Abstract for presentation at 11th International Congress of Human Genetics

Mutations in ND5 gene rather than PDHE1alpha are associated with thiamine responsive Leigh Syndrome in India

  • Ms Shalini Mani, Centre for Cellular and Molecular Biology, Hyderabad, India
  • Dr Narasimha Sidarala, Niloufer Children Hospital, Hyderabad, India
  • Mr Varaprasad Kolla, Centre for Cellular and Molecular Biology, Hyderabad, India
  • Dr Karuna Madap, Niloufer Children Hospital, Hyderabad, India
  • Mr Mohammed Idris, Centre for Cellular and Molecular Biology, Hyderabad, India
  • Dr Giriraj Chandak, Centre for Cellular and Molecular Biology, Hyderabad
  • Ke-Jun Wei, Comparative Genomics Group, Research School of Biological Sciences, The Australian National University, Canberra 2601, Australia
  • Prof Jenny Graves, Comparative Genomics Group, Research School of Biological Sciences, The Australian National University, Canberra 2601, Australia

    • Purpose: Mitochondrial diseases are a heterogeneous group of disorders, characterized by dysfunction of mitochondrial oxidative phosphorylation due to mutations in nuclear or mitochondrial DNA. Leigh syndrome (LS), a diverse neurodegenerative disorder usually presents in the childhood and is not well understood. Complex I, cytochrome c oxidase as well as pyruvate dehydrogenase deficiency are known biochemical abnormalities in this disease. Leigh syndrome in India has hardly been explored and very little data exists related to its etiology and clinical course.
    Methods: In an attempt to understand its clinical picture and genetic basis, we studied clinical features, biochemical parameters, imageological findings and therapeutic response in a large prospective cohort of 109 patients. E1a subunit of pyruvate dehydrogenase complex (PDHE1a) and ND5 genes were sequenced in 79 probands and 78 controls and genotype-phenotype association was assessed.
    Results: All patients, presented in critical condition with acute manifestations, had low erythrocyte transketolase levels and responded to thiamine. Sequencing of PDHE1α gene didn’t show any of the reported or any novel mutation, while 27 patients (34.2%) had novel mutations in ND5 gene which were also identified in 16 of 25 (64%) mothers of mutation positive probands but absent in the controls. The mutations varied markedly in the degree of evolutionary conservation of the encoded residues that are altered. Many patients had more than one mutation but no genotype-phenotype correlation was observed.
    Conclusion: We demonstrate that Leigh syndrome (LS), usually under-diagnosed, is significantly prevalent and has variable presentation. In contrast to sub-acute or chronic presentation, our patients had acute manifestations due to coupled thiamine deficiency. We also report that mutations in ND5 gene and not PDHE1a are important causes of thiamine-responsive Leigh syndrome. Thiamine deficiency and ND5 mutations are known to reduce respiratory chain Complex I activity by independent mechanisms. Awareness about this common mode of presentation may facilitate early diagnosis and timely thiamine supplementation.

    Conference Organiser - ICMS Pty Ltd