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 malemale 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.

Potential serum biomarkers from a metabolomics study of autism

“…Lower levels of L-acetylcarnitine and decanoylcarnitine have been found in children with autism and may reflect mitochondrial dysfunction. 78,79,80 A doubleblind, parallel, multicentre comparison of L-acetylcarnitine with placebo in patients with attention-deficit/hyperactivity disorder and in boys with fragile X syndrome indicated that L-actylcarnitine significantly improved social behaviour. 81 The alteration in these serum biomarkers could partly contribute to the variety of clinical manifestations of autism.…”

Autism and inborn errors of metabolism: how much is enough?

“…While this TMLHE deletion occurred in the same frequency in control males versus males with ASD in simplex families, it was found with a 2.85-fold higher frequency in multiplex probands compared with all male controls. 3 In summary, despite the recent identification of new IEMs as a cause of autism, the overall picture regarding the contribution of IEMs to autism remains relatively unaltered. It is unquestionably true that features of autism may be observed in a small portion of IEMs.…”

“…Similarly, exome sequencing has been shown to contribute to the identification of rare meaningful variants in a substantial proportion of patients with ASD. 1,2 Recent reports emphasized the causal role of inborn errors of metabolism (IEMs) in autism, [3][4][5] suggesting that some IEMs would be a preventable cause of autism. Exome sequencing has improved the ability to unravel recessive diseases in patients with ASD, especially in consanguineous families.…”

Primary Carnitine Deficiency and Newborn Screening for Disorders of the Carnitine Cycle

“…However, deletion of the TMLHE gene, which is part of the carnitine synthesis pathway and located on the X chromosome, is found more often in males with non-dysmorphic autism [20] . In the study by Celestino-Soper et al [20] , TMLHE deficiency was found to be common in control males (1 in 366) and was not increased in frequency in probands from simplex autism families (1 in 323). However, it was nearly 3-fold more frequent in probands from male-male multiplex autism families compared with controls (1 in 130).…”