Skip to main content

Advertisement

Log in

Renal dysfunction in methylmalonic acidurias: review for the pediatric nephrologist

  • Educational Review
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Methylmalonic acidurias are a heterogeneous group of inborn errors of branched-chain amino acid metabolism. Depending on the underlying etiology, acute or chronic renal disease constitutes major (long-term) complications. In recent decades, overall survival has improved due to optimized treatment strategies based on the use of standardized emergency protocols and dialysis techniques. The majority of these patients, especially those having mut°, cblB, and cblA deficiency, are at increased risk of developing chronic kidney disease secondary to tubulointerstitial nephritis to require hemo- or peritoneal dialysis. Kidney and/or liver transplantation, as organ replacement, or even gene therapy on a limited scale, are controversially discussed treatment options in methylmalonic acidurias. The pathophysiological basis of renal disease has not been clarified in detail until now, but a severe mitochondrial dysfunction and an impairment of tubular dicarboxylic acid transport due to accumulated toxic metabolic compounds has been recently proposed. Another severe renal complication of methylmalonic acidurias is the occurrence of cblC-associated infantile atypical hemolytic syndrome, which can result in acute kidney injury. Close collaboration between (pediatric) nephrologists and metabolic specialists is required for the long-term management of these patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Abbreviations

MCM:

Methylmalonyl-CoA mutase

MMA:

Methylmalonic acid

MMAurias:

Methylmalonic acidurias

CKD:

Chronic kidney disease

cTIN:

Chronic tubulointerstitial nephritis

aHUS:

Atypical hemolytic syndrome

cbl:

Cobalamin

hPTEC:

Human proximal tubule cells

ROS:

Reactive oxygen species

OH-Cbl:

Hydroxycobalamin

TC II:

Transcobalamin II

MeCbl:

Methylcobalamin

AdoCbl:

Adenosylcobalamin

TCA:

Tricarboxylic acid cycle

TX:

Transplantation

PA:

Propionic aciduria

PC:

Propionyl-CoA carboxylase

References

  1. Sniderman LC, Lambert M, Giguere R, Auray-Blais C, Lemieux B, Laframboise R, Rosenblatt DS, Treacy EP (1999) Outcome of individuals with low–moderate methylmalonic aciduria detected through a neonatal screening program. J Pediatr 134:675–680

    Article  PubMed  CAS  Google Scholar 

  2. Fenton WA, Gravel RA, Rosenblatt DS (2001) Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Valle AD (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 2165–2193

    Google Scholar 

  3. Dionisi-Vici C, Deodato F, Roschinger W, Rhead W, Wilcken B (2006) ‘Classical’ organic acidurias, propionic aciduria, methylmalonic aciduria and isovaleric aciduria: long-term outcome and effects of expanded newborn screening using tandem mass spectrometry. J Inherit Metab Dis 29:383–389

    Article  PubMed  CAS  Google Scholar 

  4. Radmanesh A, Zaman T, Ghanaati H, Molaei S, Robertson RL, Zamani AA (2008) Methylmalonic acidemia: brain imaging findings in 52 children and a review of the literature. Pediatr Radiol 38:1054–1061

    Article  PubMed  Google Scholar 

  5. Hörster F, Baumgartner MR, Viardot C, Suormala T, Burgard P, Fowler B, Hoffmann GF, Garbade SF, Kölker S, Baumgartner ER (2007) Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB). Pediatr Res 62:225–230

    Article  PubMed  Google Scholar 

  6. Cosson MA, Benoist JF, Touati G, Déchaux M, Royer N, Grandin L, Jais JP, Boddaert N, Barbier V, Desguerre I, Campeau PM, Rabier D, Valayannopoulos V, Niaudet P, de Lonlay P (2009) Long-term outcome in methylmalonic aciduria: a series of 30 French patients. Mol Genet Metab 97:172–178

    Article  PubMed  CAS  Google Scholar 

  7. D’Angio CT, Dillon MJ, Leonard JV (1991) Renal tubular dysfunction in methylmalonic acidaemia. Eur J Pediatr 150:259–263

    Article  PubMed  Google Scholar 

  8. Ohura T, Kikuchi M, Abukawa D, Hanamizu H, Aikawa J, Narisawa K, Tada K, Yunoki H (1990) Type 4 renal tubular acidosis (subtype 2) in a patient with methylmalonic acidaemia. Eur J Pediatr 150:115–118

    Article  PubMed  CAS  Google Scholar 

  9. Pela I, Gasperini S, Pasquini E, Donati MA (2006) Hyperkalemia after acute metabolic decompensation in two children with vitamin B12-unresponsive methylmalonic acidemia and normal renal function. Clin Nephrol 66:63–66

    PubMed  CAS  Google Scholar 

  10. Morita J, Ito Y, Yoshino M, Koga Y, Yano S, Yoshida I, Yamashita F (1989) Persistent hyperkalaemia in vitamin B12 unresponsive methylmalonic acidaemia. J Inherit Metab Dis 12:89–93

    Article  PubMed  CAS  Google Scholar 

  11. Dudley J, Allen J, Tizard J, McGraw M (1998) Benign methylmalonic acidemia in a sibship with distal renal tubular acidosis. Pediatr Nephrol 12:564–566

    Article  PubMed  CAS  Google Scholar 

  12. Wolff JA, Strom C, Griswold W, Sweetman F, Kulovich S, Prodanos C, Nyhan WL (1985) Proximal renal tubular acidosis in methylmalonic acidemia. J Neurogen 2:31–39

    Article  CAS  Google Scholar 

  13. Sharma AP, Greenberg CR, Prasad AN, Prasad C (2007) Hemolytic uremic syndrome (HUS) secondary to cobalamin C (cblC) disorder. Pediatr Nephrol 22:2097–2103

    Article  PubMed  Google Scholar 

  14. Guigonis V, Fremeaux-Bacchi V, Giraudier S, Favier R, Borderie D, Massy Z, Mougenot B, Rosenblatt DS, Deschênes G (2005) Late-onset thrombocytic microangiopathy caused by cblC disease: association with a factor H mutation. Am J Kidney Dis 45:588–595

    Article  PubMed  CAS  Google Scholar 

  15. Martinelli D, Deodato F, Dionisi-Vici C (2011) Cobalamin C defect: natural history, pathophysiology, and treatment. J Inherit Metab Dis 34:127–135

    Article  PubMed  CAS  Google Scholar 

  16. Brandstetter Y, Weinhouse E, Splaingard ML, Tang TT (1990) Cor pulmonale as a complication of methylmalonic acidemia and homocystinuria (Cb1-C type). Am J Med Genet 36:167–171

    Article  PubMed  CAS  Google Scholar 

  17. Brunelli SM, Meyers KE, Guttenberg M, Kaplan P, Kaplan BS (2002) Cobalamin C deficiency complicated by an atypical glomerulopathy. Pediatr Nephrol 17:800–803

    Article  PubMed  Google Scholar 

  18. Carrillo-Carrasco N, Venditti CP (2012) Combined methylmalonic acidemia and homocystinuria, cblC type. II. Complications, pathophysiology, and outcomes. J Inherit Metab Dis 35:103–114

    Article  PubMed  CAS  Google Scholar 

  19. Lerner-Ellis JP, Anastasio N, Liu J, Coelho D, Suormala T, Stucki M, Loewy AD, Gurd S, Grundberg E, Morel CF, Watkins D, Baumgartner MR, Pastinen T, Rosenblatt DS, Fowler B (2009) Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype–phenotype correlations. Hum Mutat 30:1072–1081

    Article  PubMed  CAS  Google Scholar 

  20. Morath MA, Okun JG, Müller IB, Sauer SW, Hörster F, Hoffmann GF, Kölker S (2008) Neurodegeneration and chronic renal failure in methylmalonic aciduria—a pathophysiological approach. J Inherit Metab Dis 31:35–43

    Article  PubMed  CAS  Google Scholar 

  21. Schwab MA, Sauer SW, Okun JG, Nijtmans LG, Rodenburg RJ, van den Heuvel LP, Dröse S, Brandt U, Hoffmann GF, Ter Laak H, Kölker S, Smeitink JA (2006) Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins. Biochem J 398:107–112

    Article  PubMed  CAS  Google Scholar 

  22. de Keyzer Y, Valayannopoulos V, Benoist JF, Batteux F, Lacaille F, Hubert L, Chrétien D, Chadefeaux-Vekemans B, Niaudet P, Touati G, Munnich A, de Lonlay P (2009) Multiple OXPHOS deficiency in the liver, kidney, heart, and skeletal muscle of patients with methylmalonic aciduria and propionic aciduria. Pediatr Res 66:91–95

    Article  PubMed  Google Scholar 

  23. Kölker S, Sauer SW, Surtees RA, Leonard JV (2006) The aetiology of neurological complications of organic acidaemias—a role for the blood–brain barrier. J Inherit Metab Dis 29:701–704

    Article  PubMed  Google Scholar 

  24. Sauer SW, Opp S, Haarmann A, Okun JG, Kölker S, Morath MA (2009) Long-term exposure of human proximal tubule cells to hydroxycobalamin[c-lactam] as a possible model to study renal disease in methylmalonic acidurias. J Inherit Metab Dis 32:720–727

    Article  PubMed  CAS  Google Scholar 

  25. Stamler JS, Osborne JA, Jaraki O, Rabbani LE, Mullins M, Singel D, Loscalzo J (1993) Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest 91:308–318

    Article  PubMed  CAS  Google Scholar 

  26. Hajjar KA (1993) Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor. J Clin Invest 91:2873–2879

    Article  PubMed  CAS  Google Scholar 

  27. Rodgers GM, Kane WH (1986) Activation of endogenous factor V by a homocysteine-induced vascular endothelial cell activator. J Clin Invest 77:1909–1916

    Article  PubMed  CAS  Google Scholar 

  28. Papatheodorou L, Weiss N (2007) Vascular oxidant stress and inflammation in hyperhomocysteinemia. Antioxid Redox Signal 9:1941–1958

    Article  PubMed  CAS  Google Scholar 

  29. Blau N, Hoffmann GF, Leonard J, Clarke JTR (2006) Physician’s guide to the treatment and follow-up of metabolic diseases. Springer-Verlag, Heidelberg, pp 86–87

    Book  Google Scholar 

  30. Schmitt CP, Mehls O, Trefz FK, Hörster F, Weber TL, Kölker S (2004) Reversible end-stage renal disease in an adolescent patient with methylmalonic aciduria. Pediatr Nephrol 19:1182–1184

    PubMed  Google Scholar 

  31. Zwickler T, Haege G, Riderer A, Hörster F, Hoffmann GF, Burgard P, Kölker S (2012) Metabolic decompensation in methylmalonic aciduria: which biochemical parameters are discriminative? J Inherit Metab Dis. doi:10.1007/s10545-011-9426-1

  32. Chapman KA, Gropman A, MacLeod E, Stagni K, Summar M, Ueda K, Ah Mew N, Franks J, Island E, Matern D, Pena L, Smith B, Sutton R, Urv T, Venditti C, Chakrapani A (2012) Acute management of propionic acidemia. Mol Genet Metab 105:16–25

    Article  PubMed  CAS  Google Scholar 

  33. Bain MD, Till J, Jones MG, Besley GTN, Lee P, Oliveira D, Chalmers RA (2005) Methylmalonic aciduria: follow-up and enzymology on the original case after 36 years. J Inherit Metab Dis 28:1179–1180

    Article  PubMed  CAS  Google Scholar 

  34. Kamei K, Ito S, Shigeta T, Sakamoto S, Fukuda A, Horikawa R, Saito O, Muguruma T, Nakagawa S, Iijima K, Kasahara M (2011) Preoperative dialysis for liver transplantation in methylmalonic acidemia. Ther Apher Dial 15:488–492

    Article  PubMed  Google Scholar 

  35. Van Calcar SC, Harding CO, Lyne P, Hogan K, Banerjeeg R, Sollinger H, Rieselbach RE, Wolff JA (1998) Renal transplantation in a patient with methylmalonic acidaemia. J Inherit Metab Dis 21:729–737

    Article  PubMed  Google Scholar 

  36. Martinelli D, Dotta A, Massella L, Picca S, Di Pede A, Boenzi S, Aiello C, Dionisi-Vici C (2011) Cobalamin C defect presenting as severe neonatal hyperammonemia. Eur J Pediatr 170:887–890

    Article  PubMed  CAS  Google Scholar 

  37. De Baulny HO, Benoist JF, Rigal O, Touati G, Rabier D, Saudubray JM (2005) Methylmalonic and propionic acidaemias: management and outcome. J Inherit Metab Dis 28:415–423

    Article  PubMed  CAS  Google Scholar 

  38. Chen PW, Hwu WL, Ho MC, Lee NC, Chien YH, Ni YH, Lee PH (2010) Stabilization of blood methylmalonic acid level in methylmalonic acidemia after liver transplantation. Pediatr Transplant 14:337–441

    Article  PubMed  Google Scholar 

  39. Paik KH, Lee JE, Jin DK (2004) Successful dialysis in a boy with methylmalonic acidemia. Pediatr Nephrol 19:1180–1181

    Article  PubMed  Google Scholar 

  40. Lubrano R, Scoppi P, Barsotti P, Travasso E, Scateni S, Cristaldi S, Castello MA (2001) Kidney transplantation in a girl with methylmalonic academia and end-stage renal failure. Pediatr Nephol 16:848–851

    Article  CAS  Google Scholar 

  41. Coman D, Huang J, McTaggart S, Sakamoto O, Ohura T, McGill J, Burke J (2006) Renal transplantation in a 14-year-old girl with vitamin B12-responsive cblA-type methylmalonic acidaemia. Pediatr Nephrol 21:270–273

    Article  PubMed  CAS  Google Scholar 

  42. Lubrano R, Elli M, Rossi M, Travasso E, Raggi C, Barsotti P, Carducci C, Berloco P (2007) Renal transplant in methylmalonic acidemia: could it be the best option? Report on a case at 10 years and review of the literature. Pediatr Nephrol 22:1209–1214

    Article  PubMed  Google Scholar 

  43. Clothier JC, Chakrapani A, Preece MA, McKiernan P, Gupta R, Macdonald A, Hulton SA (2011) Renal transplantation in a boy with methylmalonic acidaemia. J Inherit Metab Dis 34:695–700

    Article  PubMed  Google Scholar 

  44. Nagarajan S, Enns GM, Millan MT, Winter S, Sarwal MM (2005) Management of methylmalonic acidaemia by combined liver–kidney transplantation. J Inherit Metab Dis 28:517–524

    Article  PubMed  CAS  Google Scholar 

  45. Kasahara M, Horikawa R, Tagawa M, Uemoto S, Yokoyama S, Shibata Y, Kawano T, Kuroda T, Honna T, Tanaka K, Saeki M (2006) Current role of liver transplantation for methylmalonic acidemia: a review of the literature. Pediatr Transplant 10:943–947

    Article  PubMed  Google Scholar 

  46. Kaplan P, Ficicioglu C, Mazur AT, Palmieri MJ, Berry GT (2006) Liver transplantation is not curative for methylmalonic acidopathy caused by methylmalonyl-CoA mutase deficiency. Mol Genet Metab 88:322–326

    Article  PubMed  CAS  Google Scholar 

  47. Chakrapani A, Sivakumar P, McKiernan PJ, Leonard JV (2002) Metabolic stroke in methylmalonic acidemia five years after liver transplantation. J Pediatr 140:261–263

    Article  PubMed  Google Scholar 

  48. Van't Hoff W, McKiernan PJ, Surtees RA, Leonard JV (1999) Liver transplantation for methylmalonic acidaemia. Eur J Pediatr 158(Suppl 2):S70–S74

    Article  PubMed  Google Scholar 

  49. Mc Guire PJ, Lim-Melia E, Diaz GA, Raymond K, Larkin A, Wasserstein MP, Sansaricq C (2008) Combined liver–kidney transplant for the management of methylmalonic aciduria: a case report and review of the literature. Mol Genet Metab 93:22–29

    Article  PubMed  CAS  Google Scholar 

  50. Cosson MA, Touati G, Lacaille F, Valayannnopoulos V, Guyot C, Guest G, Verkarre V, Chrétien D, Rabier D, Munnich A, Benoist JF, de Keyzer Y, Niaudet P, de Lonlay P (2008) Liver hepatoblastoma and multiple OXPHOS deficiency in the follow-up of a patient with methylmalonic aciduria. Mol Genet Metab 95:107–109

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Prof. Stefan Kölker for his kind revision of the manuscript.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marina A. Morath.

Additional information

Answers

1. d. All of the above

2. c.

3. e. All of the above

4. b.

5. d.

Questions

Questions

  1. 1.

    Metabolic crises in methylmalonic acidurias are triggered by

    1. a.

      Diarrhea

    2. b.

      Fasting

    3. c.

      Vomiting

    4. d.

      All of the above

  2. 2.

    Which fact about renal disease in methylmalonic acidurias is correct?

    1. a.

      mostly affecting distal tubule cells

    2. b.

      occurring only in adulthood

    3. c.

      existence of a genotype–phenotype correlation

    4. d.

      correlation with cumulative urinary 2-methylcitrate excretion over time

    5. e.

      in most cases curable

  3. 3.

    Which pathomechanisms of cTIN have been proposed?

    1. a.

      mitochondrial glutathione depletion

    2. b.

      impaired mtDNA homeostasis

    3. c.

      synergism of accumulated toxic metabolites

    4. d.

      impaired function of tubule dicarboxylate transporters

    5. e.

      All of the above

  4. 4.

    Which is not a treatment strategy of methylmalonic acidurias?

    1. a.

      high caloric intake

    2. b.

      high protein intake

    3. c.

      carnitine supplementation

    4. d.

      antibiotics

    5. e.

      organ transplantation

  5. 5.

    Atypical hemolytic syndrome

    1. a.

      often results in acute kidney injury

    2. b.

      is a complication of cblC disorder

    3. c.

      is by definition associated with diarrhea

    4. d.

      a and b are correct

    5. e.

      b and c are correct.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morath, M.A., Hörster, F. & Sauer, S.W. Renal dysfunction in methylmalonic acidurias: review for the pediatric nephrologist. Pediatr Nephrol 28, 227–235 (2013). https://doi.org/10.1007/s00467-012-2245-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-012-2245-2

Keywords

Navigation