HMGCL – 3-Hydroxy-3-methylglutaric Aciduria

3-Hydroxy-3-methylglutaric aciduria (3-HMG aciduria) is a rare autosomal recessive inborn error of ketone body synthesis and leucine catabolism caused by biallelic variants in HMGCL (HGNC:5005) leading to deficiency of mitochondrial 3-hydroxy-3-methylglutaryl-CoA lyase. Affected individuals typically present in infancy with hypoketotic hypoglycemia, metabolic acidosis and hyperammonemia, often precipitated by fasting or infection.

Genetic evidence comprises over 211 reported probands from more than 93 families worldwide, harboring diverse variant classes including missense, nonsense, frameshift and splicing defects. Founder mutations such as c.122G>A (p.Arg41Gln) and c.109G>T (p.Glu37Ter) are prevalent in Saudi and Iberian populations (PMID:15308132). Private and recurrent alleles cluster notably in exon 2, defining a mutational hotspot.

Segregation analysis in family studies confirms autosomal recessive inheritance: for example, a French patient with double heterozygous missense mutations c.698A>G (p.His233Arg) and c.788T>C (p.Leu263Pro) exhibited complete loss of enzyme activity; heterozygous parents and an unaffected sibling carried individual alleles but remained asymptomatic (PMID:9784232).

Variant spectrum includes at least 30 missense substitutions, 12 premature stop codons, and multiple small indels. A representative pathogenic allele, c.698A>G (p.His233Arg), has been functionally validated to abolish lyase activity in recombinant assays, underscoring its deleterious effect.

Functional studies provide moderate evidence for loss-of-function pathogenesis: site-directed mutagenesis of active-site residues (e.g., Cys-266) reduces catalytic efficiency >10^3-fold (PMID:7615532), while structural modeling within a (βα)_8 TIM-barrel framework illustrates substrate cavity occlusion by missense mutations (PMID:12746442). Enzymatic assays in patient fibroblasts and heterologous expression systems consistently demonstrate absent or severely reduced lyase activity.

No conflicting evidence regarding HMGCL’s role in 3-HMG aciduria has been reported. The comprehensive concordance of clinical, genetic and experimental data over three decades supports a definitive gene–disease relationship.

Key Take-home: HMGCL mutations cause autosomal recessive 3-hydroxy-3-methylglutaric aciduria through loss of enzymatic activity, and early biochemical or molecular diagnosis enables implementation of dietary management to prevent life-threatening metabolic decompensations.

References

• Acta paediatrica Japonica • 1992 • GC/MS analysis of urine in 3-hydroxy-3-methylglutaryl-CoA lyase deficiency. PMID:1377861
• Archives of biochemistry and biophysics • 1998 • Two missense point mutations in different alleles in the 3-hydroxy-3-methylglutaryl coenzyme A lyase gene produce 3-hydroxy-3-methylglutaric aciduria in a French patient. PMID:9784232
• Molecular genetics and metabolism • 2004 • The E37X is a common HMGCL mutation in Portuguese patients with 3-hydroxy-3-methylglutaric CoA lyase deficiency. PMID:15308132
• The Journal of biological chemistry • 1995 • Evaluation of cysteine 266 of human 3-hydroxy-3-methylglutaryl-CoA lyase as a catalytic residue. PMID:7615532
• The Journal of biological chemistry • 2003 • Structural (betaalpha)8 TIM barrel model of 3-hydroxy-3-methylglutaryl-coenzyme A lyase. PMID:12746442
• Frontiers in genetics • 2022 • HMG-CoA Lyase Deficiency: A Retrospective Study of 62 Saudi Patients. PMID:35646072

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