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Journal of Pediatric Biochemistry 2016; 06(01): 039-045
DOI: 10.1055/s-0036-1582253
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Neuronopathic Gaucher Disease

Simona Sestito
1   Department of Medical and Surgical Sciences, Pediatric Unit, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
,
Francesca Falvo
1   Department of Medical and Surgical Sciences, Pediatric Unit, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
,
Michele Grisolia
1   Department of Medical and Surgical Sciences, Pediatric Unit, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
,
Angela Nicoletti
1   Department of Medical and Surgical Sciences, Pediatric Unit, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
,
Elisa Pascale
1   Department of Medical and Surgical Sciences, Pediatric Unit, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
,
Maria Teresa Moricca
1   Department of Medical and Surgical Sciences, Pediatric Unit, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
,
Sara Esposito
1   Department of Medical and Surgical Sciences, Pediatric Unit, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
,
Vincenzo Salpietro
2   Department of Pediatrics, University of Messina, Messina, Italy
3   Institute of Neurogenetics, National Hospital for Neurology and Neurosurgery, University College London Hospitals, London, United Kingdom
,
Agata Polizzi
4   National Centre for Rare Diseases, Istituto Superiore di Sanità, Rome, Italy
,
Martino Ruggieri
5   Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
,
Daniela Concolino
1   Department of Medical and Surgical Sciences, Pediatric Unit, University “Magna Graecia” of Catanzaro, Catanzaro, Italy
› Author Affiliations
Further Information

Publication History

10 December 2015

21 January 2016

Publication Date:
26 April 2016 (online)

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Abstract

Gaucher disease (GD) has been classically divided into three phenotypes primarily according to the absence (type 1 GD or nonneuronopathic GD) or presence and severity (types 2 and 3 GD or neuronopathic GD) of neurological involvement. Despite such distinction, neurological manifestations have been recorded also in patients with type 1 GD: in this latter form, however, such manifestations are different and, in the majority of cases, of much less severity than those associated with types 2 and 3 GD. Significant advances in therapy have been achieved, primarily after the advent of enzyme replacement therapy (ERT). As it occurs in patients with type 1 GD, ERT is able to reverse systemic and extraneurological manifestations of type 3 GD, although evidence suggests that ERT is not able to prevent the progression of neurological involvement in the long term. Thus, it is necessary to better understand the pathophysiological mechanism underlying neurological involvement in GD patients, allowing the development of new therapeutic approaches capable of improving central nervous system manifestations in GD.

Keywords

Gaucher disease - type 1 Gaucher disease - type 2 Gaucher disease - type 3 Gaucher disease - neuronopathic GD - nonneuronopathic GD - lysosomal storage disease
 

  • References

  • 1 Beutler E, Grabowski GA. Glucosylceramid lipidoses: Gaucher disease. In: Scriver CR, Baudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 1995: 2641-2670
    Search in Google Scholar
  • 2 Beutler E. Gaucher disease: multiple lessons from a single gene disorder. Acta Paediatr Suppl 2006; 95 (451) 103-109
    CrossrefPubMedSearch in Google Scholar
  • 3 Brady RO, Barton NW, Grabowski GA. The role of neurogenetics in Gaucher disease. Arch Neurol 1993; 50 (11) 1212-1224
    CrossrefPubMedSearch in Google Scholar
  • 4 Chérin P, Rose C, de Roux-Serratrice C , et al. The neurological manifestations of Gaucher disease type 1: the French Observatoire on Gaucher disease (FROG). J Inherit Metab Dis 2010; 33 (4) 331-338
    CrossrefPubMedSearch in Google Scholar
  • 5 Goker-Alpan O, Schiffmann R, LaMarca ME, Nussbaum RL, McInerney-Leo A, Sidransky E. Parkinsonism among Gaucher disease carriers. J Med Genet 2004; 41 (12) 937-940
    CrossrefPubMedSearch in Google Scholar
  • 6 Tsuang D, Leverenz JB, Lopez OL , et al. GBA mutations increase risk for Lewy body disease with and without Alzheimer disease pathology. Neurology 2012; 79 (19) 1944-1950
    CrossrefPubMedSearch in Google Scholar
  • 7 Ziegler SG, Eblan MJ, Gutti U , et al. Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease. Mol Genet Metab 2007; 91 (2) 195-200
    CrossrefPubMedSearch in Google Scholar
  • 8 Pastores GM. Neuropathic Gaucher disease. Wien Med Wochenschr 2010; 160 (23–24) 605-608
    CrossrefPubMedSearch in Google Scholar
  • 9 Vellodi A, Tylki-Szymanska A, Davies EH , et al; European Working Group on Gaucher Disease. Management of neuronopathic Gaucher disease: revised recommendations. J Inherit Metab Dis 2009; 32 (5) 660-664
    CrossrefPubMedSearch in Google Scholar
  • 10 Charrow J, Andersson HC, Kaplan P , et al. The Gaucher registry: demographics and disease characteristics of 1698 patients with Gaucher disease. Arch Intern Med 2000; 160 (18) 2835-2843
    CrossrefPubMedSearch in Google Scholar
  • 11 Erikson A. Gaucher disease—Norrbottnian type (III). Neuropaediatric and neurobiological aspects of clinical patterns and treatment. Acta Paediatr Scand Suppl 1986; 326: 1-42
    PubMedSearch in Google Scholar
  • 12 Tylki-Szymañska A, Keddache M, Grabowski GA. Characterization of neuronopathic Gaucher disease among ethnic Poles. Genet Med 2006; 8 (1) 8-15
    CrossrefPubMedSearch in Google Scholar
  • 13 Abrahamov A, Elstein D, Gross-Tsur V , et al. Gaucher's disease variant characterised by progressive calcification of heart valves and unique genotype. Lancet 1995; 346 (8981) 1000-1003
    CrossrefPubMedSearch in Google Scholar
  • 14 Stone DL, Tayebi N, Orvisky E, Stubblefield B, Madike V, Sidransky E. Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease. Hum Mutat 2000; 15 (2) 181-188
    CrossrefPubMedSearch in Google Scholar
  • 15 Hruska KS, LaMarca ME, Scott CR, Sidransky E. Gaucher disease: mutation and polymorphism spectrum in the glucocerebrosidase gene (GBA). Hum Mutat 2008; 29 (5) 567-583
    CrossrefPubMedSearch in Google Scholar
  • 16 Schueler UH, Kolter T, Kaneski CR , et al. Toxicity of glucosylsphingosine (glucopsychosine) to cultured neuronal cells: a model system for assessing neuronal damage in Gaucher disease type 2 and 3. Neurobiol Dis 2003; 14 (3) 595-601
    CrossrefPubMedSearch in Google Scholar
  • 17 Pelled D, Trajkovic-Bodennec S, Lloyd-Evans E, Sidransky E, Schiffmann R, Futerman AH. Enhanced calcium release in the acute neuronopathic form of Gaucher disease. Neurobiol Dis 2005; 18 (1) 83-88
    CrossrefPubMedSearch in Google Scholar
  • 18 Farfel-Becker T, Vitner EB, Kelly SL , et al. Neuronal accumulation of glucosylceramide in a mouse model of neuronopathic Gaucher disease leads to neurodegeneration. Hum Mol Genet 2014; 23 (4) 843-854
    CrossrefPubMedSearch in Google Scholar
  • 19 Kim EY, Hong YB, Go SH, Lee B, Jung SC. Downregulation of neurotrophic factors in the brain of a mouse model of Gaucher disease; implications for neuronal loss in Gaucher disease. Exp Mol Med 2006; 38 (4) 348-356
    CrossrefPubMedSearch in Google Scholar
  • 20 Vitner EB, Salomon R, Farfel-Becker T , et al. RIPK3 as a potential therapeutic target for Gaucher's disease. Nat Med 2014; 20 (2) 204-208
    CrossrefPubMedSearch in Google Scholar
  • 21 Vaccaro AM, Motta M, Tatti M , et al. Saposin C mutations in Gaucher disease patients resulting in lysosomal lipid accumulation, saposin C deficiency, but normal prosaposin processing and sorting. Hum Mol Genet 2010; 19 (15) 2987-2997
    CrossrefPubMedSearch in Google Scholar
  • 22 Tayebi N, Stone DL, Sidransky E. Type 2 gaucher disease: an expanding phenotype. Mol Genet Metab 1999; 68 (2) 209-219
    CrossrefPubMedSearch in Google Scholar
  • 23 Gupta N, Oppenheim IM, Kauvar EF, Tayebi N, Sidransky E. Type 2 Gaucher disease: phenotypic variation and genotypic heterogeneity. Blood Cells Mol Dis 2011; 46 (1) 75-84
    CrossrefPubMedSearch in Google Scholar
  • 24 Tylki-Szymańska A, Vellodi A, El-Beshlawy A, Cole JA, 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; 33 (4) 339-346
    CrossrefPubMedSearch in Google Scholar
  • 25 Mignot C, Gelot A, Bessières B , et al. Perinatal-lethal Gaucher disease. Am J Med Genet A 2003; 120A (3) 338-344
    CrossrefPubMedSearch in Google Scholar
  • 26 Tayebi N, Reissner KJ, Lau EK , et al. Genotypic heterogeneity and phenotypic variation among patients with type 2 Gaucher's disease. Pediatr Res 1998; 43 (5) 571-578
    CrossrefPubMedSearch in Google Scholar
  • 27 Mignot C, Doummar D, Maire I, De Villemeur TB ; French Type 2 Gaucher Disease Study Group. Type 2 Gaucher disease: 15 new cases and review of the literature. Brain Dev 2006; 28 (1) 39-48
    CrossrefPubMedSearch in Google Scholar
  • 28 Kolodny EH, Ullman MD, Mankin HJ, Raghavan SS, Topol J, Sullivan JL. Phenotypic manifestations of Gaucher disease: clinical features in 48 biochemically verified type 1 patients and comment on type 2 patients. Prog Clin Biol Res 1982; 95: 33-65
    PubMedSearch in Google Scholar
  • 29 Park JK, Orvisky E, Tayebi N , et al. Myoclonic epilepsy in Gaucher disease: genotype-phenotype insights from a rare patient subgroup. Pediatr Res 2003; 53 (3) 387-395
    CrossrefPubMedSearch in Google Scholar
  • 30 Pavone P, Spalice A, Polizzi A, Parisi P, Ruggieri M. Ohtahara syndrome with emphasis on recent genetic discovery. Brain Dev 2012; 34 (6) 459-468
    CrossrefPubMedSearch in Google Scholar
  • 31 Pavone P, Striano P, Falsaperla R, Pavone L, Ruggieri M. Infantile spasms syndrome, West syndrome and related phenotypes: what we know in 2013. Brain Dev 2014; 36 (9) 739-751
    CrossrefPubMedSearch in Google Scholar
  • 32 Kraoua I, Sedel F, Caillaud C , et al. A French experience of type 3 Gaucher disease: Phenotypic diversity and neurological outcome of 10 patients. Brain Dev 2011; 33 (2) 131-139
    CrossrefPubMedSearch in Google Scholar
  • 33 Dreborg S, Erikson A, Hagberg B. Gaucher disease—Norrbottnian type. I. General clinical description. Eur J Pediatr 1980; 133 (2) 107-118
    CrossrefPubMedSearch in Google Scholar
  • 34 Grabowski GA, Andria G, Baldellou A , et al. Pediatric non-neuronopathic Gaucher disease: presentation, diagnosis and assessment. Consensus statements. Eur J Pediatr 2004; 163 (2) 58-66
    CrossrefPubMedSearch in Google Scholar
  • 35 Jeong SY, Park SJ, Kim HJ. Clinical and genetic characteristics of Korean patients with Gaucher disease. Blood Cells Mol Dis 2011; 46 (1) 11-14
    CrossrefPubMedSearch in Google Scholar
  • 36 Tylki-Szymańska A, Czartoryska B. Enzyme replacement therapy in type III Gaucher disease. J Inherit Metab Dis 1999; 22 (2) 203-204
    CrossrefPubMedSearch in Google Scholar
  • 37 Giraldo P, Capablo JL, Alfonso P, Latre P, García B, Pocoví M. Grupo Español sobre Enfermedad de Gaucher. Neurological manifestations inpatients with Gaucher disease and in their relatives. Med Clin (Barc) 2008; 13: 175-179
    PubMedSearch in Google Scholar
  • 38 DePaolo J, Goker-Alpan O, Samaddar T, Lopez G, Sidransky E. The association between mutations in the lysosomal protein glucocerebrosidase and parkinsonism. Mov Disord 2009; 24 (11) 1571-1578
    CrossrefPubMedSearch in Google Scholar
  • 39 Biegstraaten M, van Schaik IN, Aerts JM, Hollak CE. ‘Non-neuronopathic’ Gaucher disease reconsidered. Prevalence of neurological manifestations in a Dutch cohort of type I Gaucher disease patients and a systematic review of the literature. J Inherit Metab Dis 2008; 31 (3) 337-349
    CrossrefPubMedSearch in Google Scholar
  • 40 Patay Z. Metabolic disorders. In: Tortori-Donati P, ed. Pediatric Neuroradiology. Brain. Berlin: Springer-Verlag; 2005: 543-722
    CrossrefSearch in Google Scholar
  • 41 Barkovich AJ. Pediatric Neuroradiology. 5th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2012
    Search in Google Scholar
  • 42 Machaczka M, Rucinska M, Skotnicki AB, Jurczak W. Parkinson's syndrome preceding clinical manifestation of Gaucher's disease. Am J Hematol 1999; 61 (3) 216-217
    CrossrefPubMedSearch in Google Scholar
  • 43 Tayebi N, Callahan M, Madike V , et al. Gaucher disease and parkinsonism: a phenotypic and genotypic characterization. Mol Genet Metab 2001; 73 (4) 313-321
    CrossrefPubMedSearch in Google Scholar
  • 44 Neudorfer O, Giladi N, Elstein D , et al. Occurrence of Parkinson's syndrome in type I Gaucher disease. QJM 1996; 89 (9) 691-694
    CrossrefPubMedSearch in Google Scholar
  • 45 Tayebi N, Walker J, Stubblefield B , et al. Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism?. Mol Genet Metab 2003; 79 (2) 104-109
    CrossrefPubMedSearch in Google Scholar
  • 46 Goker-Alpan O, Lopez G, Vithayathil J, Davis J, Hallett M, Sidransky E. The spectrum of parkinsonian manifestations associated with glucocerebrosidase mutations. Arch Neurol 2008; 65 (10) 1353-1357
    PubMedSearch in Google Scholar
  • 47 Halperin A, Elstein D, Zimran A. Increased incidence of Parkinson disease among relatives of patients with Gaucher disease. Blood Cells Mol Dis 2006; 36 (3) 426-428
    CrossrefPubMedSearch in Google Scholar
  • 48 Sidransky E, Nalls MA, Aasly JO , et al. Multicenter analysis of glucocerebrosidase mutations in Parkinson's disease. N Engl J Med 2009; 361 (17) 1651-1661
    CrossrefPubMedSearch in Google Scholar
  • 49 Bras J, Singleton A, Cookson MR, Hardy J. Emerging pathways in genetic Parkinson's disease: Potential role of ceramide metabolism in Lewy body disease. FEBS J 2008; 275 (23) 5767-5773
    CrossrefPubMedSearch in Google Scholar
  • 50 Beutler E, Beutler L, West C. Mutations in the gene encoding cytosolic beta-glucosidase in Gaucher disease. J Lab Clin Med 2004; 144 (2) 65-68
    CrossrefPubMedSearch in Google Scholar
  • 51 Bultron G, Kacena K, Pearson D , et al. The risk of Parkinson's disease in type 1 Gaucher disease. J Inherit Metab Dis 2010; 33 (2) 167-173
    CrossrefPubMedSearch in Google Scholar
  • 52 Ida H, Rennert OM, Iwasawa K, Kobayashi M, Eto Y. Clinical and genetic studies of Japanese homozygotes for the Gaucher disease L444P mutation. Hum Genet 1999; 105 (1–2) 120-126
    CrossrefPubMedSearch in Google Scholar
  • 53 Uyama E, Takahashi K, Owada M , et al. Hydrocephalus, corneal opacities, deafness, valvular heart disease, deformed toes and leptomeningeal fibrous thickening in adult siblings: a new syndrome associated with beta-glucocerebrosidase deficiency and a mosaic population of storage cells. Acta Neurol Scand 1992; 86 (4) 407-420
    CrossrefPubMedSearch in Google Scholar
  • 54 Machaczka M. Allogeneic hematopoietic stem cell transplantation for treatment of Gaucher disease. Pediatr Hematol Oncol 2013; 30 (5) 459-461
    CrossrefPubMedSearch in Google Scholar
  • 55 Altarescu G, Hill S, Wiggs E , et al. The efficacy of enzyme replacement therapy in patients with chronic neuronopathic Gaucher's disease. J Pediatr 2001; 138 (4) 539-547
    CrossrefPubMedSearch in Google Scholar
  • 56 Tajima A, Yokoi T, Ariga M , et al. Clinical and genetic study of Japanese patients with type 3 Gaucher disease. Mol Genet Metab 2009; 97 (4) 272-277
    CrossrefPubMedSearch in Google Scholar
  • 57 Sechi A, Deroma L, Dardis A , et al. Long term effects of enzyme replacement therapy in an Italian cohort of type 3 Gaucher patients. Mol Genet Metab 2014; 113 (3) 213-218
    CrossrefPubMedSearch in Google Scholar
  • 58 Schiffmann R, Fitzgibbon EJ, Harris C , et al. Randomized, controlled trial of miglustat in Gaucher's disease type 3. Ann Neurol 2008; 64 (5) 514-522
    CrossrefPubMedSearch in Google Scholar