Gene Tested

HADHA, HADHB

Disease

Long chain 3 hydroxyacyl CoA dehydrogenase (LCHAD) deficiency; Trifunctional protein deficiency (TFP)

Description

HADHA and HADHB encode the alpha (enoyl-CoA hydratase and long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD)) and beta (acetyl-CoA acetyl transferase) subunits of the mitochondrial trifunctional protein (TFP), a multienzyme complex of the fatty acid beta-oxidation cycle. 

Pathogenic variants in HADHA and HADHB can cause autosomal recessive LCHAD /TFP deficiency. LCHAD deficiency / TFP deficiency prevents the body from converting certain fats to energy, particularly during periods of fasting.  Presentation begins in infancy or early childhood with hypoketotic hypoglycemia, metabolic acidosis, liver disease, hypotonia, and cardiomyopathy and arrhythmias. TFP deficiency can also present with neuropathy, and variants in HADHB can cause a milder phenotype including peripheral polyneuropathy, episodic rhabdomyolysis and pigmentary retinopathy.

Indications

Hypoketotic hypoglycemia
Metabolic acidosis
Liver disease
Hypotonia
Cardiomyopathy and arrhythmias
Neuropathy
Rhabdomyolysis and skeletal myopathy

Testing Methodology 

PCR-based sequencing of entire coding region, intron/exon boundaries, as well as known pathogenic variants (HGMD 2017.3) in the promoter and deep intronic regions of the specified gene(s).

Sensitivity and Limitations

The analytical sensitivity of DNA sequencing is over 99% for the detection of nucleotide base changes, small deletions and insertions in the regions analyzed. Variants in regulatory regions and non-reported variants in untranslated regions may not be detected by this test. Large deletions/ duplications, large insertions and other complex genetic events will not be identified using sequencing methodology.

Turn-Around Time

7 days

CPT Codes

81406

How to Order

Testing for these genes is also available as part of the Metaboseq panel by next-generation sequencing. Deletion/duplication analysis and targeted variant analysis is also available for these genes. Download Inborn Errors of Metabolism requisition.

References

den Boer, MEJ, Dionisi-Vici, C, et al. (2003) Mitochondrial trifunctional protein deficiency: a severe fatty acid oxidation disorder with cardiac and neurologic involvement. J. Pediat. 142: 684-689.

Ibdah, JA, Zhao, Y, et al. (2001) Molecular prenatal diagnosis in families with fetal mitochondrial trifunctional protein mutations. J. Pediat. 138: 396-399.

Jackson, S, Bartlett, K, et al. (1991) Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Pediat. Res. 29: 406-411. 

Jackson, S, Kler, RS, et al. (1992) Combined enzyme defect of mitochondrial fatty acid oxidation. J. Clin. Invest. 90: 1219-1225.

Schaefer, J, Jackson, S, et al. (1996) Trifunctional enzyme deficiency: adult presentation of a usually fatal beta-oxidation defect. Ann. Neurol. 40: 597-602.

Wanders, RJA, IJlst, L, et al. (1992) Human trifunctional protein deficiency: a new disorder of mitochondrial fatty acid beta-oxidation. Biochem. Biophys. Res. Commun. 188: 1139-1145.