mostly depending upon the severity of the mutation. Most children with PMD learn to understand language, and usually have some speech. Other signs may include tremor, incoordination, involuntary movements, weakness, unsteady gait, and over time, legs and arms may become spastic.

Muscle contractures (shrinkage or shortening of a muscle) often occur over time. Mental functions may deteriorate. Some patients may have convulsions and skeletal deformation, such as scoliosis, resulting from abnormal muscular stress on bones.

Diagnosis
The diagnosis of PMD is often first suggested after identification by magnetic resonance imaging (MRI) of abnormal white matter (lumpy too) throughout the brain, which is typically evident by about 1 year of age, but more subtle abnormalities should be evident during infancy. Unless there is a family history consistent with sex-linked inheritance, the condition is often misdiagnosed as cerebral palsy. The most common mutations, accounting for 50 to 70% of PMD cases, that cause PMD are complete duplications of the region of the X chromosome containing the PLP1 gene. Small mutations within the PLP1 gene itself account for about 20% of cases. Some of the remaining cases are accounted for by mutations in the gap junction A12 (GJA12) gene, and are now called Pelizaeus-Merzbacher-like disease (PMLD). Other cases of apparent PMD do not have mutations in either the PLP1 or GJA12 genes, and are presumed to be caused either by mutations in other genes, or by mutations not detected by sequencing the PLP1 gene exons and neighboring intronic regions of the gene. Once a PLP1 or GJA12 mutation is identified, prenatal diagnosis or preimplantation genetic diagnostic testing is possible.

Treatment
There is no cure for PMD, nor is there a standard course of treatment. Treatment, which is symptomatic and supportive, may include medication for seizures and spasticity. Regular evaluations by physical medicine and rehabilitation, orthopedic, developmental and neurologic specialists should be made to ensure optimal therapy and educational resources. The prognosis for those with Pelizaeus-Merzbacher disease is highly variable, with children with the most severe form (so-called connatal) usually not surviving to adolescence, but survival into the sixth or even seventh decades is possible, especially with attentive care. Genetic counseling should be provided to the family of a child with PMD.