HMG-CoA Lyase Deficiency and Metabolic Disorders

3-Hydroxy-3-methylglutaryl-CoA (HMG-CoA) lyase deficiency is a rare autosomal recessive disorder that disrupts both ketogenesis and leucine catabolism. The enzyme HMG-CoA lyase catalyses the final step of ketone body synthesis, converting HMG-CoA into acetoacetate and acetyl-CoA. Loss of enzyme activity leads to insufficient ketone production during fasting or stress, resulting in hypoketotic hypoglycaemia, metabolic acidosis and hyperammonaemia. Clinical onset typically occurs in early infancy with acute metabolic decompensation, although milder or late-onset presentations are reported. Long-term management centres on emergency protocols during intercurrent illness and dietary modification, including controlled protein and fat intake, supplemented by glucose and ketone precursors. Advances in molecular genetics have revealed a spectrum of HMGCL gene mutations, including large deletions, point variants and uniparental disomy, some of which display regional founder effects. Beyond acute crises, patients may develop neurological or hepatic complications, underlining the wider relevance of HMG-CoA lyase to energy homeostasis and organ development. Emerging insights into the structure, subcellular isoforms and regulation of HMG-CoA lyase promise to inform future therapies and broaden understanding of metabolic flexibility in health and disease.

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HMG-CoA Lyase Deficiency and Metabolic Disorders publication trend

The graph below shows the total number of articles in hmg-coa lyase deficiency and metabolic disorders across all publications each year (not limited to Nature Index journals).

Technical terms

HMG-CoA Lyase: Mitochondrial enzyme that cleaves 3-hydroxy-3-methylglutaryl-CoA to generate ketone bodies and acetyl-CoA.

Ketogenesis: Metabolic pathway by which the liver produces ketone bodies as alternative energy fuels during fasting.

Leucine Catabolism: Breakdown of the branched-chain amino acid leucine, part of which converges on the HMG-CoA lyase reaction.

Hypoketotic Hypoglycaemia: Low blood glucose levels accompanied by an inadequate production of ketone bodies.

Hyperammonaemia: Elevated ammonia in the blood, a consequence of impaired nitrogen metabolism during metabolic crises.

Metabolic Acidosis: Acid–base disturbance marked by decreased blood pH due to accumulation of organic acids.

References

1. Treatment of HMG-CoA Lyase Deficiency—Longitudinal Data on Clinical and Nutritional Management of 10 Australian Cases. Nutrients (2023).
2. 3-Hydroxy-3-Methylglutaric Acid Disrupts Brain Bioenergetics, Redox Homeostasis, and Mitochondrial Dynamics and Affects Neurodevelopment in Neonatal Wistar Rats. Biomedicines (2024).
3. HMG-CoA Lyase Deficiency: A Retrospective Study of 62 Saudi Patients. Frontiers in Genetics (2022).
4. 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: one disease - many faces. Orphanet Journal of Rare Diseases (2020).
5. Application of multiplex ligation-dependent probe amplification, and identification of a heterozygous Alu-associated deletion and a uniparental disomy of chromosome 1 in two patients with 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. International Journal of Molecular Medicine (2015).
6. More Than One HMG-CoA Lyase: The Classical Mitochondrial Enzyme Plus the Peroxisomal and the Cytosolic Ones. International Journal of Molecular Sciences (2019).