eMedicine Specialties > Neurology > Pediatric Neurology

Metabolic Disease and Stroke - Propionic Acidemia

Author: Pitchaiah Mandava, MD, PhD, Assistant Professor, Department of Neurology, Baylor College of Medicine; Consulting Staff, Department of Neurology, Michael E DeBakey Veterans Affairs Medical Center
Coauthor(s): Thomas A Kent, MD, Professor, Department of Neurology, Baylor College of Medicine; Neurology Care Line Executive, Michael E DeBakey Veterans Affairs Medical Center
Contributor Information and Disclosures

Updated: Nov 4, 2008

Introduction

Background

Propionic acidemia is a metabolic disorder in which a defective enzyme, propionyl-coenzyme A (CoA) carboxylase, results in an accumulation of propionic acid. Patients may present with vomiting, dehydration, lethargy, and encephalopathy. Clinical and imaging evidence suggests that propionic acidemia predisposes patients to bilateral infarcts of the basal ganglia involving the caudate, putamen, and globus pallidus. Milder forms may be characterized by the absence of some these clinical characteristics.

See also Propionic Acidemia (Propionyl CoA Carboxylase Deficiency).

For related information, see Medscape's CME Activity The Unusual Suspects: Genetic Metabolic Disorders in the Newborn.

Pathophysiology

Metabolism of isoleucine, valine, threonine, and methionine produces propionyl-CoA. To a lesser degree, cholesterol and odd-chain fatty acids also contribute to propionyl-CoA levels. The defective enzyme propionyl-CoA carboxylase, which requires biotin as a cofactor, catalyzes conversion of propionyl-CoA to methylmalonyl-CoA. Several genetic mutations broadly categorized as defects in 2 subunits of the propionyl-CoA carboxylase gene (PCCA and PCCB) may give rise to varying levels of functioning propionyl-CoA carboxylase.

Defects in the metabolic pathway produce several potentially toxic metabolites. Numerous theories regarding basal ganglial infarction (resulting from effects of toxic metabolites) have been suggested. Hamilton et al suggested that metabolites of the dysfunctional propionic acid and methylmalonic acid pathways may be selectively toxic to the endothelial cells in the basal ganglia. Endothelial damage is the presumed basis for strokes. The authors confirmed that basal ganglial lesions were not due to hypoxemia because the hippocampus, which is relatively more sensitive to hypoxemia, was spared.

An alternative hypothesis implicates direct basal ganglia damage due to dysfunction of cytochrome-c oxidase. Accumulation of propionic acid apparently results in an abnormal cytochrome-c oxidase. Another competing hypothesis states that hyperammonemia, which is often associated with propionic acidemia, leads to an accumulation of glutamine and/or glutamate in astrocytes. This excess glutamate may be excitotoxic to neuronal cells in the basal ganglia.

A mouse model that lack thePCCA gene has been developed. Experiments with this model may improve our understanding of the pathophysiology of this disease.

Anti-sense morpholino oligonucleotides directed at intronic pseudoexons have been shown to increase propionyl-CoA carboxylase activity to normal levels in fibroblast cell lines derived from patients suffering from propionic acidemia. 

Frequency

United States

The prevalence is reportedly 1 case per 35,000-75,000 population. The true prevalence may be higher because many neonatal deaths may be caused by undocumented acidopathies.

International

Mild forms of the disease due to differences in the mutations of PCCA or PCCB may exist in different parts of the world, and the true incidence may be as high as 1 case in 18,000 people.

Mortality/Morbidity

Surtees et al divided patients with propionic acidemia into 2 subgroups: Those with early-onset disease presenting in the first week of life and those with late-onset disease presenting after 6 weeks of age.1

  • The early-onset group was characterized by mental retardation and early death. The median survival of the early-onset group was 3 years.
  • The late-onset group was characterized by severe movement disorders and dystonias.

Sex

In a study of 65 patients, a slight female predominance was found, with a female-to-male ratio of 1.4:1.

Age

Patients present in the neonatal period or during early infancy. Patients with mild forms of the disease may present later in life.

Clinical

History

  • Patients with propionic acidemia may present with vomiting, seizures, lethargy, hypotonia, and encephalopathy. These symptoms may be recurrent, with episodes triggered by the onset of feeding, a change in feeding, or an infection.
  • The patient may have a family history of the disease, especially a history of unexplained neonatal death or a sibling with acidopathy.

Physical

  • In patients in whom propionic acidemia was previously diagnosed, the acute onset of movement disorders caused by an infarction of the basal ganglia may be a presenting feature. Dystonia, rigidity, choreoathetosis, and dementia in a child with a previous diagnosis of propionic acidemia suggest a basal ganglial infarction.
  • Case reports suggest that propionic acidemia should be considered in patients with new choreoathetoid movements, even if the traditional symptoms of metabolic decompensation are absent.

Causes

  • Propionic acidemia is an inherited disease (autosomal recessive).
  • Although most children have neurologic damage during a metabolic crisis, rare cases without an identifiable precipitating factor have been reported. The metabolic crisis may result from changes in feeding, or they may be secondary to an infection.

More on Metabolic Disease and Stroke - Propionic Acidemia

Overview: Metabolic Disease and Stroke - Propionic Acidemia
Differential Diagnoses & Workup: Metabolic Disease and Stroke - Propionic Acidemia
Treatment & Medication: Metabolic Disease and Stroke - Propionic Acidemia
Follow-up: Metabolic Disease and Stroke - Propionic Acidemia
References
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References

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  2. Leonard JV, Walter JH, McKiernan PJ. The management of organic acidaemias: the role of transplantation. J Inherit Metab Dis. Apr 2001;24(2):309-11. [Medline].

  3. Al-Essa M, Bakheet S, Patay Z, et al. 18Fluoro-2-deoxyglucose (18FDG) PET scan of the brain in propionic acidemia: clinical and MRI correlations. Brain Dev. Jul 1999;21(5):312-7. [Medline].

  4. Bergman AJ, Van der Knaap MS, Smeitink JA, et al. Magnetic resonance imaging and spectroscopy of the brain in propionic acidemia: clinical and biochemical considerations. Pediatr Res. Sep 1996;40(3):404-9. [Medline].

  5. Brismar J, Ozand PT. CT and MR of the brain in disorders of the propionate and methylmalonate metabolism. AJNR Am J Neuroradiol. Sep 1994;15(8):1459-73. [Medline].

  6. Brismar J, Ozand PT. CT and MR of the brain in the diagnosis of organic acidemias. Experiences from 107 patients. Brain Dev. Nov 1994;16 Suppl:104-24. [Medline].

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  8. Fenichel GM. Clinical Pediatric Neurology: A Signs and Systems Approach. 1996:11-2.

  9. Fenton WA, Rosenberg LE. Disorders of propionate and methyl-malonate metabolism. In: The Metabolic and Molecular Bases of Inherited Disease. Vol 1. 1995:1423-9.

  10. Haas RH, Marsden DL, Capistrano-Estrada S, et al. Acute basal ganglia infarction in propionic acidemia. J Child Neurol. Jan 1995;10(1):18-22. [Medline].

  11. Hamilton RL, Haas RH, Nyhan WL, et al. Neuropathology of propionic acidemia: a report of two patients with basal ganglia lesions. J Child Neurol. Jan 1995;10(1):25-30. [Medline].

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  20. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. 1999;245-54. [Full Text].

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  24. Zweifler RM. Management of acute stroke. South Med J. Apr 2003;96:380-5. [Medline].

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Further Reading

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Keywords

propionic acidemia, propionyl-coenzyme A, CoA, carboxylase, bilateral basal ganglia infarcts, caudate infarct, putaminal infarct, globus pallidus infarct, PCCA, PCCB, metabolic disease and stroke, metabolic disorder, accumulation of propionic acid, biotin

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Contributor Information and Disclosures

Author

Pitchaiah Mandava, MD, PhD, Assistant Professor, Department of Neurology, Baylor College of Medicine; Consulting Staff, Department of Neurology, Michael E DeBakey Veterans Affairs Medical Center
Pitchaiah Mandava, MD, PhD is a member of the following medical societies: American Academy of Neurology, Sigma Xi, and Stroke Council of the American Heart Association
Disclosure: Nothing to disclose.

Coauthor(s)

Thomas A Kent, MD, Professor, Department of Neurology, Baylor College of Medicine; Neurology Care Line Executive, Michael E DeBakey Veterans Affairs Medical Center
Thomas A Kent, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, New York Academy of Sciences, Royal Society of Medicine, Sigma Xi, and Stroke Council of the American Heart Association
Disclosure: Nothing to disclose.

Medical Editor

Richard M Zweifler, MD, Chief of Neurology, Sentara Healthcare, Norfolk, VA
Richard M Zweifler, MD is a member of the following medical societies: American Academy of Neurology, American Heart Association, American Medical Association, American Stroke Association, Royal Society of Medicine, and Stroke Council of the American Heart Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Howard S Kirshner, MD, Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center
Howard S Kirshner, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Heart Association, American Medical Association, American Neurological Association, American Society of Neurorehabilitation, National Stroke Association, Phi Beta Kappa, and Tennessee Medical Association
Disclosure: Boehringer Ingelheim Honoraria Speaking and teaching; BMS/Sanofi Honoraria Speaking and teaching; Novartis Honoraria Speaking and teaching

CME Editor

Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital
Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Chief Editor

Helmi L Lutsep, MD, Professor, Department of Neurology, Oregon Health and Science University; Associate Director, Oregon Stroke Center
Helmi L Lutsep, MD is a member of the following medical societies: American Academy of Neurology and American Stroke Association
Disclosure: Co-Axia Consulting fee Review panel membership; Talecris Consulting fee Review panel membership; AGA Medical Consulting fee Review panel membership; Boehringer Ingelheim Honoraria Speaking and teaching; Concentric Medical Consulting fee Review panel membership; Abbott Consulting fee Consulting; Sanofi  Consulting

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