Department of Genetics and Endocrinology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Tianhe District, Guangzhou, Guangdong, 510623, P.R. China.
Orphanet J Rare Dis. 2024 May 15;19(1):198. doi: 10.1186/s13023-024-03210-0.
Methylmalonic aciduria (MMA) is a group of rare genetic metabolic disorders resulting from defects in methylmalonyl coenzyme A mutase (MCM) or intracellular cobalamin (cbl) metabolism. MMA patients show diverse clinical and genetic features across different subtypes and populations.
We retrospectively recruited 60 MMA patients from a single center and diagnosed them based on their clinical manifestations and biochemical assays. We then performed genetic analysis to confirm the diagnosis and identify the causal variants.
We confirmed the common clinical manifestations of MMA reported previously. We also described four rare MMA cases with unusual symptoms or genetic variants, such as pulmonary hypertension or limb weakness in late-onset patients. We identified 15 MMACHC and 26 MMUT variants in 57 patients, including 6 novel MMUT variants. Two patients had only one MMAA variant each, and one patient had mild MMA due to mitochondrial DNA depletion syndrome caused by a SUCLA2 variant. Among 12 critically ill patients, isolated MMA was associated with higher C3, blood ammonia, and acidosis, while combined MMA was linked to hydrocephalus on skull MRI. MMACHC c.658-660delAAG and MMUT c.1280G > A variants were correlated with more severe phenotypes.
Our study demonstrates the clinical and genotypic heterogeneity of MMA patients and indicates that metabolic screening and genetic analysis are useful tools to identify rare cases.
甲基丙二酸血症（MMA）是一组罕见的遗传性代谢紊乱疾病，由甲基丙二酰辅酶 A 变位酶（MCM）或细胞内钴胺素（cbl）代谢缺陷引起。MMA 患者在不同亚型和人群中表现出不同的临床和遗传特征。
我们回顾性地从一家中心招募了 60 名 MMA 患者，根据他们的临床表现和生化检测结果进行诊断。然后我们进行了基因分析以确认诊断并确定致病变异。
我们证实了先前报道的 MMA 的常见临床表现。我们还描述了 4 例罕见的 MMA 病例，这些病例具有不常见的症状或遗传变异，如晚期发病患者的肺动脉高压或肢体无力。我们在 57 名患者中发现了 15 种 MMACHC 和 26 种 MMUT 变异，包括 6 种新的 MMUT 变异。两名患者各有一种 MMAA 变异，一名患者因 SUCLA2 变异导致线粒体 DNA 耗竭综合征而患有轻度 MMA。在 12 名危重症患者中，孤立性 MMA 与更高的 C3、血氨和酸中毒相关，而合并性 MMA 与头颅 MRI 上的脑积水相关。MMACHC c.658-660delAAG 和 MMUT c.1280G > A 变异与更严重的表型相关。
我们的研究表明 MMA 患者存在临床和基因型异质性，表明代谢筛查和基因分析是识别罕见病例的有用工具。
