Conditions · Metabolism (biochemistry)
Pyruvate carboxylase deficiency !
Without pyruvate carboxylase, pyruvate cannot become oxaloacetate: babies have lactic acidosis, low sugar, ketosis and brain damage.
Updated 2026-11-01
Structures involved
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What it is
An inherited mitochondrial disorder in which pyruvate carboxylase (gene PC), the biotin enzyme that turns pyruvate into oxaloacetate, is missing or weak.
Who gets it
Rare: about 1 in 250,000 births worldwide; type A is much more frequent in some Algonkian First Nations in eastern Canada. No Colombian figures are published.
Causes
- Autosomal recessive variants in the PC gene
Risk factors
- Parents who are carriers; consanguinity
- Affected sibling
Pathophysiology
Pyruvate carboxylase is the first step of gluconeogenesis and the main anaplerotic reaction that refills oxaloacetate for the Krebs cycle. Without it, pyruvate piles up and turns into lactate and alanine; glucose cannot be made from lactate, alanine or glycerol-derived pyruvate, so fasting causes hypoglycaemia. Low oxaloacetate slows the Krebs cycle, so acetyl-CoA goes to ketone bodies (paradoxical ketosis with lactic acidosis), and low aspartate impairs the urea cycle (high ammonia and citrulline in type B). The brain lacks energy and neurotransmitter carbon skeletons, causing developmental delay and white matter damage.
Classification
- Type A (infantile): lactic acidosis from early infancy, developmental delay, survival into childhood is limited
- Type B (severe neonatal): lactic acidosis, hyperammonaemia, high citrulline and lysine, hypoglycaemia; often fatal within months
- Type C (intermittent/benign): episodes of lactic acidosis with near-normal development
Symptoms and signs
- Vomiting, poor feeding and fast breathing in the first months
- Low muscle tone and abnormal movements
- Developmental delay and seizures
- Crises during infections or fasting
Diagnosis
- Clinical
- Infant with lactic acidosis, ketosis, hypoglycaemia and neurological signs, worse with fasting or illness.
- Tests
- Blood lactate, pyruvate and the lactate/pyruvate ratio, glucose, ketones, ammonia; plasma amino acids (high alanine, citrulline and lysine in type B; low aspartate). Enzyme activity in fibroblasts and PC gene testing. Biotinidase and holocarboxylase synthetase deficiency must be ruled out.
- Imaging
- Brain MRI: periventricular cysts, white matter changes and reduced brain growth.
Treatment
- Acute
- Intravenous glucose to stop catabolism and correct hypoglycaemia during crises
- Acute
- Correction of acidosis and treatment of high ammonia in a metabolic unit
- Medical
- Anaplerotic supplements (citrate, aspartate) and a trial of biotin, as directed by the metabolic team; ketogenic diets are avoided
- Lifestyle
- Frequent feeding and avoidance of fasting
- Follow-up
- Follow-up of growth, development and seizures
Complications
- Recurrent lactic acidosis crises
- Severe intellectual disability and epilepsy
- Early death in type B
Prognosis
Poor in types A and B; type C has a much better outlook.
Test yourself
Think of the answer, then tap the question to see it.
Why do patients with pyruvate carboxylase deficiency have ketosis together with lactic acidosis?
Oxaloacetate is low, so acetyl-CoA cannot enter the Krebs cycle and is diverted to ketone bodies, while pyruvate builds up as lactate.
Why does fasting cause hypoglycaemia in this disease?
Pyruvate carboxylase is the first step of gluconeogenesis from lactate, alanine and pyruvate.
Which vitamin is the cofactor of pyruvate carboxylase, and which related disorders must be excluded?
Biotin; biotinidase and holocarboxylase synthetase deficiencies also lower carboxylase activity but respond to biotin.
Which amino acids rise in plasma in type B?
Alanine, citrulline and lysine, with low aspartate because oxaloacetate is scarce.
Related conditions
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Pyruvate carboxylase deficiency: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); PC gene: MedlinePlus Genetics (MedlinePlus, US National Library of Medicine, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).
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