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A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism.

Patrícia B. S. Celestino-Soper 1 Sara Violante 2, 3 Emily L. Crawford 4 Rui Luo 5 Anath C. Lionel 6 Elsa Delaby 7 Guiqing Cai 8 Bekim Sadikovic 1 Kwanghyuk Lee 1 Charlene Lo 1 Kun Gao 5 Richard E. Person 1 Timothy J. Moss 1 Jennifer R. German 1 Ni Huang 9 Marwan Shinawi 1, 10 Diane Treadwell-Deering 11, 10 Peter Szatmari 12 Wendy Roberts 13 Bridget Fernandez 14 Richard J. Schroer 15 Roger E. Stevenson 15 Joseph D. Buxbaum 8 Catalina Betancur 7 Stephen W. Scherer 6, 13 Stephan J. Sanders 16 Daniel H. Geschwind 5 James S. Sutcliffe 4 Matthew E. Hurles 9 Ronald J. A. Wanders 2 Chad A. Shaw 1 Suzanne M. Leal 1 Edwin H. Cook 17 Robin P. Goin-Kochel 1, 10, 18 Frédéric M. Vaz 2 Arthur L. Beaudet 1, 10, 18, * 
Abstract : 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 γ-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 (metaanalysis 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.
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Submitted on : Thursday, May 10, 2012 - 7:44:08 PM
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Patrícia B. S. Celestino-Soper, Sara Violante, Emily L. Crawford, Rui Luo, Anath C. Lionel, et al.. A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism.. Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2012, 109 (21), pp.7974-7981. ⟨10.1073/pnas.1120210109⟩. ⟨inserm-00696112⟩



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