Pyruvate Carboxylase Deficiency

A number sign (#) is used with this entry because pyruvate carboxylase deficiency is caused by homozygous or compound heterozygous mutation in the pyruvate carboxylase gene (PC; 608786) on chromosome 11q13.

Clinical Features

PC deficiency may be categorized into 3 phenotypic subgroups. Patients from North America ('group A') have lactic acidemia and psychomotor retardation, whereas those from France and the United Kingdom ('group B') have a more complex biochemical phenotype with increased serum lactate, ammonia, citrulline, and lysine, as well as an intracellular redox disturbance in which the cytosolic compartment is more reduced and the mitochondrial compartment is more oxidized. Patients in group B have decreased survival compared to group A, and usually do not survive beyond 3 months of age (Robinson et al., 1987). Group C is relatively benign.

North American Phenotype ('Group A')

Tada et al. (1969) reported a family in which 2 sisters were presumably affected with the same physical and mental retardation. The proband had elevated serum alanine and pyruvate, normal SGPT and liver pyruvate decarboxylase activities, but decreased activity of pyruvate carboxylase. Hyperalaninemia was likely secondary to the increased level of pyruvate.

Delvin et al. (1972) noted that 2 forms of pyruvate carboxylase exist in liver, one with a high Km and the other with a low Km for pyruvate. They reported a patient with abnormality of gluconeogenesis and elevated plasma levels of pyruvate, lactate, and alanine in which the low Km enzyme was deficient.

Atkin et al. (1979) reported a child with lactic acidosis, severe mental and developmental retardation, and proximal renal acidosis. Laboratory studies showed severe hepatic, renal cortical, and cerebral deficiencies of pyruvate carboxylase activity. Postmortem neuropathologic examination revealed no signs of Leigh syndrome (256000), but developmental and degenerative lesions were observed. Oizumi et al. (1983) reported a patient with PC deficiency associated with renal tubular acidosis and cystinuria.

Haworth et al. (1981) reported 2 unrelated Canadian Indian infants with PC deficiency. Both presented in infancy with metabolic acidosis. Laboratory findings included increased plasma lactate, pyruvate, glutamic acid, proline, and alanine, and low PC activity in skin fibroblasts and liver. Both survived until at least 2 years of age with severe mental retardation.

Gilbert et al. (1983) reported a case of Leigh necrotizing encephalopathy due to pyruvate carboxylase deficiency.

Carbone et al. (1998) studied 11 males and 6 females from several Canadian Indian populations. Presentation was at birth in 7, and 1 to 8.5 months in 10. Presenting signs included metabolic acidosis in 10, seizures in 5, respiratory distress in 4, pneumonia in 3, and hypotonia in 3. The clinical course was characterized by frequent lactic acidosis, severe developmental delay, and muscular hypotonia in 17, seizures in 8, hypoglycemia in 4, and other CNS involvement (clonus or athetosis) in 4. Eleven patients died between ages 3 months and 4.75 years; 6 were surviving at ages ranging from 3 months to 19 years.

'French form' ('Group B')

The second form of PC deficiency, reported particularly from France, presents early with lactic acidosis, but also shows elevated blood levels of ammonia, citrulline, proline, and lysine. In addition, there is an intracellular redox disturbance, with increased lactate/pyruvate and acetoacetate/beta-hydroxybutyrate ratios.

Saudubray et al. (1976) reported 2 familial cases of neonatal congenital lactic acidosis with liver PC deficiency. Disease onset was immediately after birth, characterized by major neurologic symptoms, hyperammonemia, and hyperketonemia. Hyperlactic acidemia was associated with an increased lactate/pyruvate ratio and an increased acetoacetate/beta-hydroxybutyrate ratio. The authors suggested that the unusual metabolic pattern resulted from decreased oxaloacetate synthesis resulting from PC deficiency and impaired oxaloacetate-dependent mitochondrial redox shuttles. The disease course was rapidly fatal. Coude et al. (1981) and Bartlett et al. (1984) also reported patients with the group B type of PC deficiency.

Robinson et al. (1984) reported 8 patients from 7 families from Canada with pyruvate carboxylase deficiency. Five were of full Amerindian descent, 2 were unrelated Caucasians, and 1 was the offspring of related Egyptian parents. All presented from soon after birth to age 5 months with chronic metabolic acidosis, and 4 had at least 1 episode of hypoglycemia. Six patients died by age 2 years (range 10 days to 2 years), and the 2 living patients were mentally and physically retarded. Using (3)H-biotin labeling and (35)S-streptavidin to detect biotin-containing proteins, and immunodetection with PC antibodies, Robinson et al. (1984) distinguished 2 groups of patients: group 'A' synthesized PC subunits with a normal molecular mass and recognized by antibodies against PC, but showed very little enzymatic activity, (termed CRM(+ve) or type I), whereas group 'B' had no detectable PC subunits and no protein recognized by the antibody (termed CRM(-ve), or type II). The 2 patients with CRM(-ve) results, the Egyptian patient and 1 of the Caucasian patients, had additional biochemical features, including hyperammonemia, citrullinemia, lysinemia, and altered redox states (in 1 patient) similar to the features of patients reported in France. These 2 patients also died early (10 days and 7 weeks) and had hepatomegaly due to excessive fat storage. Robinson et al. (1984) concluded that the 2 subtle types of PC deficiency result from 2 different mutations in the PC gene, 1 that synthesizes an inactive protein and 1 that results in lack of protein expression.

In a follow-up study of cultured skin fibroblasts from 16 patients with either French or American PC deficiency, Robinson et al. (1987) confirmed that the North American cases are associated with the presence of a mature biotin-containing protein of the correct molecular weight. Three families with the French presentation had absence of immunoreactive PC protein and PC mRNA; however, another 3 families with the French presentation had evidence of protein production as well as PC mRNA. Robinson et al. (1987) concluded that when a PC enzyme is produced in French cases, it has no activity.

Pineda et al. (1995) reported an infant with what they termed the 'French' type of pyruvate carboxylase deficiency, with somewhat less severity. The initial neonatal symptoms were respiratory distress, severe metabolic acidosis, and a tendency to hypoglycemia. At age 6 months, he presented with acute neurologic symptoms, lactic acidosis, and hyperammonemia, and died of pneumonia, cardiac failure, and renal insufficiency. Pyruvate carboxylase deficiency was confirmed by enzymatic studies. Postmortem analysis showed periventricular cysts and diffuse hypomyelination.

Brun et al. (1999) reported brother and sister with the severe form of PC deficiency. Both had macrocephaly and severe ischemia-like brain lesions at birth and died in the first week of life with intractable lactic acidemia. In the girl, increased head circumference and periventricular leukomalacia were detected on fetal ultrasonography at 29.4 weeks of gestation. PC activity in cultured skin fibroblasts was less than 2% of control. The lesions were detected at a time of maximal periventricular metabolic demand. Brun et al. (1999) postulated that energy deprivation induced by PC deficiency impairs astrocytic buffering capacity against excitotoxic insult and compromises normal microvascular morphogenesis and autoregulation, both mechanisms leading to cystic degeneration of the periventricular white matter. The authors noted that discovery of cystic periventricular leukomalacia on cerebral ultrasound at birth in a newborn presenting with primary lactic acidemia is highly suggestive of PC deficiency.

'Benign' type ('Group C')

Van Coster et al. (1991) reported a 7-year-old girl with metabolic and biochemical features of the North American type of PC deficiency who had a benign disease course with preservation of motor and mental abilities. She had several episodes of metabolic acidosis with elevated lactate, pyruvate, alanine, beta-hydroxybutyrate, acetoacetate, lysine, and proline values, which were well-managed by rehydration and bicarbonate therapy. PC activity was 1.8% of normal, and she was CRM(+ve). The authors commented on the unique phenotypic expression in this patient.

Schiff et al. (2006) reported a patient with atypical PC deficiency and long survival. He presented at 3 days of age with acute ketoacidosis, tachypnea, and hypotonia. Laboratory studies showed lactacidemia with normal plasma amino acids and ammonia. After successful treatment, he was discharged with an increased lactate-to-pyruvate ratio and avoidance of fasting was advised. During the first 2 years of life, he had mild psychomotor delay and failure to thrive with intermittent acute decompensation. PC activity in cultured skin fibroblasts was severely decreased, leading to the correct diagnosis. Brain MRI at age 18 months showed bilateral high signal intensities in frontoparietal subcortical white matter. At the time of the report, he was 9 years old and showed mild and global psychomotor delay with dysarthria and dysgraphia. Treatment included biotin, L-carnitine, sodium bicarbonate, sodium citrate, and avoidance of fasting. Schiff et al. (2006) noted that relatively long survival into childhood is not a frequent finding for this usually very severe disease.

Diagnosis

Prenatal Diagnosis

Tsuchiyama et al. (1983) reported a patient with PC deficiency and PC activity of about 5% of normal. A prenatal diagnosis was performed in the second pregnancy and the PC activities of the cultured amniotic fluid cells obtained by amniocentesis were within normal limits.

In a family at risk for PC deficiency, Robinson et al. (1985) confirmed the diagnosis in a fetus by enzyme assay and (3)H-biotin labeling of proteins in cultured fetal skin fibroblasts.

Clinical Management

Delvin et al. (1971) found responsiveness to thiamine administration in a patient with PC deficiency. As thiamine pyrophosphate is the coenzyme for pyruvate dehydrogenase, a key enzyme for an alternate route of pyruvate metabolism, the authors suggested that thiamine restored pyruvate metabolism by facilitating an alternative mechanism for its oxidation.

Maesaka et al. (1976) described 2 sisters with pyruvate carboxylase deficiency, severe mental and motor retardation, and Leigh syndrome. The proband had lactic acidosis, low CSF glucose, hyperalaninemia, and increased urinary lactate, pyruvate, and alanine. Both sibs improved clinically and biochemically after treatment with thiamine and lipoic acid.

In a patient with PC deficiency associated with renal tubular acidosis and cystinuria, Oizumi et al. (1983) reported successful treatment with dietary supplement of aspartic acid, asparagine, glutamic acid, and glutamine.

Molecular Genetics

In 11 Ojibwa and 2 Cree patients with type A pyruvate carboxylase deficiency, Carbone et al. (1998) identified a missense mutation in the PC gene (608786.0001). Two brothers of Micmac origin had a transversion mutation in the PC gene (608786.0002). Carrier frequency was estimated to be as high as 1 in 10 in some groupings.

In 2 brothers with type B PC deficiency, Carbone et al. (2002) identified compound heterozygosity for 2 mutations in the PC gene (608786.0005; 608786.0006).

Monnot et al. (2009) identified 9 novel mutations in the PC gene (see, e.g., 608786.0007-608786.0009) in 5 unrelated patients with PC deficiency: 3 had the more severe type B PC, and 2 had type A. PC activity in cultured fibroblasts was undetectable in all patients. Three mutations were frameshift, predicted to introduce a premature termination codon, 1 was an in-frame deletion, and 5 were missense substitutions. Although most PC mutations were suggested to interfere with biotin metabolism, none of the patients was biotin-responsive.

Genotype/Phenotype Correlations

In 5 patients with PC, Monnot et al. (2009) noted that type B was consistently associated with at least 1 truncating mutation, whereas type A always resulted from 2 missense mutations.

Population Genetics

Carbone et al. (1998) noted that the Canadian Indian population had been strongly represented in their study of CRM(+ve) PC deficiency, there being cases in the Micmac, Cree, and Ojibwa. This common linguistic group was derived from a founder group in southern Ontario approximately 300 B.C. It had been suggested that there could be one or more disease-causing mutations in the PC gene that are unique to the 'Algonkian-speaking peoples' of North America.