Duplication of the proteolipid protein gene is the major cause of Pelizaeus‐Merzbacher disease

BACKGROUND/OBJECTIVE: Pelizaeus-Merzbacher disease (PMD), an X-linked recessive dysmyelination disorder, is caused by mutations in the proteolipid protein (PLP) gene. However, missense mutations were only found in a fraction of PMD patients, even in families that showed linkage with the PLP locus on Xq22. Here we describe the use of an extended protocol that includes screening for both missense mutations and duplications. METHOD: Two groups of patients were analyzed, one group with 10 independent PMD families and one group with 24 sporadic patients suspected of PMD. Missense mutations in the PLP gene were identified by sequencing. PLP gene duplications were detected by quantitative polymerase chain reaction and/or Southern blot analysis. RESULTS: Sequencing of the PLP gene revealed four mutations in group 1 and one mutation in group 2. However, inclusion of duplication analysis in the screening protocol raised the amount of mutations found in group 1 from 40 to 90%, and in group 2 from 4 to 25%. CONCLUSIONS: These results demonstrate that duplications of the PLP gene are the major cause of PMD. Furthermore, it appears that the phenotype resulting from PLP duplications is relatively mild, and that many probands are nontypical PMD patients.