Synonyms: propionyl-CoA carboxylase deficiency, ketotic hyperglycinaemia

This is a rare metabolic disorder which can present with vomiting, dehydration and encephalopathy but also with developmental delay and haematological disorders.¹

• The condition predisposes to stroke, specifically bilateral infarcts of the basal ganglia involving caudate, putamen and globus pallidus.
• Milder forms of the condition exist.
• It may be underdiagnosed.
• Propionyl-CoA is an important intermediate in the metabolism of several amino acids and is also produced by oxidation of odd-numbered fatty acids.² Patients are intolerant to protein.

Pathophysiology

• This is a genetic defect of metabolism, inherited as an autosomal recessive.
• The enzyme propionyl coenzyme A (CoA) carboxylase is deficient.
• Severe ketoacidosis is precipitated by ingestion of protein.
• A defect has been described at gene map locus 3q21-q22² but another variation with a defect on chromosome 13 has been described¹ and there may be a few variations of the condition. Online Mendelian Inheritance in Man (OMIM) lists eight.²
• The problem lies in the metabolism of the amino acids isoleucine, valine, threonine and methionine. They are essential amino acids and so management is based on keeping their dietary content low rather than total exclusion.

Epidemiology

• It is a rare condition that on a worldwide basis probably affects about 1 child in 100,000 births.
• Mild forms of the disease are probably more common and the true incidence may be as high as 1 case in 18,000 of the population.
• In certain areas like Saudi Arabia, the incidence may be as high as 1 in 2,000 to 5,000 births.
• It is difficult to assess how much is due to spontaneous mutation.
• Many cases may not be diagnosed and so the incidence may be rather higher than suspected.

Presentation

The fetus is protected in utero by the mother's circulation and metabolism and so presentation is often in infancy. This will depend upon the degree of deficiency of the enzyme. Some have divided patients into 2 subgroups:³

• Early-onset:
  • Present within the first week of life
  • Mental retardation
  • Early death
• Late-onset:
  • Present after 6 weeks of age and can (in mild forms of the disease) present much later in life
  • Characterised by severe movement disorders and dystonias

More specifically:

• Presentation can be with severe ketoacidosis and pH as low as 6.8. There is shock, hypoxia and there may be serious brain damage. Death can result.
• A more usual presentation is failure to thrive with feeding intolerance.
• Excessive levels of ammonia produce a repeated insult to the brain that causes mental retardation. Somnolence is common.
• An attack is followed by pancytopenia that predisposes to overwhelming and possibly fatal infection. The presence of infection to account for illness makes it easy to overlook the metabolic defect.
• Usually there is no family history but sometimes an older infant or young child may have a long history of episodic lethargy, anorexia, vomiting, and acidosis that responds to short hospital stays with intravenous glucose and bicarbonate administration.
• Cardiomyopathy can be rapid and fatal.⁴

Differential diagnosis

A wide variety of conditions may form part of this list, depending on the presentation.^3,5

• Aseptic meningitis
• Haemophilus meningitis
• Stroke:
  • Basilar artery thrombosis
  • Posterior cerebral artery stroke
• Metabolic disorders:
  • Disorders of carbohydrate metabolism
  • Anderson-Fabry disease
  • Homocystinuria
  • Note that, of 100 inborn errors of metabolism, only about 20 are amenable to treatment⁶
• Infective endocarditis (neurological complications)
• Tuberous sclerosis
• Haematological disorders:
  • Sickle cell disease
  • Thrombocytopenia

Investigation

The following findings help to confirm the diagnosis:

• Urine will show ketones. This is unusual in infants and should raise suspicion.
• There is metabolic acidosis with serum electrolytes showing a raised anion gap (normal range 10-18 mmol/L).
• Blood ammonia is elevated. This indicates the cause for disturbance of mental status.
• Plasma lactate is often raised but not enough to account for the anion gap. This should also raise suspicion.
• Urinary organic acids confirm the diagnosis. Large increases in beta-hydroxy propionic acid, lactic acid, and methylcitrate excretion are found.
• The ultimate test is leukocyte propionyl-CoA carboxylase activity. It gives definitive biochemical diagnosis and allows genetic counselling.
• If the diagnosis is not made in life it is unlikely to be made postmortem.

However, it is likely that the full work up of patients presenting with typical (but nonspecific) signs and symptoms will include a wider range of tests in keeping with the differential diagnoses outlined. Inborn errors of metabolism present in a variety of ways (5 main presentations have been observed⁶) and, faced with an infant's deteriorating condition, emergency treatment and investigations have to be pursued.⁶ These will include, for example:

• Full blood count (often reveals neutropenia and thrombocytopenia), electrolytes and blood gases.
• Blood sugar (to exclude other causes of acidosis).
• Liver function tests (to exclude acidosis from liver disease).
• Full range of imaging investigations (appropriate for a young patient with stroke).

Management

The severe metabolic ketoacidosis in this disorder requires vigorous alkali therapy and protein restriction. Oral antibiotic therapy to reduce gut propionate production may also prove useful.¹

• Usually the child is severely unwell on presentation and the clinical imperative is the correction of the ketoacidosis, dehydration and electrolyte imbalance. Fluid, electrolytes and bicarbonate are required. Sometimes glucose and insulin are required.
• A temporary cessation of intake of protein is required, after which the offending amino acids should be permitted in very limited amount. A protein intake below 1.5 grams per kilogram body weight per day is often required.
• If breast-feeding occurs it must be monitored carefully.⁷
• Dietary supplements may be advocated although evidence is limited. Biotin may be given at 10 mg per day. Carnitine is also used.⁸
• In the longer term it is necessary to monitor plasma amino acid levels and to adjust diet accordingly.
• Liver transplantation has had some success but a degree of dietary restriction is still required.^9,10
• Gut flora seems to be a source of proprionic acid and long-term treatment with metronidazole gives benefit.¹¹

Prognosis

• Strict adherence to the diet is required.
• Brain damage is common and life expectancy limited.¹²
• The degree of deficiency of the enzyme has great prognostic significance.

Prevention

• After genetic counselling it is possible to offer prenatal testing with a view to termination of pregnancy (TOP) as the prognosis is so very poor.¹²
• Prenatal testing can be performed:
  • Amniocentesis: propionic acidaemia can be diagnosed either by an elevated quantity of the metabolite methylcitrate in amniotic fluid or by deficient activity of propionyl-CoA carboxylase in amniocytes.^1,12
  • Chorionic villous sampling: prenatal diagnosis of an affected fetus based on DNA analysis in chorionic villus tissue can also be performed.¹
• Screening has been suggested but it is a rare condition that can be missed by the test and it is doubtful if this improves quality of life or gives value for money.¹³

Document references

1. Propionyl-CoA Carboxylase Deficiency, Online Mendelian Inheritance in Man (OMIM)
2. Propionic Acidaemia, Online Mendelian Inheritance in Man (OMIM)
3. Mandava P, Kent TA; Metabolic Disease and Stroke: Propionic Acidemia, eMedicine Nov 2008.
4. Massoud AF, Leonard JV; Cardiomyopathy in propionic acidaemia; Eur J Pediatr. 1993 May;152(5):441-5. [abstract]
5. Harkness RA; Clinical biochemistry of the neonatal period: immaturity, hypoxia, and metabolic disease; J Clin Pathol. 1987 Sep;40(9):1128-44 [abstract]
6. Saudubray JM, Nassogne MC, de Lonlay P, et al; Clinical approach to inherited metabolic disorders in neonates: an overview. Semin Neonatol. 2002 Feb;7(1):3-15. [abstract]
7. Huner G, Baykal T, Demir F, et al; Breastfeeding experience in inborn errors of metabolism other than phenylketonuria. J Inherit Metab Dis. 2005;28(4):457-65. [abstract]
8. Wolff JA, Carroll JE, Le Phuc Thuy, et al; Carnitine reduces fasting ketogenesis in patients with disorders of propionate metabolism. Lancet. 1986 Feb 8;1(8476):289-91. [abstract]
9. Yorifuji T, Kawai M, Mamada M, et al; Living-donor liver transplantation for propionic acidaemia. J Inherit Metab Dis. 2004;27(2):205-10. [abstract]
10. Saudubray JM, Touati G, Delonlay P, et al; Liver transplantation in propionic acidaemia. Eur J Pediatr. 1999 Dec;158 Suppl 2:S65-9. [abstract]
11. Thompson GN, Chalmers RA, Walter JH, et al; The use of metronidazole in management of methylmalonic and propionic acidaemias. Eur J Pediatr. 1990 Aug;149(11):792-6. [abstract]
12. van der Meer SB, Poggi F, Spada M, et al; Clinical outcome and long-term management of 17 patients with propionic acidaemia. Eur J Pediatr. 1996 Mar;155(3):205-10. [abstract]
13. Leonard JV, Vijayaraghavan S, Walter JH; The impact of screening for propionic and methylmalonic acidaemia. Eur J Pediatr. 2003 Dec;162 Suppl 1:S21-4. Epub 2003 Oct 30. [abstract]

Internet and further reading

• The British Society for Human Genetics
• Mandava P, Kent TA; Metabolic Disease and Stroke: Propionic Acidemia, eMedicine Nov 2008.

Acknowledgements