Transcript Sporadic CJD is

1st Italian Family Day on Prion Diseases
Milan, October 3, 2009
Surveillance of Human Prion Diseases
Maurizio Pocchiari
Dpt. Cell Biology and Neurosciences
E-mail:[email protected]
Surveillance of Human Prion Diseases
Overall distribution of TSE diseases in humans
(Data from the EuroCJD and NeuroCJD Surveillance)
90
80
70
Percent
60
50
40
30
20
10
0
sCJD
gTSE
iCJD
vCJD
Sporadic CJD is
•is not related to any recognizable risk factor ,
•is evenly distributed, with no significant temporal or spatial cluster,
•is not linked to any strong genetic background.
In other words, we have no clue as to how and why some people develop
sporadic CJD
The only two identified weak risk factors are
•the presence of methionine homozygosity at codon 129 of the prion protein
gene (PRNP) ,
•age greater than 60 years
Identified risk factors for sporadic CJD
Codon 129 polymorphism
Age-specific mortality rates in Italy
Accidental transmission of sporadic CJD might occur during surgery, with an
incubation period exceeding 10 years.
Sporadic CJD and prevention
• Prevention of sporadic CJD will be difficult to
achieve.
• But, it is not linked to any professional activity
and is not transmissible from person to person
during care of patients, laboratory testing, or
social or sexual contact.
• The observed increase in cases occasionally
reported in some regions is difficult to explain,
but it likely represents better case identification
by local neurologists.
Iatrogenic CJD in EUROCJD
Iatrogenic CJD
Total TSEs
Australia
4
394
Austria°
2
182
Canada°°
4
415
France
115
1710
Germany
11
1637
Italy
6
1334
Netherlands
5
268
Slovakia
-
135
Spain°
7
819
Switzerland°
4
199
UK
52
1258
210 (2.5)
8351
Total (%)
To date, >400 patients with iatrogenic CJD (dura mater grafts, hGH, corneal transplants, contaminated neurosurgical instruments,
or i.c. EEG electrodes ) have been reported worldwide
Genetic TSE diseases
gCJD
GSS
From: Wadsworth et al., 2003
FFI
Mortality rate (million people)
Genetic TSE diseases in the
EUROCJD contries
1,2
1
0,8
0,6
0,4
0,2
0
y
a
e
ia
ia
n
c
d
l
r
t
s
ra
an rma
na
t
r
u
a
F
e
A
C
us
G
A
Ita
N
ly
h
et
la
r
e
s
d
n
i
k
va
o
Sl
a
d
in
n
a
rla
Sp
e
itz
Sw
U
K
Frequency of genetic TSE in the EUROCJD
countries
40
35
Percentage
30
25
20
15
10
5
0
E200K
V210I
gCJD
D178N-129M
FFI
P102L
GSS
Frequency of positive family history for
genetic TSE
90
80
Percentage
70
60
50
40
30
20
10
0
E200K
V210I
gCJD
D178N-129M
FFI
P102L
GSS
No familial cases of CJD were found in our series
PRNP genotype in all suspected cases
TSE in Italy
(1993-2008)
Genetic TSEs
Referrals
Sporadic,
iatrogenic,
variant CJD
(Deaths)
Deaths°
Incident
cases
2561
1053
239
268
°18.5% of total cases (No.=1087)
PRNP Mutations Identified in Italy
Glu --> Lys at codon
200
CJD
Glu --> Lys at codon
196
CJD
Val --> Ile at codon
203
CJD
Arg --> His at codon
208
CJD
Val --> Ile at codon
210
CJD
Glu --> Gln at codon
211
CJD
Asp --> Asn at codon
178/val
CJD
Asp --> Asn at codon
178/met
FFI
Pro --> Leu at codon
102
GSS
Inserts (1,4,7,8) in the octapeptide repeat region
E200K and V210I genetic CJD
• Cluster
• Origin of the E200K and V210I mutation
• Penetrance and factors influencing the age at onset
• Anticipation
Regional distribution of E200K and V210I cases by place of birth
E200K
December 2008
1-3 cases
V210I
1-3 cases
4-10 cases
4-9 cases
26 cases
10-20 cases
CLUSTERS OF GENETIC E200K CJD CASES
E200K gCJD Ancestral Origin
Lee et al., 1999
V210I gCJD
E200K and V210I genetic CJD
• Cluster
• Origin of the E200K and V210I mutation
• Penetrance and factors influencing the age at onset
• Anticipation
CLUSTERS OF FAMILIAL Glu200Lys CJD CASES
Cumulative penetrance
1
Italian
Slovak
Lybian Jews
0.8
0.6
0.4
0.2
0
0
20
40
60
Age at onset
80
100
Cumulative age-dependent probability of
developing CJD for V210I carriers
CJD cases
CJD +neurological cases
Cumulative penetrance
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
<30
30-39
40-49
50-59
Age (years)
60-69
70-79
80
E200K and V210I genetic CJD
• Cluster
• Origin of the E200K and V210I mutation
• Penetrance and factors influencing the age at onset
• Anticipation
Analysis of genetic anticipation
in E200K CJD (Calabria cluster)
95
Unaffected parent carrier
Offspring with CJD
Age (years)
85
Parent with CJD
75
65
55
45
35
0
5
10
15
Number of pedigrees
20
25
Analysis of genetic anticipation in V210I CJD
Unaffected parent carrier
Offspring with CJD
100
Age, years
Parent with CJD
80
60
40
20
0
0
10
20
30
40
Number of pedigrees
50
Anticipation in genetic E200K and
V210I Creutzfeldt-Jakob disease
Evidence
or
confounding factors?
Origin of the D178N/129M mutation: Regional distribution of
cases by place of birth or residence
Birth
1-3 cases
4 cases
December 2008
Residence
1 case
2 cases
Origin of the P102L mutation: Regional distribution of
cases by place of birth or residence
Birth
*December 2008
1-2 cases
Residence
1-2 cases
3-6 cases
3-5 cases
7-9 cases
6 cases
Phenotype Variability in P102L GSS Italian cases:
Clinical patterns in GSS families
Progressive Dementia
Cerebellar Syndrome
70
Percentage
60
50
40
30
20
10
0
G1
G2
GSS Italian Families
G3
Acknowledgments
•
Families of patients
•
Neurologists and Pathologists in the EuroCJD and NeuroCJD participating countries
•
The EuroCJD Surveillance:
Australia (S Collins, C Masters), Austria (H Budka, E Gelpi), Canada (GH Jansen), France (A Alperovitch, J-P
Brandel), Germany (I Zerr, H Kretszchmar), Italy (S Almonti, A Ladogana, V Mellina, M Puopolo),
Netherlands (C van Duijn, P Sanchez-Juan), Slovakia (E Mitrova), Spain (J de Pedro Cuesta), Switzerland
(A Aguzzi), UK (R Knight, R Will)
•
N
•
ISS c Maria Puopolo, Anna Ladogana, Anna Poleggi