TMLHE (trimethyllysine hydroxylase, epsilon) encodes an enzyme that catalyzes the first committed step in carnitine biosynthesis, converting trimethyllysine to hydroxytrimethyllysine 1. Located on the X chrX, TMLHE functions in the mitochondrial matrix and is essential for carnitine production, a critical cofactor for fatty acid β-oxidation and brain function 2. TMLHE deficiency impairs carnitine biosynthesis, leading to increased trimethyllysine accumulation and decreased γ-butyrobetaine production, detectable through metabolic screening 1. The enzyme's role in carnitine metabolism links mitochondrial function to broader metabolic regulation; disrupted TMLHE function contributes to mitochondrial dysfunction and impaired carnitine homeostasis in disease states 3. TMLHE mutations are pathogenic in X-linked autism type 6, with deletions and novel variants identified in autistic individuals with intellectual disability 41. TMLHE deficiency occurs in approximately 1 in 366 males but shows 2.82-fold enrichment in male-male multiplex autism families, suggesting it is a genetic risk factor for autism with low penetrance 5. Brain carnitine deficiency from TMLHE dysfunction may contribute to 10-20% of nonsyndromic autism cases, particularly affecting males 2. Notably, carnitine supplementation has reversed regressive autism symptoms in patients with TMLHE mutations, indicating therapeutic potential 6.