Pyruvate dehydrogenase complex (PDHC) deficiencies are a group of mainly infantile onset disorders stemming from defects in pyruvate catabolism. They are characterised by severe lactic acidosis and progressive neurodegeneration.

Although the PDHA1 gene is implicated in most cases of PDHC deficiency worldwide, no pathogenic variants have been reported in South African patients to date, despite availability of PDHA1 sequencing in the state diagnostic setting.

Methods

DNA from five patients with low to absent PDHC activity in fibroblasts were subjected to PDHC deficiency gene panel analysis. Included in the panel were: PDHA1, PDHB, DLAT, DLD, PDHX, BOLA3, GLRX5, IBA57, LIAS, LIPT1, LIPT2, NFU1, PDP1, PDP2, SLC19A2, SLC19A3, SLC25A19, SLC25A26, TPK1 and FBXL4.

Results

No pathogenic variants were identified in 4 out of 5 cases investigated. A homozygous frame-shift mutation was detected in the BOLA3 gene in one patient, supporting a diagnosis of multiple mitochondrial dysfunction syndrome type 2.

Discussion

A single, novel, homozygous BOLA3 frame-shift mutation was detected in a black South African child with severe neurodegenerative disease and very low to absent PDHC enzyme activity. This finding of a homozygous mutation in a patient from a non-consanguineous background may indicate a need for further investigation in clinically similar cases as well as heterozygous carrier rates in unaffected individuals from the same ethnic background.

The paucity of identifiable mutations in 4 out of 5 South African patients with confirmed PDHC deficiency highlights the dangers in relying on Western population based genetic panels for diagnosing rare metabolic disease in genetically understudied populations.

中文翻译：

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仅依靠基因检测来诊断非西方人群遗传性代谢紊乱的陷阱——来自南非的 5 例丙酮酸脱氢酶缺乏症。

丙酮酸脱氢酶复合物 (PDHC) 缺乏症是一组主要由丙酮酸分解代谢缺陷引起的婴儿期发病障碍。它们的特征是严重的乳酸酸中毒和进行性神经变性。

尽管PDHA1基因与全世界大多数 PDHC 缺乏病例有关，但迄今为止，尽管在国家诊断环境中可以进行PDHA1测序，但南非患者中尚未报告致病性变异。

方法

对来自 5 名成纤维细胞中 PDHC 活性低或不存在的患者的 DNA 进行 PDHC 缺乏基因组分析。面板中包括：PDHA1、PDHB、DLAT、DLD、PDHX、BOLA3、GLRX5、IBA57、LIAS、LIPT1、LIPT2、NFU1、PDP1、PDP2、SLC19A2、SLC19A3、SLC25A19、SLC25A26、TPK1和FBXL4。

结果

在调查的 5 个病例中有 4 个未发现致病变异。在一名患者的BOLA3基因中检测到纯合移码突变，支持多发性线粒体功能障碍综合征 2 型的诊断。

讨论

在一名患有严重神经退行性疾病且 PDHC 酶活性极低或缺失的南非黑人儿童中检测到一个单一的、新颖的、纯合的BOLA3移码突变。在来自非近亲背景的患者中发现纯合突变可能表明需要对临床相似病例以及来自相同种族背景的未受影响个体的杂合携带率进行进一步调查。

在 5 名确诊的 PDHC 缺乏症的南非患者中，有 4 名缺乏可识别的突变，这凸显了依赖西方基于人群的基因组来诊断基因研究不足的人群中的罕见代谢疾病的危险。