THE LANCET, May 15, 1999 Codon 129 prion protein genotype and sporadic Creutzfeldt-Jakob disease

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THE LANCET, 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)