Journal of Inherited Metabolic Disease

, Volume 41, Issue 4, pp 631–640 | Cite as

Evaluation of plasma biomarkers of inflammation in patients with maple syrup urine disease

  • Giselli Scaini
  • Tássia Tonon
  • Carolina F. Moura de Souza
  • Patricia F. Schuck
  • Gustavo C. Ferreira
  • João Quevedo
  • João Seda Neto
  • Tatiana Amorim
  • Jose S. CameloJr
  • Ana Vitoria Barban Margutti
  • Rafael Hencke Tresbach
  • Fernanda Sperb-Ludwig
  • Raquel Boy
  • Paula F. V. de Medeiros
  • Ida Vanessa D. Schwartz
  • Emilio Luiz StreckEmail author
Original Article


Maple syrup urine disease (MSUD) is an autosomal recessive inherited disorder that affects branched-chain amino acid (BCAA) catabolism and is associated with acute and chronic brain dysfunction. Recent studies have shown that inflammation may be involved in the neuropathology of MSUD. However, these studies have mainly focused on single or small subsets of proteins or molecules. Here we performed a case-control study, including 12 treated-MSUD patients, in order to investigate the plasmatic biomarkers of inflammation, to help to establish a possible relationship between these biomarkers and the disease. Our results showed that MSUD patients in treatment with restricted protein diets have high levels of pro-inflammatory cytokines [IFN-γ, TNF-α, IL-1β and IL-6] and cell adhesion molecules [sICAM-1 and sVCAM-1] compared to the control group. However, no significant alterations were found in the levels of IL-2, IL-4, IL-5, IL-7, IL-8, and IL-10 between healthy controls and MSUD patients. Moreover, we found a positive correlation between number of metabolic crisis and IL-1β levels and sICAM-1 in MSUD patients. In conclusion, our findings in plasma of patients with MSUD suggest that inflammation may play an important role in the pathogenesis of MSUD, although this process is not directly associated with BCAA blood levels. Overall, data reported here are consistent with the working hypothesis that inflammation may be involved in the pathophysiological mechanism underlying the brain damage observed in MSUD patients.


Maple syrup urine disease Branched-chain amino acid Inflammation Pro-inflammatory cytokines Cell adhesion molecules 



Laboratory of Bioenergetics (Brazil) is one of the centres of the National Institute for Molecular Medicine (INCT-MM) and one of the members of the Center of Excellence in Applied Neurosciences of Santa Catarina (NENASC). This research was supported by grants from CNPq (402047/2010-9), FAPESC, and UNESC. We are also grateful to INAGEMP (Brazilian National Institute of Population Medical Genetics) for the support provided through grants FAPERGS #17/2551.0000521.0, CNPq #465549/2014-4 and CAPES #88887.136366/2017-00. The authors acknowledge all the members of the Brazilian MSUD Network, especially the LAM- SGM/HCPA group for helping us with the quantitative amino acid analysis as well as Dr. Kevin Strauss and Dr. Erik Puffenberger (Clinical for Special Children, Pennsylvania-USA) for helping us with the alloisoleucine measurement. The authors declare that they have not had any financial, personal or other relationships that have influenced the work.

Details of funding

This research was supported by grants from CNPq (402047/2010-9), FAPESC, and UNESC.

Compliance with ethical standards

Conflict of interest

G. Scaini, T. Tonon, C. F. Moura de Souza, P. F. Schuck, G. C. Ferreira, J. Quevedo, J. S. Neto, T. Amorim, J. S. Camelo Jr, A. V. B. Margutti, R. Tresbach, F. Sperb-Ludwig, R. Boy, P. F. V. de Medeiros, I. V. D. Schwartz, E. L. Streck declare that they have no conflict of interest.

Supplementary material

10545_2018_188_MOESM1_ESM.docx (22 kb)
ESM 1 (DOCX 21 kb)


  1. Abi-Warde MT, Roda C, Arnoux JB et al (2017) Long-term metabolic follow-up and clinical outcome of 35 patients with maple syrup urine disease. J Inherit Metab Dis 40:783–792CrossRefPubMedGoogle Scholar
  2. Amaral AU, Leipnitz G, Fernandes CG, Seminotti B, Schuck PF, Wajner M (2010) Alpha-ketoisocaproic acid and leucine provoke mitochondrial bioenergetic dysfunction in rat brain. Brain Res 1324:75–84CrossRefPubMedGoogle Scholar
  3. Amor S, Puentes F, Baker D, van der Valk P (2010) Inflammation in neurodegenerative diseases. Immunology 129:154–169CrossRefPubMedPubMedCentralGoogle Scholar
  4. Amor S, Peferoen LA, Vogel DY et al (2014) Inflammation in neurodegenerative diseases--an update. Immunology 142:151–166CrossRefPubMedPubMedCentralGoogle Scholar
  5. Araujo P, Wassermann GF, Tallini K et al (2001) Reduction of large neutral amino acid levels in plasma and brain of hyperleucinemic rats. Neurochem Int 38:529–537CrossRefPubMedGoogle Scholar
  6. Barschak AG, Sitta A, Deon M et al (2008) Oxidative stress in plasma from maple syrup urine disease patients during treatment. Metab Brain Dis 23:71–80CrossRefPubMedGoogle Scholar
  7. Barschak AG, Sitta A, Deon M et al (2009) Amino acids levels and lipid peroxidation in maple syrup urine disease patients. Clin Biochem 42:462–466CrossRefPubMedGoogle Scholar
  8. Bridi R, Araldi J, Sgarbi MB et al (2003) Induction of oxidative stress in rat brain by the metabolites accumulating in maple syrup urine disease. Int J Dev Neurosci Off J Int Soc Dev Neurosci 21:327–332CrossRefGoogle Scholar
  9. Bridi R, Braun CA, Zorzi GK et al (2005) Alpha-keto acids accumulating in maple syrup urine disease stimulate lipid peroxidation and reduce antioxidant defences in cerebral cortex from young rats. Metab Brain Dis 20:155–167CrossRefPubMedGoogle Scholar
  10. Bullard DC, Hu X, Schoeb TR, Collins RG, Beaudet AL, Barnum SR (2007) Intercellular adhesion molecule-1 expression is required on multiple cell types for the development of experimental autoimmune encephalomyelitis. J Immunol 178:851–857CrossRefPubMedGoogle Scholar
  11. Chuang DT, Shih VE (2001) Maple syrup urine disease (branched-chain ketoaciduria). In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 1971–2005Google Scholar
  12. Crome L, Dutton G, Ross CF (1961) Maple syrup urine disease. J Pathol Bacteriol 81:379–384CrossRefPubMedGoogle Scholar
  13. Cunningham C, Hennessy E (2015) Co-morbidity and systemic inflammation as drivers of cognitive decline: new experimental models adopting a broader paradigm in dementia research. Alzheimers Res Ther 7:33CrossRefPubMedPubMedCentralGoogle Scholar
  14. Dancis J, Hutzler J, Cox RP (1977) Maple syrup urine disease: branched-chain keto acid decarboxylation in fibroblasts as measured with amino acids and keto acids. Am J Hum Genet 29:272–279PubMedPubMedCentralGoogle Scholar
  15. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 9:46–56CrossRefPubMedPubMedCentralGoogle Scholar
  16. De Simone R, Vissicchio F, Mingarelli C et al (2013) Branched-chain amino acids influence the immune properties of microglial cells and their responsiveness to pro-inflammatory signals. Biochim Biophys Acta 1832:650–659CrossRefPubMedGoogle Scholar
  17. Deem TL, Cook-Mills JM (2004) Vascular cell adhesion molecule 1 (VCAM-1) activation of endothelial cell matrix metalloproteinases: role of reactive oxygen species. Blood 104:2385–2393CrossRefPubMedPubMedCentralGoogle Scholar
  18. Deon M, Sitta A, Faverzani JL et al (2015) Urinary biomarkers of oxidative stress and plasmatic inflammatory profile in phenylketonuric treated patients. Int J Dev Neurosci Off J Int Soc Dev Neurosci 47:259–265CrossRefGoogle Scholar
  19. Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Mashal NM, Irwin MR (2010) Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry 68:748–754CrossRefPubMedPubMedCentralGoogle Scholar
  20. Fakhoury M (2015) Role of immunity and inflammation in the pathophysiology of neurodegenerative diseases. Neurodegener Dis 15:63–69CrossRefPubMedGoogle Scholar
  21. Fingerhut R (2009) Recall rate and positive predictive value of MSUD screening is not influenced by hydroxyproline. Eur J Pediatr 168:599–604CrossRefPubMedGoogle Scholar
  22. Flaschker N, Feyen O, Fend S, Simon E, Schadewaldt P, Wendel U (2007) Description of the mutations in 15 subjects with variant forms of maple syrup urine disease. J Inherit Metab Dis 30:903–909CrossRefPubMedGoogle Scholar
  23. Funchal C, Latini A, Jacques-Silva MC et al (2006a) Morphological alterations and induction of oxidative stress in glial cells caused by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. Neurochem Int 49:640–650CrossRefPubMedGoogle Scholar
  24. Funchal C, Schuck PF, Santos AQ et al (2006b) Creatine and antioxidant treatment prevent the inhibition of creatine kinase activity and the morphological alterations of C6 glioma cells induced by the branched-chain alpha-keto acids accumulating in maple syrup urine disease. Cell Mol Neurobiol 26:67–79PubMedGoogle Scholar
  25. Gonzalez-Velasquez FJ, Reed JW, Fuseler JW et al (2010) Soluble amyloid-β protein aggregates induce nuclear factor-κB mediated upregulation of adhesion molecule expression to stimulate brain endothelium for monocyte adhesion. J Adhes Sci Technol 24:2105–2126CrossRefGoogle Scholar
  26. Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD (2009) Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry 66:407–414CrossRefPubMedPubMedCentralGoogle Scholar
  27. Henneke M, Flaschker N, Helbling C et al (2003) Identification of twelve novel mutations in patients with classic and variant forms of maple syrup urine disease. Hum Mutat 22:417CrossRefPubMedGoogle Scholar
  28. Imtiaz F, Al-Mostafa A, Allam R, Ramzan K, Al-Tassan N, Tahir AI, Al-Numair NS, Al-Hamed MH, Al-Hassnan Z, Al-Owain M, Al-Zaidan H, Al-Amoudi M, Qari A, Balobaid A, Al-Sayed M (2017) Twenty novel mutations in BCKDHA, BCKDHB and DBT genes in a cohort of 52 Saudi Arabian patients with maple syrup urine disease. Mol Genet Metab Rep 11:17-23Google Scholar
  29. Ivkovic M, Pantovic-Stefanovic M, Petronijevic N et al (2017) Predictive value of sICAM-1 and sVCAM-1 as biomarkers of affective temperaments in healthy young adults. J Affect Disord 207:47–52CrossRefPubMedGoogle Scholar
  30. Jan W, Zimmerman RA, Wang ZJ, Berry GT, Kaplan PB, Kaye EM (2003) MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation. Neuroradiology 45:393–399CrossRefPubMedGoogle Scholar
  31. Joseph MH, Marsden CA (1986) Amino acids and small peptides) In: Lim CF (ed) HPLC of small peptides. IRL Press, Oxford, pp 13–27Google Scholar
  32. Jouvet P, Rustin P, Felderhoff U et al (1998) Maple syrup urine disease metabolites induce apoptosis in neural cells without cytochrome c release or changes in mitochondrial membrane potential. Biochem Soc Trans 26:S341CrossRefPubMedGoogle Scholar
  33. Jouvet P, Kozma M, Mehmet H (2000a) Primary human fibroblasts from a maple syrup urine disease patient undergo apoptosis following exposure to physiological concentrations of branched chain amino acids. Ann N Y Acad Sci 926:116–121CrossRefPubMedGoogle Scholar
  34. Jouvet P, Rustin P, Taylor DL et al (2000b) Branched chain amino acids induce apoptosis in neural cells without mitochondrial membrane depolarization or cytochrome c release: implications for neurological impairment associated with maple syrup urine disease. Mol Biol Cell 11:1919–1932CrossRefPubMedPubMedCentralGoogle Scholar
  35. Klee D, Thimm E, Wittsack HJ et al (2013) Structural white matter changes in adolescents and young adults with maple syrup urine disease. J Inherit Metab Dis 36:945–953CrossRefPubMedGoogle Scholar
  36. Laske C, Zank M, Klein R et al (2008) Autoantibody reactivity in serum of patients with major depression, schizophrenia and healthy controls. Psychiatry Res 158:83–86CrossRefPubMedGoogle Scholar
  37. Mackenzie DY, Woolf LI (1959) Maple syrup urine disease; an inborn error of the metabolism of valine, leucine, and isoleucine associated with gross mental deficiency. Br Med J 1:90–91CrossRefPubMedPubMedCentralGoogle Scholar
  38. McLaughlin PM, Hinshaw J, Stringer AY (2013) Maple syrup urine disease (MSUD): a case with long-term follow-up after liver transplantation. Clin Neuropsychol 27:1199–1217CrossRefPubMedGoogle Scholar
  39. Menkes JH (1959) Maple syrup disease; isolation and identification of organic acids in the urine. Pediatrics 23:348–353PubMedGoogle Scholar
  40. Mescka CP, Wayhs CA, Vanzin CS et al (2013) Protein and lipid damage in maple syrup urine disease patients: l-carnitine effect. Int J Dev Neurosci Off J Int Soc Dev Neurosci 31:21–24CrossRefGoogle Scholar
  41. Mescka CP, Guerreiro G, Donida B et al (2015a) Investigation of inflammatory profile in MSUD patients: benefit of L-carnitine supplementation. Metab Brain Dis 30:1167–1174CrossRefPubMedGoogle Scholar
  42. Mescka CP, Guerreiro G, Hammerschmidt T et al (2015b) L-carnitine supplementation decreases DNA damage in treated MSUD patients. Mutat Res 775:43–47CrossRefPubMedGoogle Scholar
  43. Muelly ER, Moore GJ, Bunce SC et al (2013) Biochemical correlates of neuropsychiatric illness in maple syrup urine disease. J Clin Invest 123:1809–1820CrossRefPubMedPubMedCentralGoogle Scholar
  44. Palta P, Xue QL, Deal JA, Fried LP, Walston JD, Carlson MC (2015) Interleukin-6 and C-reactive protein levels and 9-year cognitive decline in community-dwelling older women: the women’s health and aging study II. J Gerontol A Biol Sci Med Sci 70:873–878CrossRefPubMedGoogle Scholar
  45. Popp J, Oikonomidi A, Tautvydaite D et al (2017) Markers of neuroinflammation associated with Alzheimer’s disease pathology in older adults. Brain Behav Immun 62:203–211CrossRefPubMedGoogle Scholar
  46. Quental S, Vilarinho L, Martins E et al (2010) Incidence of maple syrup urine disease in Portugal. Mol Genet Metab 100:385–387CrossRefPubMedGoogle Scholar
  47. Raison CL, Miller AH (2011) Is depression an inflammatory disorder? Curr Psychiatry Rep 13:467–475CrossRefPubMedPubMedCentralGoogle Scholar
  48. Rentzos M, Michalopoulou M, Nikolaou C et al (2005) The role of soluble intercellular adhesion molecules in neurodegenerative disorders. J Neurol Sci 228:129–135CrossRefPubMedGoogle Scholar
  49. Ribeiro CA, Sgaravatti AM, Rosa RB et al (2008) Inhibition of brain energy metabolism by the branched-chain amino acids accumulating in maple syrup urine disease. Neurochem Res 33:114–124CrossRefPubMedGoogle Scholar
  50. Ribeiro LR, Della-Pace ID, de Oliveira Ferreira AP et al (2013) Chronic administration of methylmalonate on young rats alters neuroinflammatory markers and spatial memory. Immunobiology 218:1175–1183CrossRefPubMedGoogle Scholar
  51. Rosa L, Scaini G, Furlanetto CB et al (2016) Administration of branched-chain amino acids alters the balance between pro-inflammatory and anti-inflammatory cytokines. Int J Dev Neurosci Off J Int Soc Dev Neurosci 48:24–30CrossRefGoogle Scholar
  52. Scaini G, de Rochi N, Jeremias IC et al (2012) Evaluation of acetylcholinesterase in an animal model of maple syrup urine disease. Mol Neurobiol 45:279–286CrossRefPubMedGoogle Scholar
  53. Scaini G, Comim CM, Oliveira GM et al (2013a) Chronic administration of branched-chain amino acids impairs spatial memory and increases brain-derived neurotrophic factor in a rat model. J Inherit Metab Dis 36:721–730CrossRefPubMedGoogle Scholar
  54. Scaini G, Mello-Santos LM, Furlanetto CB et al (2013b) Acute and chronic administration of the branched-chain amino acids decreases nerve growth factor in rat hippocampus. Mol Neurobiol 48:581–589CrossRefPubMedGoogle Scholar
  55. Scaini G, Morais MO, Furlanetto CB et al (2015) Acute Administration of Branched-Chain Amino Acids Increases the pro-BDNF/Total-BDNF ratio in the rat brain. Neurochem Res 40:885–893CrossRefPubMedGoogle Scholar
  56. Scaini G, Tonon T, de Souza CF et al (2016) Serum markers of neurodegeneration in maple syrup urine disease. Mol Neurobiol 54:5709–5719CrossRefPubMedGoogle Scholar
  57. Schmidt R, Schmidt H, Curb JD, Masaki K, White LR, Launer LJ (2002) Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia aging study. Ann Neurol 52:168–174CrossRefPubMedGoogle Scholar
  58. Schwarz MJ, Riedel M, Ackenheil M, Muller N (2000) Decreased levels of soluble intercellular adhesion molecule-1 (sICAM-1) in unmedicated and medicated schizophrenic patients. Biol Psychiatry 47:29–33CrossRefPubMedGoogle Scholar
  59. Seminotti B, Amaral AU, Ribeiro RT et al (2016) 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 53:6459–6475CrossRefPubMedGoogle Scholar
  60. Sgaravatti AM, Rosa RB, Schuck PF et al (2003) Inhibition of brain energy metabolism by the alpha-keto acids accumulating in maple syrup urine disease. Biochim Biophys Acta 1639:232–238CrossRefPubMedGoogle Scholar
  61. Shellmer DA, DeVito DA, Dew MA et al (2011) Cognitive and adaptive functioning after liver transplantation for maple syrup urine disease: a case series. Pediatr Transplant 15:58–64CrossRefPubMedGoogle Scholar
  62. Silberman J, Dancis J, Feigin I (1961) Neuropathological observations in maple syrup urine disease: branched-chain ketoaciduria. Arch Neurol 5:351–363CrossRefPubMedGoogle Scholar
  63. Simon E, Fingerhut R, Baumkotter J, Konstantopoulou V, Ratschmann R, Wendel U (2006) Maple syrup urine disease: favourable effect of early diagnosis by newborn screening on the neonatal course of the disease. J Inherit Metab Dis 29:532–537CrossRefPubMedGoogle Scholar
  64. Singh-Manoux A, Dugravot A, Brunner E et al (2014) Interleukin-6 and C-reactive protein as predictors of cognitive decline in late midlife. Neurology 83:486–493CrossRefPubMedPubMedCentralGoogle Scholar
  65. Sitta A, Ribas GS, Mescka CP, Barschak AG, Wajner M, Vargas CR (2014) Neurological damage in MSUD: the role of oxidative stress. Cell Mol Neurobiol 34:157–165CrossRefPubMedGoogle Scholar
  66. Strauss KA, Wardley B, Robinson D et al (2010) Classical maple syrup urine disease and brain development: principles of management and formula design. Mol Genet Metab 99:333–345CrossRefPubMedPubMedCentralGoogle Scholar
  67. Striz I, Brabcova E, Kolesar L, Sekerkova A (2014) Cytokine networking of innate immunity cells: a potential target of therapy. Clin Sci (Lond) 126(9):593–612Google Scholar
  68. Tavares RG, Santos CE, Tasca CI, Wajner M, Souza DO, Dutra-Filho CS (2000) Inhibition of glutamate uptake into synaptic vesicles of rat brain by the metabolites accumulating in maple syrup urine disease. J Neurol Sci 181:44–49CrossRefPubMedGoogle Scholar
  69. Treacy E, Clow CL, Reade TR, Chitayat D, Mamer OA, Scriver CR (1992) Maple syrup urine disease: interrelations between branched-chain amino-, oxo- and hydroxyacids; implications for treatment; associations with CNS dysmyelination. J Inherit Metab Dis 15:121–135CrossRefPubMedGoogle Scholar
  70. van Dooren FE, Schram MT, Schalkwijk CG et al (2016) Associations of low grade inflammation and endothelial dysfunction with depression - the Maastricht study. Brain Behav Immun 56:390–396CrossRefPubMedGoogle Scholar
  71. Victora CG, Huttly SR, Fuchs SC, Olinto MT (1997) The role of conceptual frameworks in epidemiological analysis: a hierarchical approach. Int J Epidemiol 26:224–227CrossRefPubMedGoogle Scholar
  72. Vogel KR, Arning E, Wasek BL, McPherson S, Bottiglieri T, Gibson KM (2014) Brain-blood amino acid correlates following protein restriction in murine maple syrup urine disease. Orphanet J Rare Dis 9:73CrossRefPubMedPubMedCentralGoogle Scholar
  73. Wajner M, Vargas CR (1999) Reduction of plasma concentrations of large neutral amino acids in patients with maple syrup urine disease during crises. Arch Dis Child 80:579CrossRefPubMedPubMedCentralGoogle Scholar
  74. Wajner M, Coelho DM, Barschak AG et al (2000) Reduction of large neutral amino acid concentrations in plasma and CSF of patients with maple syrup urine disease during crises. J Inherit Metab Dis 23:505–512CrossRefPubMedGoogle Scholar
  75. Wajner A, Burger C, Dutra-Filho CS, Wajner M, de Souza Wyse AT, Wannmacher CM (2007) Synaptic plasma membrane Na(+), K (+)-ATPase activity is significantly reduced by the alpha-keto acids accumulating in maple syrup urine disease in rat cerebral cortex. Metab Brain Dis 22:77–88CrossRefPubMedGoogle Scholar
  76. Yaffe K, Lindquist K, Penninx BW et al (2003) Inflammatory markers and cognition in well-functioning African-American and white elders. Neurology 61:76–80CrossRefPubMedGoogle Scholar
  77. Zameer A, Hoffman SA (2003) Increased ICAM-1 and VCAM-1 expression in the brains of autoimmune mice. J Neuroimmunol 142:67–74CrossRefPubMedGoogle Scholar
  78. Zielke HR, Zielke CL, Baab PJ, Collins RM (2002) Large neutral amino acids auto exchange when infused by microdialysis into the rat brain: implication for maple syrup urine disease and phenylketonuria. Neurochem Int 40:347–354CrossRefPubMedGoogle Scholar
  79. Zinnanti WJ, Lazovic J, Griffin K et al (2009) Dual mechanism of brain injury and novel treatment strategy in maple syrup urine disease. Brain J Neurol 132:903–918Google Scholar
  80. Zuliani G, Cavalieri M, Galvani M et al (2008) Markers of endothelial dysfunction in older subjects with late onset Alzheimer’s disease or vascular dementia. J Neurol Sci 272:164–170CrossRefPubMedGoogle Scholar

Copyright information

© SSIEM 2018

Authors and Affiliations

  • Giselli Scaini
    • 1
  • Tássia Tonon
    • 2
    • 3
  • Carolina F. Moura de Souza
    • 4
  • Patricia F. Schuck
    • 5
  • Gustavo C. Ferreira
    • 6
  • João Quevedo
    • 7
  • João Seda Neto
    • 8
  • Tatiana Amorim
    • 9
  • Jose S. CameloJr
    • 10
  • Ana Vitoria Barban Margutti
    • 10
  • Rafael Hencke Tresbach
    • 2
    • 11
  • Fernanda Sperb-Ludwig
    • 2
    • 11
  • Raquel Boy
    • 12
  • Paula F. V. de Medeiros
    • 13
  • Ida Vanessa D. Schwartz
    • 4
    • 11
  • Emilio Luiz Streck
    • 1
    Email author
  1. 1.Laboratório de Bioenergética e Núcleo de Excelência em Neurociências Aplicadas de Santa Catarina (NENASC), Programa de Pós-Graduação em Ciências da SaúdeUniversidade do Extremo Sul CatarinenseCriciúmaBrazil
  2. 2.BRAIN Laboratory (Basic Research and Advanced Investigations in Neurosciences)Hospital de Clínicas de Porto AlegrePorto AlegreBrazil
  3. 3.Post Graduation Program in Medicine: Medical SciencesUniversidade Federal do Rio Grande do SulPorto AlegreBrazil
  4. 4.Medical Genetics ServiceHospital de Clínicas de Porto AlegrePorto AlegreBrazil
  5. 5.Laboratório de Erros Inatos do Metabolismo, Programa de Pós-Graduação em Ciências da SaúdeUniversidade do Extremo Sul CatarinenseCriciúmaBrazil
  6. 6.Laboratório de Neuroquímica, Instituto de Biofísica Carlos ChagasUniversidade Federal do Rio de JaneiroRio de JaneiroBrazil
  7. 7.Laboratory of Neurosciences, Graduate Program in Health Sciences, Health Sciences UnitUniversity of Southern Santa Catarina (UNESC)CriciúmaBrazil
  8. 8.Hospital Sirio LibanesSão PauloBrazil
  9. 9.Associação de Pais e Amigos dos Excepcionais (APAE)SalvadorBrazil
  10. 10.Pediatrics Department, Ribeirão Preto Medical SchoolUniversity of São PauloRibeirão PretoBrazil
  11. 11.Programa de Pós-Graduação em Genética e Biologia MolecularUniversidade Federal do Rio Grande do Sul (UFRGS)Porto AlegreBrazil
  12. 12.Pediatrics Department, Hospital Universitário Pedro ErnestoUniversidade do Estado do Rio de JaneiroRio de JaneiroBrazil
  13. 13.Unidade Acadêmica de Medicina, Hospital Universitário Alcides Carneiro, Universidade Federal de Campina GrandeCampina GrandeBrazil

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