TMLHE – Autism Spectrum Disorder

This summary integrates multiple lines of evidence supporting a strong association between alterations in TMLHE and autism spectrum disorder. A detailed case report described a 4‑year‑old male with regressive autism who harbored a frameshift mutation, c.961_962del (p.Ile321fs) (PMID:25943046), and notable carnitine deficiency. Following carnitine supplementation, the patient’s developmental regression ceased, raising the possibility that deficits in carnitine biosynthesis contribute to regressive autism phenotypes.

Multi‑patient studies further support the role of TMLHE variants in autism. In one study, a nonsense mutation as well as several missense substitutions were identified in male patients with autism spectrum disorder (PMID:23092983). In addition, a separate whole‑genome sequencing analysis in ASD trios identified structural alterations affecting TMLHE, with segregation of the mutation observed in affected male siblings (PMID:39610113). These findings corroborate the initial observation that the gene is an important contributor to ASD through multiple mutational mechanisms.

The genetic evidence is bolstered by a rich variant spectrum that includes loss‑of‑function changes, missense variants, and even structural lesions. The recurrent identification of these deleterious alleles in unrelated probands as well as in families with multiple affected individuals underscores a robust X‑linked contribution to autism pathogenesis. Inheritance in these cases is consistent with an X‑linked pattern, as evidenced by the predominance of male presentations and segregation among affected male siblings.

Functional studies have provided additional support for the pathogenicity of TMLHE alterations. In vitro experiments demonstrated that mutations in TMLHE lead to a marked loss‑of‑function in the enzyme responsible for the first step of carnitine biosynthesis. Detailed analyses including mitochondrial targeting assays and promoter activity evaluations further showed that specific TMLHE isoforms are crucial for cellular metabolic regulation (PMID:15754339; PMID:17408883).

No substantial conflicting evidence has been reported; instead, the available data from both clinical case reports and high‐throughput sequencing studies converge to implicate TMLHE variants in autism spectrum disorder. While additional data are emerging that may exceed traditional scoring limits, the current evidence is sufficient to guide clinical diagnostic decision‑making and inform potential therapeutic interventions such as carnitine supplementation.

In summary, the genetic and experimental findings together provide a compelling narrative linking TMLHE dysfunction to autism spectrum disorder. Key take‑home message: testing for TMLHE variants in patients with regressive autism may enable targeted treatment approaches and improved clinical management.

References

• American journal of medical genetics. Part A • 2015 • Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation PMID:25943046
• Translational psychiatry • 2012 • Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE PMID:23092983
• Psychiatry and clinical neurosciences • 2025 • Whole-genome sequencing analysis of Japanese autism spectrum disorder trios PMID:39610113
• Journal of cellular physiology • 2005 • Functional analysis of TMLH variants and definition of domains required for catalytic activity and mitochondrial targeting PMID:15754339
• Gene • 2007 • Functional characterization of the TMLH gene: promoter analysis, in situ hybridization, identification and mapping of alternative splicing variants PMID:17408883

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