Archives for June 2009

http://www3.interscience.wiley.com/journal/122441884/abstract?CRETRY=1&SRETRY=0

Frédéric Sedel (frederic.sedel@psl.aphp.fr)

Ichraf Kraoua, MD 1, Jérôme Stirnemann, MD 2, Maria João Ribeiro, MD, PhD 3, Tiphaine Rouaud, MD 4, Marc Verin, MD, PhD 4, Agnès Annic, MD 5, Christian Rose, MD, PhD 6, Luc Defebvre, MD, PhD 5, Liliane Réménieras, MD 7, Michaël Schüpbach, MD 1, Nadia Belmatoug, MD 8, Marie Vidailhet, MD 1 9, Frédéric Sedel, MD, PhD 1 *
1Federation of Nervous System Diseases, Reference Center for Lysosomal Diseases, Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, France 2Department of Internal Medicine, Jean Verdier Hospital, Assistance Publique-Hôpitaux de Paris, Paris X111 University, France 3Service Hospitalier Frédéric Joliot, I2BM, DSV, CEA, Orsay, France 4Department of Neurology, University Hospital of Rennes, Rennes, France 5Department of Neurology, University Hospital of Lille, Lille, France 6Department of Onco-Haematology, Saint Vincent de Paul Hospital, Lille, France 7Department of Haematology, University Hospitals of Limoges, Limoges, France 8Department of Internal Medicine, Reference Center for Lysosomal Diseases, Beaujon Hospital, Assistance Publique-Hôpitaux de Paris, France 9INSERM U679, Pierre et Marie Curie (Paris 6) University, France
	email:

^*Correspondence to Frédéric Sedel, Federation of Nervous System Diseases and Reference Centre for Lysosomal Diseases, Salpêtrière Hospital, 47 Boulevard de l’Hôpital, 75651 Paris cedex 13, France

Potential conflict of interest: None reported.

Funded by:
 Genzyme

Keywords

Gaucher • glucocerebrosidase • parkinsonism • Parkinson’s disease • Lewy body dementia

Abstract

Parkinsonism has been described in patients with Gaucher’s disease (GD). We reviewed the 10 cases of patients with both parkinsonism and GD recorded in the French national GD registry, as well as 49 previously published cases. Relative to the general population, parkinsonism in GD patients (1) was more frequent, (2) occurred at an earlier age, (3) responded less well to levodopa, and (4) was more frequently associated with signs of cortical dysfunction. Enzyme replacement therapy (ERT) and substrate reduction therapy (SRT) were ineffective on GD-associated parkinsonism, suggesting that parkinsonism itself is not an indication for ERT or SRT in this setting. © 2009 Movement Disorder Society

http://brain.oxfordjournals.org/cgi/content/short/132/7/1783?rss=1

Glucocerebrosidase mutations in clinical and pathologically proven Parkinson’s disease

Juliane Neumann^1,2, Jose Bras^3,4,*, Emma Deas^1,*, Sean S. O’Sullivan¹, Laura Parkkinen¹, Robin H. Lachmann¹, Abi Li¹, Janice Holton¹, Rita Guerreiro^3,4, Reema Paudel¹, Badmavady Segarane¹, Andrew Singleton³, Andrew Lees¹, John Hardy¹, Henry Houlden¹, Tamas Revesz¹ and Nicholas W. Wood¹

1 Department of Molecular Neuroscience, Institute of Neurology, University College London, London, and Reta Lila Weston Institute, Institute of Neurology, London, UK 2 International Graduate Program Medical Neurosciences, Charité University Hospital, Berlin, Germany 3 Molecular Genetics Unit, Laboratory of Neurogeneticso, National Institutes on Aging, National Institutes of Health, Bethesda, Maryland, USA 4 Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal

Correspondence to: Nicholas W. Wood, Institute of Neurology, Queen Square House, Queen Square, WC1N 3BG London, UK E-mail: n.wood@ion.ucl.ac.uk

Mutations in the glucocerebrosidase gene (GBA) are associated with Gaucher’s disease, the most common lysosomal storage disorder. Parkinsonism is an established feature of Gaucher’s disease and an increased frequency of mutations in GBA has been reported in several different ethnic series with sporadic Parkinson’s disease. In this study, we evaluated the frequency of GBA mutations in British patients affected by Parkinson’s disease. We utilized the DNA of 790 patients and 257 controls, matched for age and ethnicity, to screen for mutations within the GBA gene. Clinical data on all identified GBA mutation carriers was reviewed and analysed. Additionally, in all cases where brain material was available, a neuropathological evaluation was performed and compared to sporadic Parkinson’s disease without GBA mutations. The frequency of GBA mutations among the British patients (33/790 = 4.18%) was significantly higher (P = 0.01; odds ratio = 3.7; 95% confidence interval = 1.12–12.14) when compared to the control group (3/257 = 1.17%). Fourteen different GBA mutations were identified, including three previously undescribed mutations, K7E, D443N and G193E. Pathological examination revealed widespread and abundant -synuclein pathology in all 17 GBA mutation carriers, which were graded as Braak stage of 5–6, and had McKeith’s limbic or diffuse neocortical Lewy body-type pathology. Diffuse neocortical Lewy body-type pathology tended to occur more frequently in the group with GBA mutations compared to matched Parkinson’s disease controls. Clinical features comprised an early onset of the disease, the presence of hallucinations in 45% (14/31) and symptoms of cognitive decline or dementia in 48% (15/31) of patients. This study demonstrates that GBA mutations are found in British subjects at a higher frequency than any other known Parkinson’s disease gene. This is the largest study to date on a non-Jewish patient sample with a detailed genotype/phenotype/pathological analyses which strengthens the hypothesis that GBA mutations represent a significant risk factor for the development of Parkinson’s disease and suggest that to date, this is the most common genetic factor identified for the disease.

 Key Words: Parkinson’s disease; GBA; Gaucher’s disease; neuropathology

 Abbreviations: AC, amygdaloid complex; BFB, basal forebrain; DMV, dorsal motor nucleus of vagus; GBA, glucocerebrosidase; HRC, human random control; LC, locus ceruleus; NBM, nucleus basalis of Meynert; SN, substantia nigra

http://www.ncbi.nlm.nih.gov/pubmed/19380242?dopt=Abstract

Kacher Y, Futerman AH.

Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.

A number of studies have shown altered cytokine levels in serum from Gaucher disease patients, including changes in levels of the anti-inflammatory cytokine, interleukin-10 (IL-10). However, the source of IL-10, or the mechanisms leading to changes in IL-10 serum levels are not known. We now show that mouse macrophages treated with an active site-directed inhibitor of glucocerebrosidase, or macrophages from a mouse model of Gaucher disease, the L444P mouse, release significantly less IL-10 than their untreated counterparts, but that TNFalpha release is unaffected. These changes are due to reduced transcription of IL-10 mRNA in macrophages. The reduction in IL-10 secretion observed in animal models of Gaucher disease macrophages may be of relevance to explain the increase in inflammation that is often observed in Gaucher disease.

Publication Types:

• Research Support, Non-U.S. Gov’t

PMID: 19380242 [PubMed – in process] Kacher Y, Futerman AH.