New variant in PLP1 gene associated with X-linked spastic paraplegia type 2: First report of a family in Colombia

Hereditary spastic paraplegias are genetic disorders characterized by spasticity in the lower limbs, weakness, and sensory disturbances. Global prevalence ranges from 1.27 to 9.6 per 100 000 individuals. Mutations in the PLP1 gene cause various X-linked hereditary spastic paraplegias phenotypes, including Pelizaeus-Merzbacher disease and spastic paraplegia type 2. A 53-year-old male presented with chronic lower limb weakness since childhood, requiring a wheelchair at age 47 and exhibiting zero strength in the lower limbs. Magnetic resonance imaging revealed periventricular leukodystrophy; similar symptoms were found in maternal uncles and a nephew. The 32-year-old nephew had gait difficulties. A genetic sequencing panel identified a hemizygous variant of uncertain significance in the PLP1 gene [c.197A>T (p.His66Leu)] in both, not reported in population genetic databases. X-linked spastic paraplegia 2 is a disease primarily affecting gait and causing lower limb weakness. Reports indicate that it may also include cognitive impairment, nystagmus, and ataxia, although in the studied family, weakness predominated without cerebellar symptoms. Thirty-six families with this condition have been documented worldwide, with cases of asymptomatic carrier females. The c.197A>T (p.His66Leu) variant in the PLP1 gene, identified in this case, is novel and, despite being classified as "of uncertain significance", could be pathogenic according to bioinformatic predictors, explaining the spastic paraplegia 2 presentation in this family.