title: A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism.
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.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Patrícia B S
authors.initials: PB
authors.lastname: Celestino-Soper
authors.forename: Sara
authors.initials: S
authors.lastname: Violante
authors.forename: Emily L
authors.initials: EL
authors.lastname: Crawford
authors.forename: Rui
authors.initials: R
authors.lastname: Luo
authors.forename: Anath C
authors.initials: AC
authors.lastname: Lionel
authors.forename: Elsa
authors.initials: E
authors.lastname: Delaby
authors.forename: Guiqing
authors.initials: G
authors.lastname: Cai
authors.forename: Bekim
authors.initials: B
authors.lastname: Sadikovic
authors.forename: Kwanghyuk
authors.initials: K
authors.lastname: Lee
authors.forename: Charlene
authors.initials: C
authors.lastname: Lo
authors.forename: Kun
authors.initials: K
authors.lastname: Gao
authors.forename: Richard E
authors.initials: RE
authors.lastname: Person
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Moss
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: German
authors.forename: Ni
authors.initials: N
authors.lastname: Huang
authors.forename: Marwan
authors.initials: M
authors.lastname: Shinawi
authors.forename: Diane
authors.initials: D
authors.lastname: Treadwell-Deering
authors.forename: Peter
authors.initials: P
authors.lastname: Szatmari
authors.forename: Wendy
authors.initials: W
authors.lastname: Roberts
authors.forename: Bridget
authors.initials: B
authors.lastname: Fernandez
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Schroer
authors.forename: Roger E
authors.initials: RE
authors.lastname: Stevenson
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Catalina
authors.initials: C
authors.lastname: Betancur
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Sanders
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Geschwind
authors.forename: James S
authors.initials: JS
authors.lastname: Sutcliffe
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Hurles
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Chad A
authors.initials: CA
authors.lastname: Shaw
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.forename: Robin P
authors.initials: RP
authors.lastname: Goin-Kochel
authors.forename: Frédéric M
authors.initials: FM
authors.lastname: Vaz
authors.forename: Arthur L
authors.initials: AL
authors.lastname: Beaudet
mesh_terms: D001321:Autistic Disorder / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D002331:Carnitine / Q000096:biosynthesis / Q000172:deficiency*; D041321:Chromosomes, Human, X / Q000235:genetics*; D003071:Cognition / Q000502:physiology; D005091:Exons / Q000235:genetics; D017353:Gene Deletion; D050172:Genes, X-Linked / Q000235:genetics*; D006801:Humans; D008297:Male; D008661:Metabolism, Inborn Errors / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000097:blood / Q000235:genetics* / Q000652:urine; D019683:Penetrance; D012307:Risk Factors; D035781:Siblings
chemical_list: D006899:Mixed Function Oxygenases; C025931:trimethyl-lysine hydroxylase; D002331:Carnitine