eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Metabolic Diseases

Methylmalonic Acidemia: Differential Diagnoses & Workup

Author: Olaf A Bodamer, MD, PhD, FACMG, Professor, Department of Pediatrics, Biochemical Genetics and Neonatal Screening Laboratories, University of Vienna Children's Hospital, Austria
Coauthor(s): Brendan Lee, MD, PhD, Associate Professor, Department of Molecular and Human Genetics, Baylor College of Medicine
Contributor Information and Disclosures

Updated: Jul 7, 2008

Differential Diagnoses

Acidosis, Metabolic
Maple Syrup Urine Disease
Propionic Acidemia (Propionyl CoA Carboxylase Deficiency)

Other Problems to Be Considered

Urea cycle defects

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.

More on Methylmalonic Acidemia

Overview: Methylmalonic Acidemia
Differential Diagnoses & Workup: Methylmalonic Acidemia
Treatment & Medication: Methylmalonic Acidemia
Follow-up: Methylmalonic Acidemia
References
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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].

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Further Reading

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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

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Contributor Information and Disclosures

Author

Olaf A Bodamer, MD, PhD, FACMG, Professor, Department of Pediatrics, Biochemical Genetics and Neonatal Screening Laboratories, University of Vienna Children's Hospital, Austria
Olaf A Bodamer, MD, PhD, FACMG is a member of the following medical societies: American Society of Human Genetics
Disclosure: Nothing to disclose.

Coauthor(s)

Brendan Lee, MD, PhD, Associate Professor, Department of Molecular and Human Genetics, Baylor College of Medicine
Brendan Lee, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and Society for Pediatric Research
Disclosure: Hyperion Grant/research funds clinical research

Medical Editor

Christian J Renner, MD, Consulting Staff, Department of Pediatrics, University Hospital for Children and Adolescents, Erlangen, Germany
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Leonard G Feld, MD, PhD, MMM, Chairman of Pediatrics, Carolinas Medical Center; Chief Medical Officer, Levine Children's Hospital, Carolinas Healthcare System
Leonard G Feld, MD, PhD, MMM is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Juvenile Diabetes Foundation International
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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