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Pyruvate Carboxylase Deficiency.

Authors

Wang D1, De Vivo D2.

Source

GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
2009 Jun 2 [updated 2015 Jul 30].

Author information

1
Department of Neurology, Columbia University, New York, New York
2
Departments of Pediatrics and Neurology, Columbia University, Neurological Institute of New York, New York, New York

Excerpt

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: type A (infantile form), in which most affected children die in infancy or early childhood; 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; and 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 rests on analysis of amino acids and organic acids and detection of deficiency of PC enzyme activity measured in fibroblasts. PC is the only gene in which mutation is known to cause PC deficiency.

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: Use of a high-carbohydrate and high-protein diet to prevent activation of 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 mutated gene and being carriers, and a 25% chance of inheriting both normal genes and not being carriers. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible by molecular genetic testing if both pathogenic variants have been identified in an affected family member.

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