Pyruvate Dehydrogenase Phosphatase Deficiency via the PDP1 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
8919 PDP1 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8919PDP181479 81479 $890 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.

For Reflex to PGxome pricing click here.

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

For Sanger Sequencing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

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

EMAIL CONTACTS

Genetic Counselors

Geneticist

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).

Patients with PDP1 deficiency can be distinguished from those with other forms of PDHc deficiency by studying the activity of PDHc from patient fibroblasts in in the presence of the kinase inhibitor dichloroacetate (DCA). Patients with other PDHc defects will not typically see an increase in PDHc activity in the presence of DCA, whereas patients with defects in the PDP1 gene have been reported to have near normal levels of PDHc activity in the presence of DCA (Maj et al. 2005).

Genetics

The PDP1 gene resides on chromosome 8 (8q22.1, 2 exons). Defects in this gene are inherited in an autosomal recessive manner. To date, PDP1 deficiency has only been reported in two patients (Maj et al. 2005; Cameron et al. 2009). The reported variants included one nonsense variant and one small deletion (Human Gene Mutation Database). The activity of 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).

Clinical Sensitivity - Sequencing with CNV PGxome

Pathogenic variants in the PDP1 gene appear to be a rare cause of Pyruvate Dehydrogenase Complex (PDHc) deficiency. Only two affected families been reported to date (Maj et al. 2005; Cameron et al. 2009). Therefore, it is difficult to precisely estimate the Clinical Sensitivity of this test. Analytical sensitivity should be high because the all reported variants are detectable by sequencing.

It is difficult to estimate the Clinical Sensitivity of this test. To date, no large deletions or duplications have been described in the PDP1 gene.

Testing Strategy

This test provides full coverage of all coding exons of the PDP1 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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

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/or patients with clinical features suggestive of PDHc deficiency are good candidates for this test. Additionally, patients with dichloroacetate (DCA) responsive PDHc activity in fibroblasts are good candidates. Family members of patients who have known PDP1 variants are also good candidates. We will sequence the PDP1 gene to determine carrier status.

Gene

Official Gene Symbol OMIM ID
PDP1 605993
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Disease

Name Inheritance OMIM ID
Pyruvate Dehydrogenase Phosphatase Deficiency AR 608782

Citations

  • Cameron J.M. et al. 2009. Human Genetics. 125: 319-26. PubMed ID: 19184109
  • Human Gene Mutation Database (Bio-base).
  • Maj M.C. et al. 2005. The Journal of Clinical Endocrinology and Metabolism. 90: 4101-7. PubMed ID: 15855260
  • 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/Specimens

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.

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


Specimen Types

Specimen Requirements and Shipping Details

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ORDER OPTIONS

View Ordering Instructions

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2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

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