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. Epub 2012 May 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Mixed Function Oxygenases
  • trimethyl-lysine hydroxylase
  • Carnitine