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

  • Proc Natl Acad Sci U S A. 2012 May 22;109(21):7974-81. doi: 10.1073/pnas.1120210109.
Patrícia B S Celestino-Soper  1 ,  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
Affiliations
  • 1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
PMID: 22566635 DOI: 10.1073/pnas.1120210109
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.