The Lancet, May 15, 1999 Codon 129 prion protein genotype and sporadic Creutzfeldt-Jakob disease

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Volume 353, Number 9165 15 May 1999

 

Codon 129 prion protein genotype and sporadic

Creutzfeldt-Jakob disease

A Alperovitch, I Zerr, M Pocchiari, E Mitrova, J

de Pedro Cuesta, I Hegyi, S , H Kretzschmar, C van Duijn, RG

Will

Methionine homozygosity at codon 129 of the prion protein (PrP) gene is a

recognised risk factor for the development of sporadic Creutzfeldt-Jakob

disease (CJD).1 Between 64 and 81% of sporadic cases have this

genotype,1-3 with an overall rate, combining the data from

three series, of 71%. PrP gene analysis is now available in 748 out of

1327 cases of definite or probable sporadic CJD, including data from

Australia (5), France (217), Germany (239), Italy (101), the Netherlands

(36), Slovakia (7), Spain (7), Switzerland (7), and the UK (129). A

current issue is whether cases of variant CJD (nvCJD), might occur in

individuals with a valine homozygous or heterozygous PrP genotype. To

date, all 36 cases of variant CJD with available genetic analysis have

been methionine homozygotes and died at an early age (mean 29 years). A

small number of cases of sporadic CJD with a relatively early age at

death have been identified in participating countries including

Australia, France, Germany, the Netherlands, and the UK. We analysed the

distribution of genotypes at codon 129 of the PrP gene by 10-year age

groups in order to determine whether there is a relative excess of young

valine homozygote or heterozygote cases of sporadic CJD.

  MM MV VV

<49 years* 43 (23) 17 (9) 41 (22)

50-59 years 65 (97) 16 (24) 19 (28)

60-69 years 75 (227) 13 (40) 12 (36)

70-79 years 73 (148) 10 (21) 17 (35)

80+ years 84 (32) 11 (4) 5 (2)

Total 70 (527) 13 (98) 16 (123)

Previous studiesÝ 71 (60) 17 (14) 12 (10)

European data 74 (252) 11 (38) 15 (51)

1993-95

European data 68 (275) 15 (60) 18 (72)

1996-98

Normal population 39 (156) 50 (198) 11 (44)

*The age of death of the youngest case for each genotype was 28 years for

MM, 20 years for MV, and 23 years for VV. ÝLaplanche J-L, et al.

Molecular genetics of prion diseases in France. Neurology 1994;

44: 2347-51, and Salvatore M, et al. Polymorphisms of the prion

protein gene in Italian patients with Creutzfeldt-Jakob disease. Hum

Genet 1995; 94: 375-79.

Percentage of codon 129 PRP genotypes in sporadic CJD by 10-year age

groups in the European study 1993-1998 (numbers of cases in parentheses),

and codon 129 distribution in the normal population and in previous

studies of sporadic CJD

The table shows data on the distribution of PrP genotypes in the normal

white population, pooling data from five studies4 (there are

no data on stratification by age in these studies), and the genotype

distribution in sporadic CJD, derived by pooling data from three studies

(table2), are also shown, together with previous data from the

European surveillance project.3 The frequencies of codon 129

PrP genotypes differ significantly across the age groups

(2=38·2, 8 df, p<0·0001) and there is a positive linear

relation between age and the frequency of the methionine homozygote

genotype (p for linear trend <0·0001). The valine homozygous genotype

is significantly more frequent in cases aged 49 years or less compared

with those aged 50 years and over (2=27·9, 2 df, p<0·0001).

In some countries only limited data are available but comparisons between

countries are possible for France, Germany, Italy, and the UK. Codon 129

distribution in these countries is not significantly different from

previous studies of sporadic CJD, and within country comparison of cases

aged less than 50 years shows a significant excess of valine homozygotes

in France, Germany, and the UK, but not in Italy. There is a

non-significant excess of heterozygote cases aged less than 50 years in

Italy, the Netherlands, and the UK.

The relative excess of valine homozygotes in sporadic CJD aged less than

50 years is unexpected. There are a number of possible reasons. There may

be a bias in the surveillance system for the identification of younger

atypical cases of sporadic CJD, because of increased interest in younger

suspect cases after the identification of variant CJD. Sporadic CJD with

an atypical clinicopathological phenotype may occur in younger patients,

particularly those with a valine homozygous genotype.4 These

cases rarely have the " typical " electroencephalogram seen in

sporadic CJD and might be over-represented in systematic surveillance

data because of ascertainment bias. It is also possible that CJD is

underdiagnosed in older valine homozygotes because of an atypical

phenotype, although the genotype distribution we have identified would

necessitate underdiagnosis in the 50-59 year age group in which

alternative causes of dementia are fairly uncommon. It is also difficult

to understand why there should be a differential bias in the diagnosis of

those aged over 50 years compared with younger cases, when suspect cases

are investigated in a standard manner, independent of age, and this often

includes 14-3-3 cerebrospinal fluid immunoassay and necropsy examination.

The percentages of heterozygote and valine homozygote cases between the

study periods 1993-95 and 1996-98 are not statistically different, and

this finding does not support the hypothesis of an increase in the

ascertainment of younger heterozygote or valine homozygote cases with

time as a result of the identification of variant CJD in March, 1996.

It is possible that the excess of valine homozygotes in younger cases is

caused by variation in the strain of infectious agent and perhaps

exogenous infection, either iatrogenic or zoonotic, for example due to

bovine spongiform encephalopathy (BSE). An excess of valine homozygotes

has been found in growth-hormone recipients with CJD,5 but

none of the cases in our report were known to have an iatrogenic

exposure. The possibility that the excess of young valine homozygote

cases reflects disease caused by BSE is unlikely because there is no

differential excess of valine homozygote cases in the UK, the country

with the greatest potential human exposure to BSE, compared with France

and Germany. Furthermore all cases of variant CJD tested to date in the

UK have been methionine homozygotes and it would be surprising if cases

of variant CJD with this genotype were not identified at the same time,

and probably earlier, than valine homozygote BSE-related cases in other

countries, should such cases actually occur. One methionine homozygote

French case of variant CJD has been identified. It is of note that

widespread florid plaque deposition, which is the neuropathological

hallmark of variant CJD, has not been found in any of the valine

homozygote cases in this series. Most of these cases have undergone

necropsy and PrP glycoform analysis in a small number of cases, including

three young valine homozygote cases in the UK, has not shown the PrP

subtype identified in variant CJD nor the type 5 subtype found in BSE

transmissions to laboratory mice expressing valine at codon 129. Further

analysis of temporal trends in codon 129 genotype distribution,

clinicopathological features, and prion protein glycoform patterns in

younger patients with CJD is being undertaken.

The data in this paper have been accumulated by many people in each

participating country. J Ironside and M Head provided the data of PrP

glycoform analysis in the UK. The study is funded by the European Union,

contract number BMH4-CT97-2216.

1 Palmer MS, Dryden AJ, JT, Collinge J. Homozygous prion protein

genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature

1991; 352: 340-41.

2 Lampe J, Kitzler H, Walter MC, Lochmuller H, Reichmann H. Methionine

homozygosity at prion protein gene codon 129 may predispose to sporadic

inclusion-body myositis. Lancet 1999; 353: 465-66.

3 Will RG, Alperovitch A, Poser S, et al. Descriptive epidemiology of

Creutzfeldt-Jakob disease in six European countries, 1993-1995. Ann

Neurol 1998; 43: 763-67.

4 Parchi P, Castellani R, Capellari S, et al. Molecular basis of

phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann

Neurol 1996; 39: 767-78.

5 Collinge J, Palmer MS, Dryden AJ. Genetic predisposition to iatrogenic

Creutzfeldt-Jakob disease. Lancet 1991; 337: 1441-442.

INSERM U.360, Hôpital La Salpêtrière 75651, Paris, cedex 13,

France; Department of Neurology and Neuropathology, University of

Göttingen, Göttingen, Germany; Istituto Superiore di Sanità, Laboratory

of Virology, 00161 Rome, Italy; Institute of Preventive and Clinical

Medicine, National Reference Centre of Slov Virus Neuroinfections, 833 01

Bratislava, Slovakia; Instituto de Salud III, Centro Nacional de

Epidemiologia, Departmento de Epidemiologia Aplicada, Madrid, Spain;

UniversitätsSpital Zürich, Institut für Neuropathologie, CH-8091 Zürich,

Switzerland; Department of Pathology, The University of Melbourne, Vic

3052, Australia; Department of Epidemiology & Biostatistics, Erasmus

University Medical School, PO Box 1738, Rotterdam, Netherlands; The

National CJD Surveillance Unit, Western General Hospital, Edinburgh, EH4

2XU, UK (R Will)