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Invitae Pyruvate Dehydrogenase Deficiency Panel
Test description
The Invitae Pyruvate Dehydrogenase (PDH) Deficiency Panel analyzes 8 genes encoding proteins involved in the PDH complex; which converts pyruvate to acetyl-CoA. Primary clinical features of PDH deficiency include lactic acidosis, neurodevelopmental delays, structural abnormalities of the brain, and hypotonia. Symptoms usually manifest within the first few months of life and lead to premature death.
Genetic testing of these genes is useful for the diagnosis of patients whose clinical symptoms or biochemical findings indicate PDH deficiency. This test may confirm a diagnosis and help guide treatment and management decisions. Identification of disease-causing variants provide accurate risk assessment and carrier status of at-risk relatives.
Genes tested
DLAT DLD LIAS MPC1 PDHA1 PDHB PDHX PDP1
Order test
Primary panel (8 genes)
Customized gene selection (0 included, 0 excluded)
DLAT DLD LIAS MPC1 PDHA1 PDHB PDHX PDP1
Clinical information
Disorders tested
- pyruvate dehydrogenase E2 deficiency (DLAT)
- dihydrolipoamide dehydrogenase, E3 deficiency (DLD)
- lipoic acid synthetase deficiency (LIAS)
- mitochondrial pyruvate carrier 1 deficiency (MPC1)
- pyruvate dehydrogenase E1-Alpha deficiency (PDHA1)
- pyruvate dehydrogenase E1-Beta deficiency (PDHB)
- pyruvate dehydrogenase complex, E3 binding protein deficiency (PDHX)
- pyruvate dehydrogenase phosphatase deficiency (PDP1)
Clinical description
Pyruvate dehydrogenase (PDH) is a mitochondrial enzyme complex which catalyzes the rate-limiting step of aerobic glucose oxidation; a process crucial to energy metabolism. PDH deficiency is a disorder of energy failure with broad clinical heterogeneity. It is typically characterized by significant lactic acidosis, neurologic and neuromuscular deterioration, and early death. Affected individuals generally present within the first few months of life with a severe lactic acidosis and/or neurologic findings that may include seizures, ataxia, optic atrophy, peripheral neuropathy, choreoathetoid movements and/or Leigh disease. Conversely, much milder phenotypes manifesting subtle or subacute neurodegeneration have also been reported. Cognitive function ranges from normal to profoundly intellectually disabled. Premature death typically occurs by early childhood, although survival into adulthood has been documented.
The PDH complex is a complicated, highly regulated, multienzyme structure. Pathogenic variants in the structural or regulatory components can lead to reduced enzymatic activity and disease.
| Gene | Function | |
|---|---|---|
| DLAT | E2 subunit | |
| DLD | E3 subunit | |
| LIAS | Lipoic acid synthase | Cofactor for E2 subunit |
| MPC1 | Pyruvate transporter | |
| PDHA1 | E1 alpha subunit | |
| PDHB | E1 beta subunit | |
| PDHX | E3 binding protein | provides structural connections to the E2 and E3 subunits |
| PDP1 | Phosphatase catalytic subunit | PDHC activation |
Pathogenic mutations in genes involved in PDH catalytic activities cause PDH deficiency. These include genes (PDHA1, PDHB, DLAT, DLD) encoding the three principal components of the PDH complex E1, E2, E3, and the PDHX gene which encodes the E3 binding protein. The E3 binding protein provides structural connections to the E2 and E3 subunits. In addition, mutations in genes encoding mitochondrial pyruvate transporter, enzyme responsible for synthesis of lipoic acid, and an essential cofactor for PDH have also been associated with PDH deficiency.
Clinical sensitivity
| Gene | % Gene Attribution |
|---|---|
| DLAT | 1% |
| DLD | 5% |
| LIAS | Unknown |
| MPC1 | Unknown |
| PDHA1 | 76% |
| PDHB | 2% |
| PDHX | 6% |
| PDP1 | Unknown |
Inheritance
PDHA1-related PDH deficiency is inherited in an X-linked manner. The other causes of PDH deficiency are inherited in an autosomal recessive manner.
Prevalence/Incidence
PDH deficiency is known as a very rare disorder, the prevalence in the general population is unknown.
Considerations for testing
PDH deficiency is indicated in individuals with elevated lactate concentrations in CSF and blood with a blood lactate:pyruvate ratio <=20.
References
- Brown, RM, et al. Mutations in the gene for the E1beta subunit: a novel cause of pyruvate dehydrogenase deficiency. Hum. Genet. 2004; 115(2):123-7. PMID: 15138885
- DeBrosse, SD, et al. Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: lack of correlation with genotype. Mol. Genet. Metab. 2012; 107(3):394-402. PMID: 23021068
- Castiglioni, C, et al. Pyruvate dehydrogenase deficiency presenting as isolated paroxysmal exercise induced dystonia successfully reversed with thiamine supplementation. Case report and mini-review. Eur. J. Paediatr. Neurol. 2015; 19(5):497-503. PMID: 26008863
- Patel, KP, et al. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol. Genet. Metab. 2012; 105(1):34-43. PMID: 22079328
- Herzig, S, et al. Identification and functional expression of the mitochondrial pyruvate carrier. Science. 2012; 337(6090):93-6. PMID: 22628554
- Tort, F, et al. Differential diagnosis of lipoic acid synthesis defects. J. Inherit. Metab. Dis. 2016; 39(6):781-793. PMID: 27586888
- Patel, MS, et al. The pyruvate dehydrogenase complexes: structure-based function and regulation. J. Biol. Chem. 2014; 289(24):16615-23. PMID: 24798336
Assay
Assay and technical information
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
| Gene | Transcript reference | Sequencing analysis | Deletion/Duplication analysis |
|---|---|---|---|
| DLAT | NM_001931.4 | ||
| DLD | NM_000108.4 | ||
| LIAS | NM_006859.3 | ||
| MPC1 | NM_016098.3 | ||
| PDHA1 | NM_000284.3 | ||
| PDHB | NM_000925.3 | ||
| PDHX | NM_003477.2 | ||
| PDP1 | NM_018444.3 |
Resources
References
- Brown, RM, et al. Mutations in the gene for the E1beta subunit: a novel cause of pyruvate dehydrogenase deficiency. Hum. Genet. 2004; 115(2):123-7. PMID: 15138885
- Castiglioni, C, et al. Pyruvate dehydrogenase deficiency presenting as isolated paroxysmal exercise induced dystonia successfully reversed with thiamine supplementation. Case report and mini-review. Eur. J. Paediatr. Neurol. 2015; 19(5):497-503. PMID: 26008863
- DeBrosse, SD, et al. Spectrum of neurological and survival outcomes in pyruvate dehydrogenase complex (PDC) deficiency: lack of correlation with genotype. Mol. Genet. Metab. 2012; 107(3):394-402. PMID: 23021068
- Herzig, S, et al. Identification and functional expression of the mitochondrial pyruvate carrier. Science. 2012; 337(6090):93-6. PMID: 22628554
- Patel, KP, et al. The spectrum of pyruvate dehydrogenase complex deficiency: clinical, biochemical and genetic features in 371 patients. Mol. Genet. Metab. 2012; 105(1):34-43. PMID: 22079328
- Patel, MS, et al. The pyruvate dehydrogenase complexes: structure-based function and regulation. J. Biol. Chem. 2014; 289(24):16615-23. PMID: 24798336
- Tort, F, et al. Differential diagnosis of lipoic acid synthesis defects. J. Inherit. Metab. Dis. 2016; 39(6):781-793. PMID: 27586888
