M. di Gaucher e M.di Parkinson: quale relazione

Bruno BembiCentro di Coordinamento Regionale per le Malattie

RareOspedale Universitario di Udine

55° CONGRESSO NAZIONALE SNO Como, 22-24 aprile 2015

Gaucher disease

• Most common lysosomal

storage disorder

• Autosomal recessive

inheritance

• Enzyme deficiency

• Progressive, multisystemic

• Different phenotypes and

genotypes

Gaucher Disease: Phenotypes

Age at onset Childhood/ Infancy ChildhoodAdulthood

Splenomegaly + +++ ++ + +++Hepatomegaly + +++ ++ + +++Skeletal disease/ - +++ -- ++ +++bone crisesPrimary CNS disease Absent +++ + +++

(1st to 5th decade)

Lifespan 6 to 80+ years ~2 years 2 to 60 yearsEthnicity/ Panethnic Panethnic Panethnicdemographic group Ashkenazi Jewish NorrbottnianFrequency ~ 1/60,000 to 1/100,000 1/50,000

1/200,000~ 1/500 to 1/1,000

(AJ)

Clinical Features Type 1 Type 2 Type 3

ENZYME REPLACEMENT THERAPY

Concepts

• Replacement of the missing enzyme to correct the underlying defect– Reverses stored substrate– Prevents further substrate accumulation

• Effectively treats the different compartments

• Has been available since 1991

• Over 8000 children & adults safely treated world wide with ERT

ERT

ERT: efficacy in Type 1 GD

• Improves/normalizes laboratory parameters: Hb, PLTs, transaminases, chitotriosidase, acid phosphatase….

• Reduces tissues storage• Normalizes growth and puberal

spurt• Improves/normalizes bone

involvement in peadiatric and adult patients

• Improves quality of life

Patient Response to ERT

Lateral profile of a 14-year-old girl before and 13 months after enzyme replacement therapy. Note the changes in abdominal contour and degree of lordosis and the onset of puberty during treatment.

Pretreatment Post-treatment

GAUCHER E PARKINSON

Clinical evidence of GD1 and PD association

1. 1989: Zimran et al, case report descrive la presenza di PD in pazienti GD1

2. 1996: Neudorfer O et al,Occurrence of Parkinson's syndrome in type I Gaucher disease. QJM. Sep;89(9):691-4.

3. 2003: Bembi B et al, Gaucher's disease with Parkinson's disease: clinical and pathological aspects. Neurology. Jul 8;61(1):99-101.

4. 2010: Chérin P et al,The neurological manifestations of Gaucher disease type 1: the French Observatoire on Gaucher disease (FROG). JIMD Aug;33(4):331-8.

4/105 pazienti affetti da GD1

5. 2013: Becker JG et al. Parkinson's disease in patients and obligate carriers of Gaucher disease. Parkinsonism Relat Disord. Jan;19(1):129-31.

8/100 pazienti GD1 Ashkenazi

Gaucher and Parkinson

Personal casuistry:

• 5 PD/91 GD1 patients (5.5%)• 3 female 2 male• average age of onset: 50.2 yrs

  Case 1 (f: 72)

Case 2(f:75†)

Case 3(f:63)

Case 4(m 64†)

Case 5(m: 65)

Age GD diagnosi

s

53 60 23 22 60

Age PD diagnosi

s

59 55 43 44 55

Genotype

N370S/g.4426 A>G

N370S/g.4426 A>G

G377S/G377S

N370S/L444P

N370S/G202R

Gaucher and Parkinson

  Case 1 (f)

Case 2 (f)

Case 3 (f)

Case 4 (m)

Case 5 (m)

Clin.Sympt.

Left limbs resting tremor, rigidity, bradikynesia 

Asymmetric onset (right) , rigidity, resting tremor akynesia

Asymmetric onset (right), rigidity, resting tremor

Asymmetric onset (right) of rigidity, resting tremor akynesia

Resting tremor left hand , rigidity upper limbs, akynesia

NMR normal nd Mild cortical atrophy 

Mild cortical atrophy 

Mild cortical athrophy

SPECT nd nd Basal ganglia hypoperfusion 

nd nd

ABR normal nd Mild latency of I-III waves

Encephalic trunk abnormalhigh tones deafness

nd

Gaucher and Parkinson

Case 1 (f)

Case 2 (f)

Case 3 (f)

Case 4 (m)

Case 5(m)

EEG normal na diffuse non specific encephalic sufference

slow left temporal activity

na

ABR normal nd mild latency of I-III waves

high tones deafness

nd

OMA 

normal na normal 

normal 

normal

VEP normal na normal reduced amplitude

 

nd

Ferritin*

1277 na 831.6 1320 1054

* nv: male 28-397 ng/ml; female: 6-159 ng/ml

Gaucher and Parkinson

  Case 1 (f)

Case 2 (f)

Case 3 (f)

Case 4 (m)

Case 5(m)

L-Dopa response

 

good good good good mild

Surgery no 

no DBS: efficacy

pallidotomy: partial

efficacy

No

ERT dosage(U/Kg/month)

60 n.d. 30-120 30-120 46-100

ERT (yrs) 12 - 15 10 5

PD response to

ERT 

absent - absent absent absent

Gaucher and Parkinson

Gaucher and Parkinson

A B C

5691 PD pts (780 Ashkenazi Jews) - 4898 controls (387 Ashkenazi Jews). Sidransky et al., NEJM, 2009

The odds ratio for any GBA mutation in PD pts versus controls was 5.43 across centers.

L’eterozigosi per mutazioni del gene GBA è il principale fattore di rischio genetico associato all’insorgenza di PD.

Il gene mutato con più alta frequenza nei casi di PD sporadici è GBA!!!

Gaucher and Parkinson

Pathogenesis of PD in GD1

• Role of ferritin : all our patients, as frequently observed in GD , showed a marked elevation in serum ferritin

• The pro-oxidant activity of ferritin stored iron has been hypothesized to be involved in the damage of the dopaminergics neurons in PD (Mizuno Y et al. 1997)

• Although the role of iron in PD is still debated, its storage could play a part in the pathogenesis of the disease (Kaur et al. Neuron 2003)

• NEURODEGENERATION

Formazione di aggregati proteici formati da proteine con folding non corretto.

Formazione di aggregati → fibre con struttura amilode = b-sheets strettamente intrecciati e impaccati

Malattia di Parkinson: formazione di aggregati di synucleina (a-syn), proteina coinvolta nel traffico delle vescicole contenenti neurotrasmettitore: corpi di Lewy

NEURODEGENERAZIONE

Meccanismo comune:

Pathogenesis of PD in GD1

a-syn si accumula in modelli animali di GD e nei pazienti PD portatori di mutazioni della GBA

M. Siebert et al @Brain 2014: 137;1304-132

J. H. Choi et al @Mol Gen Metab, 2011; 104 (1-2): 185-188

M. Siebert et al @Brain 2014: 137;1304-132

RINGRAZIAMENTO

Andrea DardisBiologo Responsabile Laboratorio PhD in Biologia Molecolare

Stefania ZampieriBiologoPhD in Medicina molecolare e rigenerativa

Erika MaliniBiologoPhD in Scienze Biomediche e Biotecnologiche

Silvia CattarossiTecnico di laboratorio Biologo

Irene ZaninTecnico di laboratorio

Annalisa PiantaBiologoPhD in in Scienze e Tecnologie Clinche

Milena RomanelloChimicoPhD in Biochimica

www.malattierare.aou.udine.it

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Regionale Malattie Rare

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