Variants of the HADHA and HADHB genes lead to different phenotypes in patients with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and trifunctional protein (TFP) deficiency, 2 types of long chain fatty acid oxidation disorders (LCFAODs), according to a new study published in Molecular Genetics and Metabolism Reports.

Therefore, it is of great importance to genetically confirm the diagnosis in patients with LCHAD deficiency and TFP deficiency, the authors said.

“In our data, biallelic HAHDA variants conferred a [LCHAD deficiency] phenotype, regardless of the presence of the common LCHAD variant,” they wrote.

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The relationship between genotype and clinical outcome is not clear in LCHAD and TFP deficiencies. To better understand this relationship, a team of researchers led by Georgianne L. Arnold, MD, FACMG, from the University of Pittsburgh School of Medicine and UPMC Children’s Hospital of Pittsburgh in Pennsylvania analyzed the natural history of the conditions using data from 30 patients with LCHAD deficiency and 15 patients with TFP deficiency.

Of these 45 patients, 30 had further genotypic analyses and were found to have biallelic HADHA (22 patients) or HADHB variants (8 patients).

Read more about the etiology of LCFAOD

The researchers found that patients with biallelic HADHA gene variants had a traditional LCHAD deficiency phenotype. They also reported that maternal and neonatal complications were more common with all HADHA variants. In contrast, those with HADHB gene variants mostly had the neuromusculoskeletal-type TFP deficiency phenotype.

“While retinopathy, rhabdomyolysis and peripheral neuropathy tended to present later in childhood, many features including initial report of cardiomyopathy and hypoglycemia presented across a wide age spectrum,” the researchers wrote.

LCHAD deficiency is caused by the HADHA gene, which encodes for part of the TFP enzyme complex, while TFP deficiency is caused by mutations in both the HADHA and HADHB genes. The HADHB gene encodes for the second enzyme in the TFP complex.


Lim CC, Vockley J, Ujah O, et al. Outcomes and genotype correlations in patients with mitochondrial trifunctional protein or isolated long chain 3-hydroxyacyl-CoA dehydrogenase deficiency enrolled in the IBEM-IS database. Mol Genet Metab Rep. Published online June 3, 2022. doi:10.1016/j.ymgmr.2022.100884