Abstract
Juvenile and adult GM1-gangliosidosis are invariably characterized by progressive neurological deterioration. To date only symptomatic therapies are available. We report for the first time the positive results of Miglustat (OGT 918, N-butyl-deoxynojirimycin) treatment on three Italian GM1-gangliosidosis patients. The first two patients had a juvenile form (enzyme activity ≤5%, GLB1 genotype p.R201H/c.1068 + 1G > T; p.R201H/p.I51N), while the third patient had an adult form (enzyme activity about 7%, p.T329A/p.R442Q). Treatment with Miglustat at the dose of 600 mg/day was started at the age of 10, 17 and 28 years; age at last evaluation was 21, 20 and 38 respectively. Response to treatment was evaluated using neurological examinations in all three patients every 4–6 months, the assessment of Movement Disorder-Childhood Rating Scale (MD-CRS) in the second patient, and the 6-Minute Walking Test (6-MWT) in the third patient. The baseline neurological status was severely impaired, with loss of autonomous ambulation and speech in the first two patients, and gait and language difficulties in the third patient. All three patients showed gradual improvement while being treated; both juvenile patients regained the ability to walk without assistance for few meters, and increased alertness and vocalization. The MD-CRS class score in the second patient decreased from 4 to 2. The third patient improved in movement and speech control, the distance covered during the 6-MWT increased from 338 to 475 m. These results suggest that Miglustat may help slow down or reverse the disease progression in juvenile/adult GM1-gangliosidosis.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- 6-MWT:
-
6-Minute Walking Test; LSD lysosomal storage disorder
- CSF:
-
Cerebral spinal fluid
- EEG:
-
Electroencephalogram
- GSL:
-
Glycosphingolipid
- IQ:
-
Intelligent quotient
- MD-CRS:
-
Movement Disorder-Childhood Rating Scale
- MRI:
-
Magnetic Resonance Imaging
- NB-DGJ:
-
butyldeoxygalactonojirimycin
- NB-DNJ:
-
N-butyldeoxynojirimycin
- SRT:
-
Substrate reduction therapy
- WAIS:
-
Wechsler Adult Intelligent Scale
References
Alfonso P, Pampin S, Estrada J, Rodriguez-Rey JC, Giraldo P, Sancho J, Pocovi M (2005) Miglustat (NB-DNJ) works as a chaperone for mutated acid beta-glucosidase in cells transfected with several Gaucher disease mutations. Blood Cells Mol Dis 35:268–276. doi:10.1016/j.bcmd.2005.05.007
Battini R et al (2008) Movement disorder-childhood rating scale: reliability and validity. Pediatr Neurol 39:259–265. doi:10.1016/j.pediatrneurol.2008.07.002
Beck M (2010) Therapy for lysosomal storage disorders. IUBMB Life 62:33–40. doi:10.1002/iub.284
Belmatoug N, Burlina A, Giraldo P, Hendriksz CJ, Kuter DJ, Mengel E, Pastores GM (2011) Gastrointestinal disturbances and their management in miglustat-treated patients. J Inherit Metab Dis 34:991–1001. doi:10.1007/s10545-011-9368-7
Bembi B et al (2006) Substrate reduction therapy in the infantile form of Tay-Sachs disease. Neurology 66:278–280. doi:10.1212/01.wnl.0000194225.78917.de
Brunetti-Pierri N, Scaglia F (2008) GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects. Mol Genet Metab 94:391–396. doi:10.1016/j.ymgme.2008.04.012
Caciotti A, Bardelli T, Cunningham J, D'Azzo A, Zammarchi E, Morrone A (2003) Modulating action of the new polymorphism L436F detected in the GLB1 gene of a type-II GM1 gangliosidosis patient. Hum Genet 113:44–50. doi:10.1007/s00439-003-0930-8
Caciotti A, Donati MA, Bardell T,d'Azzo A, Massai G, Luciani L, Zammarchi E, Morrone A (2005) Primary and Secondary Elastin-Binding Protein Defect Leads to Impaired Elastogenesis in Fibroblasts from GM1-Gangliosidosis Patients.Am J Pathol 167(6):1689–1698
Caciotti A, Donati MA, Procopio E, Filocamo M, Kleijer W, Wuyts W, Blaumeiser B, d'Azzo A, Simi L, Orlando C, McKenzie F, Fiumara A, Zammarchi E, Morrone A (2007) GM1 gangliosidosis: molecular analysis of nine patients and development of an RT-PCR assay for GLB1 gene expression profiling. Hum Mutat 28(2):204–204
Caciotti A et al (2011) GM1 gangliosidosis and Morquio B disease: an update on genetic alterations and clinical findings. Biochim Biophys Acta 1812:782–790. doi:10.1016/j.bbadis.2011.03.018
Champion H, Ramaswami U, Imrie J, Lachmann RH, Gallagher J, Cox TM, Wraith JE (2010) Dietary modifications in patients receiving miglustat. J Inherit Metab Dis 33(Suppl 3):S379–S383. doi:10.1007/s10545-010-9193-4
Cox TM (2015) Innovative treatments for lysosomal diseases. Best Pract Res Clin Endocrinol Metab 29:275–311. doi:10.1016/j.beem.2015.01.001
Elliot-Smith E et al (2008) Beneficial effects of substrate reduction therapy in a mouse model of GM1 gangliosidosis. Mol Genet Metab 94:204–211. doi:10.1016/j.ymgme.2008.02.005
Fecarotta S et al (2015) Long term follow-up to evaluate the efficacy of miglustat treatment in Italian patients with Niemann-Pick disease type C Orphanet. J Rare Dis 10:22. doi:10.1186/s13023-015-0240-y
Ginocchio VM et al (2013) Efficacy of miglustat in Niemann-Pick C disease: a single centre experience. Mol Genet Metab 110:329–335. doi:10.1016/j.ymgme.2013.07.019
Heron B et al (2012) Miglustat therapy in the French cohort of paediatric patients with Niemann-Pick disease type C Orphanet. J Rare dis 7:36. doi:10.1186/1750-1172-7-36
Hollak CE, Wijburg FA (2014) Treatment of lysosomal storage disorders: successes and challenges. J Inherit Metab Dis 37:587–598. doi:10.1007/s10545-014-9718-3
Jeyakumar M et al (1999) Delayed symptom onset and increased life expectancy in Sandhoff disease mice treated with N-butyldeoxynojirimycin. Proc Natl Acad Sci U S A 96:6388–6393
Jeyakumar M et al (2001) Enhanced survival in Sandhoff disease mice receiving a combination of substrate deprivation therapy and bone marrow transplantation. Blood 97:327–329
Jeyakumar M, Butters TD, Dwek RA, Platt FM (2002) Glycosphingolipid lysosomal storage diseases: therapy and pathogenesis. Neuropathol Appl Neurobiol 28:343–357
Jeyakumar M et al (2003) Central nervous system inflammation is a hallmark of pathogenesis in mouse models of GM1 and GM2 gangliosidosis. Brain 126:974–987
Jeyakumar M et al (2004) NSAIDs increase survival in the Sandhoff disease mouse: synergy with N-butyldeoxynojirimycin. Ann Neurol 56:642–649. doi:10.1002/ana.20242
Kaye EM, Shalish C, Livermore J,Taylor HA, Stevenson RE, Breakefield XO (1997) β-Galactosidase gene mutations in patients With Slowly Progressive GM1 Gangliosidosis. J Child Neurol 12(4):242–247
Kasperzyk JL, El-Abbadi MM, Hauser EC, D'Azzo A, Platt FM, Seyfried TN (2004) N-butyldeoxygalactonojirimycin reduces neonatal brain ganglioside content in a mouse model of GM1 gangliosidosis. J Neurochem 89:645–653. doi:10.1046/j.1471-4159.2004.02381.x
Kasperzyk JL, d'Azzo A, Platt FM, Alroy J, Seyfried TN (2005) Substrate reduction reduces gangliosides in postnatal cerebrum-brainstem and cerebellum in GM1 gangliosidosis mice. J Lipid Res 46:744–751. doi:10.1194/jlr.M400411-JLR200
Kuter DJ et al (2013) Miglustat therapy in type 1 Gaucher disease: clinical and safety outcomes in a multicenter retrospective cohort study. Blood Cells Mol Dis 51:116–124. doi:10.1016/j.bcmd.2013.04.005
Maegawa GH et al (2009) Substrate reduction therapy in juvenile GM2 gangliosidosis. Mol Genet Metab 98:215–224. doi:10.1016/j.ymgme.2009.06.005
Masciullo M, Santoro M, Modoni A, Ricci E, Guitton J, Tonali P, Silvestri G (2010) Substrate reduction therapy with miglustat in chronic GM2 gangliosidosis type Sandhoff: results of a 3-year follow-up. J Inherit Metab Dis 33(Suppl 3):S355–S361. doi:10.1007/s10545-010-9186-3
McCormack PL, Goa KL (2003) Miglustat. Drugs 63(22):2427–2434; discussion 2435-2426
Muthane U, Chickabasaviah Y, Kaneski C, Shankar SK, Narayanappa G, Christopher R, Govindappa SS (2004) Clinical features of adult GM1 gangliosidosis: report of three Indian patients and review of 40 cases. Mov Disord 19:1334–1341. doi:10.1002/mds.20193
Parenti G, Andria G, Valenzano KJ (2015) Pharmacological chaperone therapy: preclinical development, clinical translation, and prospects for the treatment of lysosomal storage disorders. Mol Ther 23:1138–1148. doi:10.1038/mt.2015.62
Pineda M et al (2010) Clinical experience with miglustat therapy in pediatric patients with Niemann-Pick disease type C: a case series. Mol Genet Metab 99:358–366. doi:10.1016/j.ymgme.2009.11.007
Platt FM et al (1997) Prevention of lysosomal storage in Tay-Sachs mice treated with N-butyldeoxynojirimycin. Science 276:428–431
Roze E et al (2005) Dystonia and parkinsonism in GM1 type 3 gangliosidosis. Mov Disord 20:1366–1369. doi:10.1002/mds.20593
Sano R et al (2009) GM1-ganglioside accumulation at the mitochondria-associated ER membranes links ER stress to Ca(2+)-dependent mitochondrial apoptosis. Mol Cell 36:500–511. doi:10.1016/j.molcel. 2009.10.021
Suzuki Y., Oshima A., Namba E. (2001) β-Galactosidase deficiency (β-galactosidosis) GM1 gangliosidosis and Morquio B disease. In: McGraw-Hill (ed) The Metabolic and Molecular Bases of Inherited Disease, vol 23. vol 1, 8th ed. edn., New-York, pp 3775–3809
Takamura A et al (2008) Enhanced autophagy and mitochondrial aberrations in murine G (M1)-gangliosidosis. Biochem Biophys Res Commun 367:616–622. doi:10.1016/j.bbrc.2007.12.187
Tallaksen CM, Berg JE (2009) Miglustat therapy in juvenile Sandhoff disease. J Inherit Metab Dis 32(Suppl 1):S289–S293. doi:10.1007/s10545-009-1224-7
Tifft C, Adams DR, Morgan CP (2007) 55 Miglustat improves function in patients with juvenile GM1 gangliosidosis. Mol Genet Metab 92:24. doi:10.1016/j.ymgme.2007.08.060
Treiber A, Morand O, Clozel M (2007) The pharmacokinetics and tissue distribution of the glucosylceramide synthase inhibitor miglustat in the rat. Xenobiotica 37:298–314. doi:10.1080/00498250601094543
Wortmann SB, Lefeber DJ, Dekomien G, Willemsen MA, Wevers RA, Morava E (2009) Substrate deprivation therapy in juvenile Sandhoff disease. J Inherit Metab Dis 32(Suppl 1):S307–S311. doi:10.1007/s10545-009-1261-2
Acknowledgements
We thank the patients and their families for their collaboration and the permission to publish data and video. We thank Actelion Pharmaceuticals for support authors meetings.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing interests.
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Electronic supplementary material
Additional file 1
Video of patient 1. Segment 1 shows patient 1 at age 9, before diagnosis; because of a severe movement disorder she had great difficulty in taking a small step and getting up from a sitting position. After one year of therapy, the patient could descend the stairs holding the banister (segment 2); she resumed the ability to stand up (segment 3), to bike a few meters (segment 4), and to eat independently (segment 5). (AVI 38814 kb)
Additional file 2
Video of patient 2. After two months of treatment she was able to stand up from a chair with support (segment 1); after four months of therapy she made some attempts to speak, through vocalizations and monosyllables (segment 2), and she walked a few steps with assistance (segment 3). Segment 4 shows the patient at age 20 (after two years of treatment). She is able to walk alone for a few meters indoors; she is still hypokinetic and rigid, but her start hesitation is less evident. (AVI 34368 kb)
Rights and permissions
About this article
Cite this article
Deodato, F., Procopio, E., Rampazzo, A. et al. The treatment of juvenile/adult GM1-gangliosidosis with Miglustat may reverse disease progression. Metab Brain Dis 32, 1529–1536 (2017). https://doi.org/10.1007/s11011-017-0044-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11011-017-0044-y