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, stereotypical, ... 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, stereotypical, 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.
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, ... 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.
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 ... 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).