title: Founder p.Arg 446* mutation in the PDHX gene explains over half of cases with congenital lactic acidosis in Roma children.
abstract: 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.
authors.affiliation: Department of Pediatrics and Medical Genetics, Plovdiv Medical University, Bulgaria.
authors.forename: Ivan S
authors.initials: IS
authors.lastname: Ivanov
authors.affiliation: Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, Australia; Department of Diagnostic Genomics, PathWest, Perth, Australia.
authors.forename: Dimitar N
authors.initials: DN
authors.lastname: Azmanov
authors.affiliation: National Genetic Laboratory, Medical University-Sofia, Bulgaria.
authors.forename: Mariya B
authors.initials: MB
authors.lastname: Ivanova
authors.affiliation: Department of Neurology, Medical University-Sofia, Bulgaria.
authors.forename: Teodora
authors.initials: T
authors.lastname: Chamova
authors.affiliation: Department of Pediatrics and Medical Genetics, Plovdiv Medical University, Bulgaria.
authors.forename: Ilyana H
authors.initials: IH
authors.lastname: Pacheva
authors.affiliation: Department of Pediatrics and Medical Genetics, Plovdiv Medical University, Bulgaria.
authors.forename: Margarita V
authors.initials: MV
authors.lastname: Panova
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Sharon
authors.initials: S
authors.lastname: Song
authors.affiliation: Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, Australia.
authors.forename: Bharti
authors.initials: B
authors.lastname: Morar
authors.affiliation: Department of Pediatrics and Medical Genetics, Plovdiv Medical University, Bulgaria.
authors.forename: Ralitsa V
authors.initials: RV
authors.lastname: Yordanova
authors.affiliation: Department of Pediatrics and Medical Genetics, Plovdiv Medical University, Bulgaria.
authors.forename: Fani K
authors.initials: FK
authors.lastname: Galabova
authors.affiliation: Department of Pediatrics and Medical Genetics, Plovdiv Medical University, Bulgaria.
authors.forename: Iglika G
authors.initials: IG
authors.lastname: Sotkova
authors.affiliation: Department of Pediatrics and Medical Genetics, Plovdiv Medical University, Bulgaria.
authors.forename: Alexandar J
authors.initials: AJ
authors.lastname: Linev
authors.affiliation: National Genetic Laboratory, Medical University-Sofia, Bulgaria.
authors.forename: Stoyan
authors.initials: S
authors.lastname: Bitchev
authors.affiliation: Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, Australia.
authors.forename: Anne-Marie J
authors.initials: AM
authors.lastname: Shearwood
authors.affiliation: Molecular Neurogenomics Group, Department of Molecular Genetics, VIB, University of Antwerp, Belgium; Department of Medical Chemistry and Biochemistry, Molecular Medicine Centre, Medical University-Sofia, Bulgaria.
authors.forename: Dalia
authors.initials: D
authors.lastname: Kancheva
authors.affiliation: Department of Biology, Faculty of Humanities and Natural Sciences, University of Presov, Slovakia.
authors.forename: Dana
authors.initials: D
authors.lastname: Gabrikova
authors.affiliation: Department of Molecular Genetics and Diagnostics, NIEH, Budapest, Hungary.
authors.forename: Veronika
authors.initials: V
authors.lastname: Karcagi
authors.affiliation: Department of Neurology, Medical University-Sofia, Bulgaria.
authors.forename: Velina
authors.initials: V
authors.lastname: Guergueltcheva
authors.affiliation: Department of Pediatrics and Medical Genetics, Plovdiv Medical University, Bulgaria.
authors.forename: Ina E
authors.initials: IE
authors.lastname: Geneva
authors.affiliation: Department of Neurology, Medical University-Sofia, Bulgaria.
authors.forename: Veneta
authors.initials: V
authors.lastname: Bozhinova
authors.affiliation: Department of Pediatrics and Medical Genetics, Plovdiv Medical University, Bulgaria.
authors.forename: Vili K
authors.initials: VK
authors.lastname: Stoyanova
authors.affiliation: National Genetic Laboratory, Medical University-Sofia, Bulgaria.
authors.forename: Ivo
authors.initials: I
authors.lastname: Kremensky
authors.affiliation: Molecular Neurogenomics Group, Department of Molecular Genetics, VIB, University of Antwerp, Belgium; Department of Medical Chemistry and Biochemistry, Molecular Medicine Centre, Medical University-Sofia, Bulgaria.
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
authors.affiliation: National Genetic Laboratory, Medical University-Sofia, Bulgaria.
authors.forename: Aleksey
authors.initials: A
authors.lastname: Savov
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Rita
authors.initials: R
authors.lastname: Horvath
authors.affiliation: The University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Australia.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Brown
authors.affiliation: Department of Neurology, Medical University-Sofia, Bulgaria; Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria.
authors.forename: Ivailo
authors.initials: I
authors.lastname: Tournev
authors.affiliation: Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, Australia; School of Chemistry and Biochemistry, The University of Western Australia, Perth, Australia.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Filipovska
authors.affiliation: Harry Perkins Institute of Medical Research and Centre for Medical Research, The University of Western Australia, Perth, Australia. Electronic address: luba.kalaydjieva@perkins.uwa.edu.au.
authors.forename: Luba
authors.initials: L
authors.lastname: Kalaydjieva
mesh_terms: D000140:Acidosis, Lactic / Q000175:diagnosis / Q000235:genetics*; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003062:Codon; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010641:Phenotype; D011768:Pyruvate Dehydrogenase Complex / Q000235:genetics*; D012383:Romania; D018154:Slovakia
chemical_list: D003062:Codon; C045867:PDHX protein, human; D011768:Pyruvate Dehydrogenase Complex
keywords: Congenital lactic acidosis; PDHX; Roma/Gypsy founder mutation