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

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.

• Authors: 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 Fernandez, Richard 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 Jr, Robin P Goin-Kochel, Frédéric M Vaz, Arthur L Beaudet
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 109 Issue 21 Pg. 7974-81 (May 22 2012) ISSN: 1091-6490 [Electronic] United States
• PMID: 22566635 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Mixed Function Oxygenases
• trimethyl-lysine hydroxylase
• Carnitine

Topics

• Autistic Disorder (epidemiology, genetics, metabolism)
• Carnitine (biosynthesis, deficiency)
• Chromosomes, Human, X (genetics)
• Cognition (physiology)
• Exons (genetics)
• Gene Deletion
• Genes, X-Linked (genetics)
• Humans
• Male
• Metabolism, Inborn Errors (epidemiology, genetics, metabolism)
• Mixed Function Oxygenases (blood, genetics, urine)
• Penetrance
• Risk Factors
• Siblings