Difficulties in recognition of pyruvate dehydrogenase complex deficiency on the basis of clinical and biochemical features. The role of next-generation sequencing.
PBN-AR
Instytucja
Instytut "Pomnik - Centrum Zdrowia Dziecka"
Informacje podstawowe
Główny język publikacji
en
Czasopismo
Molecular Genetics and Metabolism Reports
ISSN
2214-4269
EISSN
Wydawca
Elsevier B.V.
DOI
Rok publikacji
2016
Numer zeszytu
7
Strony od-do
70-76
Numer tomu
18
Identyfikator DOI
Liczba arkuszy
0,5
Słowa kluczowe
en
DLD
novel pathogenic variants
PDHA1
PDHc
pyruvate dehydrogenase complex deficiency
whole-exome sequencing
Open access
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Creative Commons — Uznanie autorstwa-Niekomercyjne-Bez utworów zależnych
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Razem z publikacją
Data udostępnienia w sposób otwarty
Streszczenia
Język
en
Treść
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.
Cechy publikacji
original-article
Inne
System-identifier
0000015124
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