HMGCS2 – Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency

Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2; HGNC:5008) catalyzes the rate-limiting step in hepatic ketogenesis. Autosomal recessive loss-of-function variants in HMGCS2 cause 3-hydroxy-3-methylglutaryl-CoA Synthase Deficiency, characterized by hypoketotic hypoglycemia, vomiting, lethargy, hepatomegaly, and encephalopathy following fasting or intercurrent illness.

Genetic studies across >20 unrelated probands (8 PMID:23751782; 6 PMID:25511235; 3 PMID:29597274; 4 PMID:32952630) have uncovered diverse biallelic variant classes including missense (e.g., p.Gly89Asp PMID:32969201), nonsense (p.Arg424Ter PMID:23751782), splice-site, frameshift, and exon-deletion events, confirming autosomal recessive inheritance.

Segregation analysis in multiple families, notably an additional affected sibling in a consanguineous pedigree PMID:16601895 and co-segregation of a novel homozygous variant in an Iranian family PMID:32969201, strengthens pathogenicity assignments.

Extensive functional assays demonstrate that missense variants such as p.Gly212Arg and p.Arg500His abolish enzyme activity in vitro PMID:11479731, while others (p.Phe174Leu) retain partial function PMID:23751782, correlating with phenotypic variability. Molecular dynamics and expression models have further elucidated the structural impact of dimerization-surface variants PMID:29597274.

Clinically, patients present with recurrent metabolic crises marked by hypoketotic hypoglycemia (HP:0001985), hepatomegaly (HP:0002240), dicarboxylic aciduria (HP:0003215), vomiting (HP:0002013), lethargy (HP:0001254), encephalopathy (HP:0001298), and occasionally coma (HP:0001259); biomarkers such as 4-hydroxy-6-methyl-2-pyrone enhance biochemical sensitivity PMID:29030856.

Integration of robust genetic, segregation, and functional data supports a definitive association between HMGCS2 and mitochondrial HMG-CoA synthase deficiency. Key take-home: Biallelic HMGCS2 variants underlie an autosomal recessive ketogenesis disorder for which early molecular diagnosis and biomarker screening guide clinical management.

References

• European Journal of Medical Genetics • 2013 • New case of mitochondrial HMG-CoA synthase deficiency. Functional analysis of eight mutations. PMID:23751782
• Journal of inherited metabolic disease • 2015 • Mitochondrial 3-hydroxy-3-methylglutaryl CoA synthase deficiency: urinary organic acid profiles and expanded spectrum of mutations. PMID:25511235
• International Journal of Molecular Sciences • 2018 • Human Mitochondrial HMG-CoA Synthase Deficiency: Role of Enzyme Dimerization Surface and Characterization of Three New Patients. PMID:29597274
• Experimental and Therapeutic Medicine • 2020 • Japanese patients with mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency: In vitro functional analysis of five novel HMGCS2 mutations. PMID:32952630
• Journal of inherited metabolic disease • 2006 • Refining the diagnosis of mitochondrial HMG-CoA synthase deficiency. PMID:16601895
• Molecular Genetics & Genomic Medicine • 2020 • Association of a novel homozygous mutation in the HMGCS2 gene with an HMGCSD in an Iranian patient. PMID:32969201
• Human Genetics • 2001 • Genetic basis of mitochondrial HMG-CoA synthase deficiency. PMID:11479731
• JIMD Reports • 2018 • Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency: Unique Presenting Laboratory Values and a Review of Biochemical and Clinical Features. PMID:29030856

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