Manifestations of X-linked pyruvate dehydrogenase complex deficiency in female PDHA1 carriers.
PDHA1
PDHc deficiency
mitochondrial
peripheral axonal neuropathy
stroke
Journal
European journal of neurology
ISSN: 1468-1331
Titre abrégé: Eur J Neurol
Pays: England
ID NLM: 9506311
Informations de publication
Date de publication:
18 Mar 2024
18 Mar 2024
Historique:
revised:
26
02
2024
received:
12
01
2024
accepted:
05
03
2024
medline:
18
3
2024
pubmed:
18
3
2024
entrez:
18
3
2024
Statut:
aheadofprint
Résumé
Pyruvate dehydrogenase complex deficiency is in up to 90% caused by pathogenic variants in the X-linked PDHA1 gene. We aimed to investigate female relatives of index patients with PDHA1-related disease to (i) describe the prevalence of female PDHA1 carriers, (ii) determine whether they had symptoms and signs, and (iii) delineate the associated phenotype. In a national population-based study, we identified 37 patients with pathogenic variants in PDHA1. Sanger sequencing for the presence of the pathogenic variant was performed in their mothers and female relatives. The identified female carriers were clinically assessed, and their medical records were reviewed. The proportion carrying a de novo variant was 86%. We identified seven female PDHA1 carriers from five families. Five of them exhibited clinical features of the disease and were previously undiagnosed; all had signs of peripheral axonal neuropathy, four presented with strokelike episodes including two with Leigh-like lesions, and three had facial stigmata. PDHA1-related disease is underrecognized in heterozygous female carriers. Peripheral axonal neuropathy, strokelike and Leigh-like changes, and facial dysmorphism should raise suspicion of the disorder. Genetic analysis and clinical examination of potential female carriers are important for genetic counseling and have implications for treatment.
Sections du résumé
BACKGROUND AND PURPOSE
OBJECTIVE
Pyruvate dehydrogenase complex deficiency is in up to 90% caused by pathogenic variants in the X-linked PDHA1 gene. We aimed to investigate female relatives of index patients with PDHA1-related disease to (i) describe the prevalence of female PDHA1 carriers, (ii) determine whether they had symptoms and signs, and (iii) delineate the associated phenotype.
METHODS
METHODS
In a national population-based study, we identified 37 patients with pathogenic variants in PDHA1. Sanger sequencing for the presence of the pathogenic variant was performed in their mothers and female relatives. The identified female carriers were clinically assessed, and their medical records were reviewed.
RESULTS
RESULTS
The proportion carrying a de novo variant was 86%. We identified seven female PDHA1 carriers from five families. Five of them exhibited clinical features of the disease and were previously undiagnosed; all had signs of peripheral axonal neuropathy, four presented with strokelike episodes including two with Leigh-like lesions, and three had facial stigmata.
CONCLUSIONS
CONCLUSIONS
PDHA1-related disease is underrecognized in heterozygous female carriers. Peripheral axonal neuropathy, strokelike and Leigh-like changes, and facial dysmorphism should raise suspicion of the disorder. Genetic analysis and clinical examination of potential female carriers are important for genetic counseling and have implications for treatment.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e16283Subventions
Organisme : Anna-Lisa och Bror Björnssons Stiftelse
Organisme : Stiftelsen Samariten
Organisme : Linnéa och Josef Carlssons Stiftelse
ID : ALFGBG-718681
Informations de copyright
© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.
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