title: Novel Homozygous Missense Mutation in SPG20 Gene Results in Troyer Syndrome Associated with Mitochondrial Cytochrome c Oxidase Deficiency.
abstract: Troyer syndrome is an autosomal recessive form of hereditary spastic paraplegia (HSP) caused by deleterious mutations in the SPG20 gene. Although the disease is associated with a loss of function mechanism of spartin, the protein encoded by SPG20, the precise pathogenesis is yet to be elucidated. Recent data indicated an important role for spartin in both mitochondrial maintenance and function. Here we report a child presenting with progressive spastic paraparesis, generalized muscle weakness, dysarthria, impaired growth, and severe isolated decrease in muscle cytochrome c oxidase (COX) activity. Whole exome sequencing identified the homozygous c.988A>G variant in SPG20 gene (p.Met330Val) resulting in almost complete loss of spartin in skeletal muscle. Further analyses demonstrated significant tissue specific reduction of COX 4, a nuclear encoded subunit of COX, in muscle suggesting a role for spartin in proper mitochondrial respiratory chain function mediated by COX activity. Our findings need to be verified in other Troyer syndrome patients in order to classify it as a form of HSP caused by mitochondrial dysfunction.
authors.affiliation: Department of Pediatrics B, Emek Medical Center, Afula, 1834111, Israel. spiegelr@zahav.net.il.|Genetic Institute, Emek Medical Center, Afula, Israel. spiegelr@zahav.net.il.|Rappaport School of Medicine, Technion, Haifa, Israel. spiegelr@zahav.net.il.
authors.forename: Ronen
authors.initials: R
authors.lastname: Spiegel
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.|Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Devorah
authors.initials: D
authors.lastname: Soiferman
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Shaag
authors.affiliation: Genetic Institute, Emek Medical Center, Afula, Israel.|Rappaport School of Medicine, Technion, Haifa, Israel.
authors.forename: Stavit
authors.initials: S
authors.lastname: Shalev
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.|Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Ann
authors.initials: A
authors.lastname: Saada
keywords: Cytochrome c oxidase; Hereditary spastic paraplegia; Mitochondria; Oxidative phosphorylation; SPG20; Troyer syndrome