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

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 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) that cause 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.

The molecular 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 case per 48,000 infants.³

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 cblH 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.⁴

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

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

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

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.

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 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

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 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.

Drug Category: Antibiotics

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

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 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).

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 must 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

1. 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].
2. 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].
3. Coulombe JT, Shih VE, Levy HL. Massachusetts Metabolic Disorders Screening Program. II. Methylmalonic aciduria. Pediatrics. Jan 1981;67(1):26-31. [Medline].
4. 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].
5. 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].
6. 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].
7. 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].
8. 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].
9. 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.
10. Fowler B. Genetic defects of folate and cobalamin metabolism. Eur J Pediatr. Apr 1998;157 Suppl 2:S60-6. [Medline].
11. 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].
12. 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].
13. Nyhan WL. Methylmalonic acidemia. In: Atlas of Metabolic Diseases. New York, NY: Chapman & Hall Medical; 1998:13-23.
14. 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].
15. Rosenblatt DS, Whitehead VM. Cobalamin and folate deficiency: acquired and hereditary disorders in children. Semin Hematol. Jan 1999;36(1):19-34. [Medline].
16. Tanpaiboon P. Methylmalonic acidemia (MMA). Mol Genet Metab. May 2005;85(1):2-6. [Medline].
17. 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: Jul 7, 2008