HADHA gene
Also known as: LCHAD deficiency; HELLP syndrome, maternal, of pregnancy; fatty liver, acute, of pregnancy #609016 https://omim.org/entry/609016
Includes:
– Mitochondrial Trifunctional Protein Deficiency (MTP) – (HADHB gene)
Also known as: Trifunctional Protein Deficiency; Trifunctional Protein deficiency with myopathy and neuropathy; OMIM#609015 https://omim.org/entry/609015
1. The Disease
Long Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHAD)/ Mitochondrial Trifunctional Protein Deficiency (MTP) are inherited disorders of fatty acid oxidation metabolism caused by mutations in the HADHA or HADHB genes respectively. These disorders are inherited in an autosomal recessive pattern – a mutation must be present in the copies inherited from both the mother and the father – for the disease to manifest itself. The metabolic error comprises a multienzyme complex which catalyses the last steps in β-oxidation of long-chain fatty acids.
2. The Symptoms
Infants are usually initially asymptomatic at birth and in the neonatal period. If untreated, symptoms often appear near 6 months of life, but onset as early as in the neonatal period and as late as adulthood has been reported. Referred signs and symptoms are hypoketotic hypoglycemia, metabolic acidosis, liver disease, hypotonia and, frequently, cardiac involvement with arrhythmias and/or enlargement of the muscles of the heart. Lack of early signs or symptoms does not exclude the diagnosis.
3. Actions to take in case of early diagnosis
- Infants with a positive genetic test (having 2 mutations or 2 copies of a single mutations in one of the two genes) should continue breastfeeding.
- Infants with a positive genetic test should have confirmatory LCHAD/MTP testing through the following method:
- Tandem mass spectrometry (MS/MS) for the detection of elevated levels of C14:1-OH, C14-OH, C16-OH, C18:1-OH, C12, C14:1, C14, C16, C18:1, C18:2, and the important specific C18-OH/C14-OH + C12-OH ratio
- LCHAD/MTP is a lifelong disease that requires lifetime compliance to dietary management and regular follow-up with a metabolic disease specialist and a multidisciplinary approach to care, including pediatrics, genetics and nutrition.
- Early treatment, through fatty acid restriction, TCM oil supplementation and avoidance of prolonged periods of fasting, is essential in preventing metabolic crises and chronic symptoms, such as cardiac, hepatic and muscle impairment. Docosahexaenoic acid (“omega 3”) must be offered to prevent retinal disease.
- The prognosis for LCHAD/MTP can be favorable with lifetime compliance to a low-fat diet and fractionated meals, but lethal cases are reported.
- Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.
4. For more information
Biblio: Diebold I, Schön U, Horvath R, et al. HADHA and HADHB gene associated phenotypes – Identification of rare variants in a patient cohort by Next Generation Sequencing. Mol Cell Probes. 2019;44:14-20. doi:10.1016/j.mcp.2019.01.003. PMID: 30682426.