PT - JOURNAL ARTICLE AU - Christian G. Bouwkamp AU - Zaid Afawi AU - Aviva Fattal-Valevski AU - Inge E. Krabbendam AU - Stefano Rivetti AU - Rafik Masalha AU - Marialuisa Quadri AU - Guido J. Breedveld AU - Hanna Mandel AU - Muhammad Abu Tailakh AU - H. Berna Beverloo AU - Giovanni Stevanin AU - Alexis Brice AU - Wilfred F.J. van IJcken AU - Meike W. Vernooij AU - Amalia M. Dolga AU - Femke M.S. de Vrij AU - Vincenzo Bonifati AU - Steven A. Kushner TI - <em>ACO2</em> homozygous missense mutation associated with complicated hereditary spastic paraplegia AID - 10.1212/NXG.0000000000000223 DP - 2018 Apr 01 TA - Neurology Genetics PG - e223 VI - 4 IP - 2 4099 - http://ng.neurology.org/content/4/2/e223.short 4100 - http://ng.neurology.org/content/4/2/e223.full SO - Neurol Genet2018 Apr 01; 4 AB - 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&gt;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.ADP=adenosine diphosphate; ATP=adenosine triphosphate; ExAC=Exome Aggregation Consortium; FCCP=carbonyl cyanide p-trifluoromethoxyphenylhydrazone; HSP=hereditary spastic paraplegia; MAF=minor allele frequency; LCL=lymphoblastoid cell line; LRT=likelihood ratio test; CADD=Combined Annotation Dependent Depletion; RCR=respiratory control ratio; SNP=single nucleotide polymorphism; TCA=tricarboxylic acid cycle