Pyruvate Carboxylase Deficiency via the PC Gene

Pyruvate Carboxylase (PC) Deficiency is an inborn error of glucose metabolism. Three different categories of PC Deficiency have been described, and they are differentiated by clinical and biochemical features (Robinson 2014; Wang and De Vivo 2015). Type A PC Deficiency (also called the infantile or North American form) presents primarily with psychomotor retardation, intellectual disability, failure to thrive, hypotonia, pyramidal tract signs, seizures and mild metabolic acidosis. The majority of patients with this form die in infancy or early childhood, although some patients have lived beyond childhood. Such patients exhibit intellectual disability and continued seizures and require special care. A large proportion of Type A PC Deficient individuals belong to Algonquian-speaking Native American tribes. Type B PC Deficiency (also called the severe neonatal or French form) presents with failure to thrive, hypotonia, developmental delay, recurrent seizures, hepatomegaly, pyramidal tract signs and abnormal movement. Biochemically, they are found to exhibit severe lactic acidemia, hyperammonemia, citrullinemia and hyperlysinemia. All patients in this category have presented during the neonatal period and the majority have died before three months of age. Type B PC Deficiency was first described in patients from France and the United Kingdom, although patients have been since described from a variety of ethnic backgrounds. Patients with Type C PC Deficiency (also called the intermittent/benign form) may have frequent episodes of metabolic acidosis in infancy, but are generally well between episodes. Clinically, patients typically develop normally or exhibit only mild delays in neurological development. Diagnosis of PC Deficient patients is generally made based on clinical symptoms, analysis of plasma and urine amino acids and organic acids, analysis of lactate, pyruvate, glutamine, glutamic acid and proline concentrations in cerebrospinal fluid (CSF), and based on PC enzyme activity assays (Wang and De Vivo 2015). Treatment focuses primarily on management of symptoms and on prevention of acute symptoms via dietary management. PC Deficient patients are put in a high-carbohydrate, high-protein diet. Fasting and the use of a ketogenic diet are contraindicated in these patients (Wang and De Vivo 2015).

Pyruvate Carboxylase Deficiency is typically inherited in an autosomal recessive fashion, although mosaicism of de novo somatic pathogenic variants has also been reported (Wang and De Vivo 2015). The PC gene is the only gene known to be involved in PC Deficiency. To date, over 30 pathogenic variants have been reported in the PC gene (Human Gene Mutation Database). The majority of reported variants are missense, although nonsense, splicing, and small insertions and deletions have also been reported. Variants are spread throughout the coding regions of the gene, with no reported mutational hotspots. In the Ojibwa and Cree tribes, the Ala610Thr missense variant has been reported to be a founder mutation. Carrier frequency of this variant in these populations is thought to be as high as 1 in 10 (Carbone et al. 1998; Robinson 2014). A genotype-phenotype correlation has been proposed to explain the different clinical outcome of different patients. Patients with Type A or C PC deficiency have all been reported to have variants thought to leave some level of residual enzyme activity, whereas the more severely affected Type B patients are found to have variants that lead to a complete loss of pyruvate carboxylase protein or enzyme activity (Robinson 2014). The pyruvate carboxylase enzyme is a homotetramer with a molecule of biotin covalently bound to each subunit. PC is located within the mitochondrial matrix, and is the most active in the liver and kidneys, although it is also active to a lesser extent in other tissues (Robinson 2014). The primary function of the PC enzyme is the conversion of pyruvate to oxaloacetate, which is the first step in gluconeogenesis. Additionally, PC plays an important role in lipogenesis as well as in replenishing the Krebs cycle, which is important for cellular energy production and the generation of neurotransmitters (Wang and De Vivo 2015).

The clinical sensitivity of this test is near 100%. In a collective total of 20 patients from different families with a clinical diagnosis of pyruvate carboxylase (PC) deficiency, pathogenic variants were detected on 39 of 40 alleles (Wang et al. 2008; Monnot et al. 2009; Ostergaard et al. 2013). Analytical sensitivity should also be close to 100% because all reported pathogenic variants are detectable by sequencing.

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

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