Associated with recessive complicated HSP
A new HSP gene (ACO2) associated with recessive complicated HSP has been discovered. The particular mutation impairs the function of mitochondria in neurons and has previously been associated with cerebellar ataxia. Mitochondrial function impairment is one of the major pathways that have been identified as causing several of the HSPs.
OBJECTIVE: To identify the clinical characteristics and genetic etiology of a family affected with hereditary spastic paraplegia (HSP).
METHODS: Clinical, genetic, and functional analyses involving genome-wide linkage coupled to whole-exome sequencing in a consanguineous family with complicated HSP.
RESULTS: A homozygous missense mutation was identified in the ACO2 gene (c.1240T>G p.Phe414Val) that segregated with HSP complicated by intellectual disability and microcephaly. Lymphoblastoid cell lines of homozygous carrier patients revealed significantly decreased activity of the mitochondrial aconitase enzyme and defective mitochondrial respiration. ACO2 encodes mitochondrial aconitase, an essential enzyme in the Krebs cycle. Recessive mutations in this gene have been previously associated with cerebellar ataxia.
CONCLUSIONS: Our findings nominate ACO2 as a disease-causing gene for autosomal recessive complicated HSP and provide further support for the central role of mitochondrial defects in the pathogenesis of HSP.
SOURCE: Neurol Genet. 2018 Mar 21;4(2):e223. doi: 10.1212/NXG.0000000000000223. eCollection 2018 Apr. PMID: 29577077
ACO2 homozygous missense mutation associated with complicated hereditary spastic paraplegia.
Bouwkamp CG1, Afawi Z1, Fattal-Valevski A1, Krabbendam IE1, Rivetti S1, Masalha R1, Quadri M1, Breedveld GJ1, Mandel H1, Tailakh MA1, Beverloo HB1, Stevanin G1, Brice A1, van IJcken WFJ1, Vernooij MW1, Dolga AM1, de Vrij FMS1, Bonifati V1, Kushner SA1.
1 Department of Psychiatry (C.G.B., S.R., F.M.S.d.V., S.A.K.) and Department of Clinical Genetics (C.G.B., M.Q., G.J.B., H.B.B., V.B.), Erasmus MC, Rotterdam, The Netherlands; Sackler School of Medicine (Z.A., A.F.-V.), Tel-Aviv University, Ramat-Aviv; Pediatric Neurology Unit (A.F.-V.), Dana Children’s Hospital, Tel-Aviv Medical Center, Israel; Department of Molecular Pharmacology (I.E.K., A.M.D.), Groningen Research Institute of Pharmacy, University of Groningen, The Netherlands; Clalit Health Services (R.M.), Sharon-Shomron, Hadera District; Faculty of Health Science (R.M.), Ben-Gurion University of the Negev, Beer Sheva; Metabolic Disease Unit (H.M.), Meyer Children’s Hospital, Rambam Health Care Campus and Technion Faculty of Medicine, Haifa; Nursing Research Unit (M.A.T.), Soroka University Medical Center and Faculty of Health Science, Ben Gurion University of the Negev, Be’er Sheva, Israel; Ecole Pratique des Hautes Etudes (G.S.), PSL Research University, Neurogenetics Laboratory; Institut du Cerveau et de la Moelle Epinière (G.S., A.B.), Sorbonne University, Pierre and Marie Curie University UMR_S1127, INSERM u1127, CNRS UMR5225, Paris, France; Center for Biomics (W.F.J.v.I.), Erasmus MC; Department of Epidemiology (M.W.V.) and Department of Radiology (M.W.V.), Erasmus MC, Rotterdam, The Netherlands.