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Pyruvate Dehydrogenase E1α Deficiency via the PDHA1 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
PDHA1 81406 81406,81405 $990
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
9727PDHA181406 81406,81405 $990 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing platform).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing platform).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

Turnaround Time

3 weeks on average for standard orders or 2 weeks on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.


Genetic Counselors


  • McKenna Kyriss, PhD

Clinical Features and Genetics

Clinical Features

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).

Clinical Sensitivity - Sequencing with CNV PGxome

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.

Testing Strategy

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).

Indications for Test

Individuals with elevated lactate and pyruvate in blood and cerebral spinal fluid (CSF) and a normal or low lactate to pyruvate ratio and patients with clinical features suggestive of PDHc deficiency are good candidates for this test. Children with affected siblings are good candidates, as are family members of patients who have known PDHA1 variants. We will also sequence the PDHA1 gene to determine carrier status.


Official Gene Symbol OMIM ID
PDHA1 300502
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT


Name Inheritance OMIM ID
Pyruvate Dehydrogenase E1-Alpha Deficiency XL 312170

Related Tests

Leigh and Leigh-Like Syndrome Panel (Nuclear Genes Only)
Pyruvate Dehydrogenase E2 Deficiency via the DLAT Gene
Pyruvate Dehydrogenase E3-Binding Protein (E3BP) Deficiency via the PDHX Gene
Pyruvate Dehydrogenase Phosphatase Deficiency via the PDP1 Gene


  • Barnerias C. et al. 2010. Developmental Medicine and Child Neurology. 52: e1-9. PubMed ID: 20002125
  • Human Gene Mutation Database (Bio-base).
  • Imbard A. et al. 2011. Molecular Genetics and Metabolism. 104: 507-16. PubMed ID: 21914562
  • Lissens W. et al. 2000. Human Mutation. 15: 209-19. PubMed ID: 10679936
  • Quintana E. et al. 2010. Clinical Genetics. 77: 474-82. PubMed ID: 20002461
  • Robinson B.H. 2014. Lactic Acidemia: Disorders of Pyruvate Carboxylase and Pyruvate Dehydrogenase. Online Metabolic & Molecular Bases of Inherited Disease, New York, NY: McGraw-Hill.


Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page

If ordering a Duo or Trio test, the proband and all comparator samples are required to initiate testing. If we do not receive all required samples for the test ordered within 21 days, we will convert the order to the most effective testing strategy with the samples available. Prior authorization and/or billing in place may be impacted by a change in test code.

Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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