Pyruvate carboxylase deficiency (ORPHA:3008)
Pyruvate carboxylase (PC) deficiency is a rare neurometabolic disorder characterized by metabolic acidosis, failure to thrive, developmental delay, and recurrent seizures at an early age in severely affected patients.
Epidemiology
The overall prevalence of PC deficiency is not known and annual incidence has been reported to be 1/250,000 births. The disorder affects males and females equally.
Clinical description
Three clinical presentations of PC deficiency, probably constituting a continuum, have been described: infantile PC deficiency (type A); severe neonatal PC deficiency (type B); and intermittent/benign PC deficiency (type C). The only common feature is metabolic acidosis. Type A is characterized by infantile onset, generally with a severe course. Type B has a very severe course with a fatal outcome in early infancy, and Type C involves only episodic metabolic acidosis.
Etiology
PC deficiency is caused by mutations in the PC gene (11q13.4-q13.5), involved in the conversion of pyruvate to oxaloacetate, an intermediate in the citric acid cycle and gluconeogenesis. Pyruvate carboxylase also participates in a wide range of other metabolic processes. Most cases are familial but some de novo mutations have been reported. Genotype-phenotype correlations have not been clearly established but missense mutations appear to be associated with infantile PC deficiency (Type A), while truncating mutations are more common in patients with the severe neonatal form (Type B).
Diagnostic methods
PC deficiency may be suspected in patients with the non-specific clinical signs of the condition. Diagnosis is based on detection of characteristic laboratory test abnormalities in amino acid, organic acid, glucose, and ammonia serum concentrations. A PC enzyme activity assay demonstrating deficiency of the PC enzyme in fibroblasts is also diagnostic, along with mutations in the PC gene identified via molecular genetic testing.
Differential diagnosis
Several inborn errors of metabolism have certain features similar to those of PC deficiency. Similar disorders to consider in the differential diagnosis include biotinidase deficiency, holocarboxylase synthase deficiency, pyruvate dehydrogenase deficiency, as well as respiratory chain disorders, tricarboxylic acid cycle disorder, and gluconeogenic defects.
Antenatal diagnosis
Prenatal testing for pregnancies at increased risk is possible and requires identification of both disease-causing alleles in an affected family member.
Genetic counseling
PC deficiency follows an autosomal recessive pattern of inheritance. Genetic counseling should be provided to affected families, particularly regarding the risk of recurrence in subsequent pregnancies.
Management and treatment
The aim of treatment is to provide alternative energy sources and to correct acute metabolic acidosis. Other management and treatment options depend on the type of PC deficiency. Current symptomatic and supportive treatments are generally ineffective.
Prognosis
Type A patients usually die in infancy or early childhood. Type B most commonly has a fatal outcome within the first three months of life. Type C is mostly a benign form of the disorder with little or no effect on life-expectancy.

                            Last update: 
                            November 2013


                            - Expert reviewer(s): 
                            Dr Darryl DE VIVO  - Dr Dong WANG