| Domain | Summary | Key details / frequencies |
|---|---|---|
| Identifiers | Disease: mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency / HMGCS2 deficiency; OMIM disease #605911; causal gene **HMGCS2** (OMIM gene #600234) (pqac-00000000, pqac-00000001, pqac-00000002) | Rare ketogenesis disorder with estimated incidence **<1/1,000,000** in the 2025 Vietnamese series/review (pqac-00000000) |
| Synonyms | Mitochondrial HMG-CoA synthase deficiency; mHS deficiency; HMGCS2 deficiency; mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase deficiency (pqac-00000002, pqac-00000004) | Defect of hepatic ketone-body synthesis due to loss of mitochondrial HMG-CoA synthase activity (pqac-00000000, pqac-00000004) |
| Inheritance | **Autosomal recessive**; caused by biallelic pathogenic variants in **HMGCS2** (pqac-00000002, pqac-00000004, pqac-00000005) | Missense, nonsense, splice, and frameshift variants reported; biallelic truncating variants are associated with more severe disease/higher mortality in aggregated analyses (pqac-00000004, pqac-00000011, pqac-00000013) |
| Typical onset / triggers | Usually infancy to early childhood; first crisis often in the **first year of life** and may occur from **10 days to 28 months** (pqac-00000000, pqac-00000004, pqac-00000009) | Vietnamese series: poor feeding **93.8%**, vomiting **56.3%**, diarrhea **25.0%**, fever **18.8%** as triggers (pqac-00000000, pqac-00000001); crises typically follow fasting or intercurrent illness (pqac-00000002, pqac-00000004, pqac-00000007) |
| Key clinical features | Acute metabolic decompensation with encephalopathy and liver involvement (pqac-00000000, pqac-00000009) | Nguyen 2025: lethargy/coma **81.3%**, rapid breathing **68.8%**, hepatomegaly **56.3%**, shock **37.5%**, seizures **18.8%** (pqac-00000000, pqac-00000001); Wu 2022: anorexia **10/10**, dyspnea **10/10**, disturbance of consciousness **10/10**, vomiting **8/10**, fever **7/10**, cough **4/10**, diarrhea **3/10**, seizures **3/10**, hepatomegaly **10/10** (pqac-00000009, pqac-00000010) |
| Key lab findings | Hallmark pattern is impaired ketogenesis with severe metabolic crisis; findings may be nonspecific and can normalize between episodes (pqac-00000001, pqac-00000010) | Metabolic acidosis: **75%** in Nguyen 2025; **10/10** in Wu 2022 (pqac-00000000, pqac-00000009). Hypoglycemia: **56.3%** in Nguyen 2025; **9/10** in Wu 2022, but absence of hypoglycemia does **not** exclude disease (pqac-00000000, pqac-00000002, pqac-00000010). Elevated transaminases: **100%** in Nguyen 2025 and **10/10** in Wu 2022 (pqac-00000000, pqac-00000009). Hyperammonemia: **31.3%** in Nguyen 2025 and **5/10** in Wu 2022 (pqac-00000000, pqac-00000010). Hypofibrinogenemia: **10/10** in Wu 2022 (pqac-00000009, pqac-00000010). Urinary dicarboxylic acids: reported during crises, often prominent, with only mild/absent ketones (pqac-00000002, pqac-00000008, pqac-00000010). Acetylcarnitine/free carnitine signal: elevated **C2/C0 ratio** proposed by Wu 2022; low free carnitine and/or elevated acetylcarnitine variably observed across patients (pqac-00000008, pqac-00000010) |
| Proposed biomarkers | No single routine biomarker is fully reliable; several candidate acute-phase markers have been proposed (pqac-00000001, pqac-00000002, pqac-00000006) | **4-hydroxy-6-methyl-2-pyrone (4HMP)** proposed as a novel marker (pqac-00000002, pqac-00000013); **3-hydroxyglutarate (3HG)** and markedly elevated **glutarate** may support diagnosis (pqac-00000002); **hypertriglyceridemia** proposed as an additional acute clue (pqac-00000002, pqac-00000010); **raised acetylcarnitine (C2)** and elevated **acetylcarnitine/free carnitine ratio** proposed as signatures in some patients (pqac-00000002, pqac-00000010) |
| Diagnostic approach | Diagnosis requires integration of acute biochemical testing with molecular confirmation; **genetic testing is now considered definitive** because enzyme assay and routine biochemical markers can be unreliable (pqac-00000000, pqac-00000001) | Suggested workup during crisis: blood gas, glucose, ammonia, liver enzymes, free fatty acids/ketones if available, plasma acylcarnitines, and urine organic acids/GC-MS (pqac-00000002, pqac-00000006, pqac-00000009). Typical clues: hypoketotic or relatively low-ketone crisis, dicarboxylic aciduria, raised C2 or C2/C0 ratio, normal/nonspecific TMS, and sometimes 4HMP/3HG (pqac-00000002, pqac-00000007, pqac-00000010). Confirm by **Sanger, targeted NGS, WES** or similar sequencing of **HMGCS2** (pqac-00000001, pqac-00000005, pqac-00000013) |
| Management / treatment | Acute care centers on reversal of catabolism with **high-glucose/dextrose infusion**, correction of acidosis, and supportive intensive care as needed; long-term care focuses on **fasting avoidance** and sick-day carbohydrate plans (pqac-00000000, pqac-00000009) | Reported acute measures: IV glucose/dextrose, sodium bicarbonate, carnitine, liver-protective/supportive therapy, mechanical ventilation, and CRRT/hemodialysis for severe crises (pqac-00000007, pqac-00000008, pqac-00000009). Vietnamese series noted that high-glucose infusion plus prevention of prolonged fasting and enteral carbohydrate/glucose during illness **reduced relapses** (pqac-00000000). Long-term diet: avoidance of prolonged fasting and often low/moderate-fat intake (pqac-00000007, pqac-00000009) |
| Prognosis / outcomes | Prognosis is often good **after diagnosis** with preventive management, but acute episodes can be life-threatening and fatalities are reported (pqac-00000000, pqac-00000011) | Nguyen 2025: **all 19 patients alive** at follow-up (ages 5 months-14 years) with normal physical development after proactive management (pqac-00000000). Wu 2022/literature aggregation: most recover fully and maintain normal growth; only limited neurologic sequelae reported, but genotype severity matters; mortality highest in the biallelic truncating group (**25%**) (pqac-00000011). Individual severe cases can progress to multiorgan failure and death (pqac-00000005, pqac-00000008) |


*Table: This table condenses identifiers, phenotype frequencies, biochemical clues, diagnostic strategy, management, and prognosis for mitochondrial HMG-CoA synthase deficiency. It is designed as a disease knowledge base quick-reference using recent case-series evidence plus key prior reports.*