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Pyruvate carboxylase deficiency (PCD) is a very rare, inherited metabolic disorder.
- Pyruvate carboxylase deficiency (PCD) is an autosomal recessive condition in which there is a defect on the gene locus 11q13.4-q13.5.
- Pyruvate carboxylase is required for the conversion of pyruvate to oxaloacetate. The oxaloacetate thus produced is needed for the first step in cellular respiration via the Krebs' cycle, for gluconeogenesis and also for the effective removal of ammonia by means of aspartic acid.
- PCD therefore results in impaired cell respiration producing increased quantities of lactic acid, alanine, acetyl-CoA and ketones.
- PCD also results in impaired gluconeogenesis, leading to poor cell function at times of low glucose levels and also increased levels of circulating ammonia due to the lack of aspartic acid.
Children born with this disorder fail to thrive and develop a progressive deterioration in neurological function, with the majority dying before the age of six months.
Three forms of this disorder have been described: A, B and C. C is the least severe.
- Infantile form (type A) is most commonly seen in North America with an incidence of approximately 1 in 250,000.
- Severe neonatal form (type B) is most common in France and the United Kingdom and has a lower survival than type A.
- Benign form (type C) is very rare with only a few recognised cases worldwide.
- Presentation will vary according to the severity of the disorder.
- A family history of the disorder may raise the possibility of the diagnosis antenatally in a fetus which appears to be small for gestational age.
- Infants born with the disorder may be small with low Apgar scales at delivery and may develop neonatal fits due to hypoglycaemia. Neonates have axial hypotonia and tachypnoea during the first hours of life.
- Other features which may be seen with this disorder include:
Other congenital metabolic disorders, eg Leigh's syndrome.
The following investigations may be helpful in confirming the diagnosis:
- Random blood glucose - reduced.
- Hyperammonaemia, hypernatraemia.
- Serum lactate and pyruvate levels - increased.
- Serum alanine, lysine and proline levels - increased.
- Genetic studies.
- CSF - increased levels of lactate and pyruvate.
- MRI scan - ventricular dilatation and cystic periventricular leukomalacia ± generalised hypomyelination.
- Various therapeutic interventions have been attempted, such as constant drip feeding to prevent hypoglycaemia and the addition of high-dose citrate and aspartate to provide oxaloacetate. Whilst these produce an improvement in the lactic acidosis and metabolic imbalance, they appear to have little effect on the neurological deterioration associated with the disorder.
- Thiamine, lipoic acid and dichloroacetate have all been used in an attempt to maximise use of alternative metabolic pathways and thus reduce the lactic acidosis.
- Anaplerotic therapy is based on the idea that an energy deficit may exist in these diseases, which could be improved by providing an alternative substrate for both the citric acid cycle (CAC) and the electron transport chain for enhanced ATP production. This is in contrast to most dietary therapy for inborn errors, which focuses on the restricting of the precursor to the affected pathway, to limit the production of toxins. This concept has been used in PCD.
- Despite all therapeutic interventions, the prognosis remains poor, with the majority of affected children dying before the age of six months.
- Some will survive for a longer period, with severe physical and mental disabilities.
- The extremely rare, milder 'C' form of the disease may be associated with mild disability and recurrent episodes of lactic acidosis.
Further reading and references
Marin-Valencia I, Roe CR, Pascual JM; Pyruvate carboxylase deficiency: mechanisms, mimics and anaplerosis. Mol Genet Metab. 2010 Sep101(1):9-17. Epub 2010 Jun 9.
Robinson BH, Oei J, Saudubray JM, et al; The French and North American phenotypes of pyruvate carboxylase deficiency, correlation with biotin containing protein by 3H-biotin incorporation, 35S-streptavidin labeling, and Northern blotting with a cloned cDNA probe. Am J Hum Genet. 1987 Jan40(1):50-9.
Garcia-Cazorla A, Rabier D, Touati G, et al; Pyruvate carboxylase deficiency: metabolic characteristics and new neurological aspects. Ann Neurol. 2006 Jan59(1):121-7.
Tsuchiyama A, Oyanagi K, Hirano S, et al; A case of pyruvate carboxylase deficiency with later prenatal diagnosis of an unaffected sibling. J Inherit Metab Dis. 19836(3):85-8.
Ahmad A, Kahler SG, Kishnani PS, et al; Treatment of pyruvate carboxylase deficiency with high doses of citrate and aspartate. Am J Med Genet. 1999 Dec 387(4):331-8.
Roe CR, Mochel F; Anaplerotic diet therapy in inherited metabolic disease: therapeutic potential. J Inherit Metab Dis. 2006 Apr-Jun29(2-3):332-40.
Mochel F, DeLonlay P, Touati G, et al; Pyruvate carboxylase deficiency: clinical and biochemical response to anaplerotic diet therapy. Mol Genet Metab. 2005 Apr84(4):305-12.
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