Methylmalonic Acidemia Brief Overview of Methylmalonic Acidemia

Updated: Sep 19, 2022
  • Author: Pradeep Kumbham, MD; Chief Editor: Helmi L Lutsep, MD  more...
  • Print
Brief Overview of Methylmalonic Acidemia

Brief Overview of Methylmalonic Acidemia

Methylmalonic acidemia is an autosomal recessive disorder of amino acid metabolism, involving a defect in the conversion of methylmalonyl-coenzyme A (CoA) to succinyl-CoA. Patients typically present at the age of 1 month to 1 year with neurologic manifestations, such as seizure, encephalopathy, and stroke. [1, 2, 3] Several cases have involved stroke in the bilateral globus pallidi as a result of methylmalonic acidemia.

Several mutations have been identified in the MUT gene resulting in MMA. There can be deletions, insertions, missense or nonmutations, and so on that lead to clinical phenotype. Mutations of the MUT gene are estimated to cause 60% of MMA cases. These mutations result in defects in the methylmalonyl-CoA mutase enzyme. The gene has been mapped to chromosome 6p12-21.2

There is reportedly 1 case of methylmalonic acidemia in 25,000-48,000 population. Nyhan and Sakati stated that the true prevalence may be higher because many neonatal deaths may be caused by unrecognized metabolic disorders. [4]

For patient education information, see eMedicineHealth's Brain and Nervous System Center, as well as Stroke.

Go to Neuro-vascular Diseases for more information on metabolic diseases and stroke.


Etiology and Neuropathology

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 [5] :

  • 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, cblE, cblF, cblG, cblJ), which appears as both methylmalonic acidemia and homocystinemia (see Homocystinuria/Homocysteinemia) [6]

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.

Based on reports of liver transplantation reports meant to address the issue of metabolic derangement in methylmalonic acidemia, the neurologic consequences of methylmalonic acidemia may not be a result of metabolic abnormalities in the liver; rather, they may be a local metabolic disturbance in the brain. Liver transplantation did not prevent further neurologic worsening or occurrence of strokelike episodes. [7, 8, 9, 10, 11]

Candidate genes for cblA, cblB, designated MMAA and MMAB, and mutations of these genes have been elucidated. [12, 13, 14, 15]

A knock-out mouse model similar to the mut0 human form of methylmalonic acidemia has been developed. [16] This model may facilitate further research into the pathophysiology of the disease and broaden its therapeutic options.

In a study of 21 Indian patients, 70 mutations were identified. Although there are 13 exons of the MUT gene, the most deleterious mutations were located in exon 12, then exon 9, exon 11, and exon 2. Though there is a wide spectrum of mutations found in MMA, this study, consistent with previous studies, showed that missense mutations were the highest contributors to the phenotype. [17]


Evaluation of Methylmalonic Acidemia

Children with methylmalonic acidemia may be healthy at birth and develop symptoms soon after starting protein intake. The patient's family history may be positive for methylmalonic acidemia (eg, siblings with similar episodes of recurrent illnesses or with acidopathy).


In most children, the disease is diagnosed in the middle of an episode of metabolic decompensation. [18] Vomiting, dehydration, lethargy, seizures, recurrent infections, and progressive encephalopathy are some features of methylmalonic acidemia. These metabolic perturbations can be caused by an infection or a change in feeding habit. Some children may present with strokes during a metabolic crisis.

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.

A case study of a 4-year-old girl with MMA with partial clbC subtype showed that onset of disease can be following aHUS as opposed to neurological damage which is more common.  [19]

There have been cases of late-onset cblC form of disease reported. Most presented with neurological symptoms including cognitive decline, hypertensive encephalopathy, unsteady gait, myelopathy, and behavioral abnormalities. One study reports two siblings with late-onset cblC which presented with manic-depressive psychosis at the first onset. As this late-onset form of MMA is rare, inclusion of psychiatric symptoms as a first symptom may help yield higher diagnostic results.  [20]


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.

The majority of MMA onset from neurological damage, but some cases may first onset with unusal presentations such as mimicked diabetic ketoacidosis, late-onset diffuse lung disease, and juvenile gout.  [19]


Diagnosis of Methylmalonic Acidemia

Signs, symptoms, and nonspecific presentation generally make the diagnosis of methylmalonic 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

The 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

Go to Inherited Metabolic Disorders, First Seizure: Pediatric Perspective, Complex Partial Seizures, Moyamoya Disease, Neurofibromatosis, Type 1, Posterior Cerebral Artery Stroke, Staphylococcal Meningitis, and Tuberous Sclerosis for more information on these topics


The following conditions should also be considered in the evaluation of cases of suspected methylmalonic acidemia:


Diagnostic Tests

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.

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.

When acidosis is suspected on the basis of electrolyte and arterial blood gas (ABG) 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.

Blood levels 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.

Complete blood cell (CBC) counts may reveal neutropenia, anemia, and thrombocytopenia, the result of the downregulation of hematopoietic growth, which may also be present during acute episodes of infection or metabolic decompensation.

Gas chromatography-mass spectrometry can be used for the organic acid in urine, blood, and cerebrospinal fluid.

Mutation analysis is the most reliable evidence for MMA and can be accomplished by Next-Generation sequencing as well as Sanger sequencing.  

The American College of Medical Genetics and National Academy of Clinical Biochemistry recommends early diagnosis by means of newborn screening. While newborn screening for metabolic disorders is not currently used in all countries, there have been improvements in reliable determination of MMA in dried blood spots. Using liquid chromatography-tandem mass spectrometry, this assay can effectively and reliably differentiate patients with propionic acidemia, methymalonic acidemias, and combined remethylation disorders. [21]


Neuroimaging, MRI, and CT Scanning

Neuroimaging study is always warranted when patients have a change in neurologic status (eg, seizures, lethargy, progressive encephalopathy, choreoathetosis, dystonia, dysarthria).

Magnetic resonance imaging (MRI) and computed tomography (CT) studies have commonly shown bilateral lesions of the globus pallidus in patients with methylmalonic acidemia. [22, 23, 24, 25, 26, 27, 28, 29, 30] 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, and intracranial hemorrhage can occur if the metabolic derangement includes a bleeding diathesis.


Management of Methylmalonic Acidemia

In an acute phase, identify and treat intercurrent infections that triggered the acidotic episode. Correct the 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. [31]

Dietary modifications must be made in a hospital setting. 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. [32, 33]

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.

Levo-carnitine (L-carnitine) is a dietary supplement that 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.

Patients with MMA are prone to anorexia and often need a temporary or permanent method for enteral feeding. When appropriate, tube feeding should be used. [34]

Medical management of methylmalonic acidemia

Treatment strategies for MMA are designed to reduce metabolic poisons and/or to accelerate their clearance. [19]

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

Cobalamin supplementation may help because cobalamin is a cofactor in the enzymatic conversion of methylmalonyl-coenzyme A (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. The typical formulation and starting dosage is hydroxocobalamin 1000 μg intramuscular once daily.

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.

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.

Medical dietary changes are often critical for therapy in inborn errors of metabolism, however, their optimal composition is under review by researchers. The combination of protein restriction and high leucine content in medical foods may have unintended effects such as imbalanced branched-chain amino acid (BCAA) content, which could lead to decreased plasma levels of valine and isoleucine and predicts impairment of brain uptake of essential amino acids. [35]

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. [7, 8, 9, 10, 11, 36, 37, 38]  Since the liver is the site of most of the metabolic conversion of propionate, replacing the liver may contribute enough enzyme activity to avert metabolic decompensation. Although liver transplant may help to protect against metabolic instability, it is not a cure and MMA patients still remain at risk for long-term complications. [39]

Low sodium bicarbonate levels should be treated aggressively. This formula can be used to calculate the mmol of base to provide for half-correction, which is an appropriate goal for the first 24 hours of treatment. [Desired bicarbonate level (mmol/L) - current bicarbonate level (mmol/L)] × [volume of distribution (0.7 in neonate; 0.6 in older child and adult) × body weight (kg)] × [0.5]. [34]

Hemodialysis is indicated when initial ammonia levels are greater than 500μmol/L. Nephrology should be consulted in this case. [34]

Consider carglumic acid (Carbaglu), which was approved as an adjunct to standard-of-care for the treatment of hyperammonemia due to MMA. Evaluation of efficacy was based on a clinical trial in which 90 hyperammonemic episodes occurring in 24 patients (propionic acidemia or MMA) showed that the carglumic acid-treated arm demonstrated a quicker reduction of ammonia compared to patients receiving placebo. [40]

Regular medical screenings for known complications of MMA are recommended for optimal management of disease. 

Transfer considerations

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.


Consult a neurologist when seizures, choreoathetosis, dysarthria, or stroke occur. Consider offering genetic counseling 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, and consider consultation with a physical and occupational therapist, as they may help in functionally retraining patients.

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.

Quality of life 

In a study of 35 families affected by MMA, health-related quality of life was evaluated using the Pediatric Quality of Life Inventory (PedsQL™)  parent version. [41]  Children with MMA mut0 had a lower mean score on the Generic Core Scales than healthy children with the most impaired domains in social and school functioning. This indicates that children living with MMA have substantial impairments in quality of life, and their families also showed significant impairments in cognitive functioning, worry, family relationships, and daily activities. [41]  

Counseling should be provided to families with newly diagnosed children in anticipation of the impaired domains in quality of life. Children with MMA may require additional educational and social support and early interventions may help improve outcomes. 


Outcomes of Methylmalonic Acidemia

Over the last 3 decades, observations of patients have revealed that their response to treatment is correlated with their prognosis. Of the 9 recognized defects in methylmalonate metabolism, cblA has the best prognosis; mut0, the worst. The remaining classes (cblB, cblC, cblD, cblE, cblF, clbG) have intermediate prognoses. cblH is a newly identified variant of cblA.

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.

While transplantation may help improve metabolic stability, the CNS remains at high ongoing risk regardless. [42]  Early transplantation may help to maintain neurological development and improve growth of patients and in one study of 13 Japanese MMA patients, 10 were free of acidosis attacks following transplantation. [43]

In a cross-sectional study of 35 patients from the United Kingdom, early-onset cobalamin-nonresponders had the worst outcomes, with a median survival of approximately 6 years. [44] Neurologic outcomes remained unchanged despite dietary modifications and management of infections.

In a case study of 4 children with combined methylmalonic acidemia and homocysteinemia, all developed diffuse lung diseases. This study indicates that the combination of MMA and homocysteinemia may be the primary cause of diffuse lung diseases in this cohort of patients. It also presents justification for combined MMA and homocysteinemia to be considered in the differential diagnosis of diffuse lung diseases. 

As more cases are evaluated, better therapies for these patients will emerge. Clinicians treating cases of MMA should stay up-to-date on progressive therapies and trials to provide optimal care to their patients.