3-Hydroxyacyl-CoA Dehydrogenase Deficiency

Disease Information

3-Hydroxyacyl-CoA Dehydrogenase Deficiency

• Overview: 3-Hydroxyacyl-CoA dehydrogenase deficiency is a rare, autosomal recessive metabolic disorder affecting the mitochondrial fatty acid β-oxidation process. This enzyme deficiency leads to the accumulation of medium to long-chain hydroxyacyl-carnitines, resulting in hypoglycemia, hypotonia, and cardiomyopathy among other symptoms.

• Key Identifiers:

• OMIM: 231530
• Orphanet: ORPHA79220
• ICD-10: E71.3
• MeSH: D019263

• Mondo: MONDO:0017715

• Common Synonyms: Hydroxyacyl-CoA Dehydrogenase Deficiency, HADH Deficiency, Mitochondrial Tri-functional Protein Deficiency.

• Data Source: Information is typically derived from aggregated disease-level studies and individual patient data from electronic health records (EHRs).

Etiology

• Causal Factors: Mainly genetic, caused by mutations in the HADH gene, which encodes the enzyme hydroxyacyl-CoA dehydrogenase. This gene's dysfunction disrupts fatty acid metabolism.

• Risk Factors:

• Genetic: Homozygous or compound heterozygous mutations in the HADH gene. (PMID: 15254104)

• Environmental: No significant non-genetic risk factors identified.

• Protective Factors: Currently, no specific protective genetic or environmental factors have been documented for this disease due to its genetic nature.

• Gene-Environment Interactions: Limited research available on this aspect due to the rarity and genetic basis of the disease.

Phenotypes

• Phenotype Type:
• Symptoms: Hypoglycemia, cardiomyopathy, hypotonia (HP:0001945, HP:0001634, HP:0003808).

• Laboratory Abnormalities: Elevated levels of hydroxyacyl carnitines.

• Phenotype Characteristics:

• Onset: Typically neonatal or early infancy.
• Severity: Ranges from moderate to severe depending on enzyme activity.
• Progression: Progressive without treatment.

• Frequency: Rare, specific prevalence not documented.

• Quality of Life: Significant impact due to metabolic crises and potential life-threatening complications.

Genetic/Molecular Information

• Causal Genes: HADH (HGNC:4846).

• Pathogenic Variants:

• Genes Affected: HADH mutations such as missense or splice-site changes.
• Variant Type: Typically frameshift and missense mutations.
• Population Frequency: Rare, not commonly observed in population databases like gnomAD.

• Origin: Germline.

• Epigenetic Information: No current evidence of epigenetic involvement.

Environmental Information

• Environmental Factors: No notable environmental contributors documented.

• Lifestyle Factors: No lifestyle factors reported to significantly influence disease expression.

Mechanism / Pathophysiology

1. Mutation in HADH Gene leads to defective enzyme activity.
2. Impaired Fatty Acid β-Oxidation results from enzyme insufficiency.
3. Accumulation of Hydroxyacyl-CoA Compounds causes metabolic dysfunction.

4. Metabolic Crises such as hypoglycemia and lactic acidosis emerge from metabolic derangement.

5. Metabolic Pathways: Fatty acid β-oxidation pathway dysfunction.

Anatomical Structures Affected

• Organ Level: Heart (cardiomyopathy), Liver (fatty liver), Muscle (hypotonia).
• Tissue Level: Cardiac and skeletal muscle tissues primarily.
• Subcellular Level: Mitochondria affected due to compromised enzyme activity.

Temporal Development

• Onset: Neonatal.
• Progression: Progressive.
• Duration: Chronic, lifelong management required.

Inheritance and Population

• Epidemiology: Extremely rare. Exact prevalence unknown.
• Inheritance Pattern: Autosomal recessive.
• Population Demographics: No specific demographic bias documented.

Diagnostics

• Clinical Tests:
• Laboratory: Blood acyl-carnitine analysis.
• Genetic Testing: Gene sequencing for HADH mutations.

• Biomarkers: Elevated 3-hydroxyacyl-carnitines.

• Imaging Studies: No specific imaging required for diagnosis.

Outcome/Prognosis

• Survival and Mortality: With treatment, survival can be improved, but severe forms may result in mortality.
• Morbidity: Significant, with metabolic crises impacting quality of life.

Treatment

• Pharmacotherapy: Diet high in carbohydrates and low in long-chain fatty acids; avoid fasting.
• Advanced Therapeutics: Experimental gene therapy under investigation.
• Supportive and Rehabilitative: Physical therapy for motor function.

Prevention

• Primary Prevention: Genetic counseling.
• Secondary Prevention: Early diagnosis through newborn screening where available.

Other Species / Natural Disease

• Species Affected: Mostly humans, no animal analogues documented.
• Comparative Biology: Limited research on disease models.

Model Organisms

• Model Types: Currently, limited animal models available for this specific metabolic disorder.

Citation Requirements

• This report references and synthesizes information from multiple sources including PubMed: (PMID: 15254104).

This comprehensive report provides a foundation for further exploration and understanding of 3-Hydroxyacyl-CoA Dehydrogenase Deficiency, suggesting key areas for ongoing research and clinical observation.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

• PMID:15254104 (2 mentions) - Reduction of nitrate leaching with haying or grazing and omission of nitrogen fertilizer.
• shared terms: none

Weighed against this report's own most characteristic terms: gene, metabolic, hadh, enzyme, fatty, documented, genetic, disease, hydroxyacyl-coa, mutation, acid, rare, dehydrogenase, affected, activity, cardiomyopathy, crise, hypoglycemia, hypotonia, limited.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

4 of 5 terms resolved to a current term; the rest could not be looked up either way.