National Institutes of Health Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH, Bethesda, MD, USA.
Brighton and Sussex University Hospitals NHS Trust, Brighton, England.
Mol Genet Genomic Med. 2021 Jun;9(6):e1692. doi: 10.1002/mgg3.1692. Epub 2021 May 7.
Complex II is an essential component of the electron transport chain, linking it with the tricarboxylic acid cycle. Its four subunits are encoded in the nuclear genome, and deleterious variants in these genes, including SDHA (OMIM 600857), are associated with a wide range of symptoms including neurological disease, cardiomyopathy, and neoplasia (paraganglioma-pheochromocytomas (PGL/PCC), and gastrointestinal stromal tumors). Deleterious variants of SDHA are most frequently associated with Leigh and Leigh-like syndromes.
Here, we describe a case of a 9-year-old boy with tremor, nystagmus, hypotonia, developmental delay, significant ataxia, and progressive cerebellar atrophy. He was found to have biallelic variants in SDHA, a known pathogenic variant (c.91C>T (p.R31*)), and a variant of unknown significance (c.454G>A (p.E152K)). Deficient activity of complexes II and III was detected in fibroblasts from the patient consistent with a diagnosis of a respiratory chain disorder.
We, therefore, consider whether c.454G>A (p.E152K) is, indeed, a pathogenic variant, and what implications it has for family members who carry the same variant.
复合物 II 是电子传递链的重要组成部分，将其与三羧酸循环连接起来。其四个亚基编码在核基因组中，这些基因中的有害变体，包括 SDHA（OMIM 600857），与广泛的症状相关，包括神经疾病、心肌病和肿瘤（副神经节瘤-嗜铬细胞瘤（PGL/PCC）和胃肠道间质瘤）。SDHA 的有害变体最常与 Leigh 和 Leigh 样综合征相关。
在这里，我们描述了一名 9 岁男孩的病例，他有震颤、眼球震颤、肌张力低下、发育迟缓、明显的共济失调和进行性小脑萎缩。他被发现 SDHA 存在两种等位基因变异，一种是已知的致病性变异（c.91C>T（p.R31*）），另一种是意义不明的变异（c.454G>A（p.E152K））。从患者的成纤维细胞中检测到复合物 II 和 III 的活性不足，符合呼吸链障碍的诊断。
因此，我们考虑 c.454G>A（p.E152K）是否确实是一种致病性变体，以及它对携带相同变体的家庭成员有何影响。
