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3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency

3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency Deep Research Fallback

⚠️ Fallback MONDO:0011614

3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency Deep Research Fallback

Provider Attempts

  • 2026-05-04T09:20Z: timeout 120 just research-disorder falcon 3-Hydroxy-3-Methylglutaryl-CoA_Synthase_Deficiency failed before provider execution because the disorder YAML did not yet exist.
  • 2026-05-04T09:21Z: timeout 120 just research-disorder falcon 3-Hydroxy-3-Methylglutaryl-CoA_Synthase_Deficiency timed out with exit code 124 after the provider command was terminated by timeout.
  • 2026-05-04T09:24Z: timeout 120 just research-disorder openai 3-Hydroxy-3-Methylglutaryl-CoA_Synthase_Deficiency timed out with exit code 124 after the provider command was terminated by timeout.

No provider-generated deep-research narrative was available within the bounded runtime. Curation therefore proceeded from generated structured Orphanet evidence and fetched PubMed caches, without hand-editing any references_cache/*.md files.

Evidence Scope Used For Curation

  • ORPHA:35701 structured record for disease definition, MONDO/OMIM exact mappings, autosomal recessive inheritance, worldwide point-prevalence band, HMGCS2 disease-gene association, childhood onset, and Orphanet HPO phenotypes.
  • PMID:39798988 for the 2025 systematic review of 93 reported cases plus two new patients, current clinical spectrum, onset range, acute crisis triggers, dicarboxylic aciduria frequency, 4HMP detection, and C2/C0 acylcarnitine diagnostic recommendation.
  • PMID:11228257 and PMID:11479731 for early molecular diagnosis papers and functional confirmation that HMGCS2 variants can abolish mitochondrial HMG-CoA synthase activity.
  • PMID:32952630 for Japanese patient cases, in vitro functional analysis of five novel HMGCS2 mutations, ketogenesis biochemistry, acute-phase acetylcarnitine rationale, and practical fasting/glucose management.
  • PMID:35308163 for a 10-patient Chinese case series covering crisis phenotype, molecular spectrum, and common biochemical abnormalities.
  • PMID:39143735 for cyclic-vomiting-like presentation and the importance of molecular testing when biochemical markers are nonspecific.
  • PMID:40548098 for neonatal hyperammonemic coma, intrafamilial variability, 4HMP after fasting, and fasting avoidance with or without L-carnitine during intercurrent illness.

Curation Conclusions

The accepted disease model is biallelic HMGCS2 loss of function causing deficient mitochondrial HMG-CoA synthase 2 activity in hepatocytes. This blocks ketone body biosynthesis from acetyl-CoA and acetoacetyl-CoA during fasting or illness, producing hypoketotic hypoglycemia and acute metabolic decompensation. The acute biochemical pattern can include dicarboxylic aciduria, urinary 4-hydroxy-6-methyl-2-pyrone, and elevated plasma C2/C0 acylcarnitine ratio. Management is preventive and emergency-focused: avoid prolonged fasting, provide carbohydrate/glucose support during poor intake or illness, consider L-carnitine during intercurrent illness where clinically appropriate, and offer genetic counseling for autosomal recessive recurrence risk.