The nosology of the inborn errors of myelin metabolism has been stymied by the lack of molecular genetic analysis. Historically,
Pelizaeus-Merzbacher disease has encompassed a host of
neurologic disorders that present with a deficit of myelin, the membrane elaborated by glial cells that encircles and successively enwraps axons. We describe here a Pelizaeus-Merzbacher pedigree of the classical type, with X-linked inheritance, a typical
clinical progression, and a pathologic loss of myelinating cells and myelin in the central nervous system. To discriminate variants of
Pelizaeus-Merzbacher disease, a set of
oligonucleotide primers was constructed to polymerase-chain-reaction (PCR) amplify and sequence the gene encoding proteolipid
protein (PLP), a structural
protein that comprises half of the
protein of the myelin sheath. The PLP gene in one of two affected males and the carrier mother of this family exhibited a single base difference in the more than 2 kb of the PLP gene sequenced, a C----T transition that would create a
serine substitution for
proline at the carboxy end of the
protein. Our results delineate the clinical features of
Pelizaeus-Merzbacher disease, define the possible molecular pathology of this dysmyelinating disorder, and address the molecular classification of inborn errors of myelin metabolism. Patients with the classical form (type I) and the more severely affected, connatal variant of
Pelizaeus-Merzbacher disease (type II) would be predicted to display mutation at the PLP locus. The other variants (types III-VI), which have sometimes been categorized as
Pelizaeus-Merzbacher disease, may represent mutations in genes encoding other structural
myelin proteins or
proteins critical to myelination.