Abstract
Gaucher disease (GD) is an autosomal recessive disorder characterized by defective function of glucocerebrosidase. GD presents a wide spectrum of manifestations, and patients and their relatives may develop neurological abnormalities more frequently than the general population. This study aims to determine the presence of neurological symptoms (NS) and Parkinson’s disease (PD) in Spanish GD patients and their relatives. We surveyed 87 GD Spanish families and validated the information obtained on the neurological involvement through their physicians, as well as the historical data included in the Spanish Gaucher Disease Registry. Neurological abnormalities were correlated with the genetic characteristics. Statistical analyses included descriptive parameters, ANOVA, t-test, correlation study and Pearson coefficient. Information was obtained from 118 patients and 324 relatives. Out of 110 patients with type 1 GD, 32 (29.1%) reported NS and 7 (6.4%) had PD. In relatives, a total of 39 (13.1%) subjects had NS, including 16 with PD (5.3%). The prevalence of NS in genetic carriers (15.9%) was greater than that in non-carriers (5.9%; p < 0.01). Patients with PD carried the following GBA mutations: S364R, D409H, L444P, R257Q, IVS4-2A > G, c.500insT, and L336P. Relatives with PD exhibited a wide spectrum of mutations: L444P, N370S, V398I, R257Q, G202R, c.1439-1445del7, [E326K; N188S], and c.953delT. We observed a high incidence of PD in type 1 GD and relative’s carriers. PD was more frequent in carriers of L444P and other rare GBA mutations. Therefore, it is important to perform a systematic neurological exam in patients with type 1 GD and carriers with high risk mutations.
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References
Aharon-Peretz J, Rosenbaum H, Gershoni-Baruch R (2004) Mutations in the glucocerebrosidase gene and Parkinson’s disease in Ashkenazi Jews. N Engl J Med 351:1972–7
Alfonso P, Aznarez S, Giralt M, Pocovi M, Giraldo P (2007) Spanish Gaucher's Disease Registry. Mutation analysis and genotype/phenotype relationships of Gaucher disease patients in Spain. J Hum Genet 52:391–6
Beutler E, Grabowski GA (2001) Gaucher disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease. McGraw-Hill, New York, pp 3635–68
Capablo JL, de Cabezón SA, Fraile J, Alfonso P, Pocoví M, Giraldo P (2008) Neurological evaluation of Gaucher disease patients diagnosed as type 1. J Neurol Neurosurg Psychiatry 79:219–22
Clark LN, Ross BM, Wang Y et al (2007) Mutations in the glucocerebrosidase gene are associated with early-onset Parkinson disease. Neurology 69:1270–7
Farrer MJ, Williams LN, Algom AA et al (2009) Glucosidase-beta variations and Lewy body disorders. Parkinsonism Relat Disord 15:414–6
Giraldo P, Capablo JL, Alfonso P, Latre P, García B, Pocoví M (2008) Grupo Español sobre Enfermedad de Gaucher. Neurological manifestations in patients with Gaucher disease and in their relatives. Med Clin Barc 131:175–9
Giraldo P, Pocoví M, Pérez-Calvo J, Rubio-Félix D, Giralt M (2000) Report of the Spanish Gaucher's disease registry: clinical and genetic characteristics. Haematologica 85:792–9
Goker-Alpan O, Lopez G, Vithayathil J, Davis J, Hallett M, Sidransky E (2008) The spectrum of Parkinsonian manifestations associated with glucocerebrosidase mutations. Arch Neurol 65:1353–57
Goker-Alpan O, Schiffmann R, La Marca ME, Nussbaum RL, McInerney-Leo A, Sidransky E (2004) Parkinsonism among Gaucher disease carriers. J Med Genet 41:937–40
Halperin A, Elstein D, Zimran A (2006) Increased incidence of Parkinson disease among relatives of patients with Gaucher disease. Blood Cells Mol Dis 36:426–8
Halperin A, Elstein D, Zimran A (2007) Are symptoms of peripheral neuropathy more prevalent in patients with Gaucher disease? Acta Neurol Scand 115:275–8
Kalinderi K, Bostantjopoulou S, Paisan-Ruiz C, Katsarou Z, Hardy J, Fidani L (2009) Complete screening for glucocerebrosidase mutations in Parkinson disease patients from Greece. Neurosci Lett 452:87–9
Kono S, Shirakawa K, Ouchi Y et al (2007) Dopaminergic neuronal dysfunction associated with parkinsonism in both a Gaucher disease patient and a carrier. J Neurol Sci 252:181–4
Mitsui J, Mizuta I, Toyoda A et al (2009) Mutations for Gaucher disease confer high susceptibility to Parkinson disease. Arch Neurol 66:571–6
Pastores GM, Barnett NL, Bathan P, Kolodny EH (2003) A neurological symptom survey of patients with type 1 Gaucher disease. J Inherit Metab Dis 26:641–5
Pastores GM, Weinreb NJ, Aerts H et al (2004) Therapeutic goals in the treatment of Gaucher disease. Semin Hematol 41(4 Suppl 5):4–14
Pocovi M, Cenarro A, Civeira F et al (1998) Beta-glucocerebrosidase gene locus as a link for Gaucher's disease and familial hypo-alpha-lipoproteinaemia. Lancet 351:1919–23
Rijk MC, Tzourio C, Breteler MMB et al (1997) Prevalence of parkinsonism and Parkinson´s disease in Europe: the Europarkinson collaborative study. J Neurol Neurosurg Psychiatry 62:10–15
Sánchez C. (2010) Impacto sociosanitario de las enfermedades neurológicas en España. Fundación Española de Enfermedades Neurológicas (FEEN): Disponible en: http:\\www.feeneurologia.com (December)
Sidransky E (2004) Gaucher disease: complexity in a « simple » disorder. Mol Genet Metab 83:6–15
Sidransky E, Nalls MA, Aasly JO et al (2009) Multicenter analysis of glucocerebrosidase mutations in Parkinson’s disease. N Engl J Med 361:1651–61
Tayebi N, Walker J, Stubblefield B et al (2003) Gaucher disease with parkinsonian manifestations: does glucocerebrosidase deficiency contribute to a vulnerability to parkinsonism? Mol Genet Metab 79:104–9
Ziegler SG, Eblan MJ, Gutti U et al (2007) Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease. Mol Genet Metab 91:195–200
Acknowledgments
This study was partially supported by the grants: FIS 06/1253, EC07/90737, FIS PS 09/2556, FEETEG and CIBERER U-752. The authors would like to thank all the members of the Spanish Gaucher Disease Group (SGDG) who provided clinical data and samples. The complete list of physicians of the SGDG who have contributed is available at: www.feeteg.org. The authors are also extremely grateful to the patients and their families whose participation made this work possible.
Disclosure
All the authors are members of the Spanish Study Group on Gaucher Disease, a group supported by the Spanish Gaucher Disease Foundation (FEETEG). The corresponding author and the majority of the others authors are researchers at the Aragonés Institute of Public Health (I + CS) and members of the Centro de Investigación Biomédica En Red de Enfermedades Raras (CIBERER), ISCIII, Zaragoza, Spain.
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Communicated by: Gregory M. Pastores
Competing interest: None declared.
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SupplementaryTablel 1
General characteristics of GD patients (DOC 133 kb)
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Giraldo, P., Capablo, J.L., Alfonso, P. et al. Neurological manifestations in patients with Gaucher disease and their relatives, it is just a coincidence?. J Inherit Metab Dis 34, 781–787 (2011). https://doi.org/10.1007/s10545-011-9298-4
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DOI: https://doi.org/10.1007/s10545-011-9298-4