Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2 (SPG2) are X-linked developmental defects of myelin formation affecting the central nervous system (CNS). They differ clinically in the onset and severity of the motor disability but both are allelic to the proteolipid protein gene (PLP), which encodes the principal protein components of CNS myelin, PLP and its spliced isoform, DM20. We investigated 52 PMD and 28 SPG families without large PLP duplications or deletions by genomic PCR amplification and sequencing of the PLP gene. We identified 29 and 4 abnormalities respectively. Patients with PLP mutations presented a large range of disease severity, with a continuum between severe forms of PMD, without motor development, to pure forms of SPG. Clinical severity was found to be correlated with the nature of the mutation, suggesting a distinct strategy for detection of PLP point mutations between severe PMD, mild PMD and SPG. Single amino-acid changes in highly conserved regions of the DM20 protein caused the most severe forms of PMD. Substitutions of less conserved amino acids, truncations, absence of the protein and PLP-specific mutations caused the milder forms of PMD and SPG. Therefore, the interactions and stability of the mutated proteins has a major effect on the severity of PLP-related diseases.

Pelizaeus-Merzbacher Disease (PMD) is an X-linked developmental defect of myelination affecting the central nervous system and segregating with the proteolipoprotein (PLP) locus. Investigating 82 strictly selected sporadic cases of PMD, we found PLP mutations in 77%; complete PLP-gene duplications were the most frequent abnormality (62%), whereas point mutations in coding or splice-site regions of the gene were involved less frequently (38%). We analyzed the maternal status of 56 cases to determine the origin of both types of PLP mutation, since this is relevant to genetic counseling. In the 22 point mutations, 68% of mothers were heterozygous for the mutation, a value identical to the two-thirds of carrier mothers that would be expected if there were an equal mutation rate in male and female germ cells. In sharp contrast, among the 34 duplicated cases, 91% of mothers were carriers, a value significantly (chi2=9. 20, P<.01) in favor of a male bias, with an estimation of the male/female mutation frequency (k) of 9.3. Moreover, we observed the occurrence of de novo mutations between parental and grandparental generations in 17 three-generation families, which allowed a direct estimation of the k value (k=11). Again, a significant male mutation imbalance was observed only for the duplications. The mechanism responsible for this strong male bias in the duplications may involve an unequal sister chromatid exchange, since two deletion events, responsible for mild clinical manifestations, have been reported in PLP-related diseases.

Pelizaeus-Merzbacher Disease is an X-linked hypomyelinatiing leukodystrophy. We report mutations in the thyroid hormone transporter gene MCT8 in 11% of 53 families affected by hypomyelinating leukodystrophies of unknown aetiology. The 12 MCT8 mutated patients express initially a Pelizaeus-Merzbacher-Like disease phenotype with a latter unusual improvement of magnetic resonance imaging white matter signal despite absence of clinical progression. This observation underlines the interest of determining both free T3 and free T4 serum concentrations to screen for MCT8 mutations in young patients (<3 y) with a severe Pelizaeus-Merzbacher-Like disease presentation or older severe mentally retarded male patients with "hypomyelinated" regions.

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