3-Hydroxy-3-methylglutaryl-CoA lyase deficiency

Signs and symptoms

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency can appear in a variety of ways in terms of clinical presentation, from a severe neonatal onset with potentially fatal consequences to an adult presentation. Clinical signs of 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency appear either early in the neonatal stage or later in the first year of life. 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.

Causes

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency is the result of HMGCL gene mutations. HMGCL is found on chromosome 1p36.11's short arm and codes for the enzyme 3-hydroxymethyl-3-methylglutaryl-coenzyme A lyase (HMG-CoA lyase). 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. Additionally, patients with MRI spectroscopy have shown 3-HIVA and 3-HMG, suggesting that these proximal metabolites may play a role in pathogenesis. 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.

Diagnosis

Since 3-hydroxy isovaleryl carnitine (C5-OH) is typically elevated in this condition, 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency can be identified during newborn screening by testing it using tandem mass spectrometry methodology. Enzyme activity testing in lymphocytes, immortalized lymphoblastoid cells, or fibroblasts, as well as HMGCL gene mutation studies, may confirm the diagnosis of 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency.

Treatment

As with other uncommon inherited metabolic illnesses, there are no controlled treatment studies for 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency. Consequently, it is impossible to make any judgments about whether a particular diet or carnitine supplements are required. Clinical reports and pathobiochemical considerations suggest that the mainstay of therapy is avoiding fasting. L-carnitine supplementation may have detoxifying properties, prevent intracellular loss of free coenzyme A, and prevent secondary L-carnitine insufficiency.

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.

References

References

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2. (2007). "Molecular genetics of HMG-CoA lyase deficiency". Elsevier BV.
3. (2009-01-28). "Ten novel''HMGCL''mutations in 24 patients of different origin with 3-hydroxy-3-methyl-glutaric aciduria". Hindawi Limited.
4. (2010-06-08). "Differential HMG-CoA lyase expression in human tissues provides clues about 3-hydroxy-3-methylglutaric aciduria". Wiley.
5. (2020). "A newborn screening approach to diagnose 3-hydroxy-3-methylglutaryl-CoA lyase deficiency". JIMD Reports.
6. (1988). "3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: review of 18 reported patients". European Journal of Pediatrics.
7. (2023-01-19). "Treatment of HMG-CoA Lyase Deficiency—Longitudinal Data on Clinical and Nutritional Management of 10 Australian Cases". MDPI AG.
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9. (2020). "3-Methylglutaric acid in energy metabolism". Elsevier BV.
10. (2017). "Coupled brain and urine spectroscopy — in vivo metabolomic characterization of HMG-CoA lyase deficiency in 5 patients". Elsevier BV.
11. (2008). "Hereditary and acquired diseases of acyl-coenzyme A metabolism". Elsevier BV.
12. (2020-02-14). "3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: one disease — many faces". Springer Science and Business Media LLC.
13. (2017). "3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: Clinical presentation and outcome in a series of 37 patients". Elsevier BV.
14. (2013). "A neonatal case of 3-hydroxy-3-methylglutaric-coenzyme A lyase deficiency". Springer Science and Business Media LLC.
15. (1976-04-29). "Patient with Defect in Leucine Metabolism". Massachusetts Medical Society.
16. (1993-02-25). "3-Hydroxy-3-methylglutaryl coenzyme A lyase (HL). Cloning of human and chicken liver HL cDNAs and characterization of a mutation causing human HL deficiency". The Journal of Biological Chemistry.