Skip to main content
SpringerLink
Log in

Neurodegeneration and chronic renal failure in methylmalonic aciduria—A pathophysiological approach

  • Review
  • Published:
Journal of Inherited Metabolic Disease

Summary

In the last decades the survival of patients with methylmalonic aciduria has been improved. However, the overall outcome of affected patients remains disappointing. The disease course is often complicated by acute life-threatening metabolic crises, which can result in multiple organ failure or even death, resembling primary defects of mitochondrial energy metabolism. Biochemical abnormalities during metabolic derangement, such as metabolic acidosis, ketonaemia/ketonuria, lactic acidosis, hypoglycaemia and hyperammonaemia, suggest mitochondrial dysfunction. In addition, long-term complications such as chronic renal failure and neurological disease are frequently found. Neuropathophysiological studies have focused on various effects caused by accumulation of putatively toxic organic acids, the so-called ‘toxic metabolite’ hypothesis. In previous studies, methylmalonate (MMA) has been considered as the major neurotoxin in methylmalonic aciduria, whereas more recent studies have highlighted a synergistic inhibition of mitochondrial energy metabolism (pyruvate dehydrogenase complex, tricarboxylic acid cycle, respiratory chain, mitochondrial salvage pathway of deoxyribonucleoside triphosphate (dNTP)) induced by propionyl-CoA, 2-methylcitrate and MMA as the key pathomechanism of inherited disorders of propionate metabolism. Intracerebral accumulation of toxic metabolites (‘trapping’ hypothesis’) is considered a biochemical risk factor for neurodegeneration. Secondary effects of mitochondrial dysfunction, such as oxidative stress and impaired mtDNA homeostasis, contribute to pathogenesis of these disorders. The underlying pathomechanisms of chronic renal insufficiency in methylmalonic acidurias are not yet understood. We hypothesize that renal and cerebral pathomechanisms share some similarities, such as an involvement of dicarboxylic acid transport. This review aims to give a comprehensive overview on recent pathomechanistic concepts for methylmalonic acidurias.

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

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Arend LJ, Thompson CI, Brandt MA, Spielman WS (1986) Elevation of intrarenal adenosine by maleic acid decreases GFR and renin release. Kidney Int 30: 656–661.

    Article  PubMed  CAS  Google Scholar 

  • Bank N, Aynedijan HS, Mutz BF (1986) Microperfusion study of proximal tubule bicarbonate transport in maleic-induced renal tubular acidosis. Am J Physiol 250: 476–482.

    Google Scholar 

  • Baumgartner ER, Viardot C and 47 colleagues from 39 hospitals from 7 European countries (1995) Long-term follow-up of 77 patients with isolated methylmalonic aciduria. J Inherit Metab Dis 18: 138–142.

    Article  Google Scholar 

  • Bremer J (1969) Pyruvate dehydrogenase, substrate specificity and product inhibition. Eur J Biochem 8: 535–540.

    Article  PubMed  CAS  Google Scholar 

  • Brock M, Buckel W (2004) On the mechanism of action of the antifungal agent propionate. Eur J Biochem 271: 3227–3241.

    Article  PubMed  CAS  Google Scholar 

  • Burckhardt BC, Burckhardt G (2003) Transport of organic anions across the basolateral membrane of proximal tubule cells. Rev Physiol Biochem Pharmacol 146: 95–158.

    Article  PubMed  CAS  Google Scholar 

  • Burckhardt BC, Lorenz J, Kobbe C, Burckhardt G (2005) Substrate specificity of the human renal sodium dicarboxylate cotransporter, hNADC-3, under voltage-clamp conditions. Am J Physiol Renal Physiol 288: 792–799.

    Article  CAS  Google Scholar 

  • Carrozzo R, Dionisi-Vici C, Steuerwald U, et al (2007) SUCLA2 mutations are associated with mild methylmalonic aciduria, Leigh-like encephalomyopathy, dystonia and deafness. Brain 130: 862–874.

    Article  PubMed  Google Scholar 

  • Chakrapani A, Sivakumar P, McKiernan PJ, et al (2002) Metabolic stroke in methylmalonic academia five years after liver transplantation. J Pediatr 140: 261–263.

    Article  PubMed  Google Scholar 

  • Cheema-Dhadli S, Leznoff CC, Halperin ML (1975) Effect of 2-methylcitrate on citrate metabolism: implications for the management of patients with propionic acidemia and methylmalonic aciduria. Pediatr Res 9: 905–908.

    PubMed  CAS  Google Scholar 

  • Chen Z, Lash L (1998) Evidence for mitochondrial uptake of glutathione by dicarboxylate and 2-oxoglutarate carriers. J Pharmacol Exp Ther 285: 608–618.

    PubMed  CAS  Google Scholar 

  • Coude FX, Sweetman L, Nyhan WL (1979) Inhibition by propionyl-coenzyme A of N-acetylglutamate synthetase in rat liver mitochondria. A possible explanation for hyperammonemia in propionic and methylmalonic acidemia. J Clin Invest 64: 1544–1551.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • DeMello CF, Begnini J, Jimenez-Bernal RE, et al (1996) Intrastriatal methylmalonic acid administration induces rotational behaviour and convulsions through glutamatergic mechanisms. Brain Res 721: 120–125.

    Article  CAS  Google Scholar 

  • DiMauro S, Hirano M, Schon EA (2006) Approaches to the treatment of mitochondrial diseases. Muscle Nerve 34: 265–283.

    Article  PubMed  CAS  Google Scholar 

  • Dionisi-Vici C, Deodato F, Röschinger 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 

  • Dutra JC, Dutra-Filho CS, Cardozo SEC, Wannmacher CM, Sarkis JJ, Wajner M (1993) Inhibition of succinate dehydrogenase and β-hydroxybutyrate dehydrogenase activities by methylmalonate in brain and liver of developing rats. J Inherit Metab Dis 16: 147–153.

    Article  PubMed  CAS  Google Scholar 

  • Elpeleg O, Miller C, Hershkovitz E, et al (2005) Deficiency of the ADP-forming succinyl-CoA synthase activity is associated with encephalomyopathy and mitochondrial DNA depletion. Am J Hum Genet 76: 1081–1086.

    Article  PubMed  CAS  Google Scholar 

  • Fenton WA, Gravel RA, Rosenblatt DS (2001) Disorders of propionate and methylmalonate metabolism. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc. eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 2165–2193.

    Google Scholar 

  • Fontella FU, Pulrolnik V, Gassen E, et al (2000) Propionic and l-methylmalonic acids induce oxidative stress in brain of young rats. Neuroreport 11: 541–544.

    Article  PubMed  CAS  Google Scholar 

  • Fighera MR, Queiroz CM, Stracke MP, et al (1999) Ascorbic acid and alpha-tocopherol attenuate methylmalonic acid-induced convulsions. Neuroreport 10: 2039–2043.

    Article  PubMed  CAS  Google Scholar 

  • Gregersen N (1981) The specific inhibition of the pyruvate dehydrogenase complex from pig kidney by propionyl-CoA and isovaleryl-CoA. Biochem Med 26: 20–27.

    Article  PubMed  CAS  Google Scholar 

  • Halperin ML, Schiller CM, Fritz IB (1971) The inhibition by methylmalonic acid of malate transport by the dicarboxylic carrier in rat liver mitochondria. J Clin Invest 50: 2276–2282.

    Article  PubMed  CAS  Google Scholar 

  • Hargreaves IP, Sheena Y, Land JM, et al (2005) Glutathione deficiency in patients with mitochondrial diseases: implications for pathogenesis and treatment. J Inherit Metab Dis 28: 81–88.

    Article  PubMed  CAS  Google Scholar 

  • Hassel B, Brathe A, Petersen D (2002) Cerebral dicarboxylate transport and metabolism studied with isotopically labelled fumarate, malate and malonate. J Neurochem 82: 410–419.

    Article  PubMed  CAS  Google Scholar 

  • Heidenreich R, Natowicz M, Hainline BE, et al (1988) Acute extrapyramidal syndrome in methylmalonic acidemia: ‘Metabolic stroke’ involving the globus pallidus. J Pediatr 113: 1022–1027.

    Article  PubMed  CAS  Google Scholar 

  • Horswill AR, Dudding AR, Escalante-Semerena JC (2001) Studies of propionate toxicity in Salmonella enterica identify 2-methylcitrate as a potent inhibitor of cell growth. J Biol Chem 276: 19094–19101.

    Article  PubMed  CAS  Google Scholar 

  • Huang W, Wang H, Kekuda R, et al (2000) Transport of N-acetylaspartate by the Na+-dependent high-affinity dicarboxylate transporter NADC3 and its relevance to the expression of the transporter in brain. J Pharmacol Exp Ther 295: 392–403.

    PubMed  CAS  Google Scholar 

  • Indo HP, Davidson M, Yen HC, et al (2007) Evidence of ROS generation by mitochondria in cells with impaired electron transport chain and mitochondrial DNA damage. Mitochondrion 7: 106–118.

    Article  PubMed  CAS  Google Scholar 

  • Kahler SG, Sherwood WG, Woolf D, et al (1994) Pancreatitis in patients with organic acidemias. J Pediatr 124: 239–243.

    Article  PubMed  CAS  Google Scholar 

  • Kaplan P, Ficicioglu C, Mazur AT, et al (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 

  • Kasahara M, Horikawa R, Tagawa M, et al (2006) Current role of liver transplantation for methylmalonic academia: a review of the literature. Pediatr Transplant 10: 943–947.

    Article  PubMed  Google Scholar 

  • Kashtan CE, Abousedira M, Rozen S, Manivel JC, McCann M, Tuchman M (1998) Chronic administration of methylmalonic acid (MMA) to rats causes proteinuria and renal tubular injury (abstract). Pediatr Res 43: 309.

    Article  Google Scholar 

  • Kölker S, Okun JG (2005) Methylmalonic acid- an endogenous toxin? Cell Mol Life Sci 62: 621–624.

    Article  PubMed  CAS  Google Scholar 

  • Kölker S, Schwab M, Hörster F, et al (2003) Methylmalonic acid, a biochemical hallmark of methylmalonic acidurias but no inhibitor of mitochondrial respiratory chain. J Biol Chem 278: 47388–47393.

    Article  PubMed  Google Scholar 

  • Kölker S, Sauer SW, Okun JG, Hoffmann GF, Koeller DM (2006a) Lysine intake and neurotoxicity in glutaric aciduria type I: towards a rationale for therapy? Brain 129: 54

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Kramer HJ, Gonick HC (1970) Experimental Fanconi syndrome. I. Effect of maleic acid on renal cortical Na-K-ATPase activity and ATP levels. J Lab Clin Med 76: 799–808.

    PubMed  CAS  Google Scholar 

  • Lehnert W, Sperl W, Suormala T, Baumgartner ER (1996) Propionic acidaemia: clinical, biochemical and therapeutic aspects. Experience in 30 patients. Eur J Pediatr 153: 68–80.

    Article  Google Scholar 

  • Massoud AF, Leonard JV (1993) Cardiomyopathy in propionic acidaemia. Eur J Pediatr 152: 441–445.

    Article  PubMed  CAS  Google Scholar 

  • McLaughlin BA, Nelson D, Silver JA, Erecinska M, Chesselet MF (1998) Methylmalonate toxicity in primary neuronal cultures. Neuroscience 86: 276–290.

    Article  Google Scholar 

  • Meyburg J, Hoffmann GF (2005) Liver transplantation for inborn errors of metabolism. Transplantation 80: 135–137.

    Article  Google Scholar 

  • Narasimhan P, Sklar R, Murrell M, Swanson RA, Sharp FR (1996) Methylmalonyl-CoA mutase induction by cerebral ischemia and neurotoxicity of the mitochondrial toxin methylmalonic acid. J Neurosci 16: 7336–7346.

    PubMed  CAS  Google Scholar 

  • Nicolaides P, Leonard JV, Surtees R (1998) The neurological outcome of methylmalonic acidaemia. Arch Dis Child 78: 508–512.

    Article  PubMed  CAS  Google Scholar 

  • Oberholzer VG, Levin B, Burgess EA, Young WF (1967) Methylmalonic aciduria: an inborn error of metabolism leading to chronic metabolic acidosis. Arch Dis Child 42: 492–504.

    PubMed  CAS  Google Scholar 

  • Ohura T, Kikuchi M, Abukawa D, et al (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 

  • Okun JG, Hörster F, Farkas LM, et al (2002) Neurodegeneration in methylmalonic aciduria involves inhibition of complex II and the tricarboxylic acid cycle, and synergistically acting excitotoxicity. J Biol Chem 277: 14674–14680.

    PubMed  CAS  Google Scholar 

  • Ostergaard E, Hansen FJ, Soernsen N, Vissing J, Horn N (2006) Methymalonic encephalomyopathy is caused by mutations in the SUCLA2 gene and has a high incidence in the Faroe Islands due to a founder effect (abstract). J Inherit Metab Dis 29: 45.

    Google Scholar 

  • Ostergaard E, Hansen FJ, Sorensen N, et al (2007) Mitochondrial encephalomyopathy with elevated methylmalonic acid is caused by SUCLA2 mutations. Brain 130: 853–861.

    Article  PubMed  Google Scholar 

  • Pajor AM (2000) Molecular properties of sodium/dicarboxylate cotransporters. J Membr Biol 175: 1–8.

    Article  PubMed  CAS  Google Scholar 

  • Pela I, Gasperini S, Pasquini E, et al (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 

  • Peters H, Nefedov M, Sarsero J, et al (2003) A knock-out mouse model for methylmalonic aciduria resulting in neonatal lethality. J Biol Chem 278: 52909–52913.

    Article  PubMed  CAS  Google Scholar 

  • Reszko AE, Kasumov T, Pierce BA, et al (2003) Assessing the reversibility of the anaplerotic reactions of the propionyl-CoA pathway in heart and liver. J Biol Chem 278: 34959–34965.

    Google Scholar 

  • Saad LO, Mirandola SR, Maciel EN, et al (2006) Lactate dehydrogenase activity is inhibited by methylmalonate in vitro. Neurochem Res 31: 541–548.

    Article  PubMed  CAS  Google Scholar 

  • Sauer SW, Okun JG, Fricker G, et al (2006) Intracerebral accumulation of glutaric and 3-hydroxyglutaric acids secondary to limited flux across the blood–brain barrier constitute a biochemical risk factor for neurodegeneration in glutaryl-CoA dehydrogenase deficiency. J Neurochem 97: 899–910.

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Schwab MA, Sauer SW, Okun JG, et al (2006) Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins. Biochem J 398: 107–112.

    Article  PubMed  CAS  Google Scholar 

  • Shikano N, Nakajima S, Kotani T, et al (2006) Detection of maleate-induced Fanconi syndrome by decreasing accumulation of 125I-3-iodo-alpha-methyl-l-tyrosine in the proximal tubule segment-1 region of renal cortex in mice: a trial of separate evaluation of reabsorption. Ann Nucl Med 20: 175–181.

    PubMed  CAS  Google Scholar 

  • Smith CV, Jones DP, Guenther TM, Lash LH, Lauterburg BH (1996) Compartmentation of glutathione: implications for the study of toxicity and disease. Toxicol Appl Pharmacol 140: 1–12.

    Article  PubMed  CAS  Google Scholar 

  • Terasaki T, Ohtsuki S (2005) Brain-to-blood transporters for endogenous substrates and xenobiotics at the blood–brain barrier: an overview of biology and methodology. NeuroRx 2: 63–72.

    Article  PubMed  Google Scholar 

  • Trinh BC, Melhem ER, Barker PB (2001) Multi-slice proton MR spectroscopy and diffusion-weighted imaging in methylmalonic acidemia: report of two cases and review of the literature. Am J Neuroradiol 22: 831–833.

    PubMed  CAS  Google Scholar 

  • Valko M, Leibfritz D, Moncol J, Cronin MT, Mazur M, Telser J (2007) Free radicals and antioxidants in normal physiological functions and human disease. Int J Biochem Cell Biol 39: 44–84.

    Article  PubMed  CAS  Google Scholar 

  • Wajner M, Coelho JC (1997) Neurological dysfunction in methyylmalonic acidaemia is probably related to the inhibitory effect of methylmalonate on brain energy production. J Inherit Metab Dis 20: 761–768.

    Article  PubMed  CAS  Google Scholar 

  • Wallace DC (2005) The mitochondrial genome in human adaptive radiation and disease: on the road to therapeutics and performance enhancement. Gene 354: 169–180.

    Article  PubMed  CAS  Google Scholar 

  • Walter JH, Michalski A, Wilson WM, Leonard JV, Barratt TM, Dillon MJ (1989) Chronic renal failure in methylmalonic acidaemia. Eur J Pediatr 148: 344–348.

    Article  PubMed  CAS  Google Scholar 

  • Wang H, Fei YJ, Kekuda R (2000) Structure, function, and genomic organization of human Na(+)-dependent high-affinity dicarboxylate transporter. Am J Physiol Cell Physiol 278: 1019–1030.

    Google Scholar 

  • Wolff JA, Strom C, Griswold D, et al (1985) Proximal renal tubular acidosis in methylmalonic acidemia. J Neurogenet 2: 31–39.

    Article  PubMed  CAS  Google Scholar 

  • Yodoya E, Wada M, Shimada A, et al (2006) Functional and molecular identification of sodium-coupled dicarboxylate transporters in rat primary cultured cerebrocortical astrocytes and neurons. J Neurochem 97: 162–173.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of General Pediatrics, Division of Inherited Metabolic Diseases, University Children’s Hospital Heidelberg, Im Neuenheimer Feld 150, 69120, Heidelberg, Germany

    M. A. Morath, J. G. Okun, I. B. Müller, S. W. Sauer, F. Hörster, G. F. Hoffmann & S. Kölker

Authors
  1. M. A. Morath
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. G. Okun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. I. B. Müller
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. W. Sauer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F. Hörster
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. G. F. Hoffmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. S. Kölker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. A. Morath.

Additional information

Communicating editor: Ivo Baric

Competing interests: None declared

References to electronic databases: OMIM, ExPASY for EC numbers, KEGG metabolism pathways.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morath, M.A., Okun, J.G., Müller, I.B. et al. Neurodegeneration and chronic renal failure in methylmalonic aciduria—A pathophysiological approach. J Inherit Metab Dis 31, 35–43 (2008). https://doi.org/10.1007/s10545-007-0571-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10545-007-0571-5

Keywords

Search

Navigation