AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In 1967, Oberholzer et al and Stokke et al, respectively, reported the first patients with methylmalonic acidemia (MMA). Clinical and genetic heterogeneity became evident very early when some patients responded to pharmacological doses of cobalamin (vitamin B-12), while other patients did not.

MMA encompasses a heterogeneous group of disorders that are 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 also may 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 to pyruvate. 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. Adenosylcobalamin is an essential cofactor of methylmalonyl-CoA mutase. Complementation studies revealed the presence of at least 8 different complementation groups (mut0, mut-, cblA, cblB, cblC, cblD, cblF, cblH) causing MMA. In the mut0 group, mutase activity in fibroblasts is undetectable, whereas fibroblasts of the mut- group show some residual mutase activity. CblA, cblB, and cblH are defects in the pathway of adenosylcobalamin synthesis. CblC and cblD are defects in the common pathway of cobalamin reduction, leading to combined MMA and homocystinuria, secondary to impaired adenosylcobalamin and methylcobalamin formation. CblF is caused by impaired lysosomal cobalamin transport.

Themolecular basis for all complementation groups, except for cblF and cblH, is not presently known. The gene for cblC has been recently identified. All genetic forms of MMA are inherited as autosomal recessive traits.

Frequency

United States

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

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 exists.

Age

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

CblA, cblB, cblC, and cblH forms of MMA typically present during early infancy. MMA forms CblD and cblF typically present during later infancy or childhood. On occasion, the cblC form of MMA may present during childhood and/or adolescence.

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

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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

• 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 may be signs of a stroke.
• Reduced GFR

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Urea cycle defects

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Urine organic acids by gas chromatography-mass spectrometry (GC-MS) demonstrate large amounts of methylmalonic acid, methylcitrate, propionic acid, and 3-OH propionic acid.
• Plasma amino acids typically show elevation of glycine. However, plasma glycine can also be within the reference range, even in an infant who previously had glycine levels outside of the reference range. (reference range = 100-390 mmol/L. Glycine may not be used as a metabolic marker.
• Acylcarnitine profile (dry blood spot or plasma) shows an elevation of propionylcarnitine (C3) and may show decreased free carnitine and total carnitine levels.
• Total plasma homocysteine levels in cases of combined methylmalonic acidemia (MMA) and homocystinuria (cblC, cblD, and cblF forms of MMA) (reference range for all age groups = 2-14 mmol/L)
• Plasma MMA levels for management (reference range for all age groups = <0.2 mmol/L)
• Plasma cobalamin levels (reference range = 130-785 pg/mL)
• Full blood count to rule out macrocytic anemia, neutropenia, and thrombocytopenia
• Capillary blood gas
• Ammonia (reference range for newborn infants = 90-150 mcg/dL; reference range for infants aged 0-2 weeks = 79-130 mcg/dL; reference range for those older than 1 month = 29-70 mcg/dL)
• Blood glucose (reference range for full-term newborn infants = 45-120 mg/dL; reference range for children = 60-105 mg/dL)
• Plasma lactate (venous reference range = 5-20 mg/dL; arterial reference range = 5-14 mg/dL)
• Electrolytes
• Plasma uric acid (reference range for those aged 0-2 years = 2.4-6.4 mg/dL; reference range for children aged 2-12 years = 2.4-5.9 mg/dL)
• Plasma creatinine (reference range for newborn infants = 0.6-1.2 mg/dL; reference range for infants = 0.2-0.4 mg/dL; reference range for children = 0.3-0.7 mg/dL)
• Plasma urea (reference range = 5-21 mg/dL)
• Glomerular filtration rate (GFR) in older children (reference range for newborn infants = 40-65 mL/min/1.73 m²; reference range for children older than 1 year = 98-150 mL/min/1.73 m²)
• Prenatal diagnosis is possible by measuring activity of methylmalonyl-CoA mutase in cultured amniocytes.
• The reference ranges mentioned above may vary depending on the analytical method used.

Imaging Studies

• Brain CT/MRI scans typically demonstrate involvement of basal ganglia and white matter.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 administer generous fluid and glucose intravenously (4-8 mg/kg/min IV 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 IV 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).
• Consider hemodialysis or hemofiltration for persistent hyperammonemia and/or metabolic acidosis.

Surgical Care

• Several liver and/or kidney transplantations in infants and children with MMA mut0 have been reported.
• • Despite apparent corrections of the enzyme defect, children with liver and/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.
• 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

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Drug Category: Vitamins and cofactors

In patients with cobalamin-responsive MMA, cobalamin therapy improves methylmalonyl-CoA mutase activity significantly 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.

Drug Name	Levocarnitine (Carnitor)
Description	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.
Adult Dose	100-300 mg/kg/d PO/IV divided tid
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Monitor blood chemistries, plasma carnitine concentrations, vital signs, and overall clinical condition of the patient; nausea, vomiting, abdominal cramps, and diarrhea may develop

Drug Name	Folate (Folvite)
Description	Important cofactor for enzymes used in production of red blood cells.
Adult Dose	1 mg/d PO/IM/SC qd initially; 0.5 mg/d maintenance
Pediatric Dose	Infants: 15 mcg/kg/d PO/IV (50 mcg/d) Children: 1 mg/d PO/IM/SC qd initially; 0.1-0.3 mg/d maintenance
Contraindications	Documented hypersensitivity
Interactions	Increase in seizure frequency and a decrease in subtherapeutic levels of phenytoin reported when used concurrently
Pregnancy	A - Safe in pregnancy
Precautions	Pregnancy category C if dose exceeds RDA; benzyl alcohol present in some products as preservative; has been associated with fatal gasping syndrome in premature infants; resistance to treatment may develop in patients with alcoholism and deficiencies of other vitamins

Drug Name	Betaine (Cystadane)
Description	Methyl group donor in remethylation of homocysteine to methionine. It is available as an orphan drug in the United States.
Adult Dose	250 mg/kg/d PO divided bid
Pediatric Dose	<3 years: 100 mg/kg/d PO divided bid >3 years: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	May cause nausea, vomiting, diarrhea, and gastric distress

Drug Category: Antibiotics

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

Drug Name	Neomycin (Mycifradin)
Description	Inhibits bacterial protein synthesis and growth.
Adult Dose	Adults: 500-2000 mg PO q6-8h
Pediatric Dose	50 mg/kg PO divided tid
Contraindications	Documented hypersensitivity; intestinal obstruction
Interactions	Coadministration with other aminoglycosides, penicillins, cephalosporins, and amphotericin B increases nephrotoxicity; enhances effects of neuromuscular blocking agents; causes respiratory depression; irreversible hearing loss may develop with coadministration of loop diuretics
Pregnancy	D - Unsafe in pregnancy
Precautions	Not intended for long-term therapy; caution in patients with renal failure (not on dialysis), hypocalcemia, myasthenia gravis, and conditions that depress neuromuscular transmission

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

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

In/Out Patient Meds

• L-carnitine (100-300 mg/kg PO divided tid)
• Hydroxocobalamin/cyanocobalamin. Hydroxocobalamin is by far more effective than cyanocobalamin.
• • Administer hydroxocobalamin (1 mg/d IM) to patients with cobalamin-responsive forms of MMA only.
• 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 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).

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).

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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Methylmalonic acidemia (MMA) is difficult to diagnose because of nonspecific symptoms at presentation. A family history that is positive for MMA should alert the physician to the likelihood of an underlying organic aciduria. In any neonate presents with vomiting, lethargy, and failure to thrive during the first days of life, MMA has to be ruled out despite the presence of newborn screening programs.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

• Acquaviva C, Benoist JF, Pereira S, et al. Molecular basis of methylmalonyl-CoA mutase apoenzyme defect in 40 European patients affected by mut(o) and mut- forms of methylmalonic acidemia: identification of 29 novel mutations in the MUT gene. Hum Mutat. Feb 2005;25(2):167-76. [Medline].
• Andersson HC, Shapira E. Biochemical and clinical response to hydroxocobalamin versus cyanocobalamin treatment in patients with methylmalonic acidemia and homocystinuria (cblC). J Pediatr. Jan 1998;132(1):121-4. [Medline].
• Caksen H, Atas B, Tuncer O, Odabas D. Severe generalized dystonia induced by metoclopramide in a girl with methylmalonic acidemia. Brain Dev. Mar 2003;25(2):144-5. [Medline].
• Coulombe JT, Shih VE, Levy HL. Massachusetts Metabolic Disorders Screening Program. II. Methylmalonic aciduria. Pediatrics. Jan 1981;67(1):26-31. [Medline].
• Dobson CM, Wai T, Leclerc D, et al. Identification of the gene responsible for the cblA complementation group of vitamin B12-responsive methylmalonic acidemia based on analysis of prokaryotic gene arrangements. Proc Natl Acad Sci U S A. Nov 26 2002;99(24):15554-9. [Medline].
• Fenton WA, Rosenberg LE. Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle DL, eds. The Metabolic and Molecular Bases of Inherited Disease. 1st ed. McGraw-Hill Co;1995:1423-1449.
• Fowler B. Genetic defects of folate and cobalamin metabolism. Eur J Pediatr. Apr 1998;157 Suppl 2:S60-6. [Medline].
• Huemer M, Simma B, Fowler B, et al. Prenatal and postnatal treatment in cobalamin C defect. J Pediatr. Oct 2005;147(4):469-72. [Medline].
• Lerner-Ellis JP, Tirone JC, Pawelek PD, et al. Identification of the gene responsible for methylmalonic aciduria and homocystinuria, cblC type. Nat Genet. Jan 2006;38(1):93-100. [Medline].
• Morel CF, Watkins D, Scott P, et al. Prenatal diagnosis for methylmalonic acidemia and inborn errors of vitamin B12 metabolism and transport. Mol Genet Metab. Sep-Oct 2005;86(1-2):160-71. [Medline].
• Nyhan WL. Methylmalonic acidemia. In: Atlas of Metabolic Diseases. NY: Chapman & Hall Medical;1998:13-23.
• Ostergaard E, Wibrand F, Orngreen MC, et al. Impaired energy metabolism and abnormal muscle histology in mut- methylmalonic aciduria. Neurology. Sep 27 2005;65(6):931-3. [Medline].
• Rosenblatt DS, Whitehead VM. Cobalamin and folate deficiency: acquired and hereditary disorders in children. Semin Hematol. Jan 1999;36(1):19-34. [Medline].
• Tanpaiboon P. Methylmalonic acidemia (MMA). Mol Genet Metab. May 2005;85(1):2-6. [Medline].
• Worgan LC, Niles K, Tirone JC, et al. Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype. Hum Mutat. Jan 2006;27(1):31-43. [Medline].

Article Last Updated: Apr 25, 2006