At a Glance

Pyruvate Carboxylase Deficiency (PC) is an inherited disorder of metabolism of gluconeogenesis. This mitochondrial enzyme converts pyruvate to oxaloacetate, and a defect leads to elevations of lactic acid, hypoglycemia, and hyperammonemia. PC is inherited in an autosomal recessive manner, meaning the individual inherited two abnormal copies of the PC gene (each gene containing a mutation). Both parents of an individual with PC are carriers and do not manifest any symptoms of disease.

Infants and children with PC typically present in the classic form (type A) of the disorder in the first few months (2–5 months) of life with vomiting, hypothermia, hypotonia, and decreased responsiveness. They have developmental delay and episodes of lactic acidosis triggered fasting and illness. Neurological symptoms include pyramidal signs, ataxia, nystagmus, and seizures. MRI changes include white matter changes, periventricular cysts, delayed myelination, and cerebral atrophy. Those neonates with the severe French form (type B) develop acidosis and hyperammonemia in the first few hours or days of life. They have progressive hypotonia and seizures and may die within a few months. A milder form (type C) has rarely been reported with a responsive lactic and ketoacidosis but normal development and intelligence.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Pyruvate carboxylase deficiency can be diagnosed through an elevated serum lactate, with levels reaching up to or greater than 20 µM. The lactate to pyruvate ratio will be elevated (frequently far greater than 25, normal <20). The beta-hydroxybutyrate to acetoacetate ratio will be low (less than 2, normal >2.5).

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Plasma amino acid analysis will demonstrate an elevated citrulline, unique for a lactic acidosis, with elevations of alanine, proline, and lsyine. Hyperammonemia will be present (normal <30-40 µM), although the glutamine will be low in contrast to that seen in the urea cycle disorders.

Urine organic acid analysis will show elevations of lactate, pyruvate, beta-hydroxybutyrate, and alpha-ketoglutarate.

Cerebral spinal fluid (CSF) analysis will also show an elevated lactate, pyruvate, alanine, and glutamine.

(Table 1)

Table 1.
Lactate Pyruvate Ammonia
Elevated Elevated Elevated

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Elevations of lactic acid may be seen with septic shock, hypoperfusion in cardiogenic shock, or decreased clearance in liver failure. False elevations can be seen with improper sample collection technique from the tourniquet being applied too long during venous collection.

What Lab Results Are Absolutely Confirmatory?

Enzyme analysis of PC can be done in skin fibroblasts or in fresh frozen liver tissue.

Sequence analysis of the PC gene is available.

What Confirmatory Tests Should I Request for my My Clinical Dx? In addition, what follow-up tests might be useful?

Individuals affected with PC should have evaluation looking for underlying stressors. Monitoring should include electrolytes and liver function tests. Therapy may include dextrose support of hypoglycemia, bicarbonate for acidosis, and dialysis for hyperammonemia. Supplementation with enzyme cofactors, biotin and thiamine, may be useful. Some reports have shown benefit with orthotopic liver transplantation or anaplerotic dietary therapy.

What Factors, if Any, Might Affect the Confirmatory Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?

Some differences may be seen in arterial or venous lactate. Consistent tracking of an elevated lactate is the primary concern. Consideration should be given to the lactate and pyruvate measurement. Both must be in the same units of measure for an accurate ratio.

Normal ranges for lactate, pyruvate, ammonia, and plasma amino acids are age dependent.