IEMbase 0062: HMGCL-related HMG-CoA lyase deficiency
Scope
| Field | Value |
|---|---|
| IEMbase ID | 62 |
| Nosology | 4.3.16.01 |
| Gene | HMGCL |
| External IDs | OMIM:246450 |
| Generated mapping | MAPPED by alias_exact:hmgcld |
| Candidate DisMech targets | 3-Hydroxy-3-Methylglutaric_Aciduria.yaml |
| Review date | 2026-07-07 |
IEMbase phenotype signal
IEMbase represents this as autosomal recessive HMGCL-related 3-hydroxy-3-methylglutaryl-CoA lyase deficiency, with alternate labels hydroxymethylglutaric aciduria and HMGCLD. Treatability is marked yes.
The biochemical signal includes high C5-OH and C6DC acylcarnitines in dried blood spot or plasma, low-normal free carnitine, very low fibroblast HMGCL activity, normal-high transaminases, low plasma ketones, normal-high urinary ketones/acetoacetate/3-hydroxybutyrate, normal-high free fatty acids, high urinary 3-hydroxy-3-methylglutaric acid, 3-hydroxyisovaleric acid, 3-methylglutaconic acid, and 3-methylglutaric acid, normal-high dicarboxylic acids, possible hyperammonemia, low-normal glucose, and normal-high lactate.
The characteristic clinical signal includes coma during ketoacidotic episodes, hypoketotic hypoglycemia, and lethargy during crisis. Additional features include dilated cardiomyopathy, cerebellar white-matter abnormalities, cerebral infarction, hepatomegaly, neonatal seizures, pancreatitis, seizures, and stroke-like encephalopathy. Treatments are avoidance of fasting, protein-defined diet, and sick-day management.
DisMech phenotype coverage
The generated mapping to 3-Hydroxy-3-Methylglutaric_Aciduria.yaml is correct.
DisMech models HMGCLD as a disorder of both ketogenesis and leucine degradation
caused by biallelic HMGCL variants. It covers failure of ketone-body production
during fasting, leucine-derived organic-acid accumulation, hypoketotic or
nonketotic hypoglycemia, metabolic acidosis, hyperammonemia, lethargy, vomiting,
seizures, leukoencephalopathy, hepatomegaly, cerebral atrophy, cardiomyopathy,
and acute liver failure.
DisMech also covers the diagnostic urinary organic-acid pattern, C5-OH acylcarnitine, ketone-body deficiency, secondary hyperammonemia through acetyl-CoA/N-acetylglutamate biology, HMG-mediated neurotoxicity, and treatments including protein/leucine restriction, fasting avoidance, carnitine, exogenous ketone therapy, acute decompensation management, newborn screening, genetic counseling, and carglumic acid for hyperammonemia.
Concordance and completeness
Judgement: correct mapping and high concordance.
IEMbase adds granular panel detail for C6DC acylcarnitine, fibroblast enzyme activity, urinary ketone subfractions, free fatty acids, dicarboxylic acids, cerebellar white-matter abnormalities, cerebral infarction, pancreatitis, and stroke-like encephalopathy. DisMech is stronger for the dual ketogenesis/leucine mechanism, secondary hyperammonemia, organic-acid neurotoxicity, and management mechanisms.
Curation actions
- Keep the generated mapping to
3-Hydroxy-3-Methylglutaric_Aciduria.yaml. - Consider whether C6DC and crisis-specific neuroimaging features should be added later as diagnostic/phenotype refinements.
- Do not use HMGCLD as a generic sink for AUH/MGA1 or OPA3/MGA3 records; those are distinct methylglutaconic aciduria disorders.