Introduction

Phosphoenolpyruvate carboxykinase is an important enzyme in gluconeogenesis. It is found in both the cytosol and mitochondria of the liver cells. The enzyme is regulated by insulin, glucocorticoids, cyclic adenosine monophosphate (cAMP) and diet to maintain glucose homeostasis.

Two types of phosphoenolpyruvate carboxykinase exist:

1. PCK1, PEPCK1 - soluble in the cytosol¹
2. PCK2, PEPCK2 - soluble in the mitochondria²

Epidemiology

• Both conditions are extremely rare.
• They have been reported in siblings.
• Both are autosomal recessive inheritance.
• The enzyme mutation in PCK1 is at gene map locus 20q13.31, and in PCK2 at 14q11.2-q12.

Presentation

• Hypoglycaemia - difficulty keeping blood sugars high.
• Drowsiness due to hypoglycaemia.
• Failure to thrive.
• Metabolic acidosis from accumulation of lactic acid.
• Mild icterus with hepatomegaly.³
• 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, maturity-onset diabetes in the young (MODY).^4,5

Investigations

• Fasting provokes lactic acidosis.
• LFTs are abnormal and liver biopsy shows giant cell hepatitis.
• Culture of skin fibroblasts shows reduced activity of phosphoenolpyruvate carboxykinase.³

Differential diagnosis

Other causes of neonatal hypoglycaemia, for example:

• Glucose-6-phosphate deficiency
• Fructose-1,6,-diphosphatase deficiency
• Pyruvate carboxylase deficiency

Management and prognosis

• Presumably regular feeding would prevent or reduce hypoglycaemia but the impression is of a relentless disease that causes early death(within first 6 months).
• Autopsy shows considerable fatty infiltration of both the liver and the kidneys.⁶ Fatty infiltration of other tissues also occurs but is less marked.
• Genetic counselling may be given as for any other autosomal recessive disorder. There is no literature about antenatal detection.

Document references

1. Phosphoenolpyruvate carboxykinase 1, Soluble; PCK1, Online Mendelian Inheritance in Man (OMIM)
2. Phosphoenolpyruvate carboxykinase 2, Mitochondrial; PCK2, Online Mendelian Inheritance in Man (OMIM)
3. Clayton PT, Hyland K, Brand M, et al; Mitochondrial phosphoenolpyruvate carboxykinase deficiency. Eur J Pediatr. 1986 Apr;145(1-2):46-50. [abstract]
4. Cao H, van der Veer E, Ban MR, et al; Promoter polymorphism in PCK1 (phosphoenolpyruvate carboxykinase gene) associated with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2004 Feb;89(2):898-903. [abstract]
5. Ting CN, Burgess DL, Chamberlain JS, et al; Phosphoenolpyruvate carboxykinase (GTP): characterization of the human PCK1 gene and localization distal to MODY on chromosome 20. Genomics. 1993 Jun;16(3):698-706. [abstract]
6. Hommes FA, Bendien K, Elema JD, et al; Two cases of phosphoenolpyruvate carboxykinase deficiency. Acta Paediatr Scand. 1976 Mar;65(2):233-40. [abstract]

Internet and further reading

• CLIMB, Children Living with Inherited Metabolic Diseases

Acknowledgements