Phosphoenolpyruvate Carboxylase Deficiency

• Phosphoenolpyruvate carboxykinase 2 soluble, PCK1, PEPCK1 - very rare enzyme deficiency that is listed by OMIM at +261680.¹
• Phosphoenolpyruvate carboxykinase 2 mitochondrial, PCK2, PEPCK2 - very rare enzyme deficiency that is listed by OMIM at +261650.²

• Both conditions are extremely rare.
• They have been reported in siblings.
• OMIM does not state a mode of inheritance but an enzyme deficiency that affects sibs and is lethal in early life would suggest a recessive inheritance.

Phosphoenolpyruvate carboxykinase is an important enzyme in gluconeogenesis. It is found in both the cytosol and mitochondria of the liver, differentiating PCK1 and PCK2 respectively. The gene is regulated by insulin, glucocorticoids, cAMP and diet to maintain glucose homeostasis.

The enzyme mutation in PCK1 is at gene map locus 20q13.31 but for PCK2 it does not appear to have been identified.

Deficiency of the enzyme causes hypoglycaemia, metabolic acidosis and failure to thrive. Death occurs in early life, usually in the first 6 months. Autopsy shows considerable fatty infiltration of both liver and kidneys.³ Fatty infiltration of other tissues also occurs but is less marked.

• Hypoglycaemia - difficult to keep blood sugars high.
• Drowsiness due to hypoglycaemia.
• Failure to thrive.
• Metabolic acidosis from accumulation of lactate acid.
• Mild icterus with hepatomegaly.⁴
• Generalised muscle weakness.

Deficiency of the enzyme can cause persistent neonatal hypoglycaemia but failure of downregulation has also been linked with type 2 diabetes mellitus and especially MODY (maturity onset diabetes in the young).^5,6

• Fasting provokes lactic acidosis.
• LFTs are abnormal and liver biopsy shows giant cell hepatitis.
• Culture of skin fibroblasts shows reduced activity of phosphoenolpyruvate carboxykinase.⁴

Other causes of neonatal hypoglycaemia due to enzyme deficiencies include deficiencies of glucose-6-phosphate, fructose-1,6,-diphosphatase and pyruvate carboxylase. The first should not be confused with glucose-6-phosphate dehydrogenase deficiency nor the second with phosphofructokinase deficiency.

There is remarkably little written about the management of this condition. Presumably regular feeding would prevent or reduce hypoglycaemia but the impression is of a relentless disease that causes early death. Genetic counselling may be given as for any other autosomal recessive. There is no literature about antenatal detection.