New therapeutic strategies for the treatment of metachromatic leukodystrophy



Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

Metachromatic leukodystrophy is an autosomal recessive hereditary neurodegenerative disease belonging to the group of lysosomal storage diseases, which is characterized by the damage of the myelin sheath that covers most of the nerve fibers of the central and peripheral nervous systems. Metachromatic leukodystrophy caused by the deficiency of arylsulfatase A (ARSA) lysosomal enzyme (OMIM 250100) or sphingolipid activator protein B (SapB or saposin B) (OMIM 249900). Clinical manifestations of metachromatic leukodystrophy are progressive motor and cognitive impairment in patients. ARSA and SapB protein deficiency are caused by the mutations in the ARSA and PSAP genes, respectively. The severity of clinical signs in metachromatic leukodystrophy is determined by the residual ARSA activity, depending on the type of mutation. There is currently no effective treatment for this disease. Clinical cases of bone marrow or cord blood transplantation have been described, however, the therapeutic effectiveness of these methods remains insufficient to prevent aggravation of neurological disorders in patients. Encouraging results were obtained using gene therapy for delivering the wild-type ARSA gene using vectors based on various serotypes of adeno-associated viruses, as well as using mesenchymal stem cells and combined gene-cell therapy. This review discusses therapeutic strategies for the treatment of metachromatic leukodystrophy, as well as diagnostic methods for this disease.

Full Text

Restricted Access

About the authors

A. A Shaimardanova

Kazan Federal University

Kazan, Russia

D. S Chulpanova

Kazan Federal University

Kazan, Russia

V. V Solovyeva

Kazan Federal University

Kazan, Russia

A. I Mullagulova

Kazan Federal University

Kazan, Russia

K. V Kitaeva

Kazan Federal University

Kazan, Russia

AA. A Rizvanov

Kazan Federal University

Email: rizvanov@gmail.com
Kazan, Russia

References

  1. Rosenberg J.B., Kaminsky S.M., Aubourg P. et al. Gene therapy for metachromatic leukodystrophy. J. Neurosci. Res. 2016; 94(11): 1169-79.
  2. Gomez-Ospina N., Adam M.P., Ardinger H.H. et al. Arylsulfatase A Deficiency. Seattle (WA): University of Washington; 1993, https://www.ncbi.nlm.nih.gov/books/NBK1130/.
  3. Simonaro C.M. Lysosomes, Lysosomal Storage Diseases, and Inflammation. J. Inborn Errors Metab. Screen. 2016; 4: 1-8.
  4. Wanner M.R., Karmazyn B., Fan R. Multidetector CT diagnosis of massive hemobilia due to gallbladder polyposis in a child with metachromatic leukodystrophy. Pediatr. Radiol. 2015; 45(13): 2017-20.
  5. Almarzooqi S., Quadri A., Albawardi A. Gallbladder Polyps in Metachromatic Leukodystrophy. Fetal Pediatr. Pathol. 2018; 37(2): 102-8.
  6. Kim J., Sun Z., Ezekian B. et al. Gallbladder abnormalities in children with metachromatic leukodystrophy. J. Surg. Res. 2017; 208: 187-91.
  7. McFadden K., Ranganathan S. Pathology of the gallbladder in a child with metachromatic leukodystrophy. Pediatr. Dev. Pathol. 2015; 18(3): 228-30.
  8. Kurian J.J., Jacob T.J.K. An unusual presentation of gall bladder papillomatosis in association with metachromatic leukodystrophy. BMJ Case Rep. 2018; 2018: bcr2017224162.
  9. Van der Knaap M.S., Bugiani M. Leukodystrophies: A proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathol. 2017; 134(3): 351-82.
  10. Hyde T.M., Ziegler J.C., Weinberger D.R. Psychiatric disturbances in metachromatic leukodystrophy. Insights into the neurobiology of psychosis. Arch. Neurol. 1992; 49(4): 401-6.
  11. Ali Mallick M.S., Godil A., Khetpal A. et al. Infantile metachromatic leukodystrophy in an 18 month old girl. J. Pak. Med. Assoc. 2016; 66(9): 1197-200.
  12. Liaw H.R., Lee H.F., Chi C.S. et al. Late infantile metachromatic leukodystrophy: Clinical manifestations of five Taiwanese patients and Genetic features in Asia. Orphanet J. Rare Dis. 2015; 10: 144.
  13. Barkovich A.J. Concepts of myelin and myelination in neuroradiology. AJNR. Am. J. Neuroradiol. 2000; 21(6): 1099-109.
  14. Thibert K.A., Raymond G.V., Tolar J. et al. Cerebral spinal fluid levels of cytokines are elevated in patients with metachromatic leukodystrophy. Sci. Rep. 2016; 6: 24579.
  15. Koski C.L., Vanguri P., Shin M.L. Activation of the alternative pathway of complement by human peripheral nerve myelin. J. Immunol. 1985; 134(3): 1810-14.
  16. Beerepoot S., Nierkens S., Boelens J.J. et al. Peripheral neuropathy in metachromatic leukodystrophy: Current status and future perspective. Orphanet J. Rare Dis. 2019; 14(1): 240.
  17. Doherty K., Frazier S.B., Clark M. et al. A closer look at ARSA activity in a patient with metachromatic leukodystrophy. Mol. Genet. Metab. Rep. 2019; 19: 100460.
  18. Fluharty A.L., Meek W.E., Kihara H. Pseudo arylsulfatase a deficiency: Evidence for a structurally altered enzyme. Biochem. Biophys. Res. Commun. 1983; 112(1): 191-7.
  19. Gieselmann V., Polten A., Kreysing J. et al. Arylsulfatase a pseudodeficiency: Loss of a polyadenylylation signal and N-glycosylation site. PNAS USA 1989; 86(23): 9436-40.
  20. Tang D., Fakiola M., Syn G. et al. Arylsulphatase A Pseudodeficiency (ARSA-PD), hypertension and chronic renal disease in Aboriginal Australians. Sci. Rep. 2018; 8(1): 10912.
  21. Cesani M., Lorioli L., Grossi S. et al. Mutation update of ARSA and PSAP genes causing metachromatic leukodystrophy. Hum. Mutat. 2016; 37(1): 16-27.
  22. Furst W., Sandhoff K. Activator proteins and topology of lysosomal sphingolipid catabolism. Biochim. Biophys. Acta 1992; 1126(1): 1-16.
  23. Lukatela G., Krauss N., Theis K. et al. Crystal structure of human arylsulfatase A: the aldehyde function and the metal ion at the active site suggest a novel mechanism for sulfate ester hydrolysis. Biochemistry 1998; 37(11): 3654-64.
  24. Sommerlade H.J., Selmer T., Ingendoh A. et al. Glycosylation and phosphorylation of arylsulfatase A.J. Biol. Chem. 1994; 269(33): 20977-81.
  25. Doerr J., Bockenhoff A., Ewald B. et al. Arylsulfatase A overexpressing human IPSC-derived neural cells reduce CNS sulfatide storage in a mouse model of metachromatic leukodystrophy. Mol. Ther. 2015; 23(9): 1519-31.
  26. Honke K., Hirahara Y., Dupree J. et al. Paranodal junction formation and spermatogenesis require sulfoglycolipids. PNAS USA 2002; 99(7): 4227-32.
  27. Takahashi T., Suzuki T. Role of sulfatide in normal and pathological cells and tissues. J. Lipid Res. 2012; 53(8): 1437-50.
  28. Saville J.T., Smith N.J., Fletcher J.M. et al. Quantification of plasma sulfatides by mass spectrometry: utility for metachromatic leukodystrophy. Anal. Chim. Acta 2017; 955: 79-85.
  29. Moyano A.L., Li G., Lopez-Rosas A. et al. Distribution of C16:0, C18:0, C24:1, and C24:0 sulfatides in central nervous system lipid rafts by quantitative ultra-high-pressure liquid chromatography tandem mass spectrometry. Anal. Biochem. 2014; 467: 31-9.
  30. Eckhardt M. The role and metabolism of sulfatide in the nervous system. Mol. Neurobiol. 2008; 37(2-3): 93-103.
  31. Lee-Vaupel M., Conzelmann E. A simple chromogenic assay for arylsulfatase A. Clin. Chim. Acta 1987; 164(2): 171-80.
  32. Henseler M., Klein A., Reber M. et al. Analysis of a splice-site mutation in the sap-precursor gene of a patient with metachromatic leukodystrophy. Am. J. Hum. Genet.1996; 58(1): 65-74.
  33. Spiegel R., Bach G., Sury V. et al. A mutation in the saposin A coding region of the prosaposin gene in an infant presenting as Krabbe disease: first report of saposin A deficiency in humans. Mol. Genet. Metab. 2005; 84(2): 160-6.
  34. Tamargo R.J., Velayati A., Goldin E. et al. The role of saposin C in gaucher disease. Mol. Genet. Metab. 2012; 106(3): 257-63.
  35. Brown T.M., Martin S., Fehnel S.E. et al. Development of the impact of juvenile metachromatic leukodystrophy on physical activities scale. J. Patient. Rep. Outcomes 2017; 2(1): 15.
  36. Shahzad M.A., Khaliq S., Amar A. et al. Metachromatic leukodystrophy (MLD): a pakistani family with novel ARSA Gene Mutation. J. Mol. Neurosci. 2017; 63(1): 84-90
  37. Alam S.T., Akhter S., Rahman M.M. et al. A rare case of metachromatic leukodystrophy confirmed by arylsulfatase A. Mymensingh Med. J. 2015; 24(4): 864-7.
  38. van Rappard D.F., de Vries A.L.C., Oostrom K.J. et al. Slowly progressive psychiatric symptoms: think metachromatic leukodystrophy. J. Am. Acad. Child. Adolesc. Psychiatry 2018; 57(2): 74-6.
  39. Kumperscak H.G., Paschke E., Gradisnik P. et al. Adult metachromatic leukodystrophy: disorganized schizophrenia-like symptoms and postpartum depression in 2 sisters. J. Psychiatry Neurosci. 2005; 30(1): 33-6.
  40. Kohlmann R., Barenberg K., Anders A. et al. Acetobacter indone-siensis bacteremia in child with metachromatic leukodystrophy. Emerg. Infect. Dis. 2016; 22(9): 1681-3.
  41. Black D.N., Taber K.H., Hurley R.A. Metachromatic leukodystrophy: a model for the study of psychosis. J. Neuropsychiatry. Clin. Neurosci. 2003; 15(3): 289-93.
  42. Espejo L.M., de la Espriella R., Hernandez J.F. [Metachromatic Leukodystrophy. Case presentation]. Rev. Colomb. Psiquiatr. 2017; 46(1): 44-9.
  43. Bostantjopoulou S., Katsarou Z., Michelakaki H. et al. Seizures as a presenting feature of late onset metachromatic leukodystrophy. Acta Neurol. Scand. 2000; 102(3): 192-5.
  44. Stoeck K., Psychogios M.N., Ohlenbusch A. et al. Late-onset metachromatic leukodystrophy with early onset dementia associated with a novel missense mutation in the arylsulfatase A Gene. J. Alzheimers Dis. 2016; 51(3): 683-7.
  45. Kohler W., Curiel J., Vanderver A. Adulthood leukodystrophies. Nat. Rev. Neurol. 2018; 14(2): 94-105.
  46. Elgun S., Waibel J., Kehrer C. et al. Phenotypic variation between siblings with metachromatic leukodystrophy. Orphanet J. Rare Dis. 2019; 14(1): 136.
  47. Velakoulis D., Ting A., Winton-Brown T. et al. Metachromatic leukodystrophy presenting as bipolar disorder. Aust. N. Z.J. Psychiatry 2014; 48(12): 1171-2.
  48. Sessa M., Lorioli L., Fumagalli F. et al. Lentiviral haemopoietic stemcell gene therapy in early-onset metachromatic leukodystrophy: an ad-hoc analysis of a non-randomised, open-label, phase 1/2 trial. Lancet 2016; 388(10043): 476-87.
  49. Rip J.W., Gordon B.A. A simple spectrophotometric enzyme assay with absolute specificity for arylsulfatase A. Clin. Biochem. 1998; 31(1): 29-31.
  50. Spacil Z., Babu Kumar A., Liao H.C. et al. Sulfatide Analysis by Mass Spectrometry for Screening of Metachromatic Leukodystrophy in Dried Blood and Urine Samples. Clin. Chem. 2016; 62(1): 279-86
  51. Eichler F., Grodd W., Grant E. et al. Metachromatic leukodystrophy: a scoring system for brain MR imaging observations. Am. J. Neuroradiol. 2009; 30(10): 1893-7.
  52. Barkhof F., Scheltens P. Imaging of white matter lesions. Cerebrovasc. Dis. 2002; 13 Suppl 2: 21-30.
  53. Singh P., Kaur R. Diffusion-weighted magnetic resonance imaging findings in a case of metachromatic leukodystrophy. J. Pediatr. Neurosci. 2016; 11(2): 131-3.
  54. Chauhan N.S., Sharma M., Bhardwaj A. Classical case of late-infantile form of metachromatic leukodystrophy. J. Neurosci. Rural Pract. 2016; 7(3): 473-5.
  55. Groeschel S., Kehrer C., Engel C. et al. Metachromatic leukodystrophy: natural course of cerebral MRI changes in relation to clinical course. J. Inherit. Metab. Dis. 2011; 34(5): 1095-102.
  56. Kihara H., Ho C.K., Fluharty A.L. et al. Prenatal diagnosis of metachromatic leukodystrophy in a family with pseudo arylsulfatase A deficiency by the cerebroside sulfate loading test. Pediatr. Res. 1980; 14(3): 224-7.
  57. Verma J., Bijarnia-Mahay S., Verma I.C. Prenatal diagnosis of lysosomal storage disorders using chorionic Villi. Methods Mol. Biol. 2017; 1594: 265-91.
  58. Verma J., Thomas D.C., Sharma S. et al. Inherited metabolic disorders: prenatal diagnosis of lysosomal storage disorders. Prenat. Diagn. 2015; 35(11): 1137-47
  59. Bellettato C.M., Scarpa M. Possible strategies to cross the blood-brain barrier. Ital. J. Pediatr. 2018; 44(2): 131.
  60. Dong X. Current strategies for brain drug delivery. Theranostics 2018; 8(6): 1481-93.
  61. Penati R., Fumagalli F., Calbi V. et al. Gene therapy for lysosomal storage disorders: recent advances for metachromatic leukodystrophy and mucopolysaccaridosis I.J. Inherit. Metab. Dis. 2017; 40(4): 543-54.
  62. Kidd D., Nelson J., Jones F. et al. Long-term stabilization after bone marrow transplantation in juvenile metachromatic leukodystrophy. Arch. Neurol. 1998; 55(1): 98-9.
  63. Groeschel S., Kuhl J.S., Bley A.E. et al. Long-term outcome of allogeneic hematopoietic stem cell transplantation in patients with juvenile metachromatic leukodystrophy compared with nontransplanted control patients. JAMA Neurol. 2016; 73(9): 1133-40.
  64. Stein A., Stroobants S., Gieselmann V. et al. Anti-inflammatory therapy with simvastatin improves neuroinflammation and CNS function in a mouse model of metachromatic leukodystrophy. Mol. Ther. 2015; 23(7): 1160-8.
  65. Bredius R.G., Laan L.A., Lankester A.C. et al. Early marrow transplantation in a pre-symptomatic neonate with late infantile metachromatic leukodystrophy does not halt disease progression. Bone Marrow Transplant. 2007; 39(5): 309-10.
  66. Boucher A.A., Miller W., Shanley R. et al. Long-term outcomes after allogeneic hematopoietic stem cell transplantation for metachromatic leukodystrophy: the largest single-institution cohort report. Orphanet J. Rare Dis. 2015; 10: 94.
  67. Solders M., Martin D.A., Andersson C. et al. Hematopoietic SCT: a useful treatment for late metachromatic leukodystrophy. Bone Marrow Transplant. 2014; 49(8): 1046-51.
  68. van Rappard D.F., Boelens J.J., van Egmond M.E. et al. Efficacy of hematopoietic cell transplantation in metachromatic leukodystrophy: the Dutch experience. Blood 2016; 127(24): 3098-101.
  69. Chen X., Gill D., Shaw P. et al. Outcome of early juvenile onset metachromatic leukodystrophy after unrelated cord blood transplantation: a case series and review of the literature. J. Child Neurol. 2016; 31(3): 338-44.
  70. Galieva L.R., Mukhamedshina Y.O., Arkhipova S.S. et al. Human umbilical cord blood cell transplantation in neuroregenerative strategies. Front. Pharmacol. 2017; 8: 628.
  71. Martin H.R., Poe M.D., Provenzale J.M. et al. Neurodevelopmental outcomes of umbilical cord blood transplantation in metachromatic leukodystrophy. Biol. Blood Marrow Transplant. 2013; 19(4): 616-24.
  72. Goncalves K.A., Li S., Brooks M. et al. Mgta-456, a First-in-class cell therapy with high doses of CD34+CD90+ Cells, enhances speed and level of human microglia engraftment in the brains of NSG Mice. Biol. Blood Marrow Transplant. 2019; 25: 92-3.
  73. Koc O.N., Peters C., Aubourg P. et al. Bone marrow-derived mesenchymal stem cells remain host-derived despite successful hematopoietic engraftment after allogeneic transplantation in patients with lysosomal and peroxisomal storage diseases. Exp. Hematol. 1999; 27(11): 1675-81.
  74. Azizi S.A., Stokes D., Augelli B.J. et al. Engraftment and migration of human bone marrow stromal cells implanted in the brains of albino rats--similarities to astrocyte grafts. PNAS USA 1998; 95(7): 3908-13.
  75. Koc O.N., Day J., Nieder M. et al. Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant. 2002; 30(4): 215-22.
  76. Meuleman N., Vanhaelen G., Tondreau T. et al. Reduced intensity conditioning haematopoietic stem cell transplantation with mesenchymal stromal cells infusion for the treatment of metachromatic leukodystrophy: a case report. Haematologica 2008; 93(1): 11-3.
  77. Matzner U., Herbst E., Hedayati K.K. et al. Enzyme replacement improves nervous system pathology and function in a mouse model for metachromatic leukodystrophy. Hum. Mol. Genet. 2005; 14(9): 1139-52.
  78. Stroobants S., Gerlach D., Matthes F. et al. Intracerebroventricular enzyme infusion corrects central nervous system pathology and dysfunction in a mouse model of metachromatic leukodystrophy. Hum. Mol. Genet. 2011; 20(14): 2760-9.
  79. Matthes F., Stroobants S., Gerlach D. et al. Efficacy of enzyme replacement therapy in an aggravated mouse model of metachromatic leukodystrophy declines with age. Hum. Mol. Genet. 2012; 21(11): 2599-609.
  80. Hui E.K.W., Lu J.Z., Boado R.J. et al. Preclinical studies of a brain penetrating IgG Trojan horse-arylsulfatase fusion protein in the metachromatic leukodystrophy mouse. Mol. Genet. Metab. 2019; 126: 177.
  81. Boado R.J., Lu J.Z., Hui E.K. et al. Pharmacokinetics and brain uptake in the rhesus monkey of a fusion protein of arylsulfatase a and a monoclonal antibody against the human insulin receptor. Biotechnol. Bioeng. 2013; 110(5): 1456-65.
  82. Taymans J.M., Vandenberghe L.H., Haute C.V. et al. Comparative analysis of adeno-associated viral vector serotypes 1,2, 5, 7, and 8 in mouse brain. Hum. Gene Ther. 2007; 18(3): 195-206.
  83. Sevin C., Benraiss A., Van Dam D. et al. Intracerebral adeno-associated virus-mediated gene transfer in rapidly progressive forms of metachromatic leukodystrophy. Hum. Mol. Genet. 2006; 15(1): 53-64.
  84. Miyake N., Miyake K., Asakawa N. et al. Long-term correction of biochemical and neurological abnormalities in MLD mice model by neonatal systemic injection of an AAV serotype 9 vector. Gene Ther. 2014; 21(4): 427-33.
  85. Kurai T., Hisayasu S., Kitagawa R. et al. AAV1 mediated co-expression of formylglycine-generating enzyme and arylsulfatase a efficiently corrects sulfatide storage in a mouse model of metachromatic leukodystrophy. Mol. Ther. 2007; 15(1): 38-43.
  86. Cearley C.N., Wolfe J.H. Transduction characteristics of adeno-associated virus vectors expressing cap serotypes 7, 8, 9, and Rh10 in the mouse brain. Mol. Ther. 2006; 13(3): 528-37.
  87. Piguet F., Sondhi D., Piraud M. et al. Correction of brain oligodendrocytes by AAVrh.10 intracerebral gene therapy in metachromatic leukodystrophy mice. Hum. Gene Ther. 2012; 23(8): 903-14.
  88. Rosenberg J.B., Sondhi D., Rubin D.G. et al. Comparative efficacy and safety of multiple routes of direct CNS administration of adeno-associated virus gene transfer vector serotype rh.10 expressing the human arylsulfatase A cDNA to nonhuman primates. Hum. Gene Ther. Clin. Dev. 2014; 25(3): 164-77.
  89. Zerah M., Piguet F., Colle M.A. et al. Intracerebral gene therapy using AAVrh.10-hARSA recombinant vector to treat patients with early-onset forms of metachromatic leukodystrophy: preclinical feasibility and safety assessments in nonhuman primates. Hum. Gene Ther. Clin. Dev. 2015; 26(2): 113-24
  90. Sevin C., Roujeau T., Cartier N. et al. Intracerebral gene therapy in children with metachromatic leukodystrophy: Results of a phase I/II trial. Mol. Genet. Metab. 2018; 123(2): 129.
  91. Matzner U., Hartmann D., Lullmann-Rauch R. et al. Bone marrow stem cell-based gene transfer in a mouse model for metachromatic leukodystrophy: effects on visceral and nervous system disease manifestations. Gene Ther. 2002; 9(1): 53-63.
  92. Biffi A., Capotondo A., Fasano S. et al. Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. J. Clin. Invest. 2006; 116(11): 3070-82.
  93. Biffi A., Montini E., Lorioli L. et al. Lentiviral hematopoietic stem cell gene therapy benefits metachromatic leukodystrophy. Science 2013; 341(6148): 1233158.
  94. Meneghini V., Frati G., Sala D. et al. Generation of human induced pluripotent stem cell-derived bona fide neural stem cells for ex vivo gene therapy of metachromatic leukodystrophy. Stem Cells Transl. Med. 2017; 6(2): 352-68.
  95. Ashrafi M.R., Amanat M., Garshasbi M. et al. An update on clinical, pathological, diagnostic, and therapeutic perspectives of childhood leukodystrophies. Expert Rev. Neurother. 2020; 20(1): 65-84.
  96. Assadi M., Wang D.J., Anderson K. et al. Vitamin k antagonist warfarin for palliative treatment of metachromatic leukodystrophy, a compassionate study of four subjects. J. Cent. Nerv. Syst. Dis. 2012; 4: 73-9.
  97. Sundaram K.S., Lev M. Warfarin administration reduces synthesis of sulfatides and other sphingolipids in mouse brain. J. Lipid Res. 1988; 29(11): 1475-9.
  98. Roy A., Pahan K. Prospects of statins in parkinson disease. Neuroscientist 2011; 17(3): 244-55.
  99. Orange J.S., Hossny E.M., Weiler C.R. et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J. Allergy Clin. Immunol. 2006; 117(4): 525-53.
  100. Roi D., Mankad K., Kaliakatsos M. et al. Thickening of the optic nerves in metachromatic leucodystrophy: A new MRI finding. Neuroradiol. J. 2016; 29(2): 134-6.
  101. Haberlandt E., Scholl-Burgi S., Neuberger J. et al. Peripheral neuropathy as the sole initial finding in three children with infantile metachromatic leukodystrophy. Eur. J. Paediatr. Neurol. 2009; 13(3): 257-60.
  102. Gonorazky H.D., Amburgey K., Yoon G. et al. Subacute demyelinating peripheral neuropathy as a novel presentation of late infantile metachromatic leukodystrophy. Muscle Nerve 2017; 56(5): 41-4.
  103. Nevo Y., Pestronk A., Lopate G. et al. Neuropathy of metachromatic leukodystrophy: improvement with immunomodulation. Pediatr. Neurol. 1996; 15(3): 237-9.
  104. Dubey R., Chakrabarty B., Gulati S. et al. M. Leukodystrophy presenting as acute-onset polyradiculoneuropathy. Pediatr. Neurol. 2014; 50(6): 616-8.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2020 Eco-Vector


СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: 

This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies