Autism, Susceptibility To, X-Linked 6

A number sign (#) is used with this entry because of evidence that susceptibility to X-linked autism-6 (AUTSX6) is conferred by mutation in the TMLHE gene (300777) on chromosome Xq28.

Description

X-linked autism-6 is a neurodevelopmental disorder that affects only males. Some patients may respond favorably to carnitine supplementation (summary by Ziats et al., 2015).

Autism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996; Risch et al., 1999). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (see ASPG1; 608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008). Genetic studies in autism often include family members with these less stringent diagnoses (Schellenberg et al., 2006).

For a discussion of heterogeneity of autism, see 209850.

Clinical Features

Celestino-Soper et al. (2012) found that the cognitive function of TMLHE-deficient males with autism varies widely, with a full-scale IQ ranging from 38 to 143. Five of 21 with available data were in the range of intellectual disability, and 3 of 21 were reported as untestable. One proband had seizures. Six of 6 patients for whom information was available were described as nondysmorphic.

Nava et al. (2012) reported 4 boys, including 2 brothers, from 3 unrelated families with AUTSX6. The brothers, who were from Maghreb, also had moderate intellectual disability and mild variable dysmorphic features, such as ptosis, small mouth, short philtrum, large forehead, and macrosomia. Plasma available from the brothers and 1 of the unrelated patients showed increased trimethyllysine (TML) and slightly decreased or normal plasma carnitine.

Ziats et al. (2015) reported a boy with autism diagnosed at age 3 years after an episode of developmental regression associated with infection. At age 4 years 11 months, he had another episode of developmental regression of unclear etiology. Detailed laboratory studies showed low plasma levels of gamma butyrobetaine (gBB) and free carnitine. TML plasma levels were normal, but urinary levels were increased, and the TML:gBB ratio was elevated.

Clinical Management

Ziats et al. (2015) reported a boy with genetically confirmed TMLHED and autism who responded favorably to carnitine supplementation. After the initiation of treatment at age 4 years, 11 months, he showed improved language and social skills and acquired new developmental milestones.

Molecular Genetics

In a single patient with autism, Celestino-Soper et al. (2011) identified deletion of exon 2 of the TMLHE gene (300777.0001), which encodes the first enzyme in the biosynthesis of carnitine. This deletion was also identified in the patient's mother.

Celestino-Soper et al. (2012) performed further analysis of TMLHE deletions. 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 gamma-butyrobetaine) in plasma and urine. TMLHE deficiency was 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, 6 of 7 autistic male sibs 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 = 0.00037), although with low penetrance (2 to 4%). Celestino-Soper et al. (2012) concluded that their data suggested 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.

Celestino-Soper et al. (2012) noted 2 clinical investigations being initiated at that time. One involved studying carnitine metabolites in the cerebrospinal fluid of infants with autism with or without TMLHE deficiency. The other concerned treating very young infants with autism with or without TMLHE deficiency with carnitine or gamma-butyrobetaine (gamma-BB).

In 2 brothers with AUTSX6, Nava et al. (2012) identified a hemizygous truncating mutation in the TMLHE gene (R77X; 300777.0002). The mutation was found by X-chromosome exome sequencing of 12 unrelated families who each had at least 2 males with autism. Screening of the TMLHE gene in 501 additional male patients with autism identified 2 unrelated boys with hemizygous missense mutations (D244H, 300777.0003 and E369D, 300777.0004). Functional studies of the missense variants were not performed. In all 3 families, the mutation was inherited from the heterozygous unaffected mother.

In a boy with TMLHE deficiency and autism, Ziats et al. (2015) identified a hemizygous truncating mutation in the TMLHE gene (300777.0005). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was heterozygous in the unaffected mother. Subsequent to this finding, the mutation was also found in a 13-month-old male maternal first cousin of the proband whose development had been normal until that time; he was started on preventative carnitine supplementation.