POTENTIAL LINK BETWEEN GAUCHER DISEASE PATHWAYS

AND THOSE OF PARKINSON DISEASE

Hanna Rosenbaum , MD

Hematology and Bone Marrow TransplantationRambam Medical Center and

Bruce Rappaport Faculty of Medicine Haifa, Israel

Phillip Gaucher James Parkinson 1882 1817

C C CH2 O

C O

H H

OH

OH

N

CH2OH

OH

OH

OH

O

Glucocerebroside + H20 Ceramide + GlucoseGlucocerebrosidase

Macrophage Gaucher MacrophageSidransky and LaMarca, 2003

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

Type 1

Type 2

Type 3Sidransky and LaMarca, 2003

Gaucher Disease Phenotypes

Sidransky and LaMarca, 2003

Mutations in Glucocerebrosidase

84GG1023C DEL

1VS2+1

R120Q

A176N

G202R P182T

L444PΨΨΨΨ

K157Q

P122S

N188SΨΨΨΨF213 I ΨΨΨΨ

D140H

R463C

Y212H

D399NV394LD409HΨΨΨΨP415R

N370S

55 bp del ΨΨΨΨ

W378G

D380N

D380A

F417V

A309V

G478S

T3231

G325RΨΨΨΨ

W312CS364TC342GE326K

Y313HR359Q

D409V

R496HR463C R463Q

L425E

Complex Allele B (Rec TL)ΨΨΨΨD409H, L444P, A456P, V460VComplex Allele A (Rec Nci)ΨΨΨΨ

L444P, A456P, V460V

1

2

3

4

5

6

7

8

9

10

11

R285CR257QF216YP289L

Type 1 Gaucher Disease: Affected Organs and Manifestations

Macrophages

Bone Marrow

Beutler and Grabowski, The Metabolic and Molecular Bases of Inherited Disease 2001

Skeletal pathology

Pulmonary hypertension

Hepatomegaly Splenomegaly

HEMATOLOGICAL MANIFESTATIONS

Splenomegaly

Pancytopenia : anemia,thrombocytopenia

Leucopenia, impaired neutrophil function

Bleeding tendency

Marrow infiltration and fibrosis

Monoclonal gammopathies

Autoimmune phenomena

Skeletal Involvement

Parkinson disease

� Prevalence: 1/100

� Main symptoms:

Resting tremor, Akinesia, Rigidity Postural instability

Neurobehavioral changes

� Pathophysiology:

Degeneration of dopaminergic neurons SN pars compacta

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

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 38.

� 4 years later kyphotic posture and gait disturbance.

� Bilateral Parkinsonian features since age 48 including : cogwheel rigidity, bradykinesia,

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.

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).

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

Methods (1)

Patients population

� 157 consecutive Ashkenazi Jewish patients

with idiopathic Parkinson disease.

Control population

� 74 patients with Alzheimer disease.

� 1543 healthy Ashkenazi individuals

Results (1)

N370S other carriers (%) 95% CI

Parkinson

n=157

31 *het

5 ♦ homo

4 het (84GG)

3 het (R496H)

43(27.4 %) 19.6-34.4%

Alzheimer

n=74

2 het 1 het (84GG) 3 (4.1% ) 0.0-8.5

Controls

n=1543

92 het 3 het (84GG) 95 (6.2%)

♦homozygote

*heterozygote

5-7.4

Results (2)

Frequency of mutant allele

�Parkinson patients N370S 1:3.65

84GG 1:39.75

�Control population N370S 1:16.7

84GG 1:514

Results (3)

Number of Gaucher disease carriers among Parkinson patients exceeds that observed among normal controls

OR = 5.7 CI 3.7-8.8 p<0.0001

Number of Gaucher disease carriers amongParkinson disease patients exceeds that observed among Alzheimer patients

OR =8.9 CI 2.5-25.2 p=0.0008

November 2004

Clinical characteristics of Type I GD and PD

Pt Sex Age GD

PD fam. history

Age of

PD onset

GD PD

1 F 28 50 Splenectomy

(30) AVN, HIP

Limited response to

L-DOPA, psychosis

died at 61

2 F 30 47 Bleeding bone crisis organomegaly

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

Responsive to L-DOPA excellent response to DBS*

5 F 58 Mother 58 Pulmonary, hypertension, osteopenia

Responsive to L-DOPA

6 M 18 49 Splenomegaly, bone infarcts, osteopenia

Lt Hem PD.

PD in family members of Ashkenazi GD patients

12/43 (28%) GD patients have relatives with PDAdditionalGDPD onsetPD family historyGenotypeSexAge

severe50-55mother+2 gf84GG/1604f18

Dementiasevere50grandfather84GG/1226m20

Retinal GD?mild552 uncles1226/1226f59

PHTsevere46sister1226/1226m31

mild65grandmother1226/1226m18

mildmother1226/1226f27

mild70father + aunt1226/1226m18

Nephrotic syndromemild55, 672 aunts ident twins1226/1226f32

65aunt1226/1226m40

mild40mother1226/1226f61

mild70grandmother1226/1226m8

Dementiasevere60,64mother + aunt1226/1226f13

Incidence of PD among Relatives of GD

Patients

Goker-Alpan, NIH 2004 9/40 families (22%)

Halperin, Jerusalem 2006 (27.3%)

Pedigree of Gaucher patient with family

history of Parkinson (1)

5555

50 52

/1604 84GG/

GD GD

84GG/1604 84GG/1604 84GG/1604

GD

28 24 18

Pedigree of Gaucher patient with family

history of Parkinson (2)

GD

1226/ 1226

55 67

Identical twins

In summary (1)

Gaucher mutations among Parkinson patients

� A high frequency of the mutant N370Sglucocerebrosidase 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).

(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).

(3)Clinical, pathologic, and genetic studies

suggest:

� Glucocerebrosidase deficiency may predispose

subjects to the development of Parkinson disease.

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

The link between Gaucher Disease and Parkinson

Gaucher cells Lewy body

� Glucocerebrosidase mutations are the most common geneticrisk 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 areassociated with cell death and neurodegeneration.

LEWY BODIES AND THE ROLE OF Α-SYNUCLEIN

Model of interactions among proteins

in Parkinsons disease

Feany MB NEJM 351:1937 2004

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

Putative models for α- Synuclein turn over pathways affected in Gaucher disease

Westbroek W et al, Trend in Molecular Medicine, 2011

Impaired ERAD-mediated breakdown of GCase

Westbroek W et al, Trend in Molecular Medicine, 2011

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

A timeline of the generation of mouse models of GD.

Farfel-Becker T et al. Dis. Model. Mech. 2011

In vivo α-syn-GCase interaction.

Yap T L et al. J. Biol. Chem. 2011

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.

Whoever saves one life

saves the entire world

SANHEDRIN