Mitochondrial Trifunctional Protein Deficiency and Long-Chain 3-Hydroxyacyl CoA Dehydrogenase Deficiency Panel

Mitochondrial trifunctional protein (MTP) deficiency is a rare disorder of long-chain fatty acid oxidation. MTP deficiency can be classified into two biochemical phenotypes: general (complete) MTP deficiency, which results in reduced activity from all three enzymes of the MTP complex, and isolated long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency. Of the two disorders, LCHAD deficiency is more common, with an estimated incidence of 1 in 75,000 and 1 in 100,000 in the American and European populations, respectively (Shahrokhi et al. 2017. PubMed ID: 28112527). Except for differences in enzymatic activities, however, LCHAD and general MTP deficiencies are clinically indistinguishable (Boutron et al. 2011. PubMed ID: 21549624).

MTP deficiency may be categorized into three types depending on onset and severity of disease: lethal type (neonatal-onset), intermediate/hepatic type (infantile-onset), and neuromyopathic type (adult-onset) (Spiekerkoetter et al. 2004. PubMed ID: 14630990; Boutron et al. 2011. PubMed ID: 21549624). Neonatal-onset is generally characterized by severe cardiomyopathy, hypoketotic hypoglycemia, and neonatal death. During infantile-onset, patients initially present during a period of prolonged fasting or illness, and symptoms may include feeding difficulties, breathing difficulties, lethargy, hypoketotic hypoglycemia, hypotonia, lactic academia, hepatopathy, cardiomyopathy, retinopathy, and coma (Karall et al. 2015. PubMed ID: 25888220; Shahrokhi et al. 2017. PubMed ID: 28112527). In adolescents and adults, hypotonia, rhabdomyolysis, and peripheral neuropathy are more common clinical symptoms of this disease. Regardless of age, all affected individuals show increased levels of long-chain 3-OH-acylcarnitines upon blood acylcarnitine (AC) analysis.

Both MTP and LCHAD deficiencies are inherited in an autosomal recessive manner.

The mitochondrial trifunctional protein (MTP) is an inner mitochondrial membrane protein that consists of four α-subunits with LCEH (long-chain 2,3-enoyl-CoA hydratase) and LCHAD (long-chain 3-hydroxyacyl CoA dehydrogenase) activities, and four β-subunits that have LCKT (long-chain 3-ketoacyl-CoA thiolase) activity (Uchida et al. 1992. PubMed ID: 1730633). These enzymes catalyze the three final steps of the β-oxidation cycle of long-chain fatty acids. Two nuclear genes, HADHA and HADHB, encode the α and β subunits of the MTP complex, respectively (Boutron et al. 2011. PubMed ID: 21549624).

Defects in HADHA or HADHB can result in general MTP deficiency, a condition where all three enzyme activities of the MTP complex are significantly reduced (Boutron et al. 2011. PubMed ID: 21549624; Shahrokhi et al. 2017. PubMed ID: 28112527). One particular HADHA missense variant (p.Glu510Gln) may result in an isolated LCHAD deficiency, leaving the remaining two enzymes unaffected.

Approximately 60 causative variants have been reported in the HADHA gene to date, while approximately 50 have been reported in the HADHB gene (Human Gene Mutation Database). The majority of these variants are missense, but splicing and nonsense variants have also been described, as well as a number of small deletions and insertions/duplications. Two gross deletions in HADHA have been reported, in addition to three gross deletions in HADHB.

The most common pathogenic variant in HADHA is p.Glu510Gln (also known as p.Glu474Gln), which accounted for 54/90 pathogenic alleles (60%) in one study (Boutron et al. 2011. PubMed ID: 21549624). This variant, located in the LCHAD catalytic domain, appears to affect only LCHAD function and results in isolated LCHAD deficiency when present in the homozygous state.

Clinical sensitivity for this test is expected to be very high for patients with a biochemical diagnosis of long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) deficiency or mitochondrial trifunctional protein (MTP) deficiency. In a cohort of 52 patients with biochemically-diagnosed MTP deficiency, Boutron and colleagues identified causative variants in 52 (100%) patients; 45 (~86.5%) had homozygous or compound heterozygous pathogenic variants in HADHA, while the remaining 7 (13.5%) patients carried homozygous or compound heterozygous pathogenic variants in HADHB (Boutron et al. 2011. PubMed ID: 21549624).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).