eMedicine Specialties > Neurology > Neuro-vascular Diseases

Metabolic Disease and Stroke - Methylmalonic 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: Dec 11, 2008

Introduction

Background

Methylmalonic acidemia is a disorder of amino acid metabolism, involving a defect in the conversion of methylmalonyl-coenzyme A (CoA) to succinyl-CoA. Patients with this disorder present with neurologic manifestations, such as seizure, encephalopathy, and stroke. Several cases have involved stroke in the bilateral globus pallidi as a result of methylmalonic acidemia.

Pathophysiology

The main pathway of methylmalonyl-CoA production involves the metabolism of isoleucine, valine, threonine, and methionine. To a lesser extent, odd-chain fatty acid and cholesterol degradation also contribute.

Conversion of methylmalonyl-CoA to succinyl-CoA requires the enzyme methylmalonyl-CoA mutase and the cofactor 5'-deoxyadenosylcobalamin. Methylmalonic acidemia can manifest itself differently depending on the following factors:

  • Absence of enzyme (mut0)
  • Reduction in enzyme activity (mut-)
  • Defect in the synthesis of 5'-deoxyadenosylcobalamin (cblA, cblB, cblH)
  • Defect in cobalamin metabolism (cblC, cblD, cblF), which appears as both methylmalonic acidemia and homocystinemia (see Metabolic Disease and Stroke: Homocystinuria/Homocystinemia)

Reduced blood flow or faulty oxidative metabolism may cause strokes in methylmalonic acidemia. The sequence of events in reduced blood flow may be acidosis, hypocapnia, and vasoconstriction. Several magnetic resonance spectroscopic studies have shown that lactate accumulates in areas of the brain that are damaged in methylmalonic acidemia.

Some authors suggest that the accumulation of methylmalonic acid and odd-chain fatty acids may be directly toxic to neuronal and glial cells. This toxic effect may impair oxidative metabolism, leading to infarctions. An alternate hypothesis suggests that toxic metabolites may result from treatment with cyanocobalamin, which metabolizes to cyanide, a known central nervous system toxin.

Liver transplantation meant to address the issue of metabolic derangement in methylmalonic acidemia did not prevent further neurologic worsening or occurrence of strokelike episodes. Therefore, the neurologic consequences of methylmalonic acidemia may not be a result of metabolic abnormalities in the liver, but rather, they may be a local metabolic disturbance in the brain.

Candidate genes for cblA, cblB, designated MMAA and MMAB, and mutations of these genes have been elucidated.

A knock-out mouse model similar to the mut0 human form of methylmalonic acidemia has been developed. This model may facilitate further research into the pathophysiology of the disease and broaden its therapeutic options.

Frequency

United States

The prevalence of methylmalonic acidemia is reportedly 1 case in 25,000-48,000 population. In 1987, Nyhan and Sakati stated that the true prevalence may be higher because many neonatal deaths may be caused by unrecognized metabolic disorders.1

Mortality/Morbidity

  • Children may be healthy at birth and develop symptoms soon after starting protein intake.
  • Over the last 3 decades, observations of patients have revealed that their response to treatment is correlated with their prognosis.
  • Patients with cblA disease have the best prognosis; mut0 patients, the worst; and other patients, intermediate prognoses.
  • In a cross-sectional study of 35 patients from the United Kingdom, patients were classified into cobalamin-responsive and cobalamin-nonresponsive groups.
    • Patients with cobalamin-responsive disease may reach some early developmental milestones, and they may have long-term prognoses better than those of the other group. However, this group remains at risk for acute decompensation, which may result in clinical signs and symptoms of globus pallidal lesions.
    • The cobalamin-nonresponsive group was subdivided into those with early-onset and those with late-onset disease. Early-onset nonresponders had the worst outcomes, with a median survival of approximately 6 years. Neurologic outcomes remained unchanged despite dietary modifications and management of infections.

Sex

A retrospective analysis demonstrated no sex predilection.

Age

Patients typically present at the age of 1 month to 1 year.

Clinical

History

  • Vomiting, dehydration, lethargy, seizures, recurrent infections, and progressive encephalopathy are some features of methylmalonic acidemia. These repetitive events may be a result of metabolic decompensation caused by a change in diet or an overwhelming infection.
  • Methylmalonic acidemia due to derangement of adenosylcobalamin synthesis (cblA, cblB, cblH) and cobalamin catabolism (cblC, cblD, cblF) may have features not shared by pure methylmalonyl-CoA mutase disorders.
  • The patient's family history may be positive (eg, siblings with similar episodes of recurrent illnesses or with acidopathy).

Physical

  • Hypotonia, lethargy, failure to thrive, hepatosplenomegaly, and monilial infections are some classic findings.
  • In patients with methylmalonic acidemia, acute onset of choreoathetosis, dystonia, dysphagia, or dysarthria should alert the physician to the possibility of stroke.
  • Neurologic manifestations may be present, even in the absence of more traditional findings.

Causes

  • The inheritance pattern of methylmalonic acidemia is autosomal recessive.
  • In most children, the disease is diagnosed in the middle of an episode of metabolic decompensation. This metabolic perturbation can be caused by an infection or a change in feeding habit.
  • Some children may present with strokes during a metabolic crisis.

More on Metabolic Disease and Stroke - Methylmalonic Acidemia

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

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Further Reading

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Keywords

methylmalonic acidemia, metabolic disease and stroke, MMA, amino acid metabolism, methylmalonyl-coenzyme A, CoA, succinyl-CoA, seizure, encephalopathy, stroke, globus pallidi bilaterally, methylmalonic acidemia, MMAA, MMAB

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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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