Mutations in MTHFR and POLG impaired activity of the mitochondrial respiratory chain in 46-year-old twins with spastic paraparesis

Hereditary spastic paraplegias(HSPs) are characterized by lower extremity spasticityand weakness. HSP is often caused by mutations in SPG genes, but it may also be produced by inborn errorsof metabolism. We performed next-generation sequencing of 4813 genes in one adult twin pair with HSP and severe muscular weaknessoccurring at the same age. We found two pathogenic compound heterozygous variants in MTHFR, including a variant not referenced in international databases, c.197C>T (p.Pro66Leu) and a known variant, c.470G>A (p.Arg157Gln), and two heterozygous pathogenic variants in POLG, c.1760C>T (p.Pro587Leu) and c.752C>T (p.Thr251Ile). MTHFR and POLG mutations were consistent with the severe muscle weaknessand the metabolic changes, including hyperhomocysteinemiaand decreased activity of both N(5,10) methylenetetrahydrofolate reductase(MTHFR) and complexes I and II of the mitochondrial respiratory chain. These data suggest the potential role of MTHFR and POLG mutations through consequences on mitochondrial dysfunction in the occurrence of spasticparaparesis phenotype with combined metabolic, muscular, and neurological components.