Pyruvate Dehydrogenase Deficiency: PDHA1 Gene Sequencing

Condition Description

Mutationin the E1-alpha subunit gene PDHA1 (Xp22.2-p22.1) of the pyruvate dehydrogenase complex (PDH) is one of the mostcommon causes of primary lactic acidosis in children. The clinical spectrum ofPDH deficiency is broad, ranging from fatal lactic acidosis in the newborn tochronic neurologic dysfunction with structural abnormalities in the CNS withoutsystemic acidosis.

Ingeneral, there are two major presentations of PDH deficiency, metabolic andneurologic, which occur at equal frequency. The metabolic form presents assevere lactic acidosis in the newborn period, usually leading to death.Patients with the neurologic presentation are hypotonic and lethargic, anddevelop seizures, mental retardation, and spasticity. They often havestructural abnormalities in the central nervous system with minimal or absentmetabolic abnormalities. Between these two extremes, there is a continuousspectrum of intermediate forms characterized by intermittent episodes of lacticacidosis associated with cerebellar ataxia. Many patients fit into the categoryof Leigh syndrome.

A highproportion of heterozygous females manifest severe symptoms, although they mayalso be unaffected. Affected females may have severe developmental delay froman early age, agenesis of the corpus callosum, cortical atrophy, microcephaly,and spastic quadriplegia. The severity of the deficiency in affected femaleslargely depends on the pattern of X inactivation in the brain. There areconsiderable difficulties in establishing the diagnosis in females based onmeasurements of enzyme activity and immunoreactive protein.

The sexratio of PDH E1-alpha deficiency appears to be approximately 1:1, but mostmutations identified in males have been missense mutations while most mutationsfound in females have been deletions or insertions. One study showed that inthe parents of the affected patients, the mutation was never present in thesomatic cells of the father; in 63 mothers studied, 16 (25%) were carriers. Infour families, the origin of the mutation was determined to be twice paternaland twice maternal.

PDHdeficiency can also be caused by mutation in other subunits of the PDH complex,including a form caused by mutation in the E3 gene (DLD) which is also associated with a variant form of maple syrupurine disease (MSUD).

For patients with suspected pyruvate dehydrogenase deficiency, sequence analysis is recommended as the first step in mutation identification. For patients in whom mutations are not identified by full gene sequencing, deletion/duplication analysis is appropriate.

Click here for the OMIM summary on this condition.

Genes (1)

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This test is indicated for:

  • Confirmation of a clinical/biochemical diagnosis of pyruvate dehydrogenase deficiency
  • Carrier testing in adult females with a family history of pyruvate dehydrogenase deficiency


PCR amplification of 11 exons contained in the PDHA1 gene is performed on the patient's genomic DNA. Direct sequencing of amplification products is performed in both forward and reverse directions, using automated fluorescence dideoxy sequencing methods. The patient's gene sequences are then compared to a normal reference sequence. Sequence variations are classified as mutations, benign variants unrelated to disease, or variations of unknown clinical significance. Variants of unknown clinical significance may require further studies of the patient and/or family members. This assay does not interrogate the promoter region, deep intronic regions, or other regulatory elements, and does not detect large deletions.


Clinical Sensitivity: Unknown. Mutations in the promoter region, some mutations in the introns and other regulatory element mutations cannot be detected by this analysis. Large deletions will not be detected by this analysis. Results of molecular analysis should be interpreted in the context of the patient's biochemical phenotype.

Analytical Sensitivity: ~99%

Specimen Requirements

Listed below are EGL's preferred sample criteria. For any questions, please call 470.378.2200 and ask to speak with a laboratory genetic counselor (
Submit only 1 of the following specimen types

Oragene™ Saliva Collection Kit
Orangene™ Saliva Collection Kit used according to manufacturer instructions. Please contact EGL for a Saliva Collection Kit for patients that cannot provide a blood sample.
Collection and Shipping
Please do not refrigerate or freeze saliva sample. Please store and ship at room temperature.
Whole Blood (EDTA)

EDTA (Purple Top)
Infants and Young Children (<2 years of age): 2-3 ml
Children > 2 years of age to 10 years old: 3-5 ml
Older Children & Adults: 5-10 ml
Autopsy: 2-3 ml unclotted cord or cardiac blood
Collection and Shipping
Ship sample at room temperature for receipt at EGL within 72 hours of collection. Do not freeze.
DNA, Isolated

Isolation using the Perkin Elmer™Chemagen™ Chemagen™ Automated Extraction method or Qiagen™ Puregene kit for DNA extraction is recommended.
Collection and Shipping
Refrigerate until time of shipment in 100 ng/µL in TE buffer. Ship sample at room temperature with overnight delivery.

Special Instructions

Submit copies of diagnostic biochemical test results with the sample, if appropriate. Contact the laboratory if further information is needed.

Sequence analysis is required before deletion/duplication analysis by targeted CGH array. If sequencing is performed outside of EGL Genetics, please submit a copy of the sequencing report with the test requisition.

  • Deletion/duplication analysis of the PDHA1 gene by CGH array is available for those individuals in whom sequence analysis is negative (YO).
  • A CGH array-based test for deletion/duplication analysis of 64 different X-linked intellectual disability genes is available (OL).
  • Custom diagnostic mutation analysis (KM) is available to family members if mutations are identified by targeted mutation testing or sequencing analysis.
  • Prenatal testing is available to adult females who are confirmed carriers of mutations. Please contact the laboratory genetic counselor to discuss appropriate testing prior to collecting a prenatal specimen.

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