Pyruvate Dehydrogenase Complex Deficiency Panel

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 (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 worldwide prevalence of PDHc deficiency is unknown, though it is expected to be quite rare and is estimated at less than 1 in 1,000,000 (Orphanet). 

Approximately 75% of patients with a pyruvate oxidation disorder have a defect in one of the core PDHc enzyme subunits (Sperl et al. 2015. PubMed ID: 25526709). Other affected patients have been found to have defects in genes encoding regulatory proteins or involved in cofactor biosynthesis (Sperl et al. 2015. PubMed ID: 25526709; Meldau et al. 2020. PubMed ID: 32742935). Therefore, in addition to disorders caused by defects in the core PDHc components, this panel includes testing for a number of other disorders that occur due to defects in pyruvate metabolism or transport, regulation of the PDH enzyme complex activity, or metabolism of the PDHc coenzymes thiamine pyrophosphate or lipoic acid (Robinson. 2014; Meldau et al. 2020. PubMed ID: 32742935). Many of these disorders lead to similar clinical and/or biochemical features to those observed in patients with PDHc defects, as described above (Wang and De Vivo. 2018. PubMed ID: 20301764). However, patients with thiamine metabolism dysfunction syndrome type 1 (due to defects in the SLC19A2 gene) typically present with anemia, deafness, and diabetes mellitus, and those with defects in the PDK3 gene have been described as presenting with a Charcot-Marie-Tooth type phenotype (Marcé-Grau et al. 2019. PubMed ID: 31095747; Kennerson et al. 2013. PubMed ID: 23297365).

Molecular testing can be useful for confirmation of a genetic cause of suspected pyruvate dehydrogenase deficiency. Molecular diagnosis for a patient with suspected PDH deficiency may help with determining appropriate treatment measures, assessment of recurrence risks, and allow for appropriate screening for potential future symptoms. 

The majority of the genes included in this sequencing panel are associated with autosomal recessive disorders, with the exception of PDHA1 and PDK3, which reside on the X chromosome and thus defects in these two genes are inherited in an X-linked manner. With regards to the PDHA1 gene, approximately equal numbers of affected males and females have ben reported, with phenotypes ranging from mild to severe in males, and asymptomatic to severe in females (additional details are available on the PDHA1 gene summary page). With regards to PDK3, only a small number of affected individuals have been reported. Based on the clinical descriptions from the reported families, it appears that males with PDK3 pathogenic variants are more severely affected than females (Kennerson et al. 2013. PubMed ID: 23297365; Kennerson et al. 2016. PubMed ID: 26801680).

Documented pathogenic variants in the majority of these genes include missense and various types of truncating variants, although only missense variants have been reported to date in LIPT2 and MPC1. Large deletions have only been reported in NFU1, PDHA1, PDHX, SLC19A2, SLC19A3, and TPK1 (Human Gene Mutation Database). The majority of pathogenic variants in the genes on this panel are inherited. However, de novo somatic pathogenic variants have been reported in the PC gene (Wang and De Vivo. 2018. PubMed ID: 20301764), and the majority of pathogenic PDHA1 variants 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. PubMed ID: 10679936; Quintana et al. 2010. PubMed ID: 20002461; Robinson 2014).

The PDHc contains three catalytic subunits (E1, E2 and E3), all of which are present in multiple copies in the PDHc. 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). The second subunit (E2) is the dihydrolipoamide acetyltransferase subunit (encoded by the DLAT gene), and the third subunit (E3) is dihydrolipoamide dehydrogenase (encoded by the DLD gene) (Robinson. 2014). In addition to the catalytic subunits of PDHc, 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. The activity of the PDHc is regulated by the reversible phosphorylation of serine residues within the E1α subunit. Phosphorylation of these serine residues is inhibitory and is accomplished by PDH kinase (encoded by the PDK1 through PDK4 genes), whereas dephosphorylation is activating and is performed by PDH phosphatase (encoded by the PDP1 and PDP2 genes) (Robinson. 2014). To date, no variants in the PDK1, PDK2, PDK4 or PDP2 genes have been shown to be causative for PDHc deficiency, and thus they are not included in this panel. 

In addition to the genes encoding the core PDHc subunits and regulatory proteins, this panel includes the MPC1 gene (encoding a mitochondrial pyruvate carrier), the PC gene (encoding pyruvate carboxylase, which converts pyruvate to oxaloacetate), the BOLA3, LIAS, LIPT1, LIPT2, and NFU1 genes (encode proteins involved in metabolism of the lipoic acid coenzyme), and the SLC19A2, SLC19A3, and TPK1 genes (involved in thiamine metabolism, important for the thiamine pyrophosphate coenzyme). 

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants.

Pathogenic variants in the PDHA1 gene are the most frequent cause of Pyruvate Dehydrogenase Complex (PDHc) deficiency, and have been reported to cause nearly 80% of the cases (Barnerias et al. 2010. PubMed ID: 20002125; Imbard et al. 2011. PubMed ID: 21914562; Robinson. 2014). Pathogenic variants in the PDHX and PDHB genes appear to be the next most common causes of PDHc deficiency, accounting for ~13% and ~8%, respectively, based on a large study of 82 patients with confirmed PDHc deficiency (Imbard et al. 2011). The remaining causes of PDHc deficiency appear to be quite rare, with only a few individuals identified with pathogenic variants in the DLAT, DLD and PDP1 genes (Head et al. 2005. PubMed ID: 16049940; Maj et al. 2005. PubMed ID: 15855260; Cameron et al. 2009. PubMed ID: 19184109; McWilliam et al. 2010. PubMed ID: 20022530; Imbard et al. 2011. PubMed ID: 21914562). In another study of patients with a pyruvate oxidation disorder, ~75% were due to variants in genes encoding core PDHc subunits, ~13% were in genes encoding proteins involved in thiamine pyrophosphate metabolism, ~11% were in genes encoding proteins involved in lipoic acid metabolism (which also includes Iron-Sulfur cluster metabolism), and ~1% were in genes encoding components involved in regulation or pyruvate carriers (Sperl et al. 2015. PubMed ID: 25526709). Analytical sensitivity of this test should be high because nearly all the reported variants in these genes are detectable by sequencing.

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).