A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism
A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism
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DOI：
10.1073/pnas.1120210109
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发表时间：
2012-05-22
影响因子：
11.1
通讯作者：
Beaudet, Arthur L.
中科院分区：
文献类型：
--
作者：
Celestino-Soper, Patricia B. S.;Violante, Sara;Beaudet, Arthur L.
我们最近报道了一个自闭症先显子三甲基赖氨酸羟化酶（TMLHE）基因外显子2的缺失。TMLHE定位于X染色体，编码肉毒碱生物合成中的第一个酶，6- n -三甲基赖氨酸双加氧酶。TMLHE外显子2的缺失导致酶缺乏，导致血浆和尿液中底物浓度（6- n -三甲基赖氨酸）升高和产物水平（3-羟基-6- n -三甲基赖氨酸和γ -丁甜菜碱）降低。TMLHE缺陷在对照男性中很常见（8,787 / 24或366 / 1），在单纯性自闭症家庭的先证中没有显著增加（2,904 / 9或323 / 1）。然而，与对照组相比，男性-男性多重自闭症家庭的先证者的频率高出2.82倍（909人中有7人，130人中有1人；P = 0.023）。此外，在男性-男性多重家族中，先证的7个自闭症男性兄弟姐妹中有6个有缺失，这表明TMLHE缺陷是自闭症的一个危险因素（荟萃分析Z-score = 2.90, P = 0.0037），尽管外显率较低（2-4%）。这些数据表明，肉碱代谢失调可能在非畸形自闭症中很重要；肉毒碱摄入、丢失、运输或合成的异常可能在很大一部分非畸形自闭症病例中很重要；肉碱途径可能为治疗或预防自闭症提供一个新的靶点。
We recently reported a deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene in a proband with autism. TMLHE maps to the X chromosome and encodes the first enzyme in carnitine biosynthesis, 6-N-trimethyllysine dioxygenase. Deletion of exon 2 of TMLHE causes enzyme deficiency, resulting in increased substrate concentration (6-N-trimethyllysine) and decreased product levels (3-hydroxy-6-N-trimethyllysine and gamma-butyrobetaine) in plasma and urine. TMLHE deficiency is common in control males (24 in 8,787 or 1 in 366) and was not significantly increased in frequency in probands from simplex autism families (9 in 2,904 or 1 in 323). However, it was 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 or 1 in 130; P = 0.023). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (meta-analysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism.