Founder p.Arg 446* mutation in the PDHX gene explains over half of cases with congenital lactic acidosis in Roma children

Ivan S. Ivanov, Dimitar N. Azmanov, Mariya B. Ivanova, Teodora Chamova, Ilyana H. Pacheva, Margarita V. Panova, Sharon Song, Bharti Morar, Ralitsa V. Yordanova, Fani K. Galabova, Iglika G. Sotkova, Alexandar J. Linev, Stoyan Bitchev, Anne Marie J. Shearwood, Dalia Kancheva, Dana Gabrikova, Veronika Karcagi, Velina Guergueltcheva, Ina E. Geneva, Veneta BozhinovaVili K. Stoyanova, Ivo Kremensky, Albena Jordanova, Aleksey Savov, Rita Horvath, Matthew A. Brown, Ivailo Tournev, Aleksandra Filipovska, Luba Kalaydjieva

Research output: Contribution to journalArticle

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Investigation of 31 of Roma patients with congenital lactic acidosis (CLA) from Bulgaria identified homozygosity for the R446* mutation in the PDHX gene as the most common cause of the disorder in this ethnic group. It accounted for around 60% of patients in the study and over 25% of all CLA cases referred to the National Genetic Laboratory in Bulgaria. The detection of a homozygous patient from Hungary and carriers among population controls from Romania and Slovakia suggests a wide spread of the mutation in the European Roma population.The clinical phenotype of the twenty R446* homozygotes was relatively homogeneous, with lactic acidosis crisis in the first days or months of life as the most common initial presentation (15/20 patients) and delayed psychomotor development and/or seizures in infancy as the leading manifestations in a smaller group (5/20 patients). The subsequent clinical picture was dominated by impaired physical growth and a very consistent pattern of static cerebral palsy-like encephalopathy with spasticity and severe to profound mental retardation seen in over 80% of cases. Most patients had a positive family history.We propose testing for the R446* mutation in PDHX as a rapid first screening in Roma infants with metabolic acidosis. It will facilitate and accelerate diagnosis in a large proportion of cases, allow early rehabilitation to alleviate the chronic clinical course, and prevent further affected births in high-risk families.

Original languageEnglish
Pages (from-to)76-83
Number of pages8
JournalMolecular Genetics and Metabolism
Issue number1
Publication statusPublished - Sep 1 2014



  • Congenital lactic acidosis
  • PDHX
  • Roma/Gypsy founder mutation

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Endocrinology

Cite this

Ivanov, I. S., Azmanov, D. N., Ivanova, M. B., Chamova, T., Pacheva, I. H., Panova, M. V., Song, S., Morar, B., Yordanova, R. V., Galabova, F. K., Sotkova, I. G., Linev, A. J., Bitchev, S., Shearwood, A. M. J., Kancheva, D., Gabrikova, D., Karcagi, V., Guergueltcheva, V., Geneva, I. E., ... Kalaydjieva, L. (2014). Founder p.Arg 446* mutation in the PDHX gene explains over half of cases with congenital lactic acidosis in Roma children. Molecular Genetics and Metabolism, 113(1), 76-83.