5,10‐Methylenetetrahydrofolate reductase (MTHFR) deficiency usually presents as a severe neonatal disease. This study aimed to characterize natural history, biological and molecular data, and response to treatment of patients with late‐onset MTHFR deficiency. The patients were identified through the European Network and Registry for Homocystinuria and Methylation Defects and the Adult group of the French Society for Inherited Metabolic Diseases; data were retrospectively colleted. To identify juvenile to adult‐onset forms of the disease, we included patients with a diagnosis established after the age of 10 years. We included 14 patients (median age at diagnosis: 32 years; range: 11‐54). At onset (median age: 20 years; range 9‐38), they presented with walking difficulties (n = 8), cognitive decline (n = 3) and/or seizures (n = 3), sometimes associated with mild mental retardation (n = 6). During the disease course, symptoms were almost exclusively neurological with cognitive dysfunction (93%), gait disorders (86%), epilepsy (71%), psychiatric symptoms (57%), polyneuropathy (43%), and visual deficit (43%). Mean diagnostic delay was 14 years. Vascular events were observed in 28% and obesity in 36% of the patients. One patient remained asymptomatic at the age of 55 years. Upon treatment, median total homocysteine decreased (from 183 μmol/L, range 69‐266, to 90 μmol/L, range 20‐142) and symptoms improved (n = 9) or stabilized (n = 4). Missense pathogenic variants in the C‐terminal regulatory domain of the protein were over‐represented compared to early‐onset cases. Residual MTHFR enzymatic activity in skin fibroblasts (n = 4) was rather high (17%‐58%). This series of patients with late‐onset MTHFR deficiency underlines the still unmet need of a prompt diagnosis of this treatable disease.

中文翻译：

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迟发性 MTHFR 缺乏症成年患者的临床和分子特征

5,10-亚甲基四氢叶酸还原酶 (MTHFR) 缺乏症通常表现为严重的新生儿疾病。本研究旨在表征自然史、生物学和分子数据，以及对迟发性 MTHFR 缺乏症患者的治疗反应。这些患者是通过欧洲高胱氨酸尿症和甲基化缺陷网络和登记处以及法国遗传性代谢疾病协会的成人组确定的；数据被追溯收集。为了确定该疾病的青少年至成人发病形式，我们纳入了在 10 岁后确诊的患者。我们纳入了 14 名患者（诊断时的中位年龄：32 岁；范围：11-54）。发病时（中位年龄：20 岁；范围 9-38），他们出现行走困难（n = 8）、认知能力下降（n = 3）和/或癫痫发作（n = 3），有时伴有轻度智力低下（n = 6）。在病程中，症状几乎完全是神经性的，包括认知功能障碍 (93%)、步态障碍 (86%)、癫痫 (71%)、精神症状 (57%)、多发性神经病 (43%) 和视力缺陷 (43%) ）。平均诊断延迟为 14 年。在 28% 的患者中观察到血管事件，在 36% 的患者中观察到肥胖。一名患者在 55 岁时仍无症状。治疗后，中位总同型半胱氨酸降低（从 183 μmol/L，范围 69-266，到 90 μmol/L，范围 20-142），症状改善（n = 9）或稳定（n = 4）。与早发病例相比，蛋白质 C 端调节域中的错义致病变异被过度表达。皮肤成纤维细胞 (n = 4) 中残留的 MTHFR 酶活性相当高 (17%-58%)。