TMLH gene deficiency, carnitine levels, and autism spectrum disorder: a paradigm-shifting discovery by LIOS researchers

Researchers at the Laboratory of Pharmaceutical Pharmacology (LIOS), in collaboration with Prof. Schiöth from Uppsala University, have made a significant discovery. Contrary to previous assumption, they found that TMLH gene deficiency is not associated with autism spectrum disorder (ASD) phenotypes or motor dysfunction, despite the presence of low carnitine levels. This research will encourage scientists to reevaluate previous findings and seek the role of carnitine.

Large-sample and well-designed studies have identified a deletion of exon 2 of the trimethyllysine hydroxylase epsilon (TMLHE) gene and linked this deletion with autism spectrum disorder (ASD). TMLHE encodes the first enzyme in carnitine biosynthesis, N6-trimethyllysine dioxygenase (TMLD), which suggests that carnitine levels are important in ASD as well as cognitive and social functioning.
Carnitine, a widely used component in food supplements with an annual global market of 386 million USD, has been suggested as a potential therapeutic approach to address lower carnitine levels in ASD.

Prof. Maija Dambrova and Edgars Liepinsh, PhD have studied the biochemistry and metabolism of acylcarnitines for many years (Dambrova and Liepinsh, Exp Clin Endocrinol Diabetes 2015 and Dambrova et al., Pharmacol Rev. 2022). Given this expertise, they decided to explore the hypothesis that low carnitine levels might be linked to ASD.

The team developed a mouse model with a TMLD enzyme knockout, aiming to understand the impact of carnitine levels on ASD, cognitive function, and social behavior.
The mouse model exhibited a phenotype with a large increase in levels of the enzyme substrate trimethyllysine (TML) and very low carnitine levels. However, researchers did not observe any significant changes in social, cognitive, or repetitive-behavior phenotypes associated with ASD in the knockout mice; additionally, muscle strength and coordination were not affected. Therefore researchers concluded that TMLH gene inactivation in mice did not induce the ASD phenotype or motor dysfunction despite very low carnitine and in γ-butyrobetaine (GBB) concentrations. Moreover, the inactivation of TMLD did not yield a phenotype that aligned with previously described primary carnitine deficiency. Furthermore, obtained results showed that low levels of carnitine allow adequate energy production, muscle function and social behavior in mice.

The research has been published in the journal Molecular Autism (IF=6.2).

Read the article:

Liepinsh, E.*; Svalbe, B.; Stelfa, G.; Grinberga,S.; Zvejniece, L.; Schiöth, H.B.; Dambrova, M.
Knockout of Tmlhe in mice is not associated with autism spectrum disorder phenotypes or motor dysfunction despite low carnitine levels.
Molecular Autism 14, 29 (2023). DOI: