X-Linked Autism Type 9 Caused by a Hemizygote Pathogenic Variant in the TMLHE Gene: Etiological Diagnosis in an Adult...

Levocarnitine is essential for brain functioning and fatty acid metabolism and stems largely from dietary sources. The Epsilon-Trimethyllysine Hydroxylase (TMLHE) gene encodes the enzyme N-Trimethyllysine hydroxylase (TMLH) which catalyses the first step in the biosynthesis of carnitine. Lack of TMLH enzyme activity is associated with developmental delay and autistic behaviours described as X-linked recessive autism, type 6 (OMIM#300872).

Here, an institutionalized adult male patient with intellectual disability, autism, and challenging behaviours is presented in whom genetic analysis disclosed a novel pathogenic variant in the TMLHE gene. Extensive somatic, neurological, psychiatric, and neuropsychological investigations were performed next to examination of hematological and biochemical parameters including plasma carnitine status. Also, Whole Exome Sequencing (WES) and Next-Generation Metabolic Screening (NGMS) were performed.

Moderate intellectual disability along with obsessive and aggressive behaviour in the context of autism spectrum disorders was established as well as symptoms from the catatonic spectrum. With WES, a novel variant in the TMHLE gene was identified and using NGMS, increased concentration of trimethyllysine and decreased concentration of γ-butyrobetaine were found resulting in a significantly decreased BB/TML ratio, confirming the pathogenicity of this variant.

X-linked autism type 6 is characterized by moderate intellectual disability and symptoms from the autism spectrum in the absence of any dysmorphisms. To prevent regressive autistic episodes in young children, it is highly recommended to consider next-generation sequencing techniques as the first step in the differential diagnostic process of autism.