Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Department of Pediatrics, Queen Silvia Children's Hospital, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden.
Eur J Neurol. 2024 Jul;31(7):e16283. doi: 10.1111/ene.16283. Epub 2024 Mar 18.
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.
丙酮酸脱氢酶复合物缺陷症高达 90%由 X 连锁 PDHA1 基因突变引起。我们旨在研究 PDHA1 相关疾病患者的女性亲属，以：（i）描述女性 PDHA1 携带者的患病率；（ii）确定她们是否有症状和体征；（iii）描述相关表型。
在一项全国性的基于人群的研究中，我们鉴定了 37 名 PDHA1 致病性变异患者。对其母亲和女性亲属进行 PDHA1 致病性变异的 Sanger 测序。鉴定出的女性携带者进行临床评估，并对其病历进行回顾。
携带新生变异的比例为 86%。我们从五个家系中鉴定出了 7 名 PDHA1 女性携带者。其中 5 名存在疾病的临床特征，以前未确诊；均有周围轴索神经病的体征，4 名出现类似中风的发作，包括 2 名具有 Leigh 样病变，3 名有面部畸形。
杂合子女性携带者中 PDHA1 相关疾病认识不足。周围轴索神经病、类似中风和 Leigh 样改变以及面部畸形应引起对该疾病的怀疑。对潜在女性携带者进行基因分析和临床检查对于遗传咨询很重要，并且对治疗有影响。
