Pyruvate Dehydrogenase E1α Deficiency via the PDHA1 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 first subunit (E1) of the PDH complex is the pyruvate dehydrogenase enzyme, itself comprised of two alpha and two beta subunits (αα'ββ', encoded by the PDHA1 and PDHB genes, respectively) (Robinson 2014). The PHDA1 gene resides on the X chromosome (Xp22.12, 12 exons). Defects in this gene are inherited in an X-linked manner. To date, approximately equal numbers of affected males and females have been reported (Lissens et al. 2000; Quintana et al. 2010; Robinson 2014). Clinically, males range from severely to mildly affected; no asymptomatic males have been reported. Affected males tend to carry pathogenic variants that lead to decreased PDHα activity rather than complete loss of activity of the protein. It has been proposed that PDHA1 variants that would abolish PDHc activity in males would be incompatible with life. Heterozygous female patients range from severely affected to only mildly affected or asymptomatic. Genetically, females frequently carry PDHA1 variants that lead to a more severe effect on the PDH alpha protein, which they are better able to tolerate due to X-chromosome inactivation (Lissens et al. 2000; Quintana et al. 2010; Robinson 2014).

The majority of reported pathogenic variants in the PDHA1 gene arise de novo, although they are occasionally inherited from a mildly affected or asymptomatic mother, or from a parent with gonadal mosaicism (Lissens et al. 2000; Quintana et al. 2010; Robinson 2014). In addition, it should be noted that somatic mosaicism has been reported in some patients (Imbard et al. 2011). To date, over 150 pathogenic variants have been reported in the PDHA1 gene. Approximately half of the reported variants are missense, although nonsense, splicing, small deletions, insertions and indels, as well as gross deletions and duplications have been reported (Human Gene Mutation Database). The majority of causative variants are located in exons 5 through 12, with insertion and deletion variants occuring most commonly in exons 10 and 11 (Lissens et al. 2000; Robinson 2014).

Pathogenic variants in the PDHA1 gene are the most frequent cause of Pyruvate Dehydrogenase Complex (PDHc) deficiency, and have been reported to cause approximately 80% of the cases (Barnerias et al. 2010; Imbard et al. 2011; Robinson 2014). Analytical sensitivity should be high because the vast majority of reported causative variants are detectable by sequencing.

It is difficult to estimate the clinical sensitivity of CNV detection as only a small number of gross deletions have been reported in the PDHA1 gene (Lissens et al. 2000; Imbard et al. 2011). However, the clinical sensitivity appears to be relatively low.

This test provides full coverage of all coding exons of the PDHA1 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).