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Learning how an abnormality of a single gene produces dysfunction of the nervous system is a major challenge for clinicians. A wide range of phenotypes can arise from different mutations in a single gene. Indeed, clinical presentations of some neurogenetic disorders are so diverse as to defy reason. Point mutations in the gene encoding hexosaminidase A cause typical Tay–Sachs disease. It seems astounding that other mutations in this gene result in the phenotype of amyotrophic lateral sclerosis or spinal muscular atrophy.
The neurologic disorders caused by mutations in genes encoding structural proteins, such as those in myelin, have similar phenotypic diversity. In Tay–Sachs and other catalytic protein diseases, disease expression is generally due to deficient enzyme activity. In contrast, inherited disorders involving myelin proteins appear to reflect a variety of pathogenetic mechanisms.
Pelizaeus–Merzbacher disease (PMD) is a prime example. PMD (OMIM #312080) is an X-linked recessive disorder caused by mutations in the proteolipid protein (PLP) gene (PLP) located at Xq221 resulting in abnormal expression or production …
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