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

I.S. Ivanov, Dimitar Azmanov, M.B. Ivanova, T. Chamova, I.H. Pacheva, M.V. Panova, S. Song, Bharti Morar, R.V. Yordanova, F.K. Galabova, I.G. Sotkova, A.J. Linev, S. Bitchev, Anne-Marie Shearwood, D. Kancheva, D. Gabriková, V. Karcagi, V. Guergueltcheva, I.E. Geneva, V. Bozhinova & 9 others V.K. Stoyanova, I.M. Kremensky, A.G. Jordanova, A.S. Savov, R. Horváth, M.A. Brown, I. Tournev, Aleksandra Filipovska, Luba Kalaydjieva

Research output: Contribution to journalArticle

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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.
Original languageEnglish
Pages (from-to)76-83
JournalMolecular Genetics and Metabolism
Volume113
Issue number1-2
Early online date21 Jul 2014
DOIs
Publication statusPublished - Sep 2014

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Roma
Lactic Acidosis
Genes
Mutation
Bulgaria
Patient rehabilitation
Screening
Romania
Slovakia
Population Control
Hungary
Homozygote
Brain Diseases
Testing
Cerebral Palsy
Acidosis
Ethnic Groups
Intellectual Disability
Milk
Seizures

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Ivanov, I.S. ; Azmanov, Dimitar ; Ivanova, M.B. ; Chamova, T. ; Pacheva, I.H. ; Panova, M.V. ; Song, S. ; Morar, Bharti ; Yordanova, R.V. ; Galabova, F.K. ; Sotkova, I.G. ; Linev, A.J. ; Bitchev, S. ; Shearwood, Anne-Marie ; Kancheva, D. ; Gabriková, D. ; Karcagi, V. ; Guergueltcheva, V. ; Geneva, I.E. ; Bozhinova, V. ; Stoyanova, V.K. ; Kremensky, I.M. ; Jordanova, A.G. ; Savov, A.S. ; Horváth, R. ; Brown, M.A. ; Tournev, I. ; Filipovska, Aleksandra ; Kalaydjieva, Luba. / Founder p.Arg 446* mutation in the PDHX gene explains over half of cases with congenital lactic acidosis in Roma children. In: Molecular Genetics and Metabolism. 2014 ; Vol. 113, No. 1-2. pp. 76-83.
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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.",
author = "I.S. Ivanov and Dimitar Azmanov and M.B. Ivanova and T. Chamova and I.H. Pacheva and M.V. Panova and S. Song and Bharti Morar and R.V. Yordanova and F.K. Galabova and I.G. Sotkova and A.J. Linev and S. Bitchev and Anne-Marie Shearwood and D. Kancheva and D. Gabrikov{\'a} and V. Karcagi and V. Guergueltcheva and I.E. Geneva and V. Bozhinova and V.K. Stoyanova and I.M. Kremensky and A.G. Jordanova and A.S. Savov and R. Horv{\'a}th and M.A. Brown and I. Tournev and Aleksandra Filipovska and Luba Kalaydjieva",
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Ivanov, IS, Azmanov, D, Ivanova, MB, Chamova, T, Pacheva, IH, Panova, MV, Song, S, Morar, B, Yordanova, RV, Galabova, FK, Sotkova, IG, Linev, AJ, Bitchev, S, Shearwood, A-M, Kancheva, D, Gabriková, D, Karcagi, V, Guergueltcheva, V, Geneva, IE, Bozhinova, V, Stoyanova, VK, Kremensky, IM, Jordanova, AG, Savov, AS, Horváth, R, Brown, MA, Tournev, I, Filipovska, A & 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, vol. 113, no. 1-2, pp. 76-83. https://doi.org/10.1016/j.ymgme.2014.07.017

Founder p.Arg 446* mutation in the PDHX gene explains over half of cases with congenital lactic acidosis in Roma children. / Ivanov, I.S.; Azmanov, Dimitar; Ivanova, M.B.; Chamova, T.; Pacheva, I.H.; Panova, M.V.; Song, S.; Morar, Bharti; Yordanova, R.V.; Galabova, F.K.; Sotkova, I.G.; Linev, A.J.; Bitchev, S.; Shearwood, Anne-Marie; Kancheva, D.; Gabriková, D.; Karcagi, V.; Guergueltcheva, V.; Geneva, I.E.; Bozhinova, V.; Stoyanova, V.K.; Kremensky, I.M.; Jordanova, A.G.; Savov, A.S.; Horváth, R.; Brown, M.A.; Tournev, I.; Filipovska, Aleksandra; Kalaydjieva, Luba.

In: Molecular Genetics and Metabolism, Vol. 113, No. 1-2, 09.2014, p. 76-83.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Founder p.Arg 446* mutation in the PDHX gene explains over half of cases with congenital lactic acidosis in Roma children

AU - Ivanov, I.S.

AU - Azmanov, Dimitar

AU - Ivanova, M.B.

AU - Chamova, T.

AU - Pacheva, I.H.

AU - Panova, M.V.

AU - Song, S.

AU - Morar, Bharti

AU - Yordanova, R.V.

AU - Galabova, F.K.

AU - Sotkova, I.G.

AU - Linev, A.J.

AU - Bitchev, S.

AU - Shearwood, Anne-Marie

AU - Kancheva, D.

AU - Gabriková, D.

AU - Karcagi, V.

AU - Guergueltcheva, V.

AU - Geneva, I.E.

AU - Bozhinova, V.

AU - Stoyanova, V.K.

AU - Kremensky, I.M.

AU - Jordanova, A.G.

AU - Savov, A.S.

AU - Horváth, R.

AU - Brown, M.A.

AU - Tournev, I.

AU - Filipovska, Aleksandra

AU - Kalaydjieva, Luba

PY - 2014/9

Y1 - 2014/9

N2 - 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.

AB - 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.

U2 - 10.1016/j.ymgme.2014.07.017

DO - 10.1016/j.ymgme.2014.07.017

M3 - Article

VL - 113

SP - 76

EP - 83

JO - Molecular Genetics and Metabolism

JF - Molecular Genetics and Metabolism

SN - 1096-7192

IS - 1-2

ER -