Annals of the Russian academy of medical sciencesAnnals of the Russian academy of medical sciencesВестник Российской академии медицинских наук0869-60472414-3545"Paediatrician" Publishers LLC48910.15690/vramn.v70.i4.1407PEDIATRICS: CURRENT ISSUESАКТУАЛЬНЫЕ ВОПРОСЫ ПЕДИАТРИИSanfilippo SyndromeСиндром СанфилиппоOsipovaL. A.ОсиповаЛилия Александровна
Russian Federation

Moscow

заочный аспирант, врач-невролог консультативного отделения КДЦ,

119991, Москва, Ломоносовский пр-т, д. 2, стр. 1

osipova_la@nczd.ruKuzenkovaL. M.КузенковаЛюдмила Михайловна
Russian Federation

Moscow

доктор медицинских наук, профессор, руководитель отделения психоневрологии и психосоматической патологии,

119991, Москва, Ломоносовский пр-т, д. 2, стр. 1

kuzenkova@nczd.ruNamazova-BaranovaL. S.Намазова-БарановаЛейла Сеймуровна
Russian Federation

Moscow

доктор медицинских наук, профессор, член-корреспондент РАН, директор Научно-исследовательского института педиатрии,

119991, Москва, Ломоносовский пр-т, д. 2, стр. 1

namazova@nczd.ruGevorkyanA. K.ГеворкянАнаит Казаровна
Russian Federation

Moscow

кандидат медицинских наук, главный врач КДЦ,

119991, Москва, Ломоносовский пр-т, д. 2, стр. 1

gevorkyan@nczd.ruPodkletnovaT. V.ПодклетноваТатьяна Владимировна
Russian Federation

Moscow

кандидат медицинских наук, научный сотрудник отделения психоневрологиии психосоматической патологии,

119991, Москва, Ломоносовский пр-т, д. 2, стр. 1

tvp80@mail.ruVashakmadzeN. D.ВашакмадзеНато Джумберовна
Russian Federation

Moscow

кандидат медицинских наук, заведующая отделением восстановительного лечения детей с заболеваниями сердечно-сосудистой системы НИИ ППиВЛ,

119991, Москва, Ломоносовский пр-т, д. 2, стр. 1

vashakmadze@nczd.ruScientific Centre of Children’s HealthНаучный центр здоровья детейSechenov First Moscow State Medical UniversityПервый Московский государственный медицинский университет им. И.М. СеченоваN.I. Pirogov Russian National Medical Research UniversityРоссийский национальный исследовательский медицинский университет им. Н.И. Пирогова290920157044194272809201528092015Copyright ©; 2015, "Paediatrician" Publishers LLCCopyright ©; 2015, Издательство "Педиатръ"2015"Paediatrician" Publishers LLCИздательство "Педиатръ"https://vestnikramn.spr-journal.ru/jour/about/submissionshttps://vestnikramn.spr-journal.ru/jour/article/view/489

Sanfilippo syndrome (mucopolysaccharidosis type III) is a lysosomal disorder caused by a defect in the catabolism of heparan sulfate. Mucopolysaccharidosis type III is the most common type of all mucopolysaccharidoses. The pathogenic basis of the disease consists of the storage of undegraded substrate in the central nervous system. Progressive cognitive decline resulting in dementia and behavioural abnormalities are the main clinical characteristics of Sanfilippo syndrome. Mucopolysaccharidosis type III may be misdiagnosed as other forms of developmental delay, attention deficit/hyperactivity disorder and autistic spectrum disorders because of lack of somatic symptoms, presence of mild and atypical forms of the disease. Patients with Sanfilippo syndrome may have comparatively low urinary glycosaminoglycans levels resulting in false negative urinary assay. Definitive diagnosis is made by enzyme assay on leucocytes and cultured fibroblasts. There is currently no effective treatment of mucopolysaccharidosis type III, though ongoing researches of gene, substrate reduction and intrathecal enzyme replacement therapies expect getting curative method to alter devasting damage of central nervous system in near future.

Синдром Санфилиппо (мукополисахаридоз III типа) — заболевание, относящееся к группе лизосомных болезней накопления, обусловленное нарушением катаболизма гепарансульфата. Мукополисахаридоз III типа — наиболее распространенный среди всех мукополисахаридозов. Патогенетической основой синдрома является накопление продуктов аномального метаболизма в центральной нервной системе. Ведущие клинические признаки заболевания заключаются в нарушении поведения и прогрессирующем регрессе психического развития с исходом в деменцию. Отсутствие выраженных соматических проявлений, наличие легких и атипичных форм течения приводят к трудностям дифференциальной диагностики с другими формами задержки речевого и психического развития, синдромом дефицита внимания и гиперактивности и заболеваниями из группы аутистического спектра. Для некоторых пациентов с синдром Санфилиппо характерны относительно низкие значения экскретируемых гликозаминогликанов, в связи с чем возможно получение ложноотрицательных результатов исследования мочи на гиперэкскрецию данных метаболитов. Точный диагноз устанавливают при анализе содержания фермента в культуре кожных фибробластов или лейкоцитах крови. Эффективного лечения мукополисахаридоза III типа в настоящее время не существует, однако продолжающиеся исследования генной, субстратредуцирующей и интратекальной ферментозаместительной терапии позволяют надеяться на возможность получения в ближайшем будущем метода, способного предотвратить прогрессирующее поражения центральной нервной системы.

Sanfilippo syndromeneurodegenerative diseasebehavioral and sleep disturbancesmultidisciplinary surveillanceсиндром Санфилипподегенеративное поражение центральной нервной системынарушения поведения и снамультидисциплинарное наблюдение1. Neufeld E., Muenzer J. The mucopolysaccharidosis. In: Scriver C.R., Beaudet A.L., Sly W.S., Valle D. The Metabolic and Molecular Basis of Inherited Disease. New York: McGraw-Hill. 2001. Р. 3421–3452.2. Barranger J.A., Cabrera-Salazar M.A. Lysosomal Storage Disorders. New York: Springer. 2007. 564 p.3. Lyon G., Kolodny E.H., Pastores G.M. Neurology of Hereditary Metabolic Disease of Children. NY: McGraw-Hill. 2006. 542 p.4. Valstar M.J., Ruijter G.J., van Diggelen O.P., Poorthuis B.J., Wijburg F.A. Sanfilippo syndrome: a mini review. J. Inherit. Metab. Dis. 2008; 31 (2): 240–252.5. Buhrman D., Thakkar K., Poe M., Escolar M.L. Natural history of Sanfilippo syndrome type A. J. Inherit. Metab. Dis. 2014; 37 (3): 431–437.6. Cross E.M., Grant S., Jones S., Bigger B.W., Wraith J.E., Mahon L.V., Lomax M., Hare D.J. An investigation of the middle and late behavioural phenotypes of Mucopolysaccharidosis Type III. J. Neurodev. Disord. 2014; 6 (1): 46.7. Baehner F., Schmiedeskamp C., Krummenauer F., Miebach E., Bajbouj M., Whybra C., Kohlschütter A., Kampmann C., Beck M. Cumulative incidence rates of the mucopolysaccharidoses in Germany. J. Inherit. Metab. Dis. 2005; 28 (6): 1011–1017.8. Temin P.A., Kazantseva L.Z. Nasledstvennye narusheniya nervno-psikhicheskogo razvitiya detei [Hereditary Disorders of Mental Development in Children]. Moscow, Meditsina. 2001. 432 p.9. Arfi A., Richard M., Scherman D. Innovative Therapeutic Approaches for Improving Patient Life Condition with a Neurological Lysosomal Disease. 2012. Available at: http://www.intechopen.com/books/latest-findings-in-intellectual-and-developmentaldisabilities-research/innovative-therapeutic-approaches-forimproving-patient-life-condition-with-a-neurological-lysosomal (accessed: 13.05.2015).10. The human gene mutation database. Cardiff: Institute of Medical Genetics in Cardiff, Cardiff University. Available at: http://www.hgmd.cf.ac.uk/ac/index.php (accessed: 24.05.2015).11. Yogalingam G., Hopwood J.J. Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications. Hum. Mutat. 2001; 18 (4): 264–281.12. Gabrielli O., Coppa G.V., Bruni S., Villani G.R., Pontarelli G., Di Natale P. An adult Sanfilippo type A patient with homozygous mutation R206P in the sulfamidase gene. Am. J. Med. Genet. 2005; 133A (1): 85–89.13. Beesley C.E., Jackson M., Young E.P., Vellodi A., Winchester B.G. Molecular defects in Sanfilippo syndrome type B (mucopolysaccharidosis IIIB). J. Inherit. Metab. Dis. 2005; 28 (5): 759–767.14. Valstar M.J., Bruggenwirth H.T., Olmer R., Wevers R.A., Verheijen F.W., Poorthuis B.J., Halley D.J., Wijburg F.A. Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype. J. Inherit. Metab. Dis. 2010; 33 (6): 759–767.15. Weber B., Guo X.H., Kleijer W.J., van de Kamp J.J., Poorthuis B.J., Hopwood J.J. Sanfilippo type B syndrome (mucopolysaccharidosis III B): allelic heterogeneity corresponds to the wide spectrum of clinical phenotypes. Eur. J. Hum. Genet. 1999; 7 (1): 34–44.16. Ruijter G.J., Valstar M.J., van de Kamp J.M., van der Helm R.M., Durand S., van Diggelen O.P., Wevers R.A., Poorthuis B.J., Pshezhetsky A.V., Wijburg F.A. Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in The Netherlands. Mol. Genet. Metab. 2008; 93 (2): 104–111.17. Freeman C., Clements P.R., Hopwood J.J. Human liver N-acetylglucosamine 6-sulphate sulphatase. Purification and characterization. Biochem. J. 1987; 246 (2): 347–354.18. Mehta A., Winchester B. Lysosomal Storage Disease: A Practical Guide. NY: Wiley-Blackwell. 2012. 198 p.19. Giugliani R., Federhen A., Silva A.A., Bittar C.M., de Souza C.F., Netto C.B., Mayer F.Q., Baldo G., Matte U. Emerging treatment options for the mucopolysaccharidoses. Res. and Rep. in Endocrine Disorders. 2012; 2: 53–64.20. Ceuterick C., Martin J.J., Libert J., Farriaux J.P. Sanfilippo A disease in the fetus comparison with pre- and postnatal cases. Neuropadiatrie. 1980; 11 (2): 176–185.21. Wilkinson F.L., Holley R.J., Langford-Smith K.J., Badrinath S., Liao A., Langford-Smith A., Cooper J.D., Jones S.A., Wraith J.E., Wynn R.F., Merry C.L., Bigger B.W. Neuropathology in mouse models of mucopolysaccharidosis type I, IIIA and IIIB. PLoS One. 2012; 7 (4): 35787.22. Ohmi K., Greenberg D.S., Rajavel K.S., Ryazantsev S, Li H.H., Neufeld E.F. Activated microglia in cortex of mouse models of mucopolysaccharidoses I and IIIB. Proc. Natl. Acad. Sci. USA. 2003; 100 (4): 1902–1907.23. Arfi A., Richard M., Gandolphe C., Bonnefont-Rousselot D., Thérond P., Scherman D. Neuro-inflammatory and oxidative stress phenomena in MPS IIIA mouse model: the positive effect of long term aspirin treatment. Mol. Genet. Metab. 2011; 103 (1): 18–25.24. Langford-Smith A., Langford-Smith K.J., Jones S.A., Wynn R.F., Wraith J.E., Wilkinson F.L., Bigger B.W. Female mucopolysaccharidosis IIIA mice exhibit hyperactivity and a reduced sense of danger in the open field test. PLoS One. 2011; 6 (10): 25717.25. Canal M.M., Wilkinson F.L., Cooper J.D., Wraith JE, Wynn R, Bigger BW. Circadian rhythm and suprachiasmatic nucleus alterations in the mouse model of mucopolysaccharidosis IIIB. Behav. Brain Res. 2010; 209 (2): 212–220.26. Kresse H., Wiesmann U., Cantz M., Hall C.W., Neufeld E.F. Biochemical heterogeneity of the Sanfilippo syndrome: preliminary characterization of two deficient factors. Biochem. Biophys. Res. Commun. 1971; 42 (5): 892–898.27. Kresse H., Neufeld E.F. The Sanfilippo A corrective factor. Purification and mode of action. J. Biol. Chem. 1972; 247 (7): 2164–2170.28. Saudubray J., van den Berghe J., Walter J.H. Inborn Metabolic Diseases, Fifth Edition. Berlin Heidelberg: Springer-Verlag, 2012. 660 p.29. Valstar M.J., Marchal J.P., Grootenhuis M., Colland V., Wijburg F.A. Cognitive development in patients with Mucopolysaccharidosis type III (Sanfilippo syndrome). Orphanet J. Rare Dis. 2011; 6: 43.30. Wijburg F.A., Węgrzyn G., Burton B.K., Tylki-Szymańska A. Mucopolysaccharidosis type III (Sanfilippo syndrome) and misdiagnosis of idiopathic developmental delay, attention deficit/hyperactivity disorder or autism spectrum disorder. Acta Paediatr. 2013; 102 (5): 462–470.31. Krawiec P., Pac-Kożuchowska E., Mełges B., Mroczkowska-Juchkiewicz A., Skomra S., Pawłowska-Kamieniak A., Kominek K. From hypertransaminasemia to mucopolysaccharidosis IIIA. Ital. J. Pediatr. 2014; 40 (1): 97.32. Krasnopol'skaya K.D. Nasledstvennye bolezni obmena veshchestv. Spravochnoe posobie dlya vrachei [Hereditary Metabolic Diseases. Reference Guide for Physicians]. Moscow, Fokhat, 2005. 364 p.33. Van Hove J.L., Wevers R.A., Van Cleemput J., Moerman P., Sciot R., Matthijs G., Schollen E., de Jong J.G., Carey W.F., Muller V., Nicholls C., Perkins K., Hopwood J.J. Late-Onset visceral presentation with cardiomyopathy and without neurological symptoms of adult Sanfilippo syndrome. Am. J. Med. Genet. 2003; 118 A (4): 382–387.34. Meyer A., Kossow K., Gal A., Mühlhausen C., Ullrich K., Braulke T., Muschol N. Scoring evaluation of the natural course of mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics. 2007; 120 (5): 1255–1261.35. Van de Kamp J.J., Niermeijer M.F., von Figura K., Giesberts M.A. Genetic heterogeneity and clinical variability in the Sanfilippo syndrome (types A, B, and C). Clin. Genet. 1981; 20 (2): 152–160.36. De Ruijter J., Maas M., Janssen A., Wijburg F.A. High prevalence of femoral head necrosis in Mucopolysaccharidosis type III (Sanfilippo disease): a national, observational, cross sectional study. Mol. Genet. Metab. 2013; 109 (1): 49–53.37. White K.K., Karol L.A., White D.R., Hale S. Musculoskeletal manifestations of Sanfilippo Syndrome (mucopolysaccharidosis type III). J. Pediatr. Orthop. 2011; 31 (5): 594–598.38. Zafeiriou D.I., Savvopoulou-Augoustidou P.A., Sewell A., Papadopoulou F., Badouraki M., Vargiami E., Gombakis N.P., Katzos G.S. Serial magnetic resonance imaging findings in mucopolysaccharidosis IIIB (Sanfilippo’s syndrome B). Brain Dev. 2001; 23 (6): 385–389.39. Jurecka A., Tylki-Szymańska A. Gynecomastia in MPS IIIA boys: related to treatment or precocious puberty? Mol. Genet. Metab. 2014; 111 (2): 61–62.40. Aikardi Zh. Zabolevaniya nervnoi sistemy u detei [Diseases of Nervous System in Children]. Moscow, Laboratoriya znanii, 2013. 568 p.41. Moog U., van Mierlo I., van Schrojenstein Lantmande Valk H.M., Spaapen L., Maaskant M.A., Curfs L.M. Is Sanfilippo type B in your mind when you see adults with mental retardation and behavioral problems? Am. J. Med. Genet. C. Semin. Med. Genet. 2007; 145 C (3): 293–301.42. Rumsey R.K., Rudser K., Delaney K., Potegal M., Whitley C.B., Shapiro E. Acquired autistic behaviors in children with mucopolysaccharidosis type IIIA. J. Pediatr. 2014; 164 (5): 1147–1151.43. Potegal M., Yund B., Rudser K., Ahmed A., Delaney K., Nestrasil I., Whitley C.B., Shapiro E.G. Mucopolysaccharidosis Type IIIA presents as a variant of Klüver–Bucy syndrome. J. Clin. Exp. Neuropsychol. 2013; 35 (6): 608–616.44. Mahon L.V., Lomax M., Grant S., Cross E., Hare D.J., Wraith J.E., Jones S., Bigger B., Langford-Smith K., Canal M. Assessment of sleep in children with mucopolysaccharidosis type III. PLoS One. 2014; 9 (2): 84128.45. Mariotti P., Della Marca G., Iuvone L., Vernacotola S., Ricci R., Mennuni G.F., Mazza S. Sleep disorders in Sanfilippo syndrome: a polygraphic study. Clin. Electroencephalogr. 2003; 34 (1): 18–22.46. Fraser J., Gason A.A., Wraith J.E., Delatycki M.B. Sleep disturbance in Sanfilippo syndrome: a parental questionnaire study. Arch. Dis. Child. 2005; 90 (12): 1239–1242.47. Zafeiriou D.I., Batzios S.P. Brain and spinal MR imaging findings in mucopolysaccharidoses: a review. AJNR Am. J. Neuroradiol. 2013; 34 (1): 5–13.48. Barkovich A.J. Pediatric neuroimaging. Philadelphia: Williams & Wilkins. 2012. 1126 p.49. Brady J., Trehan A., Landis D., Toro C. Mucopolysaccharidosis type IIIB (MPS IIIB) masquerading as a behavioural disorder. BMJ Case Rep. 2013.50. Mayanskii N.A., Blinova T.A., Podkletnova T.V., Kuzenkova L.M., Vashakmadze N.D., Namazova-Baranova L.S., Baranov A.A. Quantitative determination of urinary glycosaminoglycans in reference individuals and patients with mucopolysaccharidoses by the dimethylmethylene blue assay. Voprosy diagnostiki v pediatrii = Diagnostics in pediatrics. 2013;5(1):21–26.51. Delgadillo V., O’Callaghan Mdel M., Artuch R., Montero R., Pineda M. Genistein supplementation in patients affected by Sanfilippo disease. J. Inherit. Metab. Dis. 2011; 34 (5): 1039–1044.52. Guerrero J.M., Pozo D., Diaz-Rodriguez J.L., Martinez--Cruz F., Vela-Campos F. Impairment of the melatonin rhythm in children with Sanfilippo syndrome. J. Pineal. Res. 2006; 40 (2): 192–193.53. Phillips L., Appleton R.E. Systematic review of melatonin treatment in children with neurodevelopmental disabilities and sleep impairment. Dev. Med. Child. Neurol. 2004; 46 (11): 771–775.54. Piotrowska E., Jakóbkiewicz-Banecka J., Barańska S., Tylki-Szymańska A., Czartoryska B., Wegrzyn A., Wegrzyn G. Genistein--mediated inhibition of glycosaminoglycan synthesis as a basis for gene expression targeted isoflavone therapy for mucopolysaccharidoses. Eur. J. Hum. Genet. 2006; 14 (7): 846–852.55. Kuzenkova L.M., Namazova-Baranova L.S., Gevorkyan A.K., Vashakmadze N.D., Podkletnova T.V., Studenikin V.M., Lazurenko S.B. Modern view of mucopolysaccharidosis type II in children: a multidisciplinary approach. Effektivnaya farmakoterapiya. Pediatriya = Effective pharmacotherapy. Pediatrics. 2012;2:28–34.56. Malinowska M., Wilkinson F.L., Langford–Smith K.J., Langford-Smith A., Brown J.R., Crawford B.E., Vanier M.T., Grynkiewicz G., Wynn R.F., Wraith J.E., Wegrzyn G., Bigger B.W. Genistein improves neuropathology and corrects behavior in a mouse model of neurodegenerative metabolic disease. PLoS One. 2010; 5(12): 14192.57. Piotrowska E., Jakóbkiewicz-Banecka J., Tylki-Szymanska A, Libere.k A., Maryniak A, Malinowska M., Czartoryska B., Puk E., Kloska A., Liberek T., Baranska S., Wegrzyn A., Wegrzyn G. Genistin rich soy isoflavone extract in substrate reduction therapy for Sanfilippo syndrome: An open-label, pilot study in 10 pediatric patients. Curr. Ther. Res. Clin. Exp. 2008; 69 (2): 166–179.58. Piotrowska E., Jakobkiewicz-Banecka J., Maryniak A., Tylki--Szymanska A., Puk E., Liberek A., Wegrzyn A., Czartoryska B., Slominska-Wojewodzka M., Wegrzyn G. Two-year follow-up ofSanfilippo Disease patients treated with a genistein rich isoflavone extract: assessment of effects on cognitive functions and general status of patients. Med. Sci. Monit. 2011; 17 (4): 196–202.59. Tardieu M., Zérah M., Husson B., de Bournonville S., Deiva K., Adamsbaum C., Vincent F., Hocquemiller M., Broissand C., Furlan V., Ballabio A., Fraldi A., Crystal R.G., Baugnon T., Roujeau T., Heard J.M., Danos O. Intracerebral administration of adeno associated viral vector serotype rh.10 carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: results of a phase I/II trial. Hum. Gene Ther. 2014; 25 (6): 506–516.60. ClinicalTrials.gov. A service of the U.S. National Institutes of Health. Available at: https://clinicaltrials.gov (accessed: 24.05.2015).