Abstract
The Norrbottnian type of Gaucher disease (GD), as described many years ago, is due to a unique neuronopathic variant (c.1448T>G; L444P) that may have appeared during or before the sixteenth century in northern Sweden. It is a well-defined nosological entity with a characteristic course of clinical manifestations. In particular, Norrbottnian patients described in Sweden and Poland seem to share identical clinical histories characterized by the early onset of significant hepatosplenomegaly, often requiring splenectomy at an early age. Neurological involvement generally appears during the first or second decade of life, and includes horizontal gaze palsy, epilepsy, myoclonic movements, ataxia, dementia and cognitive impairment. Osteopenia occurs primarily in the spine, causing a severe and progressive thoracic kyphosis, although the involvement of other skeletal sites cannot be excluded. Here, we report on four Gaucher type 3 patients with Southern Italian ancestry presenting with clinical features and disease progression comparable to those of the ‘Norrbottnian’ Swedish phenotype, particularly regarding skeletal involvement with poor responsiveness to any therapeutical approach. Although a common ancestry among Southern Italian and Swedish Norrbottnian GD patients could not be investigated, the genotype [L444P]+[L444P] is the most frequently encountered in Southern Italy.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Beutler, E. & Grabowski, G. A. in: The Metabolic and Molecular Bases of Inherited Disease (eds Scriver, C. R., Baudet, A. L., Sly, W. S. & Valle, D.) 3635–3668 (McGraw-Hill, New York, 2001).
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. 160, 2835–2843 (2000).
Dahl, N., Hillborg, P. O. & Olofsson, A. Gaucher disease (Norrbottnian type III): probable founders identified by genealogical and molecular studies. Hum. Genet. 92, 513–515 (1993).
Dreborg, S., Erikson, A. & Hagberg, B. Gaucher disease—Norrbottnian type. I. General clinical description. Eur. J. Pediatr. 133, 107–118 (1980).
Ida, H., Rennart, O. M., Iwasawa, K., Kobayashi, M. & Eto, Y. Clinical and genetic studies of Japanese homozygotes for the Gaucher disease L444P mutation. Hum. Genet. 105, 120–126 (1999).
Abdelwahab, M., Blankenship, D. & Schiffmann, R. Long-term follow-up and sudden unexpected death in Gaucher disease type 3 in Egypt. Neurol. Genet. 2, e55 (2016).
Tylki-Szymañska, A., Keddache, M. & Grabowski, G. A. Characterization of neuronopathic Gaucher disease among ethnic Poles. Genet. Med. 8, 8–15 (2006).
Tajima, A., Yokoi, T., Ariga, M., Ito, T., Kaneshiro, E., Eto, Y. et al. Clinical and genetic study of Japanese patients with type 3 Gaucher disease. Mol. Genet. Metab. 97, 272–277 (2009).
Goker-Alpan, O., Hruska, K. S., Orvisky, E., Kishnani, P. S., Stubblefield, B. K., Schiffmann, R. et al. Divergent phenotypes in Gaucher disease implicate the role of modifiers. J. Med. Genet. 42, e37 (2005).
Filocamo, M., Mazzotti, R., Stroppiano, M., Seri, M., Giona, F., Parenti, G. et al. Analysis of the glucocerebrosidase gene and mutation profile in 144 Italian Gaucher patients. Hum. Mutat. 20, 234–235 (2002).
Filocamo, M., Bonuccelli, G., Mazzotti, R., Giona, F. & Gatti, R. Identification of a novel recombinant allele in three unrelated Italian Gaucher patients: implications for prognosis and genetic counseling. Blood Cells Mol. Dis. 26, 307–311 (2000).
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. 33, 339–346 (2010).
Sidransky, E., Nalls, M. A., Aasly, J. O., Aharon-Peretz, J., Annesi, G., Barbosa, E. R. et al. Multicenter analysis of glucocerebrosidase mutations in Parkinsons disease. N. Engl. J. Med. 361, 1651–1661 (2009).
Altarescu, G., Hill, S., Wiggs, E., Jeffries, N., Kreps, C., Parker, C. C. et al. The efficacy of enzyme replacement therapy in patients with chronic neuronopathic Gaucher’s disease. J. Pediatr. 138, 539–547 (2001).
Kraoua, I., Sedel, F., Caillaud, C., Froissart, R., Stirnemann, J., Chaurand, G. et al. A French experience of type 3 Gaucher disease: phenotypic diversity and neurological outcome of 10 patients. Brain Dev. 33, 131–139 (2011).
Sechi, A., Deroma, L., Dardis, A., Ciana, G., Bertin, N., Concolino, D. et al. Long term effects of enzyme replacement therapy in an Italian cohort of type 3 Gaucher patients. Mol. Genet. Metab. 113,, 213–218 (2014).
Erikson, A., Astrom, M. & Mansson, J. E. Enzyme infusion therapy of the Norrbottnian (type 3) Gaucher disease. Neuropediatrics 26, 203–207 (1995).
Erikson, A., Forsberg, H., Nilsson, M., Aström, M. & Månsson, J. E. Ten years’ experience of enzyme infusion therapy of Norrbottnian (type 3) Gaucher disease. Acta Paediatr. 95, 312–317 (2006).
Santamaria, F., Parenti, G., Guidi, G., Filocamo, M., Strisciuglio, P., Grillo, G. et al. Pulmonary manifestations of Gaucher disease: an increased risk for L444P homozygotes? Am. J. Respir. Crit. Care Med. 157, 985–989 (1998).
Raghavan, S. S., Topol, J. & Kolodny, E. H. Leukocyte beta-glucosidase in homozygotes and heterozygotes for Gaucher disease. Am. J. Hum. Genet. 32, 158–173 (1980).
Acknowledgements
The patient samples were obtained from the ‘Cell Line and DNA Biobank from patients affected by Genetic Diseases’ (Istituto Giannina Gaslini), a member of the Telethon Network of Genetic Biobanks (project no. GTB12001). This work was partially supported by unrestricted grants from the ‘Cinque per mille e Ricerca Corrente, Ministero della Salute.’
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Sestito, S., Filocamo, M., Ceravolo, F. et al. Norrbottnian clinical variant of Gaucher disease in Southern Italy. J Hum Genet 62, 507–511 (2017). https://doi.org/10.1038/jhg.2016.158
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2016.158
