eMedicine Specialties > Neurology > Pediatric Neurology

Metabolic Disease and Stroke - Propionic Acidemia

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
Thomas A Kent, MD, Professor, Department of Neurology, Baylor College of Medicine; Neurology Care Line Executive, Michael E DeBakey Veterans Affairs Medical Center

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.

Differential Diagnoses

Other Problems to Be Considered

Brainstem syndromes
Cyanotic heart disease
Ehlers-Danlos syndrome
Marfan syndrome
Mitochondrial cytopathies
Organic acidurias
Patent foramen ovale
Sickle cell disease
Thrombocytopenia

Workup

Laboratory Studies

• When acidosis is suspected on the basis of electrolyte and arterial blood gas abnormalities, eliminate the common causes of ketoacidosis and lactic acidosis first. Seizures, diabetes, alcoholic ketoacidosis, liver disease, shock, and anoxic and/or ischemic injury of tissues are often present with acidosis.
• If the clinical picture suggests metabolic disorder, a presumptive diagnosis may be made on the basis of blood analysis for ammonia levels, amino acids, and organic acids. Serum levels of ammonia, glycine, B-hydroxybutyrate, and acetoacetate should be elevated.
  • Perform urinalysis for amino acids and organic acids. Methyl citrate, 3-hydroxy propionate, propionyl glycine, tiglate, and tiglyl glycine should be increased in the urine.
  • Make definitive diagnosis after an enzyme analysis of fibroblasts is done. The results may show a severely depressed level of propionyl-CoA carboxylase.
  • Genetic mutation analysis can also be undertaken.
• CBC counts may reveal neutropenia and thrombocytopenia.
• During the workup of a young patient with suspected stroke, exclude other causes of stroke by obtaining blood, brain, vascular, and cardiac studies.

Imaging Studies

• Acute changes in neurologic status (eg, stroke, seizure, encephalopathy) warrant neuroimaging study.
• Several reports confirm that patients with propionic acidemia and movement disorders most likely have lesions in the bilateral lenticular and caudate nuclei.
• By convention, both CT and MRI were used to identify these lesions.
• More recently, positron emission tomography has been used to show decreased glucose uptake in the basal ganglia.

Treatment

Medical Care

Medical care for patients with propionic acidemia includes the following:

• A low-protein diet (1.5-2 mg/kg/d), L-carnitine supplementation (100 mg/kg/d), and biotin supplementation (10 mg/d) are required.
• Carnitine, an enzyme involved in the metabolism of long-chain fatty acids, buffers the acyl-CoA metabolites that accumulate with protein-restricted diets. The acyl-carnitine that is produced by the buffering action is excreted in the urine.
• Biotin is a cofactor for propionyl-CoA carboxylase (and for 3 other carboxylases). Therefore, propionic acidemia may be present in a patient, as the broader metabolic problem of multiple carboxylase deficiency.
  • Biotin responsiveness may depend on the genetic heterogeneity of isolated propionic acidemia and propionic acidemia existing as a subset of multiple carboxylase deficiency.
  • In patients with biotin-unresponsive disease, restricting their intake of isoleucine, valine, threonine, and methionine is the only solution.
• Prompt dietary modification and supplementation may reverse clinical symptoms and normalize laboratory findings.
  • The success of therapy can be measured as changes in propionic acid level in the serum.
  • In-home testing of urine for ketones, especially during suspected infections, has been advocated.
• In the acute phase, identify and treat intercurrent infections that have triggered an acidotic episode.
  • Dietary modifications must be made in a hospital setting.
  • Dialysis may be required for life-threatening acute phases of illnesses that are triggered by infections or other stresses.
  • Because gastrointestinal bacteria produce propionic acid, neomycin and metronidazole have been proposed as treatments. Clinical data about this treatment regimen are limited.
• Organ transplantation of the liver or of the liver and kidney has been attempted. However, perioperative and postoperative complications are apparently high, and the long-term benefits are unclear.²

Consultations

• Consultation with a pediatric neurologist is necessary when a patient presents with stroke, seizure, or encephalopathy.
• Dietary and/or nutritional specialists may help in modifying the patient's diet.
• A physical therapist and/or an occupational therapist should also be consulted for functional assessment and therapeutic recommendations.
• After the diagnosis of propionic acidemia is confirmed, a geneticist should be consulted.

Diet

A protein-restricted diet (0.5-1.5 g/kg/d) with L-carnitine and biotin supplementation is required.

Medication

The goals of pharmacotherapy for propionic acidemia are to reduce morbidity and prevent complications.

Essential coenzyme

This is a critical cofactor for essential metabolic processes.

Biotin

Coenzyme for propionyl-CoA carboxylase as well as 3 other carboxylases.

Dosing

Adult

Pediatric

5-10 mg/d PO

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

None reported

Nutritional supplement

This is used to correct metabolic deficiencies.

Levo-carnitine (L-carnitine)

Can promote excretion of excess fatty acids in patients with defects in fatty acid metabolism or specific organic acidopathies in which acyl-CoA esters accumulate; reduced ketogenesis in response to fasting; may help with relative carnitine deficiency in propionic acidemia.

Dosing

Adult

Pediatric

100 mg/kg/d PO (IV formulation also available)

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Body odor, nausea, and gastritis; D-isomer may not be therapeutically useful in this condition; monitor blood chemistries, plasma carnitine concentrations, vital signs, and patients' overall clinical condition

Follow-up

Inpatient & Outpatient Medications

The following are indicated for patients with propionic acidemia:

• A protein-restricted diet is the cornerstone of treatment.
• Administer biotin 5-10 mg/d, the cofactor for carboxylase enzymes, and L-carnitine, a dietary supplement.

Transfer

• The incidence of propionic acidemia is low, and the expertise to deal with this disease may be available only in tertiary medical centers.
• Life-threatening issues (eg, acidosis, dehydration, seizures) can possibly be addressed locally. However, when acidemia is suspected, the patient may need to be transferred to a facility with a high level of expertise in this area.

Prognosis

• Patients whose disease is diagnosed before birth (from the family history or sibling history) or soon after birth have the best prognosis.
• Surtees et al found that patients with early-onset disease have a median survival of 3 years.¹
• Patients with late-onset disease usually have permanent neurologic damage.

Patient Education

• To improve patient outcome, educate the family to recognize early signs of dehydration, poor feeding, seizures, and respiratory distress.
• This education is important because metabolic decompensation plays a major role in the neurologic problems and sequelae observed in patients with propionic acidemia.
• For excellent patient education resources, visit eMedicine's Stroke Center. Also, see eMedicine's patient education article Stroke.

Miscellaneous

Medicolegal Pitfalls

• The low incidence of propionic acidemia coupled with nonspecific presenting symptoms make the diagnosis difficult.
• The patient's family history and sibling history must be obtained and carefully investigated when one deals with any inherited disease.
• Prenatal and neonatal diagnosis must be pursued aggressively.

References

1. Surtees RA, Matthews EE, Leonard JV. Neurologic outcome of propionic acidemia. Pediatr Neurol. Sep-Oct 1992;8(5):333-7. [Medline].

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].

7. Clavero S, Perez B, Rincon A, et al. Qualitative and quantitative analysis of the effect of splicing mutations in propionic acidemia underlying non-severe phenotypes. Hum Genet. Aug 2004;115(3):239-47. [Medline].

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].

12. Hoffmann GF, Gibson KM, Trefz FK, et al. Neurological manifestations of organic acid disorders. Eur J Pediatr. 1994;153(7 suppl 1):S94-100. [Medline].

13. Mass General Hosp. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 39-1998. A 13-year-old girl with a relapsing-remitting neurologic disorder [clinical conference]. N Engl J Med. Dec 24 1998;339(26):1914-23. [Medline].

14. Miyazaki T, Ohura T, Kobayashi M, et al. Fatal propionic acidemia in mice lacking propionyl-CoA carboxylase and its rescue by postnatal, liver-specific supplementation via a transgene. J Biol Chem. Sep 21 2001;276(38):35995-9. [Medline].

15. Nyhan WL, Bay C, Beyer EW, Mazi M. Neurologic nonmetabolic presentation of propionic acidemia. Arch Neurol. Sep 1999;56(9):1143-7. [Medline].

16. Nyhan WL, Skati NA. Propionic acidemia. In: Diagnostic Recognition of Genetic Disease. 1987:36-41.

17. Perez-Cerda C, Merinero B, Marti M, et al. An unusual late-onset case of propionic acidaemia: biochemical investigations, neuroradiological findings and mutation analysis. Eur J Pediatr. Jan 1998;157(1):50-2. [Medline].

18. Rincon A, Aguado L, Desviat LR et al. Propionic and Methylmalonic Acidemia: Antisense Therapeutics for Intronic Variations Causing Aberrantly Spliced Messenger RNA. Am J Hum Genet. 2007;81:1262-1270. [Medline].

19. Sethi KD, Ray R, Roesel RA, et al. Adult-onset chorea and dementia with propionic acidemia. Neurology. Oct 1989;39(10):1343-5. [Medline].

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].

21. Swaiman KF. Aminoacidopathies and organic acidemias resulting from deficiency of enzyme activity. In: Pediatric Neurology. Principles and Practice. 1994:1215-9.

22. Wolf B, Hsia YE, Sweetman L, et al. Propionic acidemia: a clinical update. J Pediatr. Dec 1981;ID - AM 25675/AM/NIADDK(6):835-46. [Medline].

23. Yorifuji T, Kawai M, Muroi J, et al. Unexpectedly high prevalence of the mild form of propionic acidemia in Japan: presence of a common mutation and possible clinical implications. Hum Genet. Aug 2002;111(2):161-5. [Medline].

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

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

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

© 1994- by Medscape.
All Rights Reserved
(http://www.medscape.com/public/copyright)