Service de Biochimie Métabolique, Hôpital Necker-Enfants Malades, Université Paris Descartes et Assistance Publique Hôpitaux de Paris, Paris, France.
Hum Mutat. 2011 Sep;32(9):1046-52. doi: 10.1002/humu.21534. Epub 2011 Jul 12.
Fumarase deficiency (FD), caused by biallelic alteration of the Fumarase Hydratase gene (FH), and a rare metabolic disorder that affects the Krebs cycle, causes severe neurological impairment and fumaric aciduria. Less than 30 unrelated cases are known to date. In addition, heterozygous mutations of the FH gene are responsible for hereditary leiomyomatosis and renal cell cancer (HLRCC). We report three additional patients with dramatically different clinical presentations of FD and novel missense mutations in the FH gene. One patient had severe neonatal encephalopathy, polymicrogyria, <1% enzyme activity, and mildly increased levels of urinary fumarate. The second patient had microcephaly, mental retardation, 20% of fumarase activity, and intermediate levels of urinary fumarate. The third patient had mild mental retardation, polymicrogyria, 42-61% enzyme activity in different cell types and massive amounts of urinary fumarate. In silico analysis predicted minor yet significant structural changes in the encoded proteins. The nuclear translocation of hypoxia-inducible factor (HIF)-1alpha (HIF1A) in cultured fibroblasts was similar to controls. These results extend the range of clinical and biochemical variation associated with FD, supporting the notion that patients with moderate increases in fumarate excretion should be investigated for this disease. The tumoral risk in the patients and their relatives requires adequate screening protocols.
延胡索酸酶缺乏症（FD）由延胡索酸水合酶基因（FH）的双等位基因突变引起，是一种罕见的代谢疾病，影响三羧酸循环，导致严重的神经损伤和延胡索酸尿症。迄今为止，已知不到 30 个不相关的病例。此外，FH 基因的杂合突变导致遗传性平滑肌瘤病和肾细胞癌（HLRCC）。我们报告了另外三例 FD 患者，他们具有截然不同的临床表现和 FH 基因的新型错义突变。一名患者患有严重的新生儿脑病、脑回小、<1%的酶活性和轻度增加的尿延胡索酸水平。第二名患者患有小头畸形、智力迟钝、20%的延胡索酸酶活性和中间水平的尿延胡索酸。第三名患者患有轻度智力迟钝、脑回小、不同细胞类型中 42-61%的酶活性和大量尿延胡索酸。计算机分析预测编码蛋白存在微小但显著的结构变化。培养的成纤维细胞中缺氧诱导因子（HIF）-1α（HIF1A）的核易位与对照相似。这些结果扩展了与 FD 相关的临床和生化变异范围，支持这样一种观点，即应该对排泄延胡索酸中度增加的患者进行这种疾病的调查。患者及其亲属的肿瘤风险需要适当的筛查方案。
