Genetics of Methylmalonic Acidemia 

Updated: Mar 16, 2015
Author: Brendan Lee, MD, PhD; Chief Editor: Maria Descartes, MD 

Overview

Background

Oberholzer et al and Stokke et al reported the first patients with methylmalonic acidemia (MMA).[1, 2] Clinical and genetic heterogeneity became evident very early when some patients responded to pharmacological doses of cobalamin (vitamin B-12) and others did not.

MMA encompasses a heterogeneous group of disorders characterized by accumulation of methylmalonic acid and its by-products in biological fluids. These disorders are due to a deficiency of the adenosylcobalamin-dependent enzyme methylmalonyl-CoA mutase (apoenzyme deficiency), a defect in intracellular cobalamin metabolism (coenzyme deficiency), transcobalamin II deficiency, intrinsic factor deficiency, or dietary cobalamin deficiency, which is found in vegetarians. A subset of children with defects of intracellular cobalamin metabolism may also have simultaneous homocystinuria. In addition, transient MMA can be detected in otherwise healthy infants.

In the context of this review, MMA refers to disorders resulting in methylmalonyl-CoA mutase deficiency and disorders of intracellular cobalamin metabolism.

Pathophysiology

Adenosylcobalamin-dependent methylmalonyl-CoA mutase is an enzyme that catalyses the isomerization of methylmalonyl-CoA to succinyl-CoA. Succinyl-CoA subsequently enters the tricarboxylic acid cycle, where it is converted through several steps to oxaloacetate. Methylmalonyl-CoA is derived from propionyl-CoA by the action of propionyl-CoA carboxylase, the enzyme that is deficient in patients with propionic acidemia (see Propionic Acidemia). Propionyl-CoA is formed through the catabolism of isoleucine, valine, threonine, methionine, thymine, uracil, cholesterol, or odd-chain fatty acids. Gut bacteria may generate a significant amount of propionyl-CoA.

Methylmalonyl-CoA mutase is a dimer of identical subunits to which adenosylcobalamin is tightly bound. The complimentary deoxyribonucleic acid (cDNA) of methylmalonyl-CoA mutase has been cloned and its genomic structure delineated. The gene is mapped to 6p12. Mutations in this gene have been reported to cause MMA(0) or MMA(-).[3] Adenosylcobalamin is an essential cofactor of methylmalonyl-CoA mutase. Methylmalonyl epimerase converts the D racemer of methylmalonyl-CoA to the L racemer and substrate of the mutase. Deficiency of methylmalonyl epimerase leads to mild methylmalonic aciduria and minor clinical symptoms.[4]

Complementation studies revealed the presence of at least 8 different complementation groups (mut0, mut-, cblA, cblB, cblC, cblD [and CblD variant 2], cblF, cblJ) that cause MMA.[5, 6, 7] In the mut0 group, mutase activity in fibroblasts is undetectable, whereas fibroblasts of the mut- group show some residual mutase activity.[3] CblA, and cblB are defects in the pathway of adenosylcobalamin synthesis.[8, 9] CblC, which is the most common defect in cobalamin metabolism, is a defect in the common pathway of cobalamin reduction, leading to combined MMA and homocystinuria, secondary to impaired adenosylcobalamin and methylcobalamin formation.[10]

CblD can present as combined MMA and homocystinuria, isolated homocystinuria (cblD variant 1), or isolated methylmalonic aciduria (cblD variant 2), owing to its role in intracellular cobalamin trafficking.[11] CblF and cblJ are caused by impaired lysosomal cobalamin transport.[12, 13]

The molecular bases for all complementation groups have now been identified. All genetic forms of MMA are inherited as autosomal recessive traits.

Recently, combined malonic and methylmalonic aciduria (CMAMMA) has been shown to be caused by mutations in a putative methylmalonyl CoA and malonyl CoA synthetase (ACSF3). While also a cause of elevated MMA, the finding of elevated malonic acid in urine organic acid, and as evidenced on plasma acylcarnitine profile, is a distinguishing feature.[14]

Epidemiology

Frequency

United States

Screening of infants aged 3-4 weeks in Massachusetts revealed an approximate frequency for MMA of 1 case per 48,000 infants.[15]

International

Newborn screening programs in Germany and Austria have identified approximately 1 newborn with MMA (mutase deficiency) per 250,000 newborns screened. MMA is more frequent in populations with increased rates of consanguinity.

Mortality/Morbidity

All children with genetic forms of MMA are at risk of metabolic decompensation with increased morbidity and mortality. The risk is greater for mut0 and mut- forms of MMA compared with cobalamin-responsive forms. Newborns and infants with mut0 or mut- forms of MMA may die early, before a diagnosis can be reached.

Race

MMA is prevalent in populations with increased rates of consanguinity but has been reported in all ethnic groups.

Sex

No sex predilection is reported.

Age

The mut0 and mut- forms of MMA typically present during the newborn period and early infancy, respectively.

CblA, cblB, cblC, and cblD variant 2 forms of MMA typically present during early infancy. MMA forms cblD and cblF typically present during later infancy or childhood. The cblC form of MMA may present during childhood or adolescence.

Theoretically, neonatal screening via tandem mass spectrometry should reveal all genetic forms of MMA. Some reports have shown that this may not be true for some forms of MMA, such as cblC.[16]

 

Presentation

History

A history of poor feeding, vomiting, progressive lethargy, floppiness, and muscular hypotonia in a newborn who has been healthy for the first 1-2 weeks of life is typical for methylmalonic acidemia (MMA) mut0 or MMA mut-. These newborns typically have been fed for 1-2 weeks or less.

Older infants or children with one of the other forms of MMA or mild mut- may present for the first time during an episode of decompensation with lethargy, seizures, and hypoglycemia.

Older children or adolescents with the cblC form of MMA may present with progressive myopathy, lower leg hyposensitivity, and thrombosis due to the persistent homocystinuria in the cblC form of MMA. The myopathy may not be reversible despite treatment, leading to continued gait disturbances.

Eye findings (eg, retinopathy, nystagmus, reduced visual acuity), hydrocephalus, and microcephaly have been observed in children with the cblC form of MMA.

Renal disease with reduced glomerular filtration rate (GFR) may be observed at presentation or as a long-term complication.

Family history may be positive for siblings with MMA or siblings who died during the neonatal period for reasons that are not clear.

Physical

Symptoms include the following:

  • Dehydration, failure to thrive

  • Lethargy, muscular hypotonia, floppiness

  • Developmental delay

  • Facial dysmorphism (eg, high forehead, broad nasal bridge, epicanthal folds, long smooth philtrum, triangular mouth)

  • Skin lesions (eg, moniliasis)

  • Occasional hepatomegaly

  • Acute onset of choreoathetosis, dystonia, dysphagia, and dysarthria (potentially signs of a stroke)

  • Reduced GFR

 

DDx

Diagnostic Considerations

Urea cycle defects

Differential Diagnoses

 

Workup

Laboratory Studies

The reference ranges mentioned below may vary depending on the analytical method used.

Urine organic acids measured using gas chromatography–mass spectrometry (GC-MS) reveal large amounts of methylmalonic acid, methylcitrate, propionic acid, and 3-OH propionic acid.

Plasma amino acid measurements typically reveal elevated glycine levels. However, plasma glycine levels can also be within the reference range, even in an infant who previously had glycine levels outside of the reference range. The reference range is 100-390 mmol/L. Glycine may not be used as a metabolic marker.

Acylcarnitine profile (dry blood spot or plasma) reveals an elevation of propionylcarnitine (C3) levels and may reveal decreased free carnitine and total carnitine levels.

Total plasma homocysteine levels are assessed in cases of combined methylmalonic acidemia (MMA) and homocystinuria (cblC, cblD, and cblF forms of MMA). The reference range for all age groups is 2-14 mmol/L.

Plasma MMA levels are assayed for management. The reference range for all age groups is less than 0.2 mmol/L.

Plasma cobalamin levels are assessed, and the reference range is 130-785 pg/mL.

A CBC count is obtained to rule out macrocytic anemia, neutropenia, and thrombocytopenia.

Capillary blood gas is measured.

The reference range for ammonia levels in newborn infants is 90-150 mcg/dL. The reference range for infants aged 0-2 weeks is 79-130 mcg/dL. The reference range for those older than 1 month is 29-70 mcg/dL.

The reference range for blood glucose levels in full-term newborn infants is 45-120 mg/dL. The reference range for children is 60-105 mg/dL.

Plasma lactate is measured. The venous reference range is 5-20 mg/dL, and the arterial reference range is 5-14 mg/dL.

Electrolyte levels are also obtained.

Plasma uric acid levels are obtained. The reference range for those aged 0-2 years is 2.4-6.4 mg/dL. The reference range for children aged 2-12 years is 2.4-5.9 mg/dL.

The reference range for plasma creatinine for newborn infants is 0.6-1.2 mg/dL. The reference range for infants is 0.2-0.4 mg/dL, and the reference range for children is 0.3-0.7 mg/dL.

The reference range for plasma urea is 5-21 mg/dL.

The GFR is measured in older children, and the reference range for newborn infants is 40-65 mL/min/1.73 m2. The reference range for children older than 1 year is 98-150 mL/min/1.73 m2.

Prenatal diagnosis is possible by measuring activity of methylmalonyl-CoA mutase in cultured amniocytes.

Imaging Studies

Brain CT scanning and MRI typically reveal involvement of basal ganglia and white matter.

Other Tests

The advent of next-generation sequencing has given rise to panels of DNA tests that can test for many of the genes at once. These panels offer high sensitivity and specificity, although they may miss duplication or deletion of parts of a specific gene. Here, targeted array comparative hybridization with coverage of specific genes is used. Finally, clinical whole-exome sequencing may offer the potential to identify oligogenic causes and/or new genetic causes of MMA.

 

Treatment

Medical Care

Infants and children with methylmalonic acidemia (MMA) are at increased risk for metabolic decompensation particularly during episodes of increased catabolism (eg, intercurrent infections, trauma, surgery, psychosocial stress). During these episodes, provide treatment that is swift and directed towards reversing catabolism and promoting anabolism.

Limit protein catabolism during acute metabolic crises. Stop usual protein intake and intravenously administer generous fluid and glucose (4-8 mg/kg/min, depending on age) if necessary. Cessation of protein intake should last for no longer than 24 hours.

Continue medication and increase carnitine intake to 200-300 mg/kg/d intravenously if necessary.

Provide appropriate treatment of concurrent illnesses (eg, infections).

Provide early reintroduction of protein intake (within 1-2 d after onset of acute decompensation).

N -carbamyl glutamate (100-250 mg/kg/d) orally can be used to treat hyperammonemia.

Consider hemodialysis or hemofiltration for persistent hyperammonemia and/or metabolic acidosis.

Surgical Care

Several liver and kidney transplantations in infants and children with MMA mut0 have been reported.

Despite apparent corrections of the enzyme defect, children with liver or kidney transplantations continue to excrete MMA. Some of these children also develop a movement disorder.

Consider liver transplantation early in infancy to potentially prevent some of the devastating neurological complications.

Diet

Patients require a low-protein diet that provides the minimum natural protein required for growth. Increase dietary protein according to age, weight, and (essential) plasma amino acids levels. Plasma MMA levels may be followed for metabolic control.

Metabolic formula deficient in propiogenic amino acids should be used to provide sufficient protein for growth while limiting whole protein sources to minimize MMA levels.

Avoid long fasts. Provide a late night snack and/or early breakfast to limit the duration of overnight fasting.

Provide calcium and multivitamin supplementation to avoid osteopenia and vitamin deficiency, respectively.

Activity

Do not restrict activity.

 

Medication

Vitamins and cofactors

Class Summary

In patients with cobalamin-responsive methylmalonic acidemia (MMA), cobalamin therapy significantly improves methylmalonyl-CoA mutase activity, to the extent that metabolic control becomes easier and the risk of complications is reduced. Patients with MMA are treated with L-carnitine to remove excess toxic acylcarnitine species from the mitochondria. This detoxification is particularly important at diagnosis and during episodes of metabolic decompensation. If necessary, doses can be increased and/or administered by a parenteral route. Additional nonspecific therapy with betaine and folate potentially reduces plasma homocysteine levels.

Hydroxocobalamin (Cyanokit, Hydro Cobex, Hydro-Crysti-12, LA-12)

DOC in France and Scandinavia. Hydroxocobalamin (vitamin B-12a) is an analog of cyanocobalamin (vitamin B-12). It is more highly protein bound and is retained in the body longer than cyanocobalamin. Combines with cyanide to form nontoxic cyanocobalamin (vitamin B-12). Patients with MMA potentially are responsive to cobalamin. Once patients are diagnosed, administer 1 mg/d hydroxocobalamin IM until complementation analysis confirms the definitive diagnosis.

Levocarnitine (Carnitor)

An amino acid derivative, synthesized from methionine and lysine, required in energy metabolism. Modulates intracellular coenzyme A homeostasis and is required to buffer toxic acyl-CoA compounds within the mitochondria.

Folate (Folvite)

Important cofactor for enzymes used in production of red blood cells.

Betaine (Cystadane)

Methyl group donor in remethylation of homocysteine to methionine. It is available as an orphan drug in the United States.

Antibiotics

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Metronidazole (Flagyl)

Treatment of susceptible bacteria in the lower GI tract reduces propionate production. Propionate is an important precursor of methylmalonic acid. Limited trial (1-2 mo) is warranted when metabolic control is difficult with carnitine, cobalamin, and dietary therapy.

Neomycin PO (Mycifradin)

Inhibits bacterial protein synthesis and growth.

 

Follow-up

Further Outpatient Care

Depending on age and metabolic control, follow up in regular intervals (eg, 1-4 follow-up visits or more per year) with a biochemical geneticist familiar with the management of methylmalonic acidemia (MMA).

Inpatient & Outpatient Medications

L-carnitine

L-carnitine (100-300 mg/kg orally [PO], divided 3 times daily [tid])

Hydroxocobalamin/cyanocobalamin

Hydroxocobalamin is by far more effective than cyanocobalamin. Administer hydroxocobalamin (1 mg/d intramuscularly [IM]) only to patients with cobalamin-responsive forms of MMA.

Metronidazole

Administer metronidazole (10-20 mg/kg PO divided tid) or neomycin (50 mg/kg PO, divided tid) to reduce gut propionate production. Administer a limited trial with metronidazole (1-2 mo).

Betaine

Children younger than 3 years require 100 mg/kg PO divided twice daily (bid).

Children older than 3 years require 250 mg/kg PO divided bid.

Adults require 250 mg/kg PO divided bid.

Some patients require amounts up to 20 g/d. Consider this dosage as nonspecific therapy for patients with combined MMA and homocystinuria to reduce plasma homocysteine levels.

Folate

Infants require 15 mcg/kg/d or 50 mcg/d.

Children require 1 mg/d initial dose, then 0.1-0.3 mg/d.

Adults require 1 mg/d initial dose, then 0.5 mg/d (for patients with combined MMA and homocystinuria to reduce plasma homocysteine levels).

Carglumic acid (N-carbamyl glutamate)

Children and adults need 100-250 mg/kg/d titrated to control ammonia as needed.

Some patients may not need this treatment or may need lower dosing.

Transfer

Treat children with MMA only at tertiary care facilities that have access to a multidisciplinary team of biochemical geneticists, dietitians, neonatologists, and other medical specialists.

Prognosis

Prognosis depends on the type of MMA and whether the patient's condition is well controlled (ie, in general and during episodes of metabolic decompensation).

More severe cases are at risk for secondary complications, though each of these are incompletely penetrant, as follows:

  • Developmental delay with neurological dysfunction due to metabolic stroke affecting the basal ganglia, movement disorder, and white matter changes

  • Progressive renal dysfunction with tubulointerstitial nephritis

  • Pancreatitis, which can be recurrent and/or chronic

  • Susceptibility to infection, including Gram-negative organisms

  • Optic atrophy

  • Growth failure

Patient Education

Educate caregivers about how to identify and respond to episodes of metabolic decompensation in patients with MMA. Supply a written emergency regimen and card.