Pyruvate Dehydrogenase E3-Binding Protein (E3BP) Deficiency via the PDHX Gene

The Pyruvate Dehydrogenase complex (PDHc) is responsible for catalyzing the irreversible, rate-limiting step in the aerobic oxidation of pyruvate to acetyl CoA, thereby effectively linking the cytosolic glycolysis metabolic pathway to the mitochondrial citric acid cycle. The PDHc is a large, multisubunit complex located in the mitochondrial matrix. Multiple enzymatic activities are associated with PDHc and each is carried out by a different subunit within the complex. The different subunits are encoded by several nuclear genes ( PDHA1 , PDHB, DLAT, DLD, PDHX), and activity of the complex is regulated by reversible phosphorylation and dephosphorylation accomplished by PDH kinase (encoded by the PDK1 through PDK4 genes) and PDH phosphatase (encoded by the PDP1 and PDP2 genes) (Robinson 2014).

PDHc deficiency presents with a wide spectrum of disease severity and symptoms, and substantial overlap exists between patients with PDHc deficiency caused by defects in different genes. In general, patients can be classified into three groups based on severity and clinical symptoms. The first group is the most severe, with neonatal onset and death occurring within the first six months of life. These infants typically exhibit low residual PDH activity and severe, chronic lactic acidosis. The second group of patients typically only have mild-to-moderate lactic acidosis, with the acidosis usually only occurring temporarily. Such patients often also present with psychomotor retardation and developmental delay, and approximately 25% die before 3 years of age. Features of Leigh syndrome, such as cystic lesions in the basal ganglia and cerebral atrophy, are common in such patients. The third and most mild form of PDHc deficiency includes patients who present with chronic or episodic ataxia that is often carbohydrate induced, less markedly increased blood lactate levels, varying degrees of intellectual disability, and often no detectable neuropathology, although some may slowly develop lesions in the brain that are typical of Leigh disease. Approximately one-third of PDHc deficient patients show facial dysmorphism similar to that observed in fetal alcohol syndrome patients (shortened palpebral fissures, smooth philtrum, and thin upper lip). Some PDHc deficient patients have shown improvement upon treatment with thiamine, sodium bicarbonate, carnitine, and/or a ketogenic diet (Robinson 2014).

The PHDX gene resides on chromosome 11 (11p13, 11 exons). Defects in this gene are inherited in an autosomal recessive manner. To date, approximately 20 PHDX pathogenic variants have been reported in the literature. The majority of reported variants have been nonsense and splicing, although missense, small deletions and insertions, gross deletions and complex rearrangements have also been reported (Human Gene Mutation Database).

The Pyruvate Dehydrogenase Complex (PDHc) contains three catalytic subunits (E1, E2 and E3), all of which are present in multiple copies in the PDHc. In addition, the E3-Binding Protein (E3BP; previously known as protein X), encoded by the PHDX gene is important for structurally linking the E2 and E3 subunits.

Pathogenic variants in the PDHX gene are a relatively common cause of Pyruvate Dehydrogenase Complex (PDHc) deficiency. One large study of 82 patients with confirmed PDHc deficiency found that variants in the PDHX gene accounted for ~13% of cases (Imbard et al. 2011), making this the second most common cause of PDHc deficiency. Analytical sensitivity should be relatively high because the great majority of reported variants are detectable by sequencing.

To date, only a small number of gross deletions have been reported in the PDHX gene (Schiff et al. 2006; Imbard et al. 2011).

This test provides full coverage of all coding exons of the PDHX gene 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 full 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).