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

Patrícia Celestino-Soper 1 Sara Violante 2, 3 Emily Crawford 4 Rui Luo 5 Anath Lionel 6 Elsa Delaby 7 Guiqing Cai 8 Bekim Sadikovic 1 Kwanghyuk Lee 1 Charlene Lo 1 Kun Gao 5 Richard Person 1 Timothy Moss 1 Jennifer German 1 Ni Huang 9 Marwan Shinawi 1, 10 Diane Treadwell-Deering 11, 10 Peter Szatmari 12 Wendy Roberts 13 Bridget Fernandez 14 Richard Schroer 15 Roger Stevenson 15 Joseph Buxbaum 8 Catalina Betancur 7 Stephen Scherer 6, 13 Stephan Sanders 16 Daniel Geschwind 5 James Sutcliffe 4 Matthew Hurles 9 Ronald Wanders 2 Chad Shaw 1 Suzanne Leal 1 Edwin Cook 17 Robin Goin-Kochel 1, 10, 18 Frédéric Vaz 2 Arthur Beaudet 1, 10, 18, *
* Corresponding author
1 Department of Molecular and Human Genetics
2 Laboratory Genetic Metabolic Disease
3 Metabolism and Genetics Group
4 Department of Molecular Physiology & Biophysics and Psychiatry
5 Department of Human Genetics, UCLA
6 Program in Genetics and Genomic Biology
7 Physiopathologie des Maladies du Système Nerveux Central
8 Human Genetics Center
9 Department of Neurology
10 Texas Children's Hospital [Houston, USA]
11 Department of psychiatry
12 Department of Psychiatry and Behavioural Neurosciences
13 Autism Research Unit
14 Disciplines of Genetics and Medicine
15 The Greenwood Genetic Center
16 Departments of Psychiatry and Genetics
17 Department of Psychiatry
18 Department of pediatrics
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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Patrícia Celestino-Soper, Sara Violante, Emily Crawford, Rui Luo, Anath 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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