Pelizaeus–Merzbacher disease is an X-linked neurological disorder that damages oligodendrocytes in the central nervous system. It is caused by mutations in a major myelin protein, it is characterized by hypomyelination and belongs to a group of genetic diseases referred to as leukodystrophies. Hallmark signs and symptoms of Pelizaeus–Merzbacher disease include little or no movement in the arms or legs, respiratory difficulties, characteristic horizontal movements of the eyes left to right; the onset of Pelizaeus–Merzbacher disease is in early infancy. The most characteristic early signs are low muscle tone. Motor abilities are delayed or never acquired depending upon the severity of the mutation. Most children with Pelizaeus–Merzbacher disease learn to understand language, have some speech. Other signs may include tremor, lack of coordination, involuntary movements, unsteady gait, over time, spasticity in legs and arms. Muscle contractures 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.
Pelizaeus–Merzbacher disease is caused by X-linked recessive mutations in the major myelin protein proteolipid protein 1. This causes hypomyelination in severe neurological disease; the majority of mutations result in duplications of the entire PLP1 gene. Deletions of PLP1 locus cause a milder form of Pelizaeus–Merzbacher disease than is observed with the typical duplication mutations, which demonstrates the critical importance of gene dosage at this locus for normal CNS function; the diagnosis of Pelizaeus–Merzbacher disease is first suggested after identification by magnetic resonance imaging of abnormal white matter throughout the brain, evident by about 1 year of age, but more subtle abnormalities should be evident during infancy. Unless a family history consistent with sex-linked inheritance exists, the condition is misdiagnosed as cerebral palsy. Once a PLP1 mutation is identified, prenatal diagnosis or preimplantation genetic diagnostic testing is possible; the disease is one in a group of genetic disorders collectively known as leukodystrophies that affect growth of the myelin sheath, the fatty covering—which acts as an insulator—on nerve fibers in the central nervous system.
The several forms of Pelizaeus–Merzbacher disease include classic, connatal and adult variants. Milder mutations of the PLP1 gene that cause leg weakness and spasticity, with little or no cerebral involvement, are classified as spastic paraplegia 2. No cure or standard treatment for Pelizaeus–Merzbacher disease has been developed. Outcomes are variable: people with the most severe form of the disease do not survive to adolescence, although with milder forms, survival into adulthood is possible. In December 2008, StemCells, Inc received clearance in the United States to conduct a phase I clinical trials of human neural stem cell transplantation; the trial did not show meaningful efficacy and the company has since gone bankrupt. In 2019 Paul Tesar used CRISPR and antisense therapy in a mouse model of Pelizaeus–Merzbacher with success. Iron chelation as a potential treatment is being studied; the Myelin Project The Stennis Foundation Uhlenberg, Birgit. "Mutations in the Gene Encoding Gap Junction Protein α12 Cause Pelizaeus-Merzbacher–Like Disease".
The American Journal of Human Genetics. 75: 251–260. Doi:10.1086/422763. PMC 1216059. PMID 15192806. Pelizaeus-Merzbacher Disease. NINDS/National Health Institutes. Pmd at NIH/UW GeneTests PMD Foundation
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