TY - JOUR
T1 - A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism
AU - Celestino-Soper, Patrícia B.S.
AU - Violante, Sara
AU - Crawford, Emily L.
AU - Luo, Rui
AU - Lionel, Anath C.
AU - Delaby, Elsa
AU - Cai, Guiqing
AU - Sadikovic, Bekim
AU - Lee, Kwanghyuk
AU - Lo, Charlene
AU - Gao, Kun
AU - Person, Richard E.
AU - Moss, Timothy J.
AU - German, Jennifer R.
AU - Huang, Ni
AU - Shinawi, Marwan
AU - Treadwell-Deering, Diane
AU - Szatmari, Peter
AU - Roberts, Wendy
AU - Fernandez, Bridget
AU - Schroer, Richard J.
AU - Stevenson, Roger E.
AU - Buxbaum, Joseph D.
AU - Betancur, Catalina
AU - Scherer, Stephen W.
AU - Sanders, Stephan J.
AU - Geschwind, Daniel H.
AU - Sutcliffe, James S.
AU - Hurles, Matthew E.
AU - Wanders, Ronald J.A.
AU - Shaw, Chad A.
AU - Leal, Suzanne M.
AU - Cook, Edwin H.
AU - Goin-Kochel, Robin P.
AU - Vaz, Frédéric M.
AU - Beaudet, Arthur L.
PY - 2012/5/22
Y1 - 2012/5/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84861443524&partnerID=8YFLogxK
U2 - 10.1073/pnas.1120210109
DO - 10.1073/pnas.1120210109
M3 - Article
C2 - 22566635
AN - SCOPUS:84861443524
VL - 109
SP - 7974
EP - 7981
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 21
ER -