Difficulties in recognition of pyruvate dehydrogenase complex deficiency on the basis of clinical and biochemical features. The role of next-generation sequencing

Pyruvate dehydrogenase complex (PDHc) defect is a well-known cause of mitochondrial disorders (MD) with at least six responsible genes (PDHA1, PDHB, DLAT, DLD, PDHX, PDP1). The aim of this work was to assess the diagnostic value of biochemical methods in recognition of PDHc defect in Polish patients...

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Main Authors: E. Ciara, D. Rokicki, P. Halat, A. Karkucińska-Więckowska, D. Piekutowska-Abramczuk, J. Mayr, J. Trubicka, T. Szymańska-Dębińska, M. Pronicki, M. Pajdowska, M. Dudzińska, M. Giżewska, M. Krajewska-Walasek, J. Książyk, W. Sperl, R. Płoski, E. Pronicka
Format: Article
Language:English
Published: Elsevier 2016-06-01
Series:Molecular Genetics and Metabolism Reports
Subjects:
DLD
Online Access:http://www.sciencedirect.com/science/article/pii/S2214426916300167
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spelling doaj-1d7800cfa3654508be355f228f9e59ce2020-11-24T21:09:33ZengElsevierMolecular Genetics and Metabolism Reports2214-42692016-06-017C707610.1016/j.ymgmr.2016.03.004Difficulties in recognition of pyruvate dehydrogenase complex deficiency on the basis of clinical and biochemical features. The role of next-generation sequencingE. Ciara0D. Rokicki1P. Halat2A. Karkucińska-Więckowska3D. Piekutowska-Abramczuk4J. Mayr5J. Trubicka6T. Szymańska-Dębińska7M. Pronicki8M. Pajdowska9M. Dudzińska10M. Giżewska11M. Krajewska-Walasek12J. Książyk13W. Sperl14R. Płoski15E. Pronicka16Department of Medical Genetics, The Children's Memorial Health Institute, Warsaw, PolandDepartment of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, PolandDepartment of Medical Genetics, The Children's Memorial Health Institute, Warsaw, PolandDepartment of Pathology, The Children's Memorial Health Institute, Warsaw, PolandDepartment of Medical Genetics, The Children's Memorial Health Institute, Warsaw, PolandDepartment of Pediatrics, Paracelsus Medical University, Salzburg, AustriaDepartment of Medical Genetics, The Children's Memorial Health Institute, Warsaw, PolandDepartment of Pathology, The Children's Memorial Health Institute, Warsaw, PolandDepartment of Pathology, The Children's Memorial Health Institute, Warsaw, PolandDepartment of Biochemistry and Experimental Medicine, The Children's Memorial Health Institute, Warsaw, PolandDepartment of Child Neurology, Chorzowskie Centrum Pediatrii i Onkologii, Chorzów, PolandDepartment of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology, Pomeranian Medical University, Szczecin, PolandDepartment of Medical Genetics, The Children's Memorial Health Institute, Warsaw, PolandDepartment of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, PolandDepartment of Pediatrics, Paracelsus Medical University, Salzburg, AustriaDepartment of Medical Genetics, Warsaw Medical University, Warsaw, PolandDepartment of Medical Genetics, The Children's Memorial Health Institute, Warsaw, PolandPyruvate dehydrogenase complex (PDHc) defect is a well-known cause of mitochondrial disorders (MD) with at least six responsible genes (PDHA1, PDHB, DLAT, DLD, PDHX, PDP1). The aim of this work was to assess the diagnostic value of biochemical methods in recognition of PDHc defect in Polish patients with suspicion of MD. In the first step, Western blot of the E1α subunit was performed on 86 archive muscle bioptates with suspicion of MD. In the second step, Sanger PDHA1 sequencing was performed in 21 cases with low E1α expression. In the third step, 7 patients with negative results of PDHA1 sequencing were subjected to whole-exome sequencing (WES). This protocol revealed 4 patients with PDHA1 and one with DLD mutations. Four additional probands were diagnosed outside the protocol (WES or Sanger sequencing). The molecular characterization of PDHc defect was conducted in a total of 9 probands: 5 according to and 4 off the protocol. Additionally, two affected relatives were recognized by a family study. Altogether we identified seven different PDHA1 changes, including two novel variants [c.464T > C (p.Met155Thr) and c.856_859dupACTT (p.Arg288Leufs*10)] and one DLD variant. The lactate response to glucose load in the PDHA1 subset was compared to a subset of non PDHc-related MD. Opposite responses were observed, with an increase of 23% and decrease of 27%, respectively. The results show that determining lactate response to glucose load and muscle E1α expression may contribute to distinguishing PDHc-related and other MD, however, WES is becoming the method of choice for MD diagnostics.http://www.sciencedirect.com/science/article/pii/S2214426916300167Pyruvate dehydrogenase complex deficiencyPDHcPDHA1DLDNovel pathogenic variantsWhole-exome sequencing
collection DOAJ
language English
format Article
sources DOAJ
author E. Ciara
D. Rokicki
P. Halat
A. Karkucińska-Więckowska
D. Piekutowska-Abramczuk
J. Mayr
J. Trubicka
T. Szymańska-Dębińska
M. Pronicki
M. Pajdowska
M. Dudzińska
M. Giżewska
M. Krajewska-Walasek
J. Książyk
W. Sperl
R. Płoski
E. Pronicka
spellingShingle E. Ciara
D. Rokicki
P. Halat
A. Karkucińska-Więckowska
D. Piekutowska-Abramczuk
J. Mayr
J. Trubicka
T. Szymańska-Dębińska
M. Pronicki
M. Pajdowska
M. Dudzińska
M. Giżewska
M. Krajewska-Walasek
J. Książyk
W. Sperl
R. Płoski
E. Pronicka
Difficulties in recognition of pyruvate dehydrogenase complex deficiency on the basis of clinical and biochemical features. The role of next-generation sequencing
Molecular Genetics and Metabolism Reports
Pyruvate dehydrogenase complex deficiency
PDHc
PDHA1
DLD
Novel pathogenic variants
Whole-exome sequencing
author_facet E. Ciara
D. Rokicki
P. Halat
A. Karkucińska-Więckowska
D. Piekutowska-Abramczuk
J. Mayr
J. Trubicka
T. Szymańska-Dębińska
M. Pronicki
M. Pajdowska
M. Dudzińska
M. Giżewska
M. Krajewska-Walasek
J. Książyk
W. Sperl
R. Płoski
E. Pronicka
author_sort E. Ciara
title Difficulties in recognition of pyruvate dehydrogenase complex deficiency on the basis of clinical and biochemical features. The role of next-generation sequencing
title_short Difficulties in recognition of pyruvate dehydrogenase complex deficiency on the basis of clinical and biochemical features. The role of next-generation sequencing
title_full Difficulties in recognition of pyruvate dehydrogenase complex deficiency on the basis of clinical and biochemical features. The role of next-generation sequencing
title_fullStr Difficulties in recognition of pyruvate dehydrogenase complex deficiency on the basis of clinical and biochemical features. The role of next-generation sequencing
title_full_unstemmed Difficulties in recognition of pyruvate dehydrogenase complex deficiency on the basis of clinical and biochemical features. The role of next-generation sequencing
title_sort difficulties in recognition of pyruvate dehydrogenase complex deficiency on the basis of clinical and biochemical features. the role of next-generation sequencing
publisher Elsevier
series Molecular Genetics and Metabolism Reports
issn 2214-4269
publishDate 2016-06-01
description Pyruvate dehydrogenase complex (PDHc) defect is a well-known cause of mitochondrial disorders (MD) with at least six responsible genes (PDHA1, PDHB, DLAT, DLD, PDHX, PDP1). The aim of this work was to assess the diagnostic value of biochemical methods in recognition of PDHc defect in Polish patients with suspicion of MD. In the first step, Western blot of the E1α subunit was performed on 86 archive muscle bioptates with suspicion of MD. In the second step, Sanger PDHA1 sequencing was performed in 21 cases with low E1α expression. In the third step, 7 patients with negative results of PDHA1 sequencing were subjected to whole-exome sequencing (WES). This protocol revealed 4 patients with PDHA1 and one with DLD mutations. Four additional probands were diagnosed outside the protocol (WES or Sanger sequencing). The molecular characterization of PDHc defect was conducted in a total of 9 probands: 5 according to and 4 off the protocol. Additionally, two affected relatives were recognized by a family study. Altogether we identified seven different PDHA1 changes, including two novel variants [c.464T > C (p.Met155Thr) and c.856_859dupACTT (p.Arg288Leufs*10)] and one DLD variant. The lactate response to glucose load in the PDHA1 subset was compared to a subset of non PDHc-related MD. Opposite responses were observed, with an increase of 23% and decrease of 27%, respectively. The results show that determining lactate response to glucose load and muscle E1α expression may contribute to distinguishing PDHc-related and other MD, however, WES is becoming the method of choice for MD diagnostics.
topic Pyruvate dehydrogenase complex deficiency
PDHc
PDHA1
DLD
Novel pathogenic variants
Whole-exome sequencing
url http://www.sciencedirect.com/science/article/pii/S2214426916300167
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