Novel exon 3B proteolipid protein gene mutation causing late-onset spastic paraplegia type 2 with variable penetrance in female family members.

Spastic paraplegia type 2 (SPG2) is allelic to Pelizaeus-Merzbacher disease (PMD), with both conditions resulting from mutations in the proteolipid protein gene (PLP). We report an SPG2 family in which 3 male members and a heterozygous female member were affected with spastic paraplegia characterized by relatively late onset and mild clinical manifestations. A unique H147Y mutation in exon 3B of the PLP altering the proteolipid protein (PLP) but not the alternatively spliced DM20 isoform was identified as the cause of this distinct disease phenotype. Cellular pathology studies of SPG2 mutations offer an explanation for the paradoxical finding that mutations associated with the mildest phenotype in male family members also affect female carriers.

Autosomal dominant distal spinal muscular atrophy type V (dSMA-V) and Charcot-Marie-Tooth disease type 2D (CMT2D) segregate within a single large kindred and map to a refined region on chromosome 7p15.

Two separate disorders, autosomal dominant distal spinal muscular atrophy type V (dSMA-V) characterized by marked bilateral weakness in the hands and atrophy of thenar eminence and the first interosseous muscle, and Charcot-Marie-Tooth disease type 2D (CMT2D) characterized by sensory deficits in addition to the upper limb weakness and wasting, have been independently linked to chromosome 7p. We identified a multigenerational Mongolian kindred with 17 members affected with either dSMA-V or CMT2D and mapped both syndromes to the same region on chromosome 7p15. A maximum two-point lod score of 4.74 at recombination fraction zero was obtained with marker D7S474. Tight linkage without recombination was also detected with markers D7S526 and D7S632. A multipoint lod score of 6.07 suggested that the gene is located between markers D7S526 and D7S474. A single conserved haplotype was associated with dSMA-V and CMT2D. Based on informative recombination events, the disease locus was placed between markers D7S516 and D7S1514 within the 7p15 band. Data obtained from this study suggest that a single gene is responsible for both syndromes, dSMA-V and CMT2D, and extend our knowledge of the candidate region.