ACO2 homozygous missense mutation associated with complicated hereditary spastic paraplegia

Christian G. Bouwkamp, Zaid Afawi, Aviva Fattal-Valevski, Inge E. Krabbendam, Stefano Rivetti, Rafik Masalha, Marialuisa Quadri, Guido J. Breedveld, Hanna Mandel, Muhammad Abu Tailakh, H. Berna Beverloo, Giovanni Stevanin, Alexis Brice, Wilfred F.J. Van IJcken, Meike W. Vernooij, Amalia M. Dolga, Femke M.S. De Vrij, Vincenzo Bonifati, Steven A. Kushner

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


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 wholeexome 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.

Original languageEnglish
Article numbere223
JournalNeurology: Genetics
Issue number2
StatePublished - 1 Apr 2018

ASJC Scopus subject areas

  • Clinical Neurology
  • Genetics(clinical)


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