eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases
Methylmalonic Acidemia: Treatment & Medication
Updated: Jul 7, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
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).
- 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.
- 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
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.
Adult
Hydroxocobalamin: 1-3 mg/d IM
Cyanocobalamin: 1 mg PO qd
Pediatric
Administer as in adults; a trial of cyanocobalamin PO can be undertaken provided the patient is metabolically stable; after switching to cyanocobalamin PO, closely monitor plasma MMA and/or homocysteine levels; restart hydroxocobalamin IM if no response is demonstrated or biochemical deterioration is noted
Decreased absorption of cyanocobalamin from GI tract with coadministration of aminoglycosides, colchicine, extended release potassium products, aminosalicylic acid, phenytoin, and phenobarbital; chemical degradation of cyanocobalamin creates large amounts of ascorbic acid
Documented hypersensitivity; hereditary optic nerve atrophy
Pregnancy
A - Fetal risk not revealed in controlled studies in humans
Precautions
Severe hypokalemia may result in vitamin B-12–megaloblastic anemia (may be fatal) due to increased cellular potassium requirements when anemia corrects; transient (4-5 d) red discoloration of mucous membranes, plasma, and urine may develop
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.
Adult
100-300 mg/kg/d PO/IV divided tid
Pediatric
Administer as in adults
None reported
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Monitor blood chemistries, plasma carnitine concentrations, vital signs, and overall clinical condition of the patient; nausea, vomiting, abdominal cramps, and diarrhea may develop
Folate (Folvite)
Important cofactor for enzymes used in production of red blood cells.
Adult
1 mg/d PO/IM/SC qd initially; 0.5 mg/d maintenance
Pediatric
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
Increase in seizure frequency and a decrease in subtherapeutic levels of phenytoin reported when used concurrently
Documented hypersensitivity
Pregnancy
A - Fetal risk not revealed in controlled studies in humans
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
Betaine (Cystadane)
Methyl group donor in remethylation of homocysteine to methionine. It is available as an orphan drug in the United States.
Adult
250 mg/kg/d PO divided bid
Pediatric
<3 years: 100 mg/kg/d PO divided bid
>3 years: Administer as in adults
None reported
Documented hypersensitivity
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
May cause nausea, vomiting, diarrhea, and gastric distress
Antibiotics
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.
Adult
250-500 mg PO q8h
Pediatric
10-20 mg/kg/d PO divided q8h
Cimetidine may increase toxicity of metronidazole; may increase effects of anticoagulants; may increase toxicity of lithium and phenytoin; disulfiramlike reaction may occur with PO-ingested ethanol
Documented hypersensitivity; first trimester of pregnancy
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
Do not use in first trimester of pregnancy; adjust dose in hepatic disease; monitor for seizures and development of peripheral neuropathy
Neomycin (Mycifradin)
Inhibits bacterial protein synthesis and growth.
Adult
Adults: 500-2000 mg PO q6-8h
Pediatric
50 mg/kg PO divided tid
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
Documented hypersensitivity; intestinal obstruction
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
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
More on Methylmalonic Acidemia |
| Overview: Methylmalonic Acidemia |
| Differential Diagnoses & Workup: Methylmalonic Acidemia |
 Treatment & Medication: Methylmalonic Acidemia |
| Follow-up: Methylmalonic Acidemia |
| References |
| « Previous Page | Next Page » |
References
Oberholzer VG, Levin B, Burgess EA, Young WF. Methylmalonic aciduria. An inborn error of metabolism leading to chronic metabolic acidosis. Arch Dis Child. Oct 1967;42(225):492-504. [Medline].
Stokke O, Jellum E, Eldjarn L, Schnitler R. The occurrence of beta-hydroxy-n-valeric acid in a patient with propionic and methylmalonic acidemia. Clin Chim Acta. May 30 1973;45(4):391-401. [Medline].
Coulombe JT, Shih VE, Levy HL. Massachusetts Metabolic Disorders Screening Program. II. Methylmalonic aciduria. Pediatrics. Jan 1981;67(1):26-31. [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].
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].
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. New York, NY: McGraw-Hill Co; 1995:1423-49.
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].
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. New York, 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].
Further Reading
Keywords
methylmalonic acidemia, MMA, methylmalonic aciduria, methylmalonic acid, propionic acidemia, lethargy, hypoglycemia, seizures, progressive myopathy, lower leg hyposensitivity, thrombosis, retinopathy, nystagmus, reduced visual acuity, hydrocephalus, microcephaly, dehydration, failure to thrive, developmental delay, choreoathetosis, dystonia, dysphagia, dysarthria
