POTENTIAL LINK BETWEEN GAUCHER DISEASE PATHWAYS

Transcription

1 POTENTIAL LINK BETWEEN GAUCHER DISEASE PATHWAYS AND THOSE OF PARKINSON DISEASE Hanna Rosenbaum, MD Hematology and Bone Marrow Transplantation Rambam Medical Center and Bruce Rappaport Faculty of Medicine Haifa, Israel

2 Phillip Gaucher James Parkinson

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4 H H C C CH 2 O O CH 2 OH OH OH N C OH O OH OH Glucocerebroside + H 2 0 Glucocerebrosidase Ceramide + Glucose Sidransky and LaMarca, 2003 Macrophage Gaucher Macrophage

5 Gaucher Disease Subtypes Non-neuronopathic, Type 1 Prevalent in Ashkenazi Jews. Onset at any age Neuronopathic, Types 2 and 3 Type 2 (acute) Pan ethnic Onset in infancy Life expectancy 2 to 3 years Type 3 (chronic) Pan ethnic Onset in infancy/childhood

6 Gaucher Disease Phenotypes Type 1 Type 2 Sidransky and LaMarca, 2003 Type 3

7 Mutations in Glucocerebrosidase A176N G202R R257Q P289L D380N D380A 55 bp del Ψ F417V N370S R463C Y212H P182T F213 I Ψ R285C F216Y D399N V394L D409HΨ P415R W378G D409V G478S R496H Complex Allele A (Rec Nci)Ψ L444P, A456P, V460V Sidransky and LaMarca, GG 1023C DEL 1VS2+1 R120Q D140H P122S A309V W312C T3231 G325RΨ R463C L444PΨ N188SΨ K157Q Y313H R359Q S364T C342G E326K L425E R463Q Complex Allele B (Rec TL)Ψ D409H, L444P, A456P, V460V

8 Type 1 Gaucher Disease: Affected Organs and Manifestations Macrophages Splenomegaly Hepatomegaly Bone Marrow Skeletal pathology Pulmonary hypertension Beutler and Grabowski, The Metabolic and Molecular Bases of Inherited Disease 2001

9 HEMATOLOGICAL MANIFESTATIONS Splenomegaly Pancytopenia : anemia,thrombocytopenia Leucopenia, impaired neutrophil function Bleeding tendency Marrow infiltration and fibrosis Monoclonal gammopathies Autoimmune phenomena

10 Skeletal Involvement

11 Prevalence: 1/100 Parkinson disease Main symptoms: Resting tremor, Akinesia, Rigidity Postural instability Neurobehavioral changes Pathophysiology: Degeneration of dopaminergic neurons SN pars compacta

12 Etiology Familial cases are rare Most cases are sporadic Genetic factors PARK genes Park1-Synuclein on 4q Park 2-parkin on 6q ubiquitin hydrolase -L1 on 4p14 Park 7-DJ-1 1p36 Environmental factors

13 Patient No. A 50 year old Ashkenazi female. Type 1 Gaucher homozygous N370S diagnosed at age 9. Splenectomy at age 13. Hepatomegaly, no bone involvement. Obsessive-compulsive disorder at age years later kyphotic posture and gait disturbance. Bilateral Parkinsonian features since age 48 including : cogwheel rigidity, bradykinesia,

14 Cognitive examination Dysexecutative syndrome : impaired attention and concentration, perseverations Impaired memory and confabulations. Visual-spatial impairment and visual hallucinations. At age 50 developed dementia and became bedridden. Died at age 52. Dx: Parkinson disease, Lewy body dementia.

15 Background Among 90 Ashkenazi Jewish Type 1 Gaucher patients followed at the Rambam medical center in Haifa, Israel 3(3.3%) presented Parkinsonian manifestations. One of the patients was the first documented N370S/N370S genotype with Parkinsonism (Varkonyi et al,2002).

16 Goals Evaluate: Prevalence of common Gaucher mutations among Ashkenazi Jewish patients with Parkinson disease. Relevance of glucocerebrosidase mutations to the severity and progression of Parkinsonian symptoms. Incidence of Parkinson disease among relatives of Gaucher Patients

17 Patients population Methods (1) 157 consecutive Ashkenazi Jewish patients with idiopathic Parkinson disease. Control population 74 patients with Alzheimer disease healthy Ashkenazi individuals

18 Results (1) N370S other carriers (%) 95% CI Parkinson 31 *het 4 het (84GG) 43(27.4 %) % n=157 5 homo 3 het (R496H) Alzheimer n=74 2 het 1 het (84GG) 3 (4.1% ) Controls n= het 3 het (84GG) 95 (6.2%) homozygote *heterozygote 5-7.4

19 Results (2) Frequency of mutant allele Parkinson patients N370S 1: GG 1:39.75 Control population N370S 1: GG 1:514

20 Results (3) Number of Gaucher disease carriers among Parkinson patients exceeds that observed among normal controls OR = 5.7 CI p< Number of Gaucher disease carriers among Parkinson disease patients exceeds that observed among Alzheimer patients OR =8.9 CI p=0.0008

21 November 2004

22 Clinical characteristics of Type I GD and PD Pt Sex Age GD PD fam. history Age of PD onset GD PD 1 F Splenectomy (30) AVN, HIP 2 F Bleeding bone crisis organomegaly Limited response to L-DOPA, psychosis died at 61 Progression on L-DAPA died at 58 3 F 9 Aunt 48 Splenectomy (13) Progression dementia, psychosis 4 F 59 2 uncles 43 Organomegaly ocular manifestation 5 F 58 Mother 58 Pulmonary, hypertension, osteopenia 6 M Splenomegaly, bone infarcts, osteopenia Responsive to L-DOPA excellent response to DBS* Responsive to L-DOPA Lt Hem PD.

23 Age PD in family members of Ashkenazi GD patients 12/43 (28%) GD patients have relatives with PD Sex Genotype PD family history PD onset GD Additional 18 f 84GG/1604 mother+2 gf severe 20 m 84GG/1226 grandfather 50 severe Dementia 59 f 1226/ uncles 55 mild Retinal GD? 31 m 1226/1226 sister 46 severe PHT 18 m 1226/1226 grandmother 65 mild 27 f 1226/1226 mother mild 18 m 1226/1226 father + aunt 70 mild 32 f 1226/ aunts ident twins 55, 67 mild Nephrotic syndrome 40 m 1226/1226 aunt f 1226/1226 mother 40 mild 8 m 1226/1226 grandmother 70 mild 13 f 1226/1226 mother + aunt 60,64 severe Dementia

24 Incidence of PD among Relatives of GD Patients Goker-Alpan, NIH /40 families (22%) Halperin, Jerusalem 2006 (27.3%)

25 Pedigree of Gaucher patient with family history of Parkinson (1) / 84GG/ GD GD GD 84GG/ GG/ GG/1604

26 Pedigree of Gaucher patient with family history of Parkinson (2) Identical twins GD 1226/ 1226

27 In summary (1) Gaucher mutations among Parkinson patients A high frequency of the mutant N370S glucocerebrosidase allele was detected among Parkinson patients - increased by 5 -fold of healthy Ashkenazi controls. The frequency of 84GG allele was 13 times of the control group (p<0.001).

28 (2) Frequency of PD among relatives of Gaucher patients A high rate of Parkinson disease was found among relatives of Gaucher patients (confirmed and obligate carriers of Glucocerebrosidase mutations).

29 (3) Clinical, pathologic, and genetic studies suggest: Glucocerebrosidase deficiency may predispose subjects to the development of Parkinson disease.

30 The odds ratio for any GBA mutation in PD patients versus controls was 5.43 NEJM 2009

31 The link between Gaucher Disease and Parkinson Gaucher cells Lewy body

32 LEWY BODIES AND THE ROLE OF Α-SYNUCLEIN Glucocerebrosidase mutations are the most common genetic risk factor for Parkinson disease and Lewy bodies dementia. Neurodegeneration in Parkinson disease is accompanied by formation of Lewy bodies and Lewy neurites Lewy bodies contain aggregates of the presynaptic protein α-synuclein. In patients with GBA mutations Glucocerebrosidase was present in most Lewy bodies. α- Synuclein tends to aggregate into toxic oligomers which are associated with cell death and neurodegeneration.

33 Model of interactions among proteins in Parkinsons disease Feany MB NEJM 351:

34 Potential mechanisms linking mutant GCase with PD. Loss of enzymatic function owing to mutation might result in a pathogenic positive-feedback loop, as proposed by Mazzulli et al. Kinghorn K J Dis. Model. Mech. 2011

35 Putative models for α-synuclein turn over pathways affected in Gaucher disease Westbroek W et al, Trend in Molecular Medicine, 2011

36 Impaired ERAD-mediated breakdown of GCase Westbroek W et al, Trend in Molecular Medicine, 2011

37 A theoretical model for α-synuclein as a prion in GBA-associated parkinsonism Westbroek W et al, Trend in Molecular Medicine, 2011 Adapted from Goldin E Mol Genet Metab 2010

38 A timeline of the generation of mouse models of GD. Farfel-Becker T et al. Dis. Model. Mech. 2011

39 In vivo α-syn-gcase interaction. Yap T L et al. J. Biol. Chem. 2011

40 IN CONCLUSION Only a small percentage of Gaucher patients and carriers develop Parkinson Disease. The role of reduced enzyme activity and substrate accumulation on the α-synuclein pathology is yet not clear. Animal and cell models should be developed for the research of concomitant Gaucher disease and Parkinson. The challenge in the future should include recognition of risk factors and development of therapeutic agents for coexistence of Gaucher disease and Parkinson.

41 Whoever saves one life saves the entire world SANHEDRIN