Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a rare inherited metabolic disorder that affects the breakdown of fats for energy. It is classified as a fatty acid oxidation disorder. LCHAD deficiency is caused by mutations in the HADHA gene, which provides instructions for making the long-chain 3-hydroxyacyl-CoA dehydrogenase enzyme. LCHADD is a rare disease with a prevalence of approximately one case per 250.000 population.
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency genetic testing is included in Diagnostiki Athinon Monogenic Diseases Genetic Testing along with approximately 100 other inherited diseases, including cystic fibrosis (71 mutations) and hereditary breast cancer (genes BRCA1 415 mutations & BRCA2 419 mutations).
Critical features of Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency include:
- Impaired Fat Metabolism: Individuals with LCHAD deficiency have difficulty breaking down long-chain fatty acids into energy. This can lead to an accumulation of certain fatty acid metabolites in the body.
- Symptoms Onset: Symptoms of LCHAD deficiency often become apparent during fasting or illness when the body requires increased energy from fat metabolism.
- Hypoglycemia: The impaired breakdown of fatty acids can lead to hypoglycemia (low blood sugar) during periods of fasting, which may result in symptoms such as weakness, lethargy, and seizures.
- Cardiomyopathy: LCHAD deficiency can affect the heart muscles, leading to cardiomyopathy, a condition characterized by weakened heart function.
- Liver Involvement: Individuals with LCHAD deficiency may experience liver problems, including hepatomegaly (enlarged liver) and liver dysfunction.
- Muscle Weakness: Muscle weakness and pain may occur due to the inability to use fatty acids as an energy source efficiently.
- Retinal Abnormalities: Some individuals with LCHAD deficiency may develop retinal abnormalities, leading to vision impairment.
- Rhabdomyolysis: In severe cases, muscle tissue breakdown (rhabdomyolysis) may occur, releasing muscle proteins into the bloodstream and potentially leading to kidney damage.
Diagnosis of LCHAD deficiency involves biochemical testing, including analyzing specific metabolites in blood and urine. Genetic testing can confirm the presence of mutations in the HADHA gene.
Management of LCHAD deficiency includes dietary interventions to avoid prolonged fasting and ensure an appropriate balance of nutrients. This may involve frequent meals, avoiding certain fats, and supplementing specific nutrients. In some cases, specialized medical formulas may be used.
Monitoring metabolic parameters, including blood glucose levels and fatty acid profiles, is essential for managing LCHAD deficiency. Treatment may also involve supportive measures for specific symptoms, such as cardiomyopathy or liver dysfunction.
Early diagnosis and intervention are crucial for optimizing outcomes in individuals with LCHAD deficiency. Genetic counseling is essential for affected individuals and their families to understand the inheritance pattern and assess the risk of having affected children.
More Information
The HADHA (hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha) gene produces the mitochondrial trifunctional enzyme involved in the last three steps of the mitochondrial beta-oxidation pathway. Mutations in HADHA result in LCHADD.
The c.1528G>C mutation (p.Glu510Gln; E510Q) has been observed in patients with LCHADD in a homozygous state and compound heterozygosity (one copy of the c.1528G>C variant with another copy of a different pathogenic variant in the same HADHA gene). c.1528 G>C is considered the primary disease-causing mutation and significantly reduces the activity of the trifunctional enzyme. The frequency of the mutated allele in non-Finnish Europeans is 0.0016, accounting for 91% of the defective alleles of the HADHA gene.
The c.180+3A>G variant (p.Thr37SerfsX6) has also been found in some LCHADD patients, mainly in compound heterozygosity. c.180+3A>G affects a HADHA mRNA cleavage and splice site, producing exon 3 deletion and a premature stop codon. The frequency of the c.180+3A>G mutated allele in non-Finnish Europeans is 0.00023.
Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency genetic testing analyzes the 6 most frequent pathogenic mutations of the HADHA gene.
The technique used for genetic testing analyzes only the gene's specific mutations, which are the most important and frequent in the literature. However, it should be noted that there are likely other gene or chromosomal mutations in the gene to be tested that cannot be identified with this method. Different analysis techniques can be used for these cases, such as next-generation sequencing (NGS).
