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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
AOU “S.M. Misericordia”Udine
Centro di Coordinamento
Regionale Malattie Rare
Giovanni CianaPediatra