M. di Gaucher e M.di Parkinson:
quale relazione
Bruno Bembi
Centro di Coordinamento Regionale per le
Malattie Rare
Ospedale 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
Clinical Features
Age at onset
Splenomegaly
Hepatomegaly
Skeletal disease/
bone crises
Primary CNS disease
Lifespan
Ethnicity/
demographic group
Frequency
Type 1
Type 2
Type 3
Childhood/
Adulthood
Infancy
Childhood
+  +++
+  +++
-  +++
++
++
--
+  +++
+  +++
++  +++
Absent
+++
6 to 80+ years
Panethnic
Ashkenazi Jewish
~ 1/60,000 to
1/200,000
~ 1/500 to 1/1,000
(AJ)
~2 years
Panethnic
+  +++
(1st to 5th decade)
2 to 60 years
Panethnic
Norrbottnian
 1/50,000
 1/100,000
ENZYME REPLACEMENT
THERAPY
ERT
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: 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-yearold 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
Gaucher and Parkinson
Case 1
(f: 72)
Case 2
(f:75†)
Case 3
(f:63)
Case 4
(m 64†)
Case 5
(m: 65)
Age GD
diagnosis
53
60
23
22
60
Age PD
diagnosis
59
55
43
44
55
Genotype
N370S/
N370S/
G377S/
G377S
N370S/
L444P
N370S/
G202R
g.4426
A>G
g.4426 A>G
Gaucher and Parkinson
Case 1
(f)
Case 2
(f)
normal
Left limbs
Clin.
Sympt. resting
Asymmetric
onset
tremor,
(right) ,
rigidity,
rigidity,
bradikynesia resting
tremor
akynesia
NMR
SPECT
ABR
Case 3
(f)
Case 4
(m)
Case 5
(m)
Asymmetric
onset
(right),
rigidity,
resting
tremor
Asymmetric
onset
(right) of
rigidity,
resting
tremor
akynesia
nd
Mild cortical
atrophy
Mild cortical Mild cortical
atrophy
athrophy
nd
nd
Basal ganglia
hypoperfusion
normal
nd
Mild latency
of I-III
waves
nd
Encephalic
trunk
abnormal
high tones
deafness
Resting
tremor left
hand ,
rigidity upper
limbs,
akynesia
nd
nd
Gaucher and Parkinson
Case 1 Case 2
(f)
(f)
EEG
Case 3
(f)
Case 4
(m)
Case 5
(m)
normal
na
diffuse non specific
encephalic
sufference
slow left
temporal
activity
na
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
1277
na
831.6
1320
1054
ABR
Ferritin*
* 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
60
n.d.
30-120
30-120
46-100
ERT (yrs)
12
-
15
10
5
PD response
to ERT
absent
-
absent
absent
absent
(U/Kg/month)
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.
Il gene mutato con più alta frequenza nei casi di PD sporadici è GBA!!!
L’eterozigosi per mutazioni del gene GBA è il principale
fattore di rischio genetico associato all’insorgenza di PD.
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
Pathogenesis of PD in GD1
NEURODEGENERAZIONE
Meccanismo comune:
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
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
AOU “S.M. Misericordia”
Udine
Centro di Coordinamento
Regionale Malattie Rare
Giovanni Ciana
Pediatra
Andrea Dardis
Biologo Responsabile Laboratorio
PhD in Biologia Molecolare
Stefania Zampieri
Annalisa Pianta
Milena Romanello
Erika Malini
Chimico
PhD in Biochimica
Biologo
PhD in Scienze Biomediche
e Biotecnologiche
Silvia Cattarossi
Irene Zanin
Biologo
PhD in Medicina molecolare
e rigenerativa
Tecnico di laboratorio
Biologo
Biologo
PhD in in Scienze e
Tecnologie Clinche
Tecnico di laboratorio
www.malattierare.aou.udine.it