Pyruvate Carboxylase Deficiency

Clinical characteristics: Pyruvate carboxylase (PC) deficiency is characterized in most affected individuals by failure to thrive, developmental delay, recurrent seizures, and metabolic acidosis. Three clinical types are recognized:

1. Type A (infantile form), in which most affected children die in infancy or early childhood

2. Type B (severe neonatal form), in which affected infants have hepatomegaly, pyramidal tract signs, and abnormal movement and die within the first three months of life

3. Type C (intermittent/benign form), in which affected individuals have normal or mildly delayed neurologic development and episodic metabolic acidosis

Diagnosis/testing: The diagnosis of PC deficiency is established in a proband by identification of PC enzyme deficiency in fibroblasts or lymphoblasts. In individuals with PC deficiency, fibroblast PC enzyme activity is usually less than 5% of that observed in controls. The diagnosis of PC deficiency can also be established in a proband by identification of biallelic pathogenic variants in PC on molecular genetic testing.

Management: Treatment of manifestations: Intravenous glucose-containing fluids, hydration, and correction of the metabolic acidosis are the mainstays of acute management. Correction of biochemical abnormalities and supplementation with citrate, aspartic acid, and biotin may improve somatic findings but not neurologic manifestations. Orthotopic liver transplantation may be indicated in some affected individuals. Anaplerotic therapies such as triheptanoin show some promise, especially regarding the neurologic manifestations, but need to be further evaluated.

Prevention of primary manifestations: Parental education regarding factors that elicit a crisis and early signs of decompensation; written information on the child's disorder and appropriate emergency treatment to be carried at all times; minimization of intercurrent infections and environmental stressors; high-carbohydrate and high-protein diet with frequent feedings to prevent dependence on gluconeogenesis.

Prevention of secondary complications: Hospitalization for the management of fever, infection, dehydration, or trauma; intensive proactive medical support to prevent dehydration, hypotension, hypoglycemia, and increasing metabolic acidosis.

Surveillance: Regular monitoring of serum lactate concentrations.

Agents/circumstances to avoid: Fasting; the ketogenic diet.

Genetic counseling: PC deficiency is inherited in an autosomal recessive manner. De novo somatic pathogenic variants have been reported. If both parents are carriers, sibs of an individual with PC deficiency have a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being carriers, and a 25% chance of inheriting both normal genes and not being carriers. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible by molecular genetic testing if both pathogenic variants have been identified in an affected family member.