Clinical characteristics: Pyruvate carboxylase (PC) deficiency is characterized in most affected individuals by failure to gain weight and/or linear growth failure, developmental delay, epilepsy, and metabolic acidosis. Three clinical phenotypes are recognized.

Type A (infantile form) is characterized by infantile onset of metabolic and lactic acidosis, delayed motor development, intellectual disability, poor linear growth and/or weight gain, and neurologic findings (apathy, hypotonia, pyramidal and extrapyramidal signs, ataxia, and seizures). Brain anomalies can be noted. Most affected children die in infancy or early childhood.

Type B (severe neonatal form) is characterized by neonatal or infantile onset of hypothermia, respiratory distress/failure, vomiting, severe lactic acidosis, hyperammonemia, and often hypoglycemia. Neurologic findings include brain abnormalities, lethargy, hypotonia, and pyramidal and extrapyramidal signs. Death typically occurs by age eight months.

Type C (intermittent/attenuated form) is characterized by relatively normal or mildly delayed neurologic development, motor and/or gait abnormalities, (rarely) seizures, episodic movement disorders, and metabolic acidosis. Life span is unknown but survival into adulthood has been reported.

Diagnosis/testing: The diagnosis of PC deficiency is established in a proband whose newborn screening or biochemical findings suggest PC deficiency based on identification of either (1) biallelic pathogenic variants in PC on molecular genetic testing or (2) PC deficiency in whole blood.

Management: Treatment of manifestations: Intravenous glucose-containing fluids, hydration, and correction of metabolic acidosis; pharmacologic therapies (amino acid supplements, cofactors, and vitamins) may improve some findings but not neurologic manifestations; orthotopic liver transplantation may be indicated in some affected individuals; anaplerotic therapies, such as triheptanoin, have had variable success (primarily for individuals with PC deficiency type C) but need further evaluation.

Surveillance: A team of multidisciplinary specialists is often required to monitor existing manifestations, the individual's response to treatment, and the emergence of new manifestations.

Agents/circumstances to avoid: A ketogenic diet is contraindicated, and it is critical to avoid fasting.

Evaluation of relatives at risk: It is appropriate to clarify the genetic and/or biochemical status of apparently asymptomatic older and younger at-risk sibs of an affected individual with PC deficiency type C in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures.

Genetic counseling: PC deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a PC pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial PC pathogenic variants. Once the PC pathogenic variants have been identified in an affected family member, molecular genetic carrier testing for at-risk relatives, prenatal testing, and preimplantation genetic testing are possible.