HAL : inserm-00696112, version 1

PubMed : 22566635

PubMed Central : 3361440

DOI : 10.1073/pnas.1120210109

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Proceedings- National Academy of Sciences Usa 109, 21 (2012) 7974-81

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 10, 11, 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 3, Chad A. Shaw 1, Suzanne M. Leal 1, Edwin H. Cook 17, Robin P. Goin-Kochel 1, 10, 18, Frédéric M. Vaz 3, Arthur L. Beaudet (  Auteur correspondant ) 1, 10, 18

(22/05/2012)

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.

1 :	Department of Molecular and Human Genetics
	Baylor College of Medicine
2 :	Metabolism and Genetics Group
	Research Institute for Medicines and Pharmaceutical Sciences – Universidade de Lisboa
3 :	Laboratory Genetic Metabolic Disease
	Academic Medical Center – University of Amsterdam
4 :	Department of Molecular Physiology and Biophysics
	Centers for Human Genetics Research and Molecular Neuroscience – Vanderbilt University
5 :	Department of Human Genetics
	University of California, Los Angeles – Semel Institute
6 :	The Centre for Applied Genomics and Program in Genetics and Genomic Biology
	The Hospital for Sick Children
7 :	Physiopathologie des Maladies du Système Nerveux Central
	INSERM : U952 – Université Pierre et Marie Curie [UPMC] - Paris VI – CNRS : UMR7224
8 :	Seaver Autism Research Center
	Mount Sinai School of Medicine
9 :	Department of Neurology
	Johns Hopkins University
10 :	Texas Children's Hospital
	Texas Children's Hospital
11 :	Department of psychiatry
	Baylor College of Medicine
12 :	Department of Psychiatry and Behavioural Neurosciences
	McMaster University
13 :	Autism Research Unit
	The Hospital for Sick Children and Bloorview Kids Rehabilitation – University of Toronto
14 :	Disciplines of Genetics and Medicine
	Memorial University of Newfoundland
15 :	Greenwood Genetic Center
	Greenwood Genetic Center
16 :	Departments of Psychiatry and Genetics
	Yale University School of Medicine
17 :	Department of Psychiatry
	Institute for Juvenile Research – University of Illinois at Chicago
18 :	Department of pediatrics
	Baylor College of Medicine

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Contributeur : Catalina Betancur <>

Soumis le : Jeudi 10 Mai 2012, 19:44:08

Dernière modification le : Mardi 7 Août 2012, 13:17:32