Tmlhe, or trimethyllysine hydroxylase epsilon, encodes N6-trimethyllysine dioxygenase (TMLD), the first enzyme in carnitine biosynthesis [1,2,3,4,5,6,7]. Carnitine is essential for the transport of fatty acids into mitochondria for β-oxidation, thus Tmlhe is crucial for lipid metabolism [2].

In Tmlhe knockout mouse models, despite a significant decrease (more than 90%) in carnitine levels compared to wild-type mice, no significant social, cognitive, repetitive-behavior changes associated with autism spectrum disorder (ASD) were observed, nor was muscle strength and coordination affected [1]. Also, Tmlhe gene deletion in male mice lowered acylcarnitine concentrations in blood and cardiac tissues by up to 85% and decreased fatty acid oxidation by 30%, but did not impact muscle and heart function. Instead, it prevented ischaemia-reperfusion-induced mitochondrial and cardiac damage, as well as ROS production in cardiac mitochondria, leading to a 39% smaller infarct size [3]. In a child with Tmlhe deficiency and concurrent carnitine deficiency, carnitine supplementation ended the regression of autism symptoms [5].

In conclusion, Tmlhe's key role in carnitine biosynthesis is essential for lipid metabolism. Mouse knockout models have shown that, despite low carnitine levels, Tmlhe deficiency does not directly induce ASD-related phenotypes or motor dysfunction. However, it may play a protective role in preventing ischaemia-reperfusion-induced cardiac and mitochondrial damage. The case of the child with Tmlhe deficiency also indicates a potential link between Tmlhe-related carnitine deficiency and autism regression, suggesting carnitine supplementation as a possible treatment [1,3,5].