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

Patrícia B.S. Celestino-Soper, Sara Violante, Emily L. Crawford, Rui Luo, Anath C. Lionel, Elsa Delaby, Guiqing Cai, Bekim Sadikovic, Kwanghyuk Lee, Charlene Lo, Kun Gao, Richard E. Person, Timothy J. Moss, Jennifer R. German, Ni Huang, Marwan Shinawi, Diane Treadwell-Deering, Peter Szatmari, Wendy Roberts, Bridget FernandezRichard J. Schroer, Roger E. Stevenson, Joseph D. Buxbaum, Catalina Betancur, Stephen W. Scherer, Stephan J. Sanders, Daniel H. Geschwind, James S. Sutcliffe, Matthew E. Hurles, Ronald J.A. Wanders, Chad A. Shaw, Suzanne M. Leal, Edwin H. Cook, Robin P. Goin-Kochel, Frédéric M. Vaz, Arthur L. Beaudet

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89 Scopus citations


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.

Original languageEnglish
Pages (from-to)7974-7981
Number of pages8
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number21
StatePublished - May 22 2012


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