<i>MT-ATP6</i> variant as a cause of adult-onset hereditary spastic paraparesis: A case report and literature review

BackgroundHereditary spastic paraplegia (HSP) is a heterogenous group of rare genetic disorders characterized by progressive corticospinal and dorsal spinal cord axonal degeneration manifesting as muscle weakness and spasticity of the lower extremities. Over 98% of solved HSP cases are caused by pathogenic variants in the nuclear DNA.CaseWe report a family carrying the m.9035T > C [p.(Leu170Pro)] pathogenic variant in the mitochondrial <i>MT</i>-<i>ATP6</i> gene in the setting of maternally inherited, late-onset HSP. The proband (age 67 years) presented with classical, late-onset, pure HSP. Her affected daughter (age 39 years) developed late-onset, complex HSP, with asymmetrical axonal sensorimotor polyneuropathy. Her second daughter (age 46 years) carried the same pathogenic variant with high heteroplasmy but was clinically unaffected at last assessment, suggesting age-dependent or incomplete penetrance.Summary of literatureThe substitution of a leucine for a proline affects a highly conserved transmembrane helix of the subunit "a" at a key functional domain in the mitochondrial ATP synthase complex. The m.9035T > C variant has been reported in several families presenting with common phenotypic presentations of ATP6-related disorders such as maternally inherited Leigh syndrome (MILS) and the syndrome of neuropathy, ataxia, and retinitis pigmentosa (NARP). HSP is a rare presentation in ATP6-related disorders; mitochondrial ATP6-induced HSP has previously been published in only one family carrying a homoplasmic m.9176T > C [p.(Leu217Pro)] variant.ConclusionThis report highlights the role of <i>MT-ATP6</i> pathogenic variants in complex and pure HSP and raises the relevance of genetic testing of <i>MT-ATP6</i> in undiagnosed cases of sporadic or maternally inherited HSP.