Pyruvate Carboxylase Deficiency (PC)
Pyruvate carboxylase deficiency (PCD) is an autosomal recessive disorder caused by pathogenic variants in the gene PC. There are three types of PCD, with varying age of onset and clinical manifestations. All three types have characteristic lactic acidosis, which can lead to vomiting, fatigue, abdominal pain, and difficulty breathing. Type A presents in infancy with developmental delay, hypotonia, and failure to thrive. Lactic acidosis and ketoacidosis are often triggered by periods of fasting or illness. Type A has been identified predominately in individuals from North America. Death typically occurs in infancy or early childhood, though some individuals live into adulthood. Type B presents shortly after birth with severe lactic acidosis, hyperammonemia, ketoacidosis, failure to thrive and liver failure. Neurological signs include developmental delay, seizures, hypotonia, hyperreflexia, dyskinesia, abnormal eye and limb movements, and coma. Type B PCD has a high prevalence in individuals of French, German, English, and Arab descent. Death typically occurs within the first few months of life. Type C is often considered benign and affected individuals have intermittent periods of metabolic acidosis. Neurological exam is typically normal, though some individuals may have episodic ataxia and mild dystonia. Individuals with this type have a normal life expectancy. Homozygous pathogenic variants that lead to severely reduced enzyme levels typically lead to type B PCD. Type A is often caused by variants in the N-terminal protein region. Mosaicism has been observed in all types of PCD.
For information about carrier frequency and residual risk, please see the residual risk table.