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

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abstract

  • We recently reported a deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene in a proband with autism.TMLHEmaps to the X chromosome and encodes the first enzyme in carnitine biosynthesis, 6-N-trimethyllysine dioxygenase. Deletion of exon 2 ofTMLHEcauses 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.TMLHEdeficiency 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 thatTMLHEdeficiency is a risk factor for autism (metaanalysis Z-score = 2.90 andP= 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.

authors

  • Celestino-Soper, Patrícia BS
  • Violante, Sara
  • Crawford, Emily L
  • Luo, Rui
  • Lionel, Anath C
  • Delaby, Elsa
  • Cai, Guiqing
  • Sadikovic, Bekim
  • Lee, Kwanghyuk
  • Lo, Charlene
  • Gao, Kun
  • Person, Richard E
  • Moss, Timothy J
  • German, Jennifer R
  • Huang, Ni
  • Shinawi, Marwan
  • Treadwell-Deering, Diane
  • Szatmari, Peter
  • Roberts, Wendy
  • Fernandez, Bridget
  • Schroer, Richard J
  • Stevenson, Roger E
  • Buxbaum, Joseph D
  • Betancur, Catalina
  • Scherer, Stephen W
  • Sanders, Stephan J
  • Geschwind, Daniel H
  • Sutcliffe, James S
  • Hurles, Matthew E
  • Wanders, Ronald JA
  • Shaw, Chad A
  • Leal, Suzanne M
  • Cook, Edwin H
  • Goin-Kochel, Robin P
  • Vaz, Frédéric M
  • Beaudet, Arthur L

publication date

  • May 22, 2012