eMedicine Specialties > Neurology > Neuro-vascular Diseases

Metabolic Disease and Stroke - Methylmalonic 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: 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.

Differential Diagnoses

Other Problems to Be Considered

More common etiologies of stroke are broadly classified as cardiac, infectious, hematologic, vascular, genetic, or metabolic.

The following problems are associated with pediatric strokes:
Cyanotic heart disease
Diabetes mellitus
Endocarditis
Ehlers-Danlos syndrome
Marfan syndrome
Mitochondrial cytopathies
Moyamoya syndrome
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, common causes of ketoacidosis and lactic acidosis must be eliminated first. Diabetes, alcoholic ketoacidosis, liver disease, shock, anoxic and/or ischemic injury of tissues, and seizures are often associated with acidosis.
• If the clinical picture suggests a metabolic disorder, a presumptive diagnosis can be made on the basis of blood analysis for ammonia levels, amino acids, and organic acids. Also perform concomitant urinalysis for amino acids and organic acids.
  • Blood level of ammonia, glycine, and methylmalonic acid are elevated.
  • Serum levels of propionic acid, which is upstream in the metabolic pathway of amino acids, may also be elevated.
  • Urine levels of methylmalonic acid, methylcitrate, propionic acid, and 3-hydroxypropionate levels are high.
  • Definitive diagnosis is made after enzyme analysis of fibroblasts in search of the specific enzyme abnormality.
• CBC counts may reveal neutropenia, anemia, and thrombocytopenia, the result of the downregulation of hematopoietic growth, which also may be present during acute episodes of infection or metabolic decompensation.
• Perform blood, imaging, and cardiac studies as part of the workup in a patient in whom stroke is suspected. Exclude other various causes of strokes in the pediatric population.

Imaging Studies

• Neuroimaging study is always warranted when patients have a change in neurologic status (eg, seizures, lethargy, progressive encephalopathy, choreoathetosis, dystonia, dysarthria).
• MRI and CT studies have commonly shown bilateral lesions of the globus pallidus in patients with methylmalonic acidemia. Imaging abnormalities extending beyond the basal ganglia have also been reported. These abnormalities include delayed myelination, immature gyral pattern and periventricular white matter lesions.
• Small hemorrhages in the brainstem and cerebellum have also been reported. 
• Intracranial hemorrhage can occur if the metabolic derangement includes a bleeding diathesis.

Treatment

Medical Care

• Cobalamin supplementation, restriction of protein to 1.5 g/kg/d, and carnitine supplementation are suggested.
  • Cobalamin supplementation may help because cobalamin is a cofactor in the enzymatic conversion of methylmalonyl-CoA to succinyl-CoA. This therapy can be started while the diagnosis is being confirmed.
  • If cobalamin supplementation is not helpful, restrict the patient's isoleucine, threonine, methionine, and valine intake.
  • Levo-carnitine (L-carnitine), an enzyme involved in the metabolism of long-chain fatty acids, buffers the acyl-CoA metabolites that accumulate with protein-restricted diets. Acyl-carnitine produced by this buffering action is excreted in the urine.
• In an acute phase, identify and treat intercurrent infections that triggered the acidotic episode. Correct acidosis; dialysis may be required in cases of severe ketoacidosis and hyperammonemia. A case report noted a decrease in ammonia levels with the use of carbamylglutamate in preference to dialysis alone.
• Dietary modifications must be made in a hospital setting. As mentioned in Mortality/Morbidity, outcomes are better in patients with cobalamin-responsive disease than in those with the cobalamin-nonresponsive disease, in association with dietary changes and supplementation of carnitine and cobalamin.
  • Response to cobalamin supplementation and dietary changes may be monitored in terms of clinical and laboratory improvement.
  • Quantitative measurement of methylmalonic acid in the urine can monitor the success of therapy.
  • Candidal infection may be the first sign that treatment adjustments are necessary.
• Liver transplantation alone or in conjunction with kidney transplantation has been attempted. Organ transplantation may not prevent future neurologic damage or reverse old damage.

Consultations

• Consult a neurologist when seizures, choreoathetosis, dysarthria, or stroke occur.
• Genetic counseling may be offered to the patient's family, especially if more than 1 child has aminoacidopathy.
• Consultation with a registered dietitian is also in order because protein restriction is an essential part of treatment.
• Physical and occupational therapist may help in functionally retraining patients.

Diet

Implement a protein-restricted diet (0.5-1.5 g/kg/d) with L-carnitine and cobalamin supplementation.

Medication

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

Vitamins

Cobalamin supplementation may help because cobalamin is a cofactor in the enzymatic conversion of methylmalonyl-CoA to succinyl-CoA.

Cyanocobalamin (Nascobal)

Deoxyadenosylcobalamin and hydroxocobalamin are active forms of vitamin B-12; a number of patients with methylmalonic acidemia are clinically responsive; can be started if diagnosis suspected and confirmation awaited.

Dosing

Adult

Pediatric

1-3 mg IM qd

Interactions

None reported

Contraindications

Documented hypersensitivity; hereditary optic nerve atrophy

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

Caution with vitamin B-12 megaloblastic anemia (may result in severe, possibly lethal, hypokalemia)

Nutritional supplement

L-carnitine, an enzyme involved in the metabolism of long-chain fatty acid, buffers the acyl-CoA metabolites that accumulate with protein-restricted diets.

L-carnitine (Carnitor, Vitacarn)

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; reduces ketogenesis in response to fasting; may help relative carnitine deficiency in this disease state.

Dosing

Adult

Pediatric

100 mg/kg/d PO

Interactions

None reported

Contraindications

None reported

Precautions

Pregnancy

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

Precautions

Can cause GI upset (eg, nausea, vomiting, diarrhea); D-isomer is of limited use in this disease; monitor blood chemistries, plasma carnitine concentrations, vital signs, and overall clinical condition

Follow-up

Inpatient & Outpatient Medications

• Immediately prescribe a protein-restricted diet when an acidemia is a diagnostic consideration. This modification decreases the key amino acids (eg, isoleucine, valine, threonine, methionine) that enter the metabolic pathway.
• Try cyanocobalamin, even in patients whose disease does not respond while a definitive diagnosis is pending. The rationale is that adenosylcobalamin acts as a cofactor for methylmalonyl-CoA mutase, which converts methylmalonyl-CoA to succinyl CoA.
• L-carnitine, a dietary supplement, is also used to treat all patients with methylmalonic acidemia, who apparently have a relative carnitine deficiency. The D-isomer of carnitine may not be therapeutic.

Transfer

• Acidemias are complex diseases and require multispecialty care for diagnosis and treatment.
• Patients are best evaluated and treated in tertiary care centers.
• In the acute phase of illness, life-threatening issues, such as acidosis and the need for dialysis, can be assessed and treated locally.
• After stabilization, patients may be transferred if the necessary treatment and/or diagnostic modalities are not available locally.

Prognosis

Of the 6 recognized defects in methylmalonate metabolism, cblA has the best prognosis; mut0, the worst. The remaining classes (cblB, cblC, cblD, cblF) have intermediate prognoses. cblH is a newly identified variant of cblA.

Patient Education

• Education of the patient's family, specifically the parents, plays a critical role in the care of patients.
• Recognition of poor feeding, vomiting, dehydration, hypotonia, respiratory distress, and seizure may help in identifying ongoing metabolic decompensation.
• For excellent patient education resources, visit eMedicine's Stroke Center. Also, see eMedicine's patient education article Stroke.

Miscellaneous

Medicolegal Pitfalls

• Signs, symptoms, and nonspecific presentation generally make the diagnosis of acidemia difficult.
• If the patient's family or sibling history suggests a diagnosis of acidemia, prenatal and neonatal diagnosis must be pursued aggressively. Early diagnosis and treatment may delay the progression of symptoms.

References

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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

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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