A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism
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 P., 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.
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.