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

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

Affiliation

  • 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.

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