Pyruvate Carboxylase Deficiency, Severe Neonatal Type

Severe neonatal pyruvate carboxylase (PC) deficiency (Type B) is a rare, extremely severe form of PC deficiency characterized by severe, early-onset metabolic acidosis, and a generally fatal outcome in early infancy.

Epidemiology

The exact prevalence of Type B pyruvate carboxylase deficiency is not known. The disorder has been reported to be more common in populations of Arab descent (Algerian, Egyptian, and Saudi Arabian). Higher incidence is also reported in France, Germany and the United Kingdom.

Clinical description

Patients develop clinical manifestations during the first 72 hours of life with severe truncal hypotonia and tachypnea. Subsequent clinical signs include anorexia, failure to thrive, hepatomegaly, myoclonic or generalized tonic-clonic seizures, stupor, pyramidal dysfunction, abnormal movements (high-amplitude tremor and dyskinesia), abnormal limb and ocular movements and severe impairment of mental and motor development. Renal tubular acidosis has been reported.

Etiology

PC deficiency is caused by mutations in the PC gene (11q13.4-q13.5).

Diagnostic methods

The biochemical hallmarks of Type B pyruvate carboxylase deficiency include elevated lactate/pyruvate (L/P) ratio, ketoacidosis with low hydroxybutyrate/acetoacetate (H/A) ratio in plasma, hypoglycemia, increased citrulline, proline, lysine and alanine levels, low glutamine, hyperammonemia and hypernatremia. Blood lactic acid levels are usually above 10 mmol/l. 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.

Genetic counseling

Pyruvate carboxylase deficiency is inherited in an autosomal recessive manner.

Prognosis

The prognosis is very poor with almost all affected infants dying within the first three months of life.