Center for Human Neurogenetics, Department of Neurology and Agnes Ginges, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
Hebrew University-Hadassah School of Medicine, Jerusalem, Israel3National Institute for Biotechnology in the Negev, Ben Gurion University, Beer Sheva, Israel.
JAMA Neurol. 2014 Jul 1;71(7):901-4. doi: 10.1001/jamaneurol.2014.116.
Hereditary spastic paraplegia is a highly heterogeneous group of neurogenetic disorders with pure and complicated clinical phenotypes. No treatment is available for these disorders. We identified 2 unrelated families, each with 2 siblings with severe methylenetetrahydrofolate reductase (MTHFR) deficiency manifesting a complicated form of adult-onset hereditary spastic paraparesis partially responsive to betaine therapy.
Both pairs of siblings presented with a similar combination of progressive spastic paraparesis and polyneuropathy, variably associated with behavioral changes, cognitive impairment, psychosis, seizures, and leukoencephalopathy, beginning between the ages of 29 and 50 years. By the time of diagnosis a decade later, 3 patients were ambulatory and 1 was bedridden. Investigations have revealed severe hyperhomocysteinemia and hypomethioninemia, reduced fibroblast MTHFR enzymatic activity (18%-52% of control participants), and 3 novel pathogenic MTHFR mutations, 2 as compound heterozygotes in one family and 1 as a homozygous mutation in the other family. Treatment with betaine produced a rapid decline of homocysteine by 50% to 70% in all 4 patients and, over 9 to 15 years, improved the conditions of the 3 ambulatory patients.
Although severe MTHFR deficiency is a rare cause of complicated spastic paraparesis in adults, it should be considered in select patients because of the potential therapeutic benefit of betaine supplementation.
遗传性痉挛性截瘫是一组高度异质性的神经遗传疾病，具有纯合和复杂的临床表型。目前尚无针对这些疾病的治疗方法。我们鉴定了 2 个无关联的家系，每个家系均有 2 名受累同胞，表现为严重亚甲基四氢叶酸还原酶（MTHFR）缺乏症，成年起病，复杂型遗传性痉挛性截瘫，部分对甜菜碱治疗有反应。
两对同胞均表现出相似的进行性痉挛性截瘫和多发性神经病，伴有行为改变、认知障碍、精神病、癫痫发作和白质脑病，发病年龄在 29 至 50 岁之间。10 年后诊断时，3 名患者可走动，1 名卧床不起。研究发现严重高同型半胱氨酸血症和低蛋氨酸血症，成纤维细胞 MTHFR 酶活性降低（对照组的 18％-52％），以及 3 种新的致病性 MTHFR 突变，1 种为复合杂合子，1 种为另一家系的纯合子突变。所有 4 名患者均接受甜菜碱治疗，同型半胱氨酸迅速降低 50％至 70％，9 至 15 年后，3 名可走动的患者病情改善。
尽管严重的 MTHFR 缺乏症是成人复杂痉挛性截瘫的罕见病因，但鉴于甜菜碱补充的潜在治疗益处，应在特定患者中考虑该病因。
