Features include always present findings: Diarrhea, Elevated circulating aspartate aminotransferase concentration, Vomiting, and Increased circulating free fatty acid level and others; and very common findings: Encephalopathy, Hepatic steatosis, Seizure, and Enlarged liver (hepatomegaly) and others. 20 total HPO annotations.

HMGCS2 encodes 3-hydroxy-3-methylglutaryl-CoA synthase 2 (508 aa). Catalyzes the first irreversible step in ketogenesis, condensing acetyl-CoA to acetoacetyl-CoA to form HMG-CoA, which is converted by HMG-CoA reductase (HMGCR) into mevalonate Highest expression in Liver (748.5 TPM) and Colon Transverse (218.1 TPM).

3-hydroxy-3-methylglutaryl-CoA synthase deficiency is caused by mutations in the HMGCS2 gene on chromosome 1.

The HMGCS2 protein participates in Expression of HMGCS2, LONP1 degrades mitochondrial matrix proteins, and acetoacetyl-CoA+acetyl-CoA = HMG-CoA + CoASH pathways.

HMGCS2 is classified as a druggable target (Druggable Genome and Enzyme categories) with score 7.5.

Genetic testing for HMGCS2 is available. Testing is considered confirmatory for diagnosis.

Phenotype severity distribution: 8 always present features, 10 very common features, 2 common features.

Estimated prevalence: <1 in 1,000,000 (VERY_RARE).

No clinical trials have been registered for 3-hydroxy-3-methylglutaryl-CoA synthase deficiency.

15 publications have been identified in PubMed for 3-hydroxy-3-methylglutaryl-CoA synthase deficiency. Research spans Case Report / Case Series (50%), Review / Meta-Analysis (21%), and Basic Science / Preclinical (21%).