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

  •  
  • Overview
  •  
  • Research
  •  
  • Identity
  •  
  • Additional Document Info
  •  
  • View All
  •  

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.

authors

  • Celestino-Soper, PBS
  • Violante, S
  • Crawford, EL
  • Luo, R
  • Lionel, AC
  • Delaby, E
  • Cai, G
  • Sadikovic, B
  • Lee, K
  • Lo, C
  • Gao, K
  • Person, RE
  • Moss, TJ
  • German, JR
  • Huang, N
  • Shinawi, M
  • Treadwell-Deering, D
  • Szatmari, Peter
  • Roberts, W
  • Fernandez, B
  • Schroer, RJ
  • Stevenson, RE
  • Buxbaum, JD
  • Betancur, C
  • Scherer, SW
  • Sanders, SJ
  • Geschwind, DH
  • Sutcliffe, JS
  • Hurles, ME
  • Wanders, RJA
  • Shaw, CA
  • Leal, SM
  • Cook, EH
  • Goin-Kochel, RP
  • Vaz, FM
  • Beaudet, AL

publication date

  • May 22, 2012