Pelizaeus-Merzbacher disease (PMD) and X-linked spastic paraplegia (SPG2) are X-linked leukodystrophies, or diseases that affect the white matter of the brain and spinal cord. Although the relationship between the conditions is not completely settled, we believe that both, as well as intermediate forms, are parts of a spectrum of disorders caused by mutations in the proteolipid protein gene (PLP). Our experience and our reading of the literature leads us to believe that when the disorder is severe, it will be called PMD, whereas the mildest form may be designated SPG2. So far, most of the molecular biological experience has been with PMD, but that is changing rapidly. SPG2 may show little more than weakness and spasticity in the legs. Onset of PMD is usually within weeks or a month or two of birth; the more severe forms appear earlier. Signs of the disease often include a rather characteristic form of nystagmus (rotary), small head size, hypotonia, ataxia, dystonia, spasticity, especially of the lower limbs, and later, contractures. Mental development may appear to be slow. Most of the patients are males (the rare female patient may be affected more mildly and may show later onset). The diagnosis is made after examination of the family history, physical examination of an affected individual, MRI (magnetic resonance imaging) of the brain and BSAER (brain stem auditory evoked response). In many families, a duplication of the proteolipid protein gene is found. In another ~10-15%, instead of duplication, a mutation is found in one copy of the proteolipid protein gene. Perhaps 40-50% of patients with a clinically good diagnosis will not have duplication or other mutation discernible with present techniques. Work is underway on correlation of the clinical picture with the type of duplication/mutation discovered in the laboratory.
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Pelizaeus-Merzbacher disease (PMD) and X-linked spastic paraplegia (SPG2) are X-linked leukodystrophies, or diseases that affect the white matter of the brain and spinal cord. Although the relationship between the conditions is not completely settled, we believe that both, as well as intermediate forms, are parts of a spectrum of disorders caused by mutations in the proteolipid protein gene (PLP). Our experience and our reading of the literature leads us to believe that when the disorder is severe, it will be called PMD, whereas the mildest form may be designated SPG2. So far, most of the molecular biological experience has been with PMD, but that is changing rapidly. SPG2 may show little more than weakness and spasticity in the legs. Onset of PMD is usually within weeks or a month or two of birth; the more severe forms appear earlier. Signs of the disease often include a rather characteristic form of nystagmus (rotary), small head size, hypotonia, ataxia, dystonia, spasticity, especially of the lower limbs, and later, contractures. Mental development may appear to be slow. Most of the patients are males (the rare female patient may be affected more mildly and may show later onset). The diagnosis is made after examination of the family history, physical examination of an affected individual, MRI (magnetic resonance imaging) of the brain and BSAER (brain stem auditory evoked response). In many families, a duplication of the proteolipid protein gene is found. In another ~10-15%, instead of duplication, a mutation is found in one copy of the proteolipid protein gene. Perhaps 40-50% of patients with a clinically good diagnosis will not have duplication or other mutation discernible with present techniques. Work is underway on correlation of the clinical picture with the type of duplication/mutation discovered in the laboratory.
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I am Director of Medical Diagnostic Services, the molecular diagnostic laboratory of the Department of Medical and Molecular Genetics.
Developmental Neurobiology, Gene Duplication, Gene Expression, Gene Mutation, Genetic Mapping, Genetic Marker, Genetic Transcription, Linkage Mapping, Molecular Genetics, Mutant, Neuron, Northern Blotting, Nucleic Acid Hybridization, Nucleic Acid Sequence, Pelizaeus-Merzbacher Disease, Polymerase Chain Reaction, Southern Blotting, X-linked Recessive, X-linked Spastic Paraplegia
