Oxidative stress and inflammation in mucopolysaccharidosis type IVA patients treated with enzyme replacement therapy.

Mucopolysaccharidosis type IVA (MPS IVA) is an inborn error of glycosaminoglycan (GAG) catabolism due to the deficient activity of N-acetylgalactosamine-6-sulfate sulfatase that leads to accumulation of the keratan sulfate and chondroitin 6-sulfate in body fluids and in lysosomes. The pathophysiology of this lysosomal storage disorder is not completely understood. The aim of this study was to investigate oxidative stress parameters, pro-inflammatory cytokine and GAG levels in MPS IVA patients. We analyzed urine and blood samples from patients under ERT (n=17) and healthy age-matched controls (n=10-15). Patients presented a reduction of antioxidant defense levels, assessed by a decrease in glutathione content and by an increase in superoxide dismutase activity in erythrocytes. Concerning lipid and protein damage, it was verified increased urine isoprostanes and di-tyrosine levels and decreased plasma sulfhydryl groups in MPS IVA patients compared to controls. MPS IVA patients showed higher DNA damage than control group and this damage had an oxidative origin in both pyrimidine and purine bases. Interleukin 6 was increased in patients and presented an inverse correlation with GSH levels, showing a possible link between inflammation and oxidative stress in MPS IVA disease. The data presented suggest that pro-inflammatory and pro-oxidant states occur in MPS IVA patients even under ERT. Taking these results into account, supplementation of antioxidants in combination with ERT can be a tentative therapeutic approach with the purpose of improving the patient's quality of life. To the best of our knowledge, this is the first study relating MPS IVA patients with oxidative stress.

[1]  L. Nitsch,et al.  Intracranial gene delivery of LV‐NAGLU vector corrects neuropathology in murine MPS IIIB , 2009, American journal of medical genetics. Part A.

[2]  M. Dizdaroglu,et al.  Substrate specificity of the Escherichia coli endonuclease III: excision of thymine- and cytosine-derived lesions in DNA produced by radiation-generated free radicals. , 1993, Biochemistry.

[3]  G. Diaz,et al.  Profiling of oxidative stress in patients with inborn errors of metabolism. , 2009, Molecular genetics and metabolism.

[4]  W. Markesbery,et al.  Changes in thiol content and expression of glutathione redox system genes in the hippocampus and cerebellum in Alzheimer's disease , 2001, Neuroscience Letters.

[5]  A. Sitta,et al.  Oxidative stress in patients with mucopolysaccharidosis type II before and during enzyme replacement therapy. , 2011, Molecular genetics and metabolism.

[6]  V. G. Pereira,et al.  Mutational and oxidative stress analysis in patients with mucopolysaccharidosis type I undergoing enzyme replacement therapy. , 2008, Clinica chimica acta; international journal of clinical chemistry.

[7]  A. Collins,et al.  DNA Oxidation, Antioxidant Effects, and DNA Repair Measured with the Comet Assay , 2010 .

[8]  C. Vargas,et al.  Glycosaminoglycans can be associated with oxidative damage in mucopolysaccharidosis II patients submitted to enzyme replacement therapy , 2014, Cell Biology and Toxicology.

[9]  Wei-Guo Zhu,et al.  The comet assay: a sensitive method for detecting DNA damage in individual cells. , 2009, Methods.

[10]  P. Meikle,et al.  Prevalence of lysosomal storage disorders. , 1999, JAMA.

[11]  J. Wraith,et al.  Mucopolysaccharidosis type IVA (morquio syndrome): A clinical review , 1996, Journal of Inherited Metabolic Disease.

[12]  M. Evans,et al.  Oxidative DNA damage: mechanisms, mutation, and disease , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[13]  J. Eaton,et al.  Lysosomal enzymes promote mitochondrial oxidant production, cytochrome c release and apoptosis. , 2003, European journal of biochemistry.

[14]  J. Winther,et al.  Quantifying the global cellular thiol–disulfide status , 2009, Proceedings of the National Academy of Sciences.

[15]  T. Taketani,et al.  Development and Testing of New Screening Method for Keratan Sulfate in Mucopolysaccharidosis IVA , 2004, Pediatric Research.

[16]  B. Halliwell,et al.  Free radicals in biology and medicine , 1985 .

[17]  A. Sitta,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 , 2010, International Journal of Developmental Neuroscience.

[18]  Anthony H. Futerman,et al.  The cell biology of lysosomal storage disorders , 2004, Nature Reviews Molecular Cell Biology.

[19]  C. Scriver,et al.  The Metabolic and Molecular Bases of Inherited Disease, 8th Edition 2001 , 2001, Journal of Inherited Metabolic Disease.

[20]  R. Wevers,et al.  Measuring urinary glycosaminoglycans in the presence of protein: an improved screening procedure for mucopolysaccharidoses based on dimethylmethylene blue. , 1992, Clinical chemistry.

[21]  T. Fleming,et al.  Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study , 2014, Journal of Inherited Metabolic Disease.

[22]  N. Di Ferrante,et al.  N-acetylgalactosamine-6-sulfate sulfatase in man. Absence of the enzyme in Morquio disease. , 1976, The Journal of clinical investigation.

[23]  J. Eaton,et al.  Lysosomal involvement in apoptosis , 2001 .

[24]  Y. Suzuki,et al.  Mucopolysaccharidosis type IVA (Morquio A disease): clinical review and current treatment. , 2011, Current pharmaceutical biotechnology.

[25]  Carmela Di Domenico,et al.  Mucopolysaccharidosis IIIB: Oxidative damage and cytotoxic cell involvement in the neuronal pathogenesis , 2009, Brain Research.

[26]  R. Browne,et al.  Reduced glutathione and glutathione disulfide. , 1998, Methods in molecular biology.

[27]  U. Brunk,et al.  Oxidative stress, accumulation of biological 'garbage', and aging. , 2006, Antioxidants & redox signaling.

[28]  T. Oron,et al.  Morquio A Syndrome-Associated Mutations: A Review of Alterations in the GALNS Gene and a New Locus-Specific Database , 2014, Human mutation.

[29]  B. Kirschbaum.  Correlative studies of urine fluorescence and free radical indicators. , 2002, Clinical nephrology.

[30]  S. Tomatsu,et al.  Growth charts for patients affected with Morquio A disease , 2008, American journal of medical genetics. Part A.

[31]  R. Roesler,et al.  Alterations in Oxidative Markers in the Cerebellum and Peripheral Organs in MPS I Mice , 2009, Cellular and Molecular Neurobiology.

[32]  A. Sitta,et al.  l-Carnitine Blood Levels and Oxidative Stress in Treated Phenylketonuric Patients , 2009, Cellular and Molecular Neurobiology.

[33]  C. Vargas,et al.  In vitro effect of genistein on DNA damage in leukocytes from mucopolysaccharidosis IVA patients. , 2014, Molecular genetics and metabolism.

[34]  C. Vargas,et al.  DNA damage in leukocytes from pretreatment mucopolysaccharidosis type II patients; protective effect of enzyme replacement therapy. , 2011, Mutation research.

[35]  Kelly Lau,et al.  Biomarker analysis of Morquio syndrome: identification of disease state and drug responsive markers , 2011, Orphanet journal of rare diseases.

[36]  A. Sitta,et al.  Evidence that oxidative stress is increased in plasma from patients with maple syrup urine disease , 2006, Metabolic Brain Disease.

[37]  G. Mitchell,et al.  Mucopolysaccharidosis IVA: correlation between genotype, phenotype and keratan sulfate levels. , 2013, Molecular genetics and metabolism.

[38]  Raymond R Tice,et al.  Fourth International Workgroup on Genotoxicity testing: results of the in vivo Comet assay workgroup. , 2007, Mutation research.

[39]  M. Haskins,et al.  Mechanism of glycosaminoglycan-mediated bone and joint disease: implications for the mucopolysaccharidoses and other connective tissue diseases. , 2008, The American journal of pathology.

[40]  M. Pap,et al.  Involvement of Proteolytic Activation of Protein Kinase R in the Apoptosis of PC12 Pheochromocytoma Cells , 2008, Cellular and Molecular Neurobiology.

[41]  L. Vargas-Roig,et al.  A Silver Staining Method for Single-cell Gel Assay , 2001, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[42]  O. H. Lowry,et al.  Protein measurement with the Folin phenol reagent. , 1951, The Journal of biological chemistry.

[43]  C. Vargas,et al.  Evidence that oxidative stress is increased in patients with X-linked adrenoleukodystrophy. , 2004, Biochimica et biophysica acta.

[44]  S. Ryazantsev,et al.  Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[45]  I. Papassotiriou,et al.  Low total antioxidant status is implicated with high 8-hydroxy-2-deoxyguanosine serum concentrations in phenylketonuria. , 2005, Clinical biochemistry.

[46]  B. Halliwell.  Reactive Species and Antioxidants. Redox Biology Is a Fundamental Theme of Aerobic Life , 2006, Plant Physiology.

[47]  E. Bourdon,et al.  The importance of proteins in defense against oxidation. , 2001, Antioxidants & redox signaling.

[48]  S. Castaldo,et al.  Cytokines, neurotrophins, and oxidative stress in brain disease from mucopolysaccharidosis IIIB , 2007, Journal of neuroscience research.

[49]  R. Tice,et al.  Single cell gel/comet assay: Guidelines for in vitro and in vivo genetic toxicology testing , 2000, Environmental and molecular mutagenesis.

[50]  J. A. Thomas,et al.  Protein sulfhydryls and their role in the antioxidant function of protein S-thiolation. , 1995, Archives of biochemistry and biophysics.

[51]  D. Scherman,et al.  Neuroinflammatory and oxidative stress phenomena in MPS IIIA mouse model: the positive effect of long-term aspirin treatment. , 2011, Molecular genetics and metabolism.

[52]  C. Vargas,et al.  Globotriaosylceramide is correlated with oxidative stress and inflammation in Fabry patients treated with enzyme replacement therapy. , 2012, Biochimica et biophysica acta.

[53]  H. Esterbauer,et al.  Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. , 1991, Free radical biology & medicine.

[54]  A. Sitta,et al.  Induction of lipid peroxidation and decrease of antioxidant defenses in symptomatic and asymptomatic patients with X-linked adrenoleukodystrophy , 2007, International Journal of Developmental Neuroscience.

[55]  R. Levine.  Carbonyl modified proteins in cellular regulation, aging, and disease. , 2002, Free radical biology & medicine.

[56]  R. Tice,et al.  A simple technique for quantitation of low levels of DNA damage in individual cells. , 1988, Experimental cell research.

[57]  S. Tomatsu,et al.  International Morquio A Registry: Clinical manifestation and natural course of Morquio A disease , 2007, Journal of Inherited Metabolic Disease.