Clinical trajectory and long-term management of 3-Hydroxy-3-Methylglutaryl-CoA lyase deficiency: Insights from a lifespan cohort.

BACKGROUND

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is an ultra-rare autosomal recessive disorder of leucine catabolism and ketogenesis. Evidence on its long-term course and management is limited, with no international consensus on treatment. We characterized the clinical, genetic, dietary, and long-term outcomes of HMGCLD in a Turkish cohort.

METHODS

We retrospectively analyzed 12 patients with HMGCLD followed at a tertiary metabolic center in Turkey between 1996 and 2026. Cross-sectional and longitudinal clinical, biochemical, dietary, and neurocognitive data were collected. Variants were classified according to ACMG/AMP guidelines.

RESULTS

Twelve patients (5 males, 7 females; 10 families; parental consanguinity, 75%; median age,19 years) were included. Eleven presented with symptoms, most within the first year of life; whereas one was identified through newborn screening abroad. Three had diagnostic delays of 5, 10, and 17 years. Five HMGCL variants were identified, including two previously unreported variants, one of uncertain significance. Six remained on a leucine-restricted diet; in four, the leucine-free amino acid mixture was discontinued under medical supervision after plasma leucine normalized. Growth was preserved, and eight of 11 assessed patients had borderline or better cognitive performance. Hepatic steatosis was present in 5/12 patients (42%). Three of six adults developed metabolic decompensation after age 18, including one fatal pregnancy-related crisis.

CONCLUSIONS

HMGCLD is a lifelong disorder with preserved growth and variable cognitive outcomes. Our findings expand the HMGCL mutational landscape, identify hepatic steatosis as a potentially underrecognized finding warranting further study, and highlight the persistent risk of adult metabolic decompensation, particularly during pregnancy.