Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

RARE DISEASES

Neurological manifestations of organic acidurias

Nature Reviews Neurology volume 15, pages 253–271 (2019)Cite this article

Subjects

Abstract

Organic acidurias (OADs) are inherited neurometabolic diseases largely caused by deficiencies in enzymes involved in amino acid degradation, which result in accumulation of organic acids in the brain and other tissues. Disease presentation usually occurs in infancy, although late-onset variants can emerge during childhood or adulthood. Patients predominantly manifest with acute encephalopathy with life-threatening systemic manifestations (classical OADs) or progressive neurological symptoms (cerebral OADs), leading to permanent cerebral abnormalities. Some OADs are treatable, and early diagnosis and treatment implementation have substantially decreased the mortality and overall morbidity from OADs. However, long-term irreversible cerebral and systemic complications are frequent because the therapeutic options are currently limited. The pathophysiology of brain dysfunction is still unclear in most OADs, and further investigation is needed to enable the development of novel therapeutic strategies. This Review focuses on current knowledge of the OADs, including epidemiology, short-term and long-term neurological and systemic features, diagnosis and prognosis, and recent advances in therapy and pathophysiology. The goal of the article is to alert neurologists and related health professionals to the existence and importance of these neurometabolic diseases and to stimulate research into the damaging factors that contribute to their neurodegenerative sequelae.

Key points

  • Organic acidurias (OADs) make up a large and prevalent group of inherited neurometabolic intoxication disorders caused by deficient enzyme activities, mostly of amino acid catabolism.

  • Acute or progressive signs of metabolic intoxication — predominantly or exclusively neurological — emerge in infancy (early onset) or during childhood or adulthood (late onset), resulting in high mortality and poor neurological outcome.

  • A diagnosis is usually reached through detection of characteristic organic acid profiles in the urine.

  • Current treatment strategies have decreased mortality and overall morbidity but do not prevent long-term systemic and neurological complications.

  • A better understanding of the precise mechanisms underlying the pathogenesis of OADs should aid the development of new therapies to target CNS injury.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Diagnosis of organic acidurias.
Fig. 2: Pathomechanisms of brain damage in organic acidurias.
Fig. 3: Presumed pathomechanisms of brain injury in glutaric acidaemia type I.

References

  1. Scriver, C. et al. The Metabolic and Molecular Bases of Inherited Disease 8th edn 3–45 (McGraw-Hill, 2001).

  2. Kolker, S. et al. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J. Inherit. Metab. Dis. 38, 1041–1057 (2015).

    PubMed  Google Scholar 

  3. Alfadhel, M. et al. Thirteen year retrospective review of the spectrum of inborn errors of metabolism presenting in a tertiary center in Saudi Arabia. Orphanet J. Rare Dis. 11, 126 (2016).

    PubMed  PubMed Central  Google Scholar 

  4. Villani, G. R., Gallo, G., Scolamiero, E., Salvatore, F. & Ruoppolo, M. “Classical organic acidurias”: diagnosis and pathogenesis. Clin. Exp. Med. 17, 305–323 (2017).

    CAS  PubMed  Google Scholar 

  5. Saudubray, J.-M., Baumgartner, M. & Walter, J. Inborn Metabolic Diseases: Diagnosis and Treatment 6th edn 658 (Springer-Verlag Berlin Heidelberg, 2016).

  6. Saudubray, J. M. & Garcia-Cazorla, A. Inborn errors of metabolism overview: pathophysiology, manifestations, evaluation, and management. Pediatr. Clin. North Am. 65, 179–208 (2018).

    PubMed  Google Scholar 

  7. Tuncel, A. T. et al. Organic acidurias in adults: late complications and management. J. Inherit. Metab. Dis. 41, 765–776 (2018).

    CAS  PubMed  Google Scholar 

  8. Hoffmann, G. F. & Kolker, S. Defects in amino acid catabolism and the urea cycle. Handb. Clin. Neurol. 113, 1755–1773 (2013).

    PubMed  Google Scholar 

  9. Kolker, S. et al. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 2: the evolving clinical phenotype. J. Inherit. Metab. Dis. 38, 1059–1074 (2015).

    PubMed  Google Scholar 

  10. Dionisi-Vici, C., Deodato, F., Roschinger, W., Rhead, W. & Wilcken, B. ‘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 (2006).

    CAS  PubMed  Google Scholar 

  11. Kolker, S., Burgard, P., Sauer, S. W. & Okun, J. G. Current concepts in organic acidurias: understanding intra- and extracerebral disease manifestation. J. Inherit. Metab. Dis. 36, 635–644 (2013).

    PubMed  Google Scholar 

  12. Knerr, I., Weinhold, N., Vockley, J. & Gibson, K. M. Advances and challenges in the treatment of branched-chain amino/keto acid metabolic defects. J. Inherit. Metab. Dis. 35, 29–40 (2012).

    CAS  PubMed  Google Scholar 

  13. Nizon, M. et al. Long-term neurological outcome of a cohort of 80 patients with classical organic acidurias. Orphanet J. Rare Dis. 8, 148 (2013).

    PubMed  PubMed Central  Google Scholar 

  14. Baumgartner, M. R. et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J. Rare Dis. 9, 130 (2014).

    PubMed  PubMed Central  Google Scholar 

  15. Aldubayan, S. H., Rodan, L. H., Berry, G. T. & Levy, H. L. Acute illness protocol for organic acidemias: methylmalonic acidemia and propionic acidemia. Pediatr. Emerg. Care 33, 142–146 (2017).

    PubMed  Google Scholar 

  16. Horster, F. et al. Newborn screening programmes in Europe, arguments and efforts regarding harmonisation: focus on organic acidurias. JIMD Rep. 32, 105–115 (2017).

    PubMed  Google Scholar 

  17. Rashed, M., Ozand, P. T., al Aqeel, A. & Gascon, G. G. Experience of King Faisal Specialist Hospital and Research Center with Saudi organic acid disorders. Brain Dev. 16 (Suppl), 1–6 (1994).

    PubMed  Google Scholar 

  18. Applegarth, D. A., Toone, J. R. & Lowry, R. B. Incidence of inborn errors of metabolism in British Columbia, 1969–1996. Pediatrics 105, e10 (2000).

    CAS  PubMed  Google Scholar 

  19. Dionisi-Vici, C. et al. Inborn errors of metabolism in the Italian pediatric population: a national retrospective survey. J. Pediatr. 140, 321–327 (2002).

    PubMed  Google Scholar 

  20. Schulze, A. et al. Expanded newborn screening for inborn errors of metabolism by electrospray ionization-tandem mass spectrometry: results, outcome, and implications. Pediatrics 111, 1399–1406 (2003).

    PubMed  Google Scholar 

  21. Sanderson, S., Green, A., Preece, M. A. & Burton, H. The incidence of inherited metabolic disorders in the West Midlands, UK. Arch. Dis. Child. 91, 896–899 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Kolker, S. et al. Networking across borders for individuals with organic acidurias and urea cycle disorders: the E-IMD Consortium. JIMD Rep. 22, 29–38 (2015).

    PubMed  PubMed Central  Google Scholar 

  23. Shibata, N. et al. Diversity in the incidence and spectrum of organic acidemias, fatty acid oxidation disorders, and amino acid disorders in Asian countries: Selective screening versus expanded newborn screening. Mol. Genet. Metab. Rep. 16, 5–10 (2018).

    PubMed  PubMed Central  Google Scholar 

  24. Hoffmann, G. F. et al. Neurological manifestations of organic acid disorders. Eur. J. Pediatr. 153, S94–S100 (1994).

    CAS  PubMed  Google Scholar 

  25. Pena, L. & Burton, B. K. Survey of health status and complications among propionic acidemia patients. Am. J. Med. Genet. A 158A, 1641–1646 (2012).

    PubMed  Google Scholar 

  26. Horster, F. et al. Long-term outcome in methylmalonic acidurias is influenced by the underlying defect (mut0, mut-, cblA, cblB). Pediatr. Res. 62, 225–230 (2007).

    PubMed  Google Scholar 

  27. Horster, F. et al. Prediction of outcome in isolated methylmalonic acidurias: combined use of clinical and biochemical parameters. J. Inherit. Metab. Dis. 32, 630 (2009).

    CAS  PubMed  Google Scholar 

  28. Argmann, C. A., Houten, S. M., Zhu, J. & Schadt, E. E. A. Next generation multiscale view of inborn errors of metabolism. Cell Metab. 23, 13–26 (2016).

    CAS  PubMed  Google Scholar 

  29. Manoli, I., Sloan, J. L. & Venditti, C. P. Isolated methylmalonic acidemia. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK1231/ (updated 1 Dec 2016).

  30. Atkinson, C., Miousse, I. R., Watkins, D., Rosenblatt, D. S. & Raiman, J. A. Clinical, biochemical, and molecular presentation in a patient with the cblD-homocystinuria inborn error of cobalamin metabolism. JIMD Rep. 17, 77–81 (2014).

    PubMed  PubMed Central  Google Scholar 

  31. Dobson, C. M. et al. Homozygous nonsense mutation in the MCEE gene and siRNA suppression of methylmalonyl-CoA epimerase expression: a novel cause of mild methylmalonic aciduria. Mol. Genet. Metab. 88, 327–333 (2006).

    CAS  PubMed  Google Scholar 

  32. Waters, P. J. et al. Methylmalonyl-coA epimerase deficiency: a new case, with an acute metabolic presentation and an intronic splicing mutation in the MCEE gene. Mol. Genet. Metab. Rep. 9, 19–24 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Fraser, J. L. & Venditti, C. P. Methylmalonic and propionic acidemias: clinical management update. Curr. Opin. Pediatr. 28, 682–693 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Gradinger, A. B. et al. Atypical methylmalonic aciduria: frequency of mutations in the methylmalonyl CoA epimerase gene (MCEE). Hum. Mutat. 28, 1045 (2007).

    PubMed  Google Scholar 

  35. Manoli, I. & Venditti, C. P. Disorders of branched chain amino acid metabolism. Transl Sci. Rare Dis. 1, 91–110 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Radmanesh, A. et al. Methylmalonic acidemia: brain imaging findings in 52 children and a review of the literature. Pediatr. Radiol. 38, 1054–1061 (2008).

    Google Scholar 

  37. Baker, E. H. et al. MRI characteristics of globus pallidus infarcts in isolated methylmalonic acidemia. AJNR Am. J. Neuroradiol. 36, 194–201 (2015).

    CAS  PubMed  Google Scholar 

  38. Niemi, A. K. et al. Treatment of methylmalonic acidemia by liver or combined liver-kidney transplantation. J. Pediatr. 166, 1455–1461 (2015).

    PubMed  Google Scholar 

  39. Spada, M. et al. Liver transplantation in severe methylmalonic acidemia: the sooner, the better. J. Pediatr. 167, 1173 (2015).

    PubMed  Google Scholar 

  40. Sakamoto, R. et al. Improvement in the prognosis and development of patients with methylmalonic acidemia after living donor liver transplant. Pediatr. Transplant. 20, 1081–1086 (2016).

    CAS  PubMed  Google Scholar 

  41. Wongkittichote, P., Ah Mew, N. & Chapman, K. A. Propionyl-CoA carboxylase — a review. Mol. Genet. Metab. 122, 145–152 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Grunert, S. C. et al. Propionic acidemia: clinical course and outcome in 55 pediatric and adolescent patients. Orphanet J. Rare Dis. 8, 6 (2013).

    PubMed  PubMed Central  Google Scholar 

  43. Schreiber, J. et al. Neurologic considerations in propionic acidemia. Mol. Genet. Metab. 105, 10–15 (2012).

    CAS  PubMed  Google Scholar 

  44. Grunert, S. C. et al. Clinical and neurocognitive outcome in symptomatic isovaleric acidemia. Orphanet J. Rare Dis. 7, 9 (2012).

    PubMed  PubMed Central  Google Scholar 

  45. Moorthie, S., Cameron, L., Sagoo, G. S., Bonham, J. R. & Burton, H. Systematic review and meta-analysis to estimate the birth prevalence of five inherited metabolic diseases. J. Inherit. Metab. Dis. 37, 889–898 (2014).

    CAS  PubMed  Google Scholar 

  46. Couce, M. L. et al. Genotype and phenotype characterization in a Spanish cohort with isovaleric acidemia. J. Hum. Genet. 62, 355–360 (2017).

    CAS  PubMed  Google Scholar 

  47. Reddy, N. et al. Neuroimaging findings of organic acidemias and aminoacidopathies. Radiographics 38, 912–931 (2018).

    PubMed  Google Scholar 

  48. Heringer, J. et al. Impact of age at onset and newborn screening on outcome in organic acidurias. J. Inherit. Metab. Dis. 39, 341–353 (2016).

    PubMed  Google Scholar 

  49. Grunert, S. C. et al. 3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency: clinical presentation and outcome in a series of 37 patients. Mol. Genet. Metab. 121, 206–215 (2017).

    PubMed  Google Scholar 

  50. Bischof, F., Nagele, T., Wanders, R. J., Trefz, F. K. & Melms, A. 3-Hydroxy-3-methylglutaryl-CoA lyase deficiency in an adult with leukoencephalopathy. Ann. Neurol. 56, 727–730 (2004).

    PubMed  Google Scholar 

  51. Zafeiriou, D. I., Vargiami, E., Mayapetek, E., Augoustidou-Savvopoulou, P. & Mitchell, G. A. 3-Hydroxy-3-methylglutaryl coenzyme a lyase deficiency with reversible white matter changes after treatment. Pediatr. Neurol. 37, 47–50 (2007).

    PubMed  Google Scholar 

  52. Sarafoglou, K. et al. Siblings with mitochondrial acetoacetyl-CoA thiolase deficiency not identified by newborn screening. Pediatrics 128, e246–e250 (2011).

    PubMed  Google Scholar 

  53. Grunert, S. C. et al. Clinical presentation and outcome in a series of 32 patients with 2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency. Mol. Genet. Metab. 122, 67–75 (2017).

    PubMed  Google Scholar 

  54. Paquay, S. et al. Mitochondrial acetoacetyl-CoA thiolase deficiency: basal ganglia impairment may occur independently of ketoacidosis. J. Inherit. Metab. Dis. 40, 415–422 (2017).

    CAS  PubMed  Google Scholar 

  55. O’Neill, M. L., Kuo, F. & Saigal, G. MRI of pallidal involvement in Beta-ketothiolase deficiency. J. Neuroimaging 24, 414–417 (2014).

    PubMed  Google Scholar 

  56. Hoffmann, G. F. & Kölker, S. in Inborn Metabolic Diseases: Diagnosis and Treatment (eds Saudubray, J.-M., van den Berghe, G. & Walter, H. J.) 333–347 (Springer, 2012).

  57. Kolker, S. et al. Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency. Pediatr. Res. 59, 840–847 (2006).

    PubMed  Google Scholar 

  58. Kranendijk, M., Struys, E. A., Salomons, G. S., Van der Knaap, M. S. & Jakobs, C. Progress in understanding 2-hydroxyglutaric acidurias. J. Inherit. Metab. Dis. 35, 571–587 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Lindner, M. et al. Neonatal screening for glutaryl-CoA dehydrogenase deficiency. J. Inherit. Metab. Dis. 27, 851–859 (2004).

    CAS  PubMed  Google Scholar 

  60. Harting, I. et al. Dynamic changes of striatal and extrastriatal abnormalities in glutaric aciduria type I. Brain 132, 1764–1782 (2009).

    PubMed  Google Scholar 

  61. Gitiaux, C. et al. Spectrum of movement disorders associated with glutaric aciduria type 1: a study of 16 patients. Mov. Disord. 23, 2392–2397 (2008).

    PubMed  Google Scholar 

  62. Harting, I. et al. 1H-MRS in glutaric aciduria type 1: impact of biochemical phenotype and age on the cerebral accumulation of neurotoxic metabolites. J. Inherit. Metab. Dis. 38, 829–838 (2015).

    CAS  PubMed  Google Scholar 

  63. Boy, N. et al. Extrastriatal changes in patients with late-onset glutaric aciduria type I highlight the risk of long-term neurotoxicity. Orphanet J. Rare Dis. 12, 77 (2017).

    PubMed  PubMed Central  Google Scholar 

  64. Boy, N. et al. Newborn screening: a disease-changing intervention for glutaric aciduria type 1. Ann. Neurol. 83, 970–979 (2018).

    CAS  PubMed  Google Scholar 

  65. Garbade, S. F. et al. Unravelling the complex MRI pattern in glutaric aciduria type I using statistical models-a cohort study in 180 patients. J. Inherit. Metab. Dis. 37, 763–773 (2014).

    CAS  PubMed  Google Scholar 

  66. Kolker, S. et al. Decline of acute encephalopathic crises in children with glutaryl-CoA dehydrogenase deficiency identified by newborn screening in Germany. Pediatr. Res. 62, 357–363 (2007).

    PubMed  Google Scholar 

  67. Struys, E. A. D-2-Hydroxyglutaric aciduria: unravelling the biochemical pathway and the genetic defect. J. Inherit. Metab. Dis. 29, 21–29 (2006).

    CAS  PubMed  Google Scholar 

  68. van der Knaap, M. S. et al. D-2-hydroxyglutaric aciduria: further clinical delineation. J. Inherit. Metab. Dis. 22, 404–413 (1999).

    PubMed  Google Scholar 

  69. Anghileri, E. et al. In-vivo brain H1-MR-Spectroscopy identification and quantification of 2-hydroxyglutarate in L-2-Hydroxyglutaric aciduria. Brain Res. 1648, 506–511 (2016).

    CAS  PubMed  Google Scholar 

  70. Steenweg, M. E. et al. L-2-Hydroxyglutaric aciduria: pattern of MR imaging abnormalities in 56 patients. Radiology 251, 856–865 (2009).

    PubMed  Google Scholar 

  71. Fourati, H. et al. MRI features in 17 patients with l2 hydroxyglutaric aciduria. Eur. J. Radiol. Open 3, 245–250 (2016).

    PubMed  PubMed Central  Google Scholar 

  72. London, F. & Jeanjean, A. Gliomatosis cerebri in L-2-hydroxyglutaric aciduria. Acta Neurol. Belg. 115, 749–751 (2015).

    PubMed  Google Scholar 

  73. Matalon, R. & Michals-Matalon, K. Canavan disease. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK1234/ (updated 13 Sep 2018).

  74. Merrill, S. T., Nelson, G. R., Longo, N. & Bonkowsky, J. L. Cytotoxic edema and diffusion restriction as an early pathoradiologic marker in canavan disease: case report and review of the literature. Orphanet J. Rare Dis. 11, 169 (2016).

    PubMed  PubMed Central  Google Scholar 

  75. Sener, R. N. Canavan disease: diffusion magnetic resonance imaging findings. J. Comput. Assist. Tomogr. 27, 30–33 (2003).

    PubMed  Google Scholar 

  76. Cakmakci, H., Pekcevik, Y., Yis, U., Unalp, A. & Kurul, S. Diagnostic value of proton MR spectroscopy and diffusion-weighted MR imaging in childhood inherited neurometabolic brain diseases and review of the literature. Eur. J. Radiol. 74, e161–e171 (2010).

    PubMed  Google Scholar 

  77. von Jonquieres, G. et al. Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy. Acta Neuropathol. 135, 95–113 (2018).

    Google Scholar 

  78. Guo, F. et al. Ablating N-acetylaspartate prevents leukodystrophy in a Canavan disease model. Ann. Neurol. 77, 884–888 (2015).

    CAS  PubMed  Google Scholar 

  79. Bannerman, P. et al. Brain Nat8l knockdown suppresses spongiform leukodystrophy in an aspartoacylase-deficient Canavan disease mouse model. Mol. Ther. 26, 793–800 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Starling, S. White matter disease: targeted aspartoacylase gene therapy reverts Canavan disease. Nat. Rev. Neurol. 14, 4 (2018).

    CAS  PubMed  Google Scholar 

  81. Burlina, A. et al. New clinical phenotype of branched-chain acyl-CoA oxidation defect. Lancet 338, 1522–1523 (1991).

    CAS  PubMed  Google Scholar 

  82. Tiranti, V. et al. Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein. Am. J. Hum. Genet. 74, 239–252 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Tiranti, V. et al. ETHE1 mutations are specific to ethylmalonic encephalopathy. J. Med. Genet. 43, 340–346 (2006).

    CAS  PubMed  Google Scholar 

  84. Dionisi-Vici, C. et al. Liver transplant in ethylmalonic encephalopathy: a new treatment for an otherwise fatal disease. Brain 139, 1045–1051 (2016).

    Google Scholar 

  85. Di Meo, I., Lamperti, C. & Tiranti, V. Ethylmalonic encephalopathy. GeneReviews https://www.ncbi.nlm.nih.gov/books/NBK453432/ (updated 21 Sep 2017).

  86. Giordano, C. et al. Morphologic evidence of diffuse vascular damage in human and in the experimental model of ethylmalonic encephalopathy. J. Inherit. Metab. Dis. 35, 451–458 (2012).

    PubMed  Google Scholar 

  87. Bhat, M. D., Prasad, C., Tiwari, S., Chandra, S. R. & Christopher, R. Diffusion restriction in ethylmalonic encephalopathy — an imaging evidence of the pathophysiology of the disease. Brain Dev. 38, 768–771 (2016).

    PubMed  Google Scholar 

  88. Tiranti, V. & Zeviani, M. Altered sulfide (H(2)S) metabolism in ethylmalonic encephalopathy. Cold Spring Harb. Perspect. Biol. 5, a011437 (2013).

    PubMed  PubMed Central  Google Scholar 

  89. Di Meo, I., Lamperti, C. & Tiranti, V. Mitochondrial diseases caused by toxic compound accumulation: from etiopathology to therapeutic approaches. EMBO Mol. Med. 7, 1257–1266 (2015).

    PubMed  PubMed Central  Google Scholar 

  90. Zafeiriou, D. I. et al. Ethylmalonic encephalopathy: clinical and biochemical observations. Neuropediatrics 38, 78–82 (2007).

    CAS  PubMed  Google Scholar 

  91. Tiranti, V. et al. Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nat. Med. 15, 200–205 (2009).

    CAS  PubMed  Google Scholar 

  92. Di Meo, I. et al. Chronic exposure to sulfide causes accelerated degradation of cytochrome c oxidase in ethylmalonic encephalopathy. Antioxid. Redox Signal. 15, 353–362 (2011).

    PubMed  Google Scholar 

  93. Amaral, A. U. et al. Ethylmalonic acid impairs brain mitochondrial succinate and malate transport. Mol. Genet. Metab. 105, 84–90 (2012).

    CAS  PubMed  Google Scholar 

  94. Cardoso, G. M. F. et al. Bioenergetics dysfunction, mitochondrial permeability transition pore opening and lipid peroxidation induced by hydrogen sulfide as relevant pathomechanisms underlying the neurological dysfunction characteristic of ethylmalonic encephalopathy. Biochim. Biophys. Acta Mol. Basis Dis. 1863, 2192–2201 (2017).

    CAS  PubMed  Google Scholar 

  95. Cecatto, C., Amaral, A. U., Leipnitz, G., Castilho, R. F. & Wajner, M. Ethylmalonic acid induces permeability transition in isolated brain mitochondria. Neurotox. Res. 26, 168–178 (2014).

    CAS  PubMed  Google Scholar 

  96. Leipnitz, G. et al. Ethylmalonic acid inhibits mitochondrial creatine kinase activity from cerebral cortex of young rats in vitro. Neurochem. Res. 28, 771–777 (2003).

    CAS  PubMed  Google Scholar 

  97. Ritter, L. et al. Disturbance of energy and redox homeostasis and reduction of Na+,K+-ATPase activity provoked by in vivo intracerebral administration of ethylmalonic acid to young rats. Biochim. Biophys. Acta 1852, 759–767 (2015).

    CAS  PubMed  Google Scholar 

  98. Sahebekhtiari, N. et al. Deficiency of the mitochondrial sulfide regulator ETHE1 disturbs cell growth, glutathione level and causes proteome alterations outside mitochondria. Biochim. Biophys. Acta Mol. Basis Dis. 1865, 126–135 (2019).

    CAS  PubMed  Google Scholar 

  99. Schuck, P. F. et al. Promotion of lipid and protein oxidative damage in rat brain by ethylmalonic acid. Neurochem. Res. 35, 298–305 (2010).

    CAS  PubMed  Google Scholar 

  100. Schuck, P. F. et al. Inhibition of creatine kinase activity in vitro by ethylmalonic acid in cerebral cortex of young rats. Neurochem. Res. 27, 1633–1639 (2002).

    CAS  PubMed  Google Scholar 

  101. Boyer, M. et al. Response to medical and a novel dietary treatment in newborn screen identified patients with ethylmalonic encephalopathy. Mol. Genet. Metab. 124, 57–63 (2018).

    CAS  PubMed  Google Scholar 

  102. Kitzler, T. M. et al. Acute and chronic management in an atypical case of ethylmalonic encephalopathy. JIMD Rep. 45, 57–63 (2019).

    PubMed  Google Scholar 

  103. Kumar, S., Mattan, N. S. & de Vellis, J. Canavan disease: a white matter disorder. Ment. Retard. Dev. Disabil. Res. Rev. 12, 157–165 (2006).

    PubMed  Google Scholar 

  104. van der Knaap, M. S. & Valk, J. Magnetic Resonance of Myelination and Myelin Disorders 3rd edn (Springer-Verlag Berlin Heidelberg, 2011).

  105. Bennett, S., Shafran, R., Coughtrey, A., Walker, S. & Heyman, I. Psychological interventions for mental health disorders in children with chronic physical illness: a systematic review. Arch. Dis. Child. 100, 308–316 (2015).

    PubMed  Google Scholar 

  106. Jamiolkowski, D. et al. Behavioural and emotional problems, intellectual impairment and health-related quality of life in patients with organic acidurias and urea cycle disorders. J. Inherit. Metab. Dis. 39, 231–241 (2016).

    PubMed  Google Scholar 

  107. Gallagher, R. C. et al. Laboratory analysis of organic acids, 2018 update: a technical standard of the American College of Medical Genetics and Genomics (ACMG). Genet. Med. 20, 683–691 (2018).

    PubMed  Google Scholar 

  108. Kobayashi, H., Hasegawa, Y., Endo, M., Purevsuren, J. & Yamaguchi, S. ESI-MS/MS study of acylcarnitine profiles in urine from patients with organic acidemias and fatty acid oxidation disorders. J. Chromatogr. B 855, 80–87 (2007).

    CAS  Google Scholar 

  109. Couce, M. L. et al. Glutaric aciduria type I: outcome of patients with early- versus late-diagnosis. Eur. J. Paediatr. Neurol. 17, 383–389 (2013).

    PubMed  Google Scholar 

  110. Manoli, I., Myles, J. G., Sloan, J. L., Shchelochkov, O. A. & Venditti, C. P. A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 1: isolated methylmalonic acidemias. Genet. Med. 18, 386–395 (2016).

    CAS  PubMed  Google Scholar 

  111. Manoli, I. et al. A critical reappraisal of dietary practices in methylmalonic acidemia raises concerns about the safety of medical foods. Part 2: cobalamin C deficiency. Genet. Med. 18, 396–404 (2016).

    CAS  PubMed  Google Scholar 

  112. Manoli, I. et al. Response to Cunningham et al. Genet. Med. 18, 414–415 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Cunningham, A. et al. Role of medical food in MMA. Genet. Med. 18, 413–414 (2016).

    CAS  PubMed  Google Scholar 

  114. Sutton, V. R. et al. Chronic management and health supervision of individuals with propionic acidemia. Mol. Genet. Metab. 105, 26–33 (2012).

    CAS  PubMed  Google Scholar 

  115. Alfadhel, M., Al-Thihli, K., Moubayed, H., Eyaid, W. & Al-Jeraisy, M. Drug treatment of inborn errors of metabolism: a systematic review. Arch. Dis. Child. 98, 454–461 (2013).

    PubMed  PubMed Central  Google Scholar 

  116. Sloan, J. L., Manoli, I. & Venditti, C. P. Liver or combined liver-kidney transplantation for patients with isolated methylmalonic acidemia: who and when? J. Pediatr. 166, 1346–1350 (2015).

    PubMed  Google Scholar 

  117. Arrizza, C. et al. Reversal of cardiomyopathy in propionic acidemia after liver transplantation: a 10-year follow-up. Transpl. Int. 28, 1447–1450 (2015).

    PubMed  Google Scholar 

  118. Djouadi, F. & Bastin, J. Species differences in the effects of bezafibrate as a potential treatment of mitochondrial disorders. Cell Metab. 14, 715–716 (2011).

    CAS  PubMed  Google Scholar 

  119. Vockley, J. et al. Long-term major clinical outcomes in patients with long chain fatty acid oxidation disorders before and after transition to triheptanoin treatment — a retrospective chart review. Mol. Genet. Metab. 116, 53–60 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Mochel, F. Triheptanoin for the treatment of brain energy deficit: a 14-year experience. J. Neurosci. Res. 95, 2236–2243 (2017).

    CAS  PubMed  Google Scholar 

  121. Tan, K. N., Simmons, D., Carrasco-Pozo, C. & Borges, K. Triheptanoin protects against status epilepticus-induced hippocampal mitochondrial dysfunctions, oxidative stress and neuronal degeneration. J. Neurochem. 144, 431–442 (2018).

    CAS  PubMed  Google Scholar 

  122. An, D. et al. Systemic messenger RNA therapy as a treatment for methylmalonic acidemia. Cell Rep. 21, 3548–3558 (2017).

    CAS  PubMed  Google Scholar 

  123. Kolker, S., Sauer, S. W., Surtees, R. A. & Leonard, J. V. The aetiology of neurological complications of organic acidaemias — a role for the blood-brain barrier. J. Inherit. Metab. Dis. 29, 701–704 (2006).

    CAS  PubMed  Google Scholar 

  124. Sauer, S. W. et al. 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 (2006).

    CAS  PubMed  Google Scholar 

  125. Sauer, S. W. et al. Glutaric aciduria type I and methylmalonic aciduria: simulation of cerebral import and export of accumulating neurotoxic dicarboxylic acids in in vitro models of the blood-brain barrier and the choroid plexus. Biochim. Biophys. Acta 1802, 552–560 (2010).

    CAS  PubMed  Google Scholar 

  126. Wajner, M., Latini, A., Wyse, A. T. & Dutra-Filho, C. S. The role of oxidative damage in the neuropathology of organic acidurias: insights from animal studies. J. Inherit. Metab. Dis. 27, 427–448 (2004).

    CAS  PubMed  Google Scholar 

  127. Wajner, M. & Goodman, S. I. Disruption of mitochondrial homeostasis in organic acidurias: insights from human and animal studies. J. Bioenerg. Biomembr. 43, 31–38 (2011).

    CAS  PubMed  Google Scholar 

  128. Mc Guire, P. J., Parikh, A. & Diaz, G. A. Profiling of oxidative stress in patients with inborn errors of metabolism. Mol. Genet. Metab. 98, 173–180 (2009).

    Google Scholar 

  129. Olsen, R. K., Cornelius, N. & Gregersen, N. Redox signalling and mitochondrial stress responses; lessons from inborn errors of metabolism. J. Inherit. Metab. Dis. 38, 703–719 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Richard, E. et al. Altered redox homeostasis in branched-chain amino acid disorders, organic acidurias, and homocystinuria. Oxid. Med. Cell. Longev. 2018, 1246069 (2018).

    PubMed  PubMed Central  Google Scholar 

  131. Richard, E., Alvarez-Barrientos, A., Perez, B., Desviat, L. R. & Ugarte, M. Methylmalonic acidaemia leads to increased production of reactive oxygen species and induction of apoptosis through the mitochondrial/caspase pathway. J. Pathol. 213, 453–461 (2007).

    CAS  PubMed  Google Scholar 

  132. Richard, E. et al. Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC). Hum. Mutat. 30, 1558–1566 (2009).

    CAS  PubMed  Google Scholar 

  133. Richard, E. et al. Quantitative analysis of mitochondrial protein expression in methylmalonic acidemia by two-dimensional difference gel electrophoresis. J. Proteome Res. 5, 1602–1610 (2006).

    CAS  PubMed  Google Scholar 

  134. Schwab, M. A. et al. Secondary mitochondrial dysfunction in propionic aciduria: a pathogenic role for endogenous mitochondrial toxins. Biochem. J. 398, 107–112 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  135. Chandler, R. J. et al. Mitochondrial dysfunction in mut methylmalonic acidemia. FASEB J. 23, 1252–1261 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. de Keyzer, Y. et al. Multiple OXPHOS deficiency in the liver, kidney, heart, and skeletal muscle of patients with methylmalonic aciduria and propionic aciduria. Pediatr. Res. 66, 91–95 (2009).

    PubMed  Google Scholar 

  137. Salmi, H., Leonard, J. V. & Lapatto, R. Patients with organic acidaemias have an altered thiol status. Acta Paediatr. 101, e505–e508 (2012).

    PubMed  Google Scholar 

  138. Jamuar, S. S. et al. Rhabdomyolysis, acute renal failure, and cardiac arrest secondary to status dystonicus in a child with glutaric aciduria type I. Mol. Genet. Metab. 106, 488–490 (2012).

    CAS  PubMed  Google Scholar 

  139. Gallego-Villar, L. et al. Functional characterization of novel genotypes and cellular oxidative stress studies in propionic acidemia. J. Inherit. Metab. Dis. 36, 731–740 (2013).

    CAS  PubMed  Google Scholar 

  140. Baruteau, J. et al. Successful reversal of propionic acidaemia associated cardiomyopathy: evidence for low myocardial coenzyme Q10 status and secondary mitochondrial dysfunction as an underlying pathophysiological mechanism. Mitochondrion 17, 150–156 (2014).

    CAS  PubMed  Google Scholar 

  141. Brasil, S. et al. Methylmalonic aciduria cblB type: characterization of two novel mutations and mitochondrial dysfunction studies. Clin. Genet. 87, 576–581 (2015).

    CAS  PubMed  Google Scholar 

  142. Dos Santos Mello, M. et al. Increased oxidative stress in patients with 3-hydroxy-3-methylglutaric aciduria. Mol. Cell. Biochem. 402, 149–155 (2015).

    PubMed  Google Scholar 

  143. Guerreiro, G. et al. Oxidative damage in glutaric aciduria type I patients and the protective effects of l-carnitine treatment. J. Cell. Biochem. 119, 10021–10032 (2018).

    CAS  PubMed  Google Scholar 

  144. Gallego-Villar, L., Perez, B., Ugarte, M., Desviat, L. R. & Richard, E. Antioxidants successfully reduce ROS production in propionic acidemia fibroblasts. Biochem. Biophys. Res. Commun. 452, 457–461 (2014).

    CAS  PubMed  Google Scholar 

  145. Ribas, G. S. et al. Reduction of lipid and protein damage in patients with disorders of propionate metabolism under treatment: a possible protective role of L-carnitine supplementation. Int. J. Dev. Neurosci. 28, 127–132 (2010).

    CAS  PubMed  Google Scholar 

  146. Sauer, S. W. et al. Bioenergetics in glutaryl-coenzyme A dehydrogenase deficiency: a role for glutaryl-coenzyme A. J. Biol. Chem. 280, 21830–21836 (2005).

    CAS  PubMed  Google Scholar 

  147. Amaral, A. U., Cecatto, C., Castilho, R. F. & Wajner, M. 2-Methylcitric acid impairs glutamate metabolism and induces permeability transition in brain mitochondria. J. Neurochem. 137, 62–75 (2016).

    CAS  PubMed  Google Scholar 

  148. Zinnanti, W. J. et al. Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I. J. Clin. Invest. 117, 3258–3270 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Zinnanti, W. J. et al. A diet-induced mouse model for glutaric aciduria type I. Brain 129, 899–910 (2006).

    PubMed  Google Scholar 

  150. Solano, A. F. et al. Induction of oxidative stress by the metabolites accumulating in isovaleric acidemia in brain cortex of young rats. Free Radic. Res. 42, 707–715 (2008).

    CAS  PubMed  Google Scholar 

  151. Zanatta, A. et al. Neurochemical evidence that the metabolites accumulating in 3-methylcrotonyl-CoA carboxylase deficiency induce oxidative damage in cerebral cortex of young rats. Cell. Mol. Neurobiol. 33, 137–146 (2013).

    CAS  PubMed  Google Scholar 

  152. Viegas, C. M. et al. Disruption of redox homeostasis and brain damage caused in vivo by methylmalonic acid and ammonia in cerebral cortex and striatum of developing rats. Free Radic. Res. 48, 659–669 (2014).

    CAS  PubMed  Google Scholar 

  153. Colin-Gonzalez, A. L. et al. Experimental evidence that 3-methylglutaric acid disturbs mitochondrial function and induced oxidative stress in rat brain synaptosomes: new converging mechanisms. Neurochem. Res. 41, 2619–2626 (2016).

    CAS  PubMed  Google Scholar 

  154. da Rosa, M. S. et al. In vivo intracerebral administration of L-2-hydroxyglutaric acid provokes oxidative stress and histopathological alterations in striatum and cerebellum of adolescent rats. Free Radic. Biol. Med. 83, 201–213 (2015).

    PubMed  Google Scholar 

  155. da Rosa, M. S. et al. Disruption of redox homeostasis and histopathological alterations caused by in vivo intrastriatal administration of D-2-hydroxyglutaric acid to young rats. Neuroscience 277, 281–293 (2014).

    PubMed  Google Scholar 

  156. da Rosa, M. S. et al. 3-Hydroxy-3-methylglutaric and 3-methylglutaric acids impair redox status and energy production and transfer in rat heart: relevance for the pathophysiology of cardiac dysfunction in 3-hydroxy-3-methylglutaryl-coenzyme A lyase deficiency. Free Radic. Res. 50, 997–1010 (2016).

    PubMed  Google Scholar 

  157. Gallego-Villar, L. et al. In vivo evidence of mitochondrial dysfunction and altered redox homeostasis in a genetic mouse model of propionic acidemia: Implications for the pathophysiology of this disorder. Free Radic. Biol. Med. 96, 1–12 (2016).

    CAS  PubMed  Google Scholar 

  158. Ribeiro, R. T. et al. Experimental evidence that in vivo intracerebral administration of L-2-hydroxyglutaric acid to neonatal rats provokes disruption of redox status and histopathological abnormalities in the brain. Neurotox. Res. 33, 681–692 (2018).

    CAS  PubMed  Google Scholar 

  159. Almad, A. & Maragakis, N. J. A stocked toolbox for understanding the role of astrocytes in disease. Nat. Rev. Neurol. 14, 351–362 (2018).

    PubMed  Google Scholar 

  160. Olivera-Bravo, S. & Barbeito, L. A role of astrocytes in mediating postnatal neurodegeneration in glutaric acidemia-type 1. FEBS Lett. 589, 3492–3497 (2015).

    CAS  PubMed  Google Scholar 

  161. Koeller, D. M. et al. Biochemical, pathologic and behavioral analysis of a mouse model of glutaric acidemia type I. Hum. Mol. Genet. 11, 347–357 (2002).

    CAS  PubMed  Google Scholar 

  162. Goodman, S. I., Norenberg, M. D., Shikes, R. H., Breslich, D. J. & Moe, P. G. Glutaric aciduria: biochemical and morphologic considerations. J. Pediatr. 90, 746–750 (1977).

    CAS  PubMed  Google Scholar 

  163. Kulkens, S. et al. Late-onset neurologic disease in glutaryl-CoA dehydrogenase deficiency. Neurology 64, 2142–2144 (2005).

    CAS  PubMed  Google Scholar 

  164. Funk, C. B. et al. Neuropathological, biochemical and molecular findings in a glutaric acidemia type 1 cohort. Brain 128, 711–722 (2005).

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  166. Ohtsuki, S. New aspects of the blood-brain barrier transporters; its physiological roles in the central nervous system. Biol. Pharm. Bull. 27, 1489–1496 (2004).

    CAS  PubMed  Google Scholar 

  167. Keyser, B. et al. Transport and distribution of 3-hydroxyglutaric acid before and during induced encephalopathic crises in a mouse model of glutaric aciduria type 1. Biochim. Biophys. Acta 1782, 385–390 (2008).

    CAS  PubMed  Google Scholar 

  168. Isasi, E., Barbeito, L. & Olivera-Bravo, S. Increased blood–brain barrier permeability and alterations in perivascular astrocytes and pericytes induced by intracisternal glutaric acid. Fluids Barriers CNS 11, 15 (2014).

    PubMed  PubMed Central  Google Scholar 

  169. Zinnanti, W. J. et al. Mechanism of metabolic stroke and spontaneous cerebral hemorrhage in glutaric aciduria type I. Acta Neuropathol. Commun. 2, 13 (2014).

    PubMed  PubMed Central  Google Scholar 

  170. Ferreira, G. C. et al. Evidence for a synergistic action of glutaric and 3-hydroxyglutaric acids disturbing rat brain energy metabolism. Int. J. Dev. Neurosci. 25, 391–398 (2007).

    CAS  PubMed  Google Scholar 

  171. Latini, A. et al. 3-Hydroxyglutaric acid moderately impairs energy metabolism in brain of young rats. Neuroscience 135, 111–120 (2005).

    CAS  PubMed  Google Scholar 

  172. Ferreira, G. C. et al. Glutaric acid administration impairs energy metabolism in midbrain and skeletal muscle of young rats. Neurochem. Res. 30, 1123–1131 (2005).

    CAS  Google Scholar 

  173. de Oliveira Marques, F. et al. Glutaric acid induces oxidative stress in brain of young rats. Brain Res. 964, 153–158 (2003).

    PubMed  Google Scholar 

  174. Latini, A. et al. 3-Hydroxyglutaric acid induces oxidative stress and decreases the antioxidant defenses in cerebral cortex of young rats. Brain Res. 956, 367–373 (2002).

    CAS  PubMed  Google Scholar 

  175. Latini, A. et al. Induction of oxidative stress by chronic and acute glutaric acid administration to rats. Cell. Mol. Neurobiol. 27, 423–438 (2007).

    CAS  PubMed  Google Scholar 

  176. Latini, A., Scussiato, K., Leipnitz, G., Dutra-Filho, C. S. & Wajner, M. Promotion of oxidative stress by 3-hydroxyglutaric acid in rat striatum. J. Inherit. Metab. Dis. 28, 57–67 (2005).

    CAS  PubMed  Google Scholar 

  177. Amaral, A. U. et al. Experimental evidence that bioenergetics disruption is not mainly involved in the brain injury of glutaryl-CoA dehydrogenase deficient mice submitted to lysine overload. Brain Res. 1620, 116–129 (2015).

    CAS  PubMed  Google Scholar 

  178. Seminotti, B. et al. Disruption of brain redox homeostasis in glutaryl-CoA dehydrogenase deficient mice treated with high dietary lysine supplementation. Mol. Genet. Metab. 108, 30–39 (2013).

    CAS  PubMed  Google Scholar 

  179. Seminotti, B. et al. Acute lysine overload provokes protein oxidative damage and reduction of antioxidant defenses in the brain of infant glutaryl-CoA dehydrogenase deficient mice: a role for oxidative stress in GA I neuropathology. J. Neurol. Sci. 344, 105–113 (2014).

    CAS  PubMed  Google Scholar 

  180. Kolker, S. et al. Chronic treatment with glutaric acid induces partial tolerance to excitotoxicity in neuronal cultures from chick embryo telencephalons. J. Neurosci. Res. 68, 424–431 (2002).

    CAS  PubMed  Google Scholar 

  181. Porciuncula, L. O. et al. Inhibition of synaptosomal [3H]glutamate uptake and [3H]glutamate binding to plasma membranes from brain of young rats by glutaric acid in vitro. J. Neurol. Sci. 173, 93–96 (2000).

    CAS  PubMed  Google Scholar 

  182. Porciuncula, L. O. et al. Glutaric acid stimulates glutamate binding and astrocytic uptake and inhibits vesicular glutamate uptake in forebrain from young rats. Neurochem. Int. 45, 1075–1086 (2004).

    CAS  PubMed  Google Scholar 

  183. Rosa, R. B. et al. Evidence that glutaric acid reduces glutamate uptake by cerebral cortex of infant rats. Life Sci. 81, 1668–1676 (2007).

    CAS  PubMed  Google Scholar 

  184. Busanello, E. N. et al. Disturbance of the glutamatergic system by glutaric acid in striatum and cerebral cortex of glutaryl-CoA dehydrogenase-deficient knockout mice: possible implications for the neuropathology of glutaric acidemia type I. J. Neurol. Sci. 346, 260–267 (2014).

    CAS  PubMed  Google Scholar 

  185. Amaral, A. U. et al. Reduction of Na+, K+-ATPase activity and expression in cerebral cortex of glutaryl-CoA dehydrogenase deficient mice: a possible mechanism for brain injury in glutaric aciduria type I. Mol. Genet. Metab. 107, 375–382 (2012).

    CAS  PubMed  Google Scholar 

  186. Rosa, R. B. et al. Evidence that 3-hydroxyglutaric acid interacts with NMDA receptors in synaptic plasma membranes from cerebral cortex of young rats. Neurochem. Int. 45, 1087–1094 (2004).

    CAS  PubMed  Google Scholar 

  187. Dalcin, K. B. et al. Age and brain structural related effects of glutaric and 3-hydroxyglutaric acids on glutamate binding to plasma membranes during rat brain development. Cell. Mol. Neurobiol. 27, 805–818 (2007).

    CAS  PubMed  Google Scholar 

  188. Lagranha, V. L. et al. Increased glutamate receptor and transporter expression in the cerebral cortex and striatum of Gcdh −/− mice: possible implications for the neuropathology of glutaric acidemia type I. PLOS ONE 9, e90477 (2014).

    PubMed  PubMed Central  Google Scholar 

  189. Rodrigues, M. D. et al. Experimental evidence that overexpression of NR2B glutamate receptor subunit is associated with brain vacuolation in adult glutaryl-CoA dehydrogenase deficient mice: a potential role for glutamatergic-induced excitotoxicity in GA I neuropathology. J. Neurol. Sci. 359, 133–140 (2015).

    CAS  PubMed  Google Scholar 

  190. Leibel, R. L. et al. Glutaric acidemia: a metabolic disorder causing progressive choreoathetosis. Neurology 30, 1163–1168 (1980).

    CAS  PubMed  Google Scholar 

  191. Stokke, O., Goodman, S. I. & Moe, P. G. Inhibition of brain glutamate decarboxylase by glutarate, glutaconate, and beta-hydroxyglutarate: explanation of the symptoms in glutaric aciduria? Clin. Chim. Acta 66, 411–415 (1976).

    CAS  PubMed  Google Scholar 

  192. Vendramin Pasquetti, M. et al. Impairment of GABAergic system contributes to epileptogenesis in glutaric acidemia type I. Epilepsia 58, 1771–1781 (2017).

    CAS  PubMed  Google Scholar 

  193. Soffer, D. et al. Striatal degeneration and spongy myelinopathy in glutaric acidemia. J. Neurol. Sci. 107, 199–204 (1992).

    CAS  PubMed  Google Scholar 

  194. Calabresi, P. et al. Striatal spiny neurons and cholinergic interneurons express differential ionotropic glutamatergic responses and vulnerability: implications for ischemia and Huntington’s disease. Ann. Neurol. 43, 586–597 (1998).

    CAS  PubMed  Google Scholar 

  195. Olivera-Bravo, S. et al. Striatal neuronal death mediated by astrocytes from the Gcdh −/− mouse model of glutaric acidemia type I. Hum. Mol. Genet. 24, 4504–4515 (2015).

    CAS  PubMed  Google Scholar 

  196. Lamp, J. et al. Glutaric aciduria type 1 metabolites impair the succinate transport from astrocytic to neuronal cells. J. Biol. Chem. 286, 17777–17784 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Muhlhausen, C. et al. Vascular dysfunction as an additional pathomechanism in glutaric aciduria type I. J. Inherit. Metab. Dis. 27, 829–834 (2004).

    CAS  PubMed  Google Scholar 

  198. Muhlhausen, C. et al. Endothelial effects of 3-hydroxyglutaric acid: implications for glutaric aciduria type I. Pediatr. Res. 59, 196–202 (2006).

    PubMed  Google Scholar 

  199. Strauss, K. A., Donnelly, P. & Wintermark, M. Cerebral haemodynamics in patients with glutaryl-coenzyme A dehydrogenase deficiency. Brain 133, 76–92 (2010).

    PubMed  Google Scholar 

  200. Varadkar, S. & Surtees, R. Glutaric aciduria type I and kynurenine pathway metabolites: a modified hypothesis. J. Inherit. Metab. Dis. 27, 835–842 (2004).

    CAS  PubMed  Google Scholar 

  201. Colin-Gonzalez, A. L. et al. Toxic synergism between quinolinic acid and organic acids accumulating in glutaric acidemia type I and in disorders of propionate metabolism in rat brain synaptosomes: relevance for metabolic acidemias. Neuroscience 308, 64–74 (2015).

    CAS  PubMed  Google Scholar 

  202. Seminotti, B. et al. Oxidative stress, disrupted energy metabolism, and altered signaling pathways in glutaryl-CoA dehydrogenase knockout mice: potential implications of quinolinic acid toxicity in the neuropathology of glutaric acidemia type I. Mol. Neurobiol. 53, 6459–6475 (2016).

    CAS  PubMed  Google Scholar 

  203. Pierozan, P. et al. Toxic synergism between quinolinic acid and glutaric acid in neuronal cells is mediated by oxidative stress: insights to a new toxic model. Mol. Neurobiol. 55, 5362–5376 (2018).

    CAS  PubMed  Google Scholar 

  204. Olivera-Bravo, S. et al. Long lasting high lysine diet aggravates white matter injury in glutaryl-CoA dehydrogenase deficient (Gcdh −/−) mice. Mol. Neurobiol. 56, 648–657 (2019).

    CAS  PubMed  Google Scholar 

  205. Hofherr, S. E. et al. Short-term rescue of neonatal lethality in a mouse model of propionic acidemia by gene therapy. Hum. Gene Ther. 20, 169–180 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  206. Peters, H. L. et al. Mouse models for methylmalonic aciduria. PLOS ONE 7, e40609 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. Forny, P. et al. Novel mouse models of methylmalonic aciduria recapitulate phenotypic traits with a genetic dosage effect. J. Biol. Chem. 291, 20563–20573 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Wang, F. et al. A small molecule inhibitor of mutant IDH2 rescues cardiomyopathy in a D-2-hydroxyglutaric aciduria type II mouse model. J. Inherit. Metab. Dis. 39, 807–820 (2016).

    PubMed  PubMed Central  Google Scholar 

  209. Rzem, R. et al. A mouse model of L-2-hydroxyglutaric aciduria, a disorder of metabolite repair. PLOS ONE 10, e0119540 (2015).

    PubMed  PubMed Central  Google Scholar 

  210. Sohn, J. et al. Suppressing N-acetyl-l-aspartate synthesis prevents loss of neurons in a murine model of Canavan leukodystrophy. J. Neurosci. 37, 413–421 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Morland, C. et al. Propionate enters GABAergic neurons, inhibits GABA transaminase, causes GABA accumulation and lethargy in a model of propionic acidemia. Biochem. J. 475, 749–758 (2018).

    CAS  PubMed  Google Scholar 

  212. Burlina, A. et al. Clinical experience with N-carbamylglutamate in a single-centre cohort of patients with propionic and methylmalonic aciduria. Mol. Genet. Metab. Rep. 8, 34–40 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Boy, N. et al. Proposed recommendations for diagnosing and managing individuals with glutaric aciduria type I: second revision. J. Inherit. Metab. Dis. 40, 75–101 (2017).

    PubMed  Google Scholar 

  214. Harrington, E. A. et al. Neutralizing antibodies against adeno-associated viral capsids in patients with mut methylmalonic acidemia. Hum. Gene Ther. 27, 345–353 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The author acknowledges all colleagues and researchers who, over the past three decades, have made substantial contributions to the diagnosis and treatment of patients with organic acidurias and to investigations into the pathomechanisms of brain injury in these diseases. Special thanks go to C. M. D. Wannmacher, C. S. Dutra-Filho, A. T. S. Wyse, G. Leipnitz, C. R. Vargas, A. U. Amaral, A. Sitta and D. M. Coelho. The author also thanks the patients and their families for their long-standing confidence and patience while diagnosis was performed and treatment implemented. The author also acknowledges the invaluable technical assistance of C. Cecatto and P. Batista da Rosa.

Author information

Authors and Affiliations

  1. Department of Biochemistry, Institute of Basic Sciences and Health, Federal University of Rio Grande do Sul, Porto Alegre, Brazil

    Moacir Wajner

  2. Medical Genetics Service, Clinical Hospital of Porto Alegre, Porto Alegre, Brazil

    Moacir Wajner

Authors
  1. Moacir Wajner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Moacir Wajner.

Ethics declarations

Competing interests

The author declares no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Databases

Online Mendelian Inheritance in Man: http://www.omim.org/

Related links

Association for Neuro-Metabolic Disorders (ANMID): http://www.kumc.edu/gec/support/neuro-me.html

European Reference Network for Hereditary Metabolic Diseases (MetabERN): https://metab.ern-net.eu/

European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD): http://www.e-imd.org/en/index.phtml

European Union Committee of Experts on Rare Diseases (EUCERD): http://www.eucerd.eu/

Metabolic Support UK: https://www.metabolicsupportuk.org/

National Organization for Rare Disorders (NORD): https://rarediseases.org/

Organic Acidemia Foundation: https://www.oaanews.org/

Propionic Acidemia Foundation: http://www.pafoundation.com/

Rights and permissions

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wajner, M. Neurological manifestations of organic acidurias. Nat Rev Neurol 15, 253–271 (2019). https://doi.org/10.1038/s41582-019-0161-9

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41582-019-0161-9

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing