3-Hydroxy-3-methylglutaryl-CoA lyase deficiency, (HMGCLD) also known as HMGCL deficiency, HMG-CoA lyase deficiency, or hydroxymethylglutaric aciduria, is an uncommon autosomal recessive inborn error in ketone body production and leucine breakdown caused by HMGCL gene mutations. Typically, nonspecific symptoms such as frequent vomiting, convulsions, and decreased alertness are displayed by patients. Typical laboratory results include higher plasma/serum transaminase activity, hyperammonemia, acidosis, hypoglycemia, and an increased anion gap. This mitochondrial enzyme contributes to the metabolism of dietary proteins by converting HMG-CoA into acetyl-CoA and acetoacetate, which is the last stage of the breakdown of leucine and fat for energy. As a result, the body is unable to produce ketone bodies, which are necessary for generating energy during fasting. 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is passed down as an autosomal recessive trait.
Mechanism
The pathophysiology of 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency, like that of many other inborn errors of metabolism, can be explained by the accumulation of potentially harmful metabolites (leucine) and a lack of products (ketone bodies). Hypoglycemia severely impairs counterregulatory compensation because it affects leucine catabolism as well as fat oxidation, which results in secondary metabolic dysfunction. Metabolite levels in the leucine oxidation pathway may be significantly raised, including 3-MGL and 3-HIVA. Depletion of Coenzyme A recycling for other activities can also result from intramitochondrial buildup of acetyl-coA. The relationship between 3-MGC accumulation as a measure of mitochondrial malfunction and leucine oxidation in terms of symptomatology is still unknown.
Outlook
The overall mortality rate of 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is 16%.
Epidemiology
The incidence of 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is fewer than 1/100,000 live births.
History
3-Hydroxy-3-methylglutaryl-CoA lyase deficiency was initially reported in 1976, and the gene was discovered and cloned in 1993. The first case in the literature was published in Western Australia in 1976, with usual findings of hypoglycemia and acidosis.