Neuropathic forms of lisosomal storage diseases in Ukraine

N.O. Pichkur


Background. To date, several thousands of hereditary diseases have been detected, characterized by the defeat of the nervous system. These include lysosomal storage diseases (LSD). Lysosomal storage desiaeses — is a large group of monogenic metabolic disorders (about 60), inherited mainly by the autosomal recessive type; most of them — are serious diseases with progressive flow that cause severe disability and early death of the patients. LSD are characterized by accumulation of enzymes substrates or products of their incomplete degradation and segregated cytoplasmic components, etc. in different cells and tissues and it causes many disorders. Depending on the accumulated substrate nature, the following LSD are distinguished: mucopolysaccharidosis, sphingolipidosis, mucolipidosis, oligosaccharidosis, etc. Certain LSD clinical flow depends on the pathological process type and location, accumulated biochemical substrate nature, and is usually multisymptomatic. Within one nosological form various phenotypes are found: from «soft» to severe; first symptoms of the disease may be nonspecific, reminiscent of other, more common diseases. Most LSD require complex stage-by-stage clinical and laboratory diagnostics. Until recently almost all LSD considered as incurable; specific correction methods were successfully developed and introduced into medical — it has become one of the most significant achievements in a worldwide medical science of recent decades. Recently, significantly expanded range of LSD laboratory diagnostics gained unique experience in clinical identification of their various forms that significantly influenced on the disease incidence revealing, allowed to analyze epidemiological indicators, to develop effective measures for early diagnosis optimization. The purpose of the study was to study the prevalence and spectrum of neuropathic forms of lysosomal accumulation diseases in Ukraine, comparing the results with epidemiological studies conducted in other countries. Materials and methods. LSD enzyme diagnostics in Ukraine is used since 1995: today it is possible to determine the activity of 25 enzymes in homozygous leukocytes, blood plasma, chorionic biopsy, skin fibroblasts cells culture that allowed to verify 30 different diseases. Each LSD has its own biochemical characteristics. The laboratory diagnostics success depends on a clear definition of a clinical problem. This approach is a key to correct diagnosis, further clinical and laboratory monitoring during LSD treatment. Data of the complex clinical and laboratory examination of patients with different forms of LSD provided in the National Specializes Children Hospital «Okhmatdit» in the period 1995–2016 have been analyzed. For LSD laboratory diagnostics we selected patients with multisymptomatic clinical picture which were grouped on the basis of certain organs and systems disorders; for each group phase-based research protocols were used. Results. The diagnosis of lysosomal disease was established in 343 patients from 324 families from all regions of Ukraine. The most numerous group in the structure of lysosomal diseases revealed sphingolipidosis (52 % of cases) and mucopolysaccharidosis (30 %). Neuropathic variants were diagnosed in 84 (47 %) of 179 patients from the sphingolipidosis group. We diagnosed Gaucher disease in 19.4 % of patients. The second type of Gauchers disease (acute neuropathic form) was detected in 3 (5 %) patients, type III in 5 (8 %). The most numerous in LSD structure were sphingolipidosis (52 %) and mucopolysaccharidosis (30 %); a significant place took GM1-gangliosidosis (8 %) and metachromatic leukodystrophy (7 %). According to our research, LSD structure in Ukraine is similar to other European countries, but in the same time the incidence of Gaucher and Fabry disease, metachromatic leukodystrophy, mucopolysaccharidosis type I was lower, probably due to LSD significant clinical polymorphism and a large number of adult patients. Conclusions. In the future we are planning to study LSD prevalence in Ukraine, to analyze the mistakes in their late diagnostics in order to develop and implement in the medical practice effective early diagnostic algorithms for certain forms of LSD, for which there are effective methods of treatment.


lysosomal storage diseases; neuropathic forms; sphingolipidosis; mucopolysaccharidosis; neuronal ceroid lipofuscinosis; metachromatic leukodystrophy; biochemical, molecular and genetic diagnosis


Korf B.R. New approaches to molecular diagnosis / B.R. Korf, H.L. Rehm // JAMA. — 2013. — Vol. 309, N 14. — P. 1511-1521.

Cox T.M. The cellular pathology of lysosomal disease / T.M. Cox, M.B. Cachon-Gonzalez // J. Pathol. — 2012. — Vol. 226, N 2. — P. 241-254.

Platt F.M. The cell biology of disease: lysosomal storage disorders: the cellular impact of lysosomal dysfunction / F.M. Platt, B. Boland, A.C. van der Spoel // J. Cell. Biol. — 2012. — Vol. 199, N 5. — P. 723-734.

Coutinho M.F. From rare to common and back again: 60 years of lysosomal dysfunction / M.F. Coutinho, S. Alves // Mol. Genet. Metab. — 2015. — Vol. 117, N 2. — P. 53-65.

Jalanko A. Neuronal ceroid lipofuscinoses / A. Jalanko, T. Braulke // Biochim. Biophys. Acta. — 2009. — Vol. 1793, N 4. — P. 697-709.

Berkovic S.F., Dibbens L.M., Oshlack A., Silver J.D., Kate­relos M., Vears D.F. [et al.]. Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis // Am. J. Hum. Genet. — 2008. — Vol. 82, N 3. — P. 673-684.

Verity C., Winstone A.M., Stellitano L., Will R., Nicoll A. The epi­demiology of progressive intellectual and neurological deterioration in childhood // Arch. Dis. Child. — 2010. — Vol. 95, N 5. — P. 361-364.

Zlotogora J., Furman-Shaharabani Y., Harris A., Barth M.L., von Figura K., Gieselmann V. A single origin for the most frequent mutation causing late infantile metachromatic leukodystrophy // J. Med. Genet. — 1994. — Vol. 31, N 6. — P. 672-674.

Schultz M.L., Tecedor L., Chang M., Davidson B.L. Clarifying lysosomal storage diseases // Trends Neurosci. — 2011. — Vol. 34, N 8. — P. 401-410.

Lysosomal storage disorders. A practical guide / Ed. by A. Mehta, B. Winchester. — Hoboken: Wiley-Blackwell, 2012. — 208 p.

Wenger D.A. Insights into the diagnosis and treatment of lysosomal storage diseases / D.A. Wenger, S. Coppola; Shu-Ling Liu // Arch Neurol. — 2003. — Vol. 60. — P. 322-328.

Macualey S.L. Combination therapies for lysosomal storage diseases:a complex answer to a simple problem / S.L. Macualey // Ped. Endocrinol. Rev. — 2016. — Vol. 13, suppl. 1. — P. 639-645.

Grabowski G.A. Enzyme therapy for lysosomal storage dise­ase: principles, practice, and prospects / G.A. Grabowski, R.J. Hopkin // Ann. Rev. Genom. Hum. Genet. — 2003. — Vol. 4. — P. 403-436.

Yew N.S. Cheng gene therapy for lysosomal storage disorders / N.S. Yew, H.S. Cheng // Ped. Endocrinol. Rev. — 2013. — Vol. 11, suppl. 1. — P. 99-105.

Dionisi-Vici C., Rizzo C., Burlina A.B., Caruso U., Sabetta G., Uziel G. [et al.]. Inborn errors of metabolism in the Italian pediatric population: a national retrospective survey // J. Pediatr. — 2002. — Vol. 140, N 3. — P. 321-327.

Pinto R., Caseiro C., Lemos M., Lopes L., Fontes A., Ribeiro H. Prevalence of lysosomal storage diseases in Portugal // Eur. J. Hum. Genet. — 2004. — Vol. 12, N 2. — P. 87-92.

Guo Y., He W., Boer A.M., Wevers R.A., de Bruijn A.M., Groener J.E. [et al.]. Elevated plasma chitotriosidase activity in various lisosomal storage disorders // J. Inher. Metab. Dis. — 1995. — Vol. 18. — P. 717-722.

Poorthuis B.J., Wevers R.A., Kleijer W.J., Groener J.E., de Jong J.G., van Weely S. [et al.]. The frequency of lysosomal storage diseases in the Netherlands // Hum. Genet. — 1999. — Vol. 105. — P. 151-156.

Miekle P.J. Prevalence of lysosomal storage disorders / P.J. Meikle, J.J. Hopwood, W.F. Clague // JAMA. — 1999. — Vol. 281. — P. 249-254.

Poupětová H., Ledvinová J., Berná L., Dvořáková L., Kožich V., Elleder M. The birth prevalence of lysosomal storage disorders in the Czech Republic: comparison with data in different populations // J. Inherit. Metab. Dis. — 2010. — Vol. 33, N 4. — P. 387-396.

Мицик Н.Й. Диференціація норми та патології методом селективного біохімічного скринінгу лізосомних хвороб накопичення, що супроводжуються підвищеною екскрецією олігосахаридів / Н.Й. Мицик, Н.В. Ольхович, Н.Г. Горовенко // Укр. біохім. журн. — 2015. — Т. 87, № 3. — P. 107-115.

Трофімова Н.С. Використання скринуючих біохімічних досліджень для ранньої діагностики мукополісахаридозів /

Н.С. Трофімова, Н.В. Ольхович, Н.Г. Горовенко // Вісн. проблем біології і медицини. — 2015. — Т. 2(123), вип. 3. — С. 245-250.

Мицик Н.Й. Селективний біохімічний скринінг лізосомних хвороб накопичення методом тонкошарової хроматографії олігосахаридів / Н.Й. Mицик, Н.В. Ольхович, Н.Г. Горовенко // Вісн. проблем біології і медицини. — 2016. — Т. 126, № 1. — С. 222-227.

Горовенко Н.Г. Молекулярно-генетичний скринінг мажорних мутацій в гені АСА у пацієнтів з метахроматичною лейкодистрофією / Н.Г. Горовенко, Н.В. Ольхович, Н.О. Пічкур // Цитология и генетика. — 2002. — Т. 36, № 5. — С. 43-49.

Wenger D.A. Screening for lysosomal disorders / D.A. Wenger, C. Williams // Techniques in diagnostics of human biochemical gene­tics. — N.Y.: Wiley-Liss, 1991. — P. 587-619.

Hartree E.F. Determination of protein: a modification of the Lowry method that gives a linear photometric response / E.F. Hartree // Annal. Biochem. — 1972. — Vol. 48, N 4. — P. 422-427.

Мицик Н.Й. Особливості оцінки активності β-галактозидази в діагностиці лізосомних хвороб накопичення серед населення України / Н.Й. Mицик, Н.В. Ольхович, Н.Г. Горовенко // Вісн. проблем біології і медицини. — 2016. — Т. 133, № 4. — С. 208-213.

Lukacs Z., Nieves Cobos P., Mengel E., Hartung R., Beck M., Deschauer M. [et al.]. Diagnostic efficacy of the fluorometric determination of enzyme activity for Pompe disease from dried blood specimens compared with lymphocytes-possibility fornewborn screening // J. Inherit. Metab. Dis. — 2010. — Vol. 33. — P. 43-50.

Горовенко Н.Г. Використання бioxiмічниx методів для визначення гетерозиготного носійства метахроматичної лейкодистрофії / Н.Г. Горовенко, Н.В. Ольхович // Проблеми екологічної та медичної генетики i клінічної імунології. — 2003. — № 3(49). — С. 35-42.

Ольхович Н.В., Грищенко О.М., Пічкур Н.О., Недобой А.М., Трофімова Н.С., Іванова Т.П. [та ін.]. Клініко-лабораторні показники ефективності ферментозамісної терапії хвороби Гоше в Україні // Лік. справа. — 2011. — № 1–2. — С. 95-104.

Mistry P.K. The glucocerebrosidase locus in Gaucher’s disease: molecular analysis of lysosomal enzyme / P.K. Mistry, T.M. Cox // J. Med. Genet. — 1993. — Vol. 30. — P. 889-894.

Polten A., Fluharty A.L., Fluharty C.B., Kappler J., von Figura K., Gieselmann V. Molecular basis of different forms of metachromatic leukodystrophy // N. Engl. J. Med. — 1991. — Vol. 324, N 1. — P. 18-22.

Lugowska A., Amaral O., Berger J., Berna L., Bosshard N.U., Chabas A. [et al.]. Mutations c.459+1G>A and p.P426L in the ARSA gene: prevalence in metachromatic leukodystrophy patients from European countries // Mol. Genet. Metab. — 2005. — Vol. 86. — P. 353-359.

Olkhovich N.V., Takamura N., Pichkur N.A., Gorovenko N.G., Aoyagi K., Yamashita S. Novel mutations in arylsulfatase A gene in three Ukrainian families with metachromatic leukodystrophy //

Mol. Genet. Metabol. — 2003. — Vol. 80, N 3. — Р. 360-363.

Трофімова Н.С. Оптимізація біохімічної та молекулярно-генетичної діагностики мукополісахаридозу І типу в Україні / Н.С. Трофімова, Н.В. Ольхович, Н.Г. Горовенко // Досягнення біології та медицини. — 2014. — № 1(23). — С. 61-65.

Tylki-Szymanska A., Millat G., Maire I., Czartoryska B. Types I and III Gaucher Disease in Poland: Incidence of the Most Common Mutations and Phenotypic Manifestations // Eur. J. Hum. Genet. — 1996. — Vol. 4. — P. 334-337.

Jakobkiewicz-Benecka J., Gabig-Ciminska M., Banecka-Majkutewicz Z., Banecki B., Wegrzyn A., Wegrzyn G. Factors and processes modulating phenotypes in neuropathic lysosomal storage diseases // Metab. Brain Dis. — 2014. — Vol. 29. — P. 1-8.

Beutler E., Grabowski G.A. Gaucher disease. In: Scri­ver C.R., Beaudet A.C., Sly W.S., Valle D. et al. The metabolic and molecular basis of inherited disease. — New York: McGraw-Hill Book Co, 1995. — 7th ed. — Vol. 2. — P. 2641-70.

Davies E.H., Mengel E., Tylki-Szymanska A., Kleinotiene G., Reinke J., Vellodi A. Four-year follow-up of chronic neuronopathic Gaucher disease in Europeans using a modified severity scoring tool // J. Inherit. Metab. Dis. — 2011. — Vol. 34, N 5. — P. 1053-1059.

Charrow J., Andersson H.C., Kaplan P., Kolodny E.H., Mistry P., Pastores G. [et al.]. The Gaucher Registry: demographics and disease characteristics of 1698 patients with Gaucher disease // Arch. Intern. Med. — 2000. — Vol. 160, N 18. — P. 2835-2843.

Tylki-Szymańska A., Vellodi A., El-Beshlawy A., Cole J.A., Kolodny E. Neuronopathic Gaucher disease: demographic and clinical features of 131 patients enrolled in the International Collaborative Gaucher Group Neurological Outcomes Subregistry // J. Inherit. Metab. Dis. — 2010. — Vol. 33, N 4. — P. 339-346.

Горовенко Н.Г., Ольхович Н.В., Недобой А.М., Пічкур Н.О. Визначення частоти мажорних мутацій в гені GBA у пацієнтів з хворобою Гоше в Україні // Цитологія і генетика. — 2007. — Т. 41, № 4. — С. 41-48.

Weber B., van de Kamp J.J.P., Kleijer W.J., Guo X.H., Blanch L., van Diggelen O.P. [et al.]. Identification of a common mutation (R245H) in Sanfilippo A patients from the Netherlands // J. Inherit. Metab. Dis. — 1998. — Vol. 21. — P. 416-422.

Trofimova N.S. Specificities of Sanfilippo A syndrome laboratory diagnostics / N.S. Trofimova, N.V. Olkhovych, N.G. Gorovenko // Biopolymers and Cell. — 2014. — Vol. 30, N 5. — P. 388-393.

Scriver C.R., Beaudet A.L., Sly W.S., Valle D. The metabolic and molecular basis of inherited diseases.— N.Y.: McGraw-Hill, 2001.

Bunge S., Ince H., Steglich C., Kleijer W.J., Beck M., Zaremba J. [et al.]. Identification of 16 sulfamidase gene mutations including the common R74C in patients with mucopolysaccharidosis type IIIA (Sanfilippo A) // Hum. Mutat. — 1997. — Vol. 10. — P. 479-485.

Moore D., Connock M.J., Wraith E., Lavery C. The prevalence of and survival in Mucopolysaccharidosis I: Hurler, Hurler-Scheie and Scheie syndromes in the UK // Orphanet. J. Rare Dis. — 2008. — Vol. 3. — P. 24.

Baehner F., Schmiedeskamp C., Krummenauer F., Miebach E., Bajbouj M., Whybra C. [et al.]. Cumulative incidence rates of the mucopolysaccharidoses in Germany // J. Inherit. Metab. Dis. — 2005. — Vol. 28, N 6. — P. 1011-1017.


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