SPG2 mimicking multiple sclerosis in a family identified using next generation sequencing.

Several single gene disorders can potentially be overlooked in the differential diagnostic evaluation of patients with multiple sclerosis (MS). Pelizaeus-Merzbacher disease and spastic paraplegia type 2 are allelic X-linked disorders associated with defective myelination of the central nervous system and mutations in PLP1. Neurological symptoms are occasionally observed in female carriers of these mutations. Two women - the proposita (Pt1) and her mother (Pt2) - reported walking difficulties since adolescence and showed progressive cognitive decline. Their neurological examinations revealed spastic gait, pyramidal tract involvement and distal muscle atrophy in the legs. Peripheral neuropathy and diffuse white matter (WM) changes on brain MRI were also observed. Both patients had a preliminary diagnosis of primary progressive MS. Using a targeted method in next generation sequencing, the novel heterozygous c.210T>G/p.Y70* in PLP1 was identified in Pt2. The same mutation was also found in Pt1 but not in five healthy relatives. The mutation showed moderate-to-severe skewed X inactivation in tissues, and Western blotting revealed a significant reduction of PLP1 and DM20 in the sural nerve of Pt2. In conclusion a mother and daughter presented an X-linked dominant disorder with skewed X inactivation. The authors suggest that PLP1 testing might be considered in the evaluation of women with spastic paraparesis, cognitive decline and WM changes.