The role of Anticipation in the incidence of CJD
with the Mutation E200K
Eva Mitrová
Washington, July 14th 2012
A short retrospective summary .....
The history of Slovak familial CJDE200K started in Orava
Geographical distribution of CJD according to the birthplace.
CJD cluster in Orava
Focal accumulation (cluster) of CJD in Orava had
two possible explanations :
1. exogenous risk :
- study on environmental factors
- zoonotic risk
2. endogenous (genetic) risk :
- epidemiological analyses (familial
cases)
- genealogical studies
00
0 0
60
1. január 1929
26. október 1990
200+
MM
0
0 0
0
0 0
0 0
61
1. január 1893
1. január 1954
71
1. január 1896
1. január 1967
František
78
0
Ž
0
F
72
A
77
J
72
M
78
G
91
Jozef
80
Kat
0
Anna
0
1. január 1872
Š
82
1. január 1865
0
1. január 1895
Alojz
0
Jozef
0
Štefan
80
0
0
Mária
66
9. december 1926
2. jún 1992
Roman
0
1. január 1913
0
Marian
0
0
0 0 0
1 2
Ján
0
1. január 1844
Dorota
0
Ján
0
1. január 1853
Zuzana
75
1. január 1848
Mária
0
1. január 1884
0
D
0
1. január 1989
0
Štefan
0
1. január 1886
0
J
41
1. január 1911
1. január 1951
0
52
1. január 1932
1. január 1984
0
0 0
0
1. január 1936
0
0 0 0
Th
62
1. január 1912
1. január 1974
E
0
1. január 1914
3 62
1. január 1919
1. január 1974
0
0 0 0 0 0
Th
62
1. január 1921
1. január 1983
0
00
0
1. január 1926
0 66
1. január 1922
1. január 1988
0
0
1. január 1947
0
0 0
0
1. január 1949
0
1. január 1950
0
0 0
4
A
0
1. január 1850
0
Mária
0
1. január 1875
Kat
0
1. január 1982
T
0
1. január 1861
0
C
0
1. január 1888
T
0
1. január 1891
Ján
0
Mária
0
M
0
0
Al
0
Ju
0
0
Štefan
0
Tereza
0
0 0
00
0
1. január 1962
0 0 0
1. január 1966
0
Perla
64
1. január 1935
6. január 1999
200-
MV
Family Or.
Result of epidemiological /genealogical studies in
CJD cluster show high percentage of familial cases.
• Slovak CJD cluster 32% (Mitrová, 1986)
...................................................................................................
• World wide occurrence : 14-15% (Masters et al. 1979)
• Chile 26% (Galvez et al. 1979
• Israel 25,5% (Kahana et al.1979)
Introduction of molecular genetic methods :
Prion protein gene< Mutations (insertions/deletions)
V
Genetic TSEs /CJD
All familial cases have mutation,
not all (47%) patients with mutation are
familial !!! (sporadic-like genetic cases)
Genetic TSEs patients
Kovács G.et al. 2005 : Genetic TSEs : EUROCJD experience
Slovakia 69,5%
Italy 17,4%
Austria 14,4%
France 9,0%
Canada 8,5%
Germany 7,6%
UK 6,6%
Netherland 2,1%
Switzerland 1,2%
Mean 10,2%
E200K - most frequent and worldwide spread
mutation of the prion protein gene
• 1st detected in 1989 (Goldgaber, Goldfarb, Brown et al.
Exper. Neurol. 1989)
• Disease specificity demonstrated in 1990 (Goldfarb,
Mitrová, Brown, et al. Lancet , 1990)
• Asymptomatic carriers found in 1991 (Goldfarb, Brown,
Mitrová et al. Europ.J. Epidemiol. 1991)
• Penetrance of the E200K mutation is uncomplete (59%)
(Mitrová and Belay 2002)
In Slovakia the annual incidence of gCJD in years 1975 -
2008 never exceeded 1,66 /1 mill.
In 2009 it significantly (p=0,006) increased to 3,2/1 mill.
Questions :
- What caused this striking increase ?
- Was this increase transitory or permanent ?
GENETIC CJD PATIENTS WITH THE E200K MUTATION
increased annual incidence in 2009 year
____________________________________________________________________________________________________
Patient Age at Gender Duration M129V Onset Exitus CJD relative
onset age at onset
–––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––-
1. A. Še.* 55 F 7 MV 07.2009 12.04.2009 father 45
2. K. Št. 56 F 4 MM 01.2009 17.04.2009
4. M. La. 64 F 3 MM 03.2009 20.05.2009
5. M. Pa.* 60 F 2 MM 04.2009 22.05.2009 onkel 68
6. A. Va. 68 F 5 MM 01.2009 14.06.2009
7. J. Da. 53 M 7 MV 02.03.2009 18.07.2009
8. M. Dar.* 58 F 6 MM 02.2009 12.07.2009 aunt 65
9. V. Ku.* 56 F 7 MM 05.2009 14.07.2009 father 68
10. M.Kub. 61 F 5 MM 04.2009 04.09.2009
11. A. Ga. 58 F 7 MM 03.2009 08.09.2009
12. O.Ma.* 54 F 5 MV 06.2009 18.10.2009 aunt 59
13. A. Bu. 61 F 8 MM 02.2009 20.10.2009
14. Š. Šľ.* 67 M 3 MM 06.09.2009 06.11.2009 son 42
15. P. Šo.* 54 M 6 MV 06.2009 18.11.2009 father 65
16. J.Csi. 60 M 3 MM 01.10.2009 16.12. 2009
17. K. Mo. 56 F 4 MM 09.09.2009 23.12.2009
....................................................................................................................................................................................................
18. M. Šr.* 53 M 31 MV 02.2009 10.10.2011 onk 68, aunt 74
* Patients from families affected with CJD in successive generations
Results (2009)
• The significant increase of gCJD in 2009 year had
a transitory character ; in years 2010 and 2011 it
considerably decreased (1,88/million and 2,07/million).
• 10 out of 17 gCJD in year 2009 were familial cases, 8
of them (47%) belonged to a 2nd affected generation.
• The mean age difference at CJD onset in patients from
different generations was 14.12 years (p= 0,001).
Questions:
- Does analysis of all familial CJD patients
confirm the significant generation age
difference (and anticipation) observed in 2009?
-Can be the recognized anticipation practicaly
utilized in prevention of gCJD ?
• Genetic testing was performed in 234 definite
CJD patients and their 426 relatives.
• Age at death and duration of the disease were
compared in fCJD from successive generations
in all cases since y. 1975 except in y. 2009 (65)
R e s u l t s
• Mutation E200K was present in 184 patients (67,9%) and 151
(35,5%) relatives.
• The mean age at death was : 62,20 ±7,219 years in the 1st and
50,04±9,52 years in the 2nd generation. The difference 12,16
years was significant (p<0,001).
• The mean duration was 5.75 ±7,52 months in the 1st and 4,41 ±
3,21months in the 2nd generation. The difference 1,34 was not
significant (p=0,773).
• Highly significant „generation age difference“ in both
evaluated intervals provide evidence of anticipation,
i.e. earlier age at onset in successive generations of
carriers of E200K.
• Confirmed anticipation has impact in prophylaxis :
It is decisive for individual (optimal) determination of
the age for starting preventive treatment in healthy
carriers of the disease - specific mutation.
Doxycycline as candidate for the prevention...
• Doxycycline treatment in CJD patients :
significantly prolonged the clinical stage of the disease
(Fincke et al. 2008, Tagliavini et al. 2008),
• Experimental doxycycline administration before the
clinical onset of the disease either :
1. prevented the clinical manifestation of the disease (Tremblay
et al, 1998, Safar et al. 2005), or
2. significantly prolonged the preclinical (incubation) period (De
Luigi et al.2008)
In summary....
Studies on the gCJDE200K demonstrate :
• Familial form represent only 53,6% of genetic patients.
• Penetrance of the mutation is uncomplete (59%).
• Anticipation (12-15 yrs.) in familial patients, as well as
its influence on the annual incidence of the disease.
Obtained data draw attention to the
decisive role of the optimal age when the preventive
drug (Doxycycline) administration should be started
and underline as important
to consider in each asymptomatic carrier (individually) :
- the age of youngest affected family member,
- the anticipation.
Many thanks to......
People involved......
Department of prion diseases.
Thank you for your attention