Mitochondrial Phosphoenolpyruvate Carboxykinase 2 Deficiency via the PCK2 Gene

Patients with mitochondrial diseases or other diseases that mimic mitochondrial diseases present with a wide variety of phenotypes and age of onset, making diagnosis of these disorders challenging (DaRe et al. 2013). Clinical features can include encephalomyopathy, combinations of multisystemic symptoms affecting at least three organ symptoms, and a progressive clinical course with episodes of worsening symptoms. Enzymology studies reveal decreased respiratory chain complex (RCC) activity, and metabolic studies may show at least one indicator of impaired RCC activity. Additional diagnostic criteria are described by Bernier et al. (2002).

Disorders of phosphoenolpyruvate carboxykinase (PEPCK) are thought to be a rare cause of childhood onset lactic acidemia. In humans, two PEPCK isozymes are found. One is located in the mitochodria and is encoded by the PCK2 gene. The second is found in the cytosol and is encoded by the PCK1 gene (Robinson 2014). A few early reports have described children with lactic acidemia, hypoglycemia, hypotonia, hepatomegaly and failure to thrive who were also found to have decreased PEPCK enzyme activity (Robinson 2014). More recently, a single PEPCK deficient patient was identified as part of a study of individuals diagnosed with or suspected of having a mitochondrial disorder. A large Next Generation sequencing panel of 447 genes was used in attempt to diagnose these patients (DaRe et al. 2013). This particular patient was found to be a compound heterozygote for two variants in the PCK2 gene, which encodes the mitochondrial PEPCK isozyme. This patient was reported to have abnormal RCC activity and/or muscle pathology, in addition to clinical symptoms consistent with a mitochondrial disorder (DaRe et al. 2013).

Mitochondrial PEPCK deficiency is thought to be inherited in an autosomal recessive manner, and is caused by pathogenic variants in the PCK2 gene (DaRe et al. 2013). To date, only missense causative variants have been reported in the PCK2 gene.

The PCK2 gene is a nuclear encoded gene containing 10 coding exons and located on chromosome 14 (14q11-q12). The PEPCK enzyme plays a critical role in gluconeogenesis by catalyzing the conversion of oxaloacetate to phosphoenolpyruvate. The PCK2 gene is expressed primarily in the pancreas, kidney and liver (Modaressi et al. 1998).

Clinical sensitivity cannot be estimated because only a single patient has been reported (DaRe et al. 2013; Robinson 2014). Analytical sensitivity may be high because all reported pathogenic variants are detectable by sequencing.

To date, no large deletions or duplications have been described in the PCK2 gene.

This test provides full coverage of all coding exons of the PCK2 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).