NR AOFD
AU Brandel,J.P.; Preece,M.; Brown,P.; Croes,E.A.; Laplanche,J.L.; Agid,Y.; Will,R.; Alperovitch,A.
TI Distribution of codon 129 genotype in human growth hormone-treated CJD patients in France and the UK
QU Lancet 2003 Jul 12; 362(9378): 128-30
PT journal article
AB Since homozygosity MM at codon 129 of the prion protein gene is a recognised risk factor in all forms of Creutzfeldt-Jakob disease (CJD), we studied the distribution of codon 129 polymorphism in patients in France and in the UK with CJD transmitted iatrogenically by human growth hormone. The overall frequencies of codon 129 genotypes in these patients differed from those in the population unaffected by CJD. An excess of VV homozygotes was noted among those with iatrogenic CJD compared with sporadic CJD cases. The proportion of MM genotype in UK patients was surprisingly low (4%) compared with that in French patients (62%). There is no evident explanation for this different distribution, which might be due to infection with different strains of prion in human growth hormone.
VT
The most frequent cause of iatrogenically transmitted Creutzfeldt-Jakob disease (CJD) in France, the USA, and the UK is treatment with pituitary human growth hormone (hGH).[1] Since the first description of a case of CJD in the USA in 1985, 140 cases have been registered up to the end of 2000 in these three countries: 81 in France, 37 in the UK, and 22 in the USA. The peripheral route of contamination and the stereotyped clinical features with predominant ataxia and late onset minimal dementia make this form more similar to Kuru than to sporadic CJD. Homozygosity at codon 129 of the prion protein (PrP) gene is a recognised risk factor for the development of hGH-transmitted CJD, and for all the other forms of CJD.
The intensive surveillance of CJD in European countries unabled us to assess the genotypes of most CJD patients after obtaining informed consent from the relatives or patients. PrP gene analysis in patients with hGH transmitted CJD was available for 95% (77 of 81) and 73% (27 of 37) of cases in France and the UK, respectively, allowing a comparison of the distribution of the codon 129 polymorphism in these two populations.
The overall frequencies of codon 129 genotypes in patients with hGH-transmitted CJD differed from those in unaffected populations (p=0.0001; table).
Those with MM and VV genotypes were at higher risk of iatrogenic CJD than the heterozygote MV genotype (odds ratio [OR]MM/MV = 2.6, 95% CI 1.6-4.4; OR-VV/MV = 5.7 95% CI 3.1-10.5). The distribution of the codon 129 polymorphism in hGH-transmitted CJD also differed from that noted in European patients with sporadic CJD (p=0.0001), with a higher proportion of VV homozygotes in iatrogenic than in sporadic cases of CJD (table). We were surprised by the significant difference in the distributions of codon 129 polymorphism in the French and UK iatrogenic CJD patients (p=0.0001; table). When iatrogenic CJD patients were compared with unaffected populations, the MM genotype seemed to be a risk factor for iatrogenic CJD in French patients (ORMM/MV=5.1, 95% CI 2.6-9.9) but a protective factor in UK patients (ORMM/MV=0.1, 95% CI 0.01-0.82). The European and US data could not be reliably compared, because few patients in the USA had codon 129 analysis (nine of 22); however, the distribution of codon 129 polymorphism in US patients was more like the pattern seen in France than that noted in the UK: among the nine genotyped US patients, five were MM (56%), two VV, and two MV.
We also investigated other characteristics of the French and UK iatrogenic CJD patients. The first case of CJD in an hGH recipient occurred in the UK in 1984, 5 years before the first iatrogenic case in France. Mean age at onset was somewhat younger in France (24.2 years) than in the UK (27.8 years; p=0.001); in France, 49.4% (40 of 81) of the patients were aged 24 years or less at disease onset, versus 22% (8 of 37) in the UK. Treatment duration did not differ between the two countries: mean duration was 6.4 years (range 1-13 years) in France and 6.5 years (2-11 years) in the UK. Mean incubation period-defined as the time interval between midpoint of treatment and date of onset-was, at the end of 2000, shorter in France (11.0 years) than in the UK (15.0 years) and tended to be shorter in homozygous than in heterozygous patients in both countries.
The temporal distributions of iatrogenic cases by codon 129 genotype were also different in France and the UK; homozygous cases in France arose significantly earlier than the heterozygous cases (Wilcoxon's test, p=0.03; figure). All 30 French iatrogenic patients with codon 129 analysis registered between 1989 and 1993 were MM or VV; the first MV patient was diagnosed in 1994, 5 years after the first homozygous cases. In the UK, VV cases had similar temporal distribution to that of heterozygous cases (Wilcoxon's test, p=0.11; figure).
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Distribution of codon 129 genotype
Number (%) of patients with codon 129 genotype
MM VV MV
Normal population* 156 (39%) 44 (11%) 198 (50%)
French normal population[2] 38 (41%) 9 (10%) 45 (49%)
UK normal population[3] 39 (37%) 13 (12%) 54 (51%)
h-GH CJD (all patients) 54 (48%) 33 (29%) 26 (23%)
French h-GH CJD 48 (62%) 17 (22%) 12 (16%)
UK h-GH CJD 1 (4%) 14 (52%) 12 (44%)
Sporadic CJD (all countries)# 1017 (68%) 240 (16%) 238 (16%)
French sporadic CJD 260 (66%) 75 (19%) 57 (15%)
UK sporadic CJD 164 (67%) 44 (18%) 36 (15%)
*From Alperovitch A, Zerr I, Pocchiari M, et al. Codon 129 prion protein genotype and sporadic Creutzfeldt-Jakob disease. Lancet 1999; 353: 1673-74.
#From European Union Collaborative Study Group of Creutzfeldt-Jakob disease (unpublished data).
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The remarkably low percentage of MM genotypes in the UK series of iatrogenic cases is difficult to explain. In all other forms of CJD (sporadic, genetic, iatrogenic after dura-mater treatment, vCJD) and in Kuru, MM is the most frequent codon 129 genotype. Because differences between the UK and French patients could be due to the temporal distribution of missing genotypes in the two countries, we verified that they were distributed at random along the period (figure). We do not think that the difference in temporal distribution between France and the UK could be accounted for by missing of first cases in the UK; data on the cause of death of hGH recipients in the UK do not show that patients died of unclear neurological disease.[4] We have no specific data on the distribution of codon 129 genotype in hGH recipients. We assumed that this distribution was similar to that in the populations without CJD, and verified that there was no difference in the distribution of the codon 129 genotype between the UK and French unaffected population samples (p=0.75).[2,3] The possibility that our findings are due to differences in the treated populations or in therapeutic modalities is unlikely. The growth hormone was produced independently in France and the UK, with different donor populations, but with very similar mechanisms of production. The modalities (several subcutaneous injections per week) and the duration of treatment were similar in both countries.
The different genotypic distributions of hGH-transmitted CJD in French and UK patients might reflect the existence of different strains of the CJD agent. Host-strain interactions are well documented in prion infections. For example, infectious inocula prepared from brains of different sheep with scrapie target the challenged sheep differently according to the PrP genotypes,[5] and human beings with MV or VV codon 129 genotypes seem to be resistant to the BSE strain of prion. The distribution of codon 129 genotypes in iatrogenic CJD might, similarly, be due to infection with different contaminating strains of the CJD agent in hGH in France and the UK.
Contributors
All authors participated in collection, analysis, and interpretation of data, and in the writing of the report.
Conflict of interest statement
None declared.
Acknowledgments
The authors thank the French Ministry of Health for permission to include data of the French growth hormone cases. The EUROCJD research group is funded by the European Commission DG Research Grant number QLK2CT199901709. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
1 Brown P, Preece M, Brandel JP, et al. Iatrogenic Creutzfeldt-Jakob disease at the millenium. Neurology 2000; 55: 1075-81.
2 Laplanche JL, Delasnerie-Laupretre, Brandel JP, et al. Molecular genetics of prion diseases in France. Neurology 1994; 44: 2347-51.
3 Palmer MS, Dryden AJ, Hughes JT, Collinge J. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature 1991; 352: 340-42.
4 Swerdlow AJ, Higgins CD, Adlard P, Preece MA. Risk of cancer in patients treated with human pituitary growth hormone in the UK, 1959-85: a cohort study. Lancet 2002; 360: 273-77.
5 Goldmann W, Hunter N, Smith G, Foster J, Hope J. PrP genotype and agent effects in scrapie: change in allelic interaction with different isolates of agent in sheep, a natural host of scrapie. J Gen Virol 1994; 989-95.
National Reference Centre of Iatrogenic CJD (Y Agid MD, J-P Brandel MD) and Institute Nationale de la Santé et de la Recherche Médicale U360 (A Alpérovitch MD, J-P Brandel MD), Salpêtrière Hospital, 75651 Paris Cedex 13, France; Institute of Child Health, 30 Guilford Street, London, UK (M Preece); Laboratory of CNS Studies, National Institutes of Health, Bethesda, MD, USA (P Brown MD); Erasmus University Medical School, Rotterdam, Netherlands (E Croes); Central Laboratory of Biochemistry, Lariboisière Hospital, Paris, France (J-L Laplanche PhD); and CJD Surveillance Unit, Western General Hospital, Edinburgh, UK (R Will MD)
Correspondence to: Dr J-P Brandel (e-mail: jean-philippe.brandel@psl.ap-hop-paris.fr)
IN
In Frankreich, den USA und England ist die Behandlung mit aus menschlichen Hypophysen gewonnenem Wachstumshormon (h-GH) die häufigste iatrogene Ursache für Creutzfeldt-Jakob-Erkrankungen. Infizierte Kleinwüchsige waren in Frankreich 1-13 Jahre lang (durchschnittlich 6,4) und im Vereinigten Königreich 2-11 Jahre lang (durchschnittlich 6,5) behandelt worden. Gemessen von der Mitte der Behandlung als mutmaßlicher Infektionsquelle betrugen die hypothetischen Inkubationszeiten bis Ende 2000 in Frankreich 11,0 und im Vereinigten Königreich 15,0 Jahre.
Die Patienten litten hauptsächlich unter einer Ataxie und einer spät beginnenden Demenz und sollen von daher eher Kuru-Patienten als sporadischen CJK-Fällen ähneln. Seit den ersten Fällen von 1984 im Vereinigten Königreich, 1985 in den USA und 1989 in Frankreich, wurden bis Ende 2000 in Frankreich 81, im Vereinigten Königreich 37 und in den USA 22 Fälle bekannt. Die Durchschnittsalter lagen bei 24,2 Jahren in Frankreich und 27,8 Jahren im Vereinigten Königreich. In Frankreich waren 49,4% (40 von 81) der Patienten zum Zeitpunkt der Erkrankung 24 Jahre alt oder jünger, während dies bei nur 22% (8 von 37) der britischen Patienten der Fall war.
Bei 77 von 81 (95%) französischen und 27 von 37 (73%) britischen Patienten konnte der Genotyp hinsichtlich des Codons 129 des Prionproteingens ermittelt und mit der Normalbevölkerung sowie unter einander verglichen werden. Von den 22 US-Patienten konnten nur 9 genotypisiert werden. Dabei zeigte sich erneut, dass Homozygote (MM und VV) ein erheblich höheres Erkrankungsrisiko und tendenziell kürzere Inkubationszeiten als Heterozygote (MV) haben. In Frankreich fand man bei den ersten 30 Genotypbestimmungen in den Jahren 1989-1993 ausschließlich Homozygote (MM oder VV). Im Vereinigten Königreich hingegen fand man keine erheblichen Unterschiede zwischen Valin-Homozygoten und Heterozygoten hinsichtlich des zeitlichen Auftretens. Außerdem fand man bei den durch Wachstumshormoninjektionen infizierten deutlich häufiger als bei den sogenannten sporadischen CJK-Fällen in Europa das Valin-Allel auf beiden Chromosomen (VV). Besonders überrascht waren die Autoren über den deutlichen Unterschied zwischen französischen und britischen Patienten. Verglichen mit der Normalbevölkerung scheint Methionin-Homozygotie in Frankreich ein Risikofaktor, in England hingegen ein Schutzfaktor im Hinblick auf iatrogene Infektionen bei behandelten Kleinwüchsigen zu sein. Die wenigen US-Patienten mit bekanntem Genotyp deuten darauf hin, dass die Allelverteilung dort eher den französischen Verhältnissen entspricht.
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Verteilung der Genotypen hinsichtlich des PrP-Codons-129
Zahl bzw. Anteil[%] der Patienten dem jeweiligen Codon-129-Genotyp
MM VV MV
normale Bevölkerung[AAFZ] 156 (39%) 44 (11%) 198 (50%)
französische Normalbvölkerung[AHAS] 38 (41%) 9 (10%) 45 (49%)
britische Normalbvölkerung[AJDZ] 39 (37%) 13 (12%) 54 (51%)
h-GH-CJK (alle Patienten) 54 (48%) 33 (29%) 26 (23%)
französische h-GH-CJK 48 (62%) 17 (22%) 12 (16%)
britische h-GH-CJK 1 (4%) 14 (52%) 12 (44%)
sporadische CJK (alle Länder)# 1017 (68%) 240 (16%) 238 (16%)
sporadische CJK in Frankreich 260 (66%) 75 (19%) 57 (15%)
sporadische CJK im UK 164 (67%) 44 (18%) 36 (15%)
#von der EU - Collaborative Study Group of Creutzfeldt-Jakob disease (noch nicht publizierte Daten)
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Die Autoren finden es schwierig, zu erklären, warum im Vereinigten Königreich nur ein einziger Kleinwüchsiger mit 129-M/M-Homozygotie erkrankte. Sie glauben nicht, dass dafür die etwas unterschiedlichen zeitlichen Muster der Erkrankungen oder die sehr geringen Unterschiede hinsichtlich der Herstellung und Anwendung der Hormone dafür verantwortlich sein könnten. Allerdings hatten England und Frankreich jeweils ihre eigenen Spendergruppen. Daher könnte es sich um unterschiedliche "Erreger"-Stämme handeln. Dies wäre allerdings sehr unwahrscheinlich, wenn nicht alle britischen Fälle von jeweils einem einzigen Spender infiziert wurden. Es wäre zu klären, ob dies überhaupt möglich ist.
MH Codon; Creutzfeldt-Jakob Syndrome/*genetics/*transmission; France; Great Britain; *Homozygote; Human; Human Growth Hormone/*adverse effects; Iatrogenic Disease; Polymorphism (Genetics); PrPsc Proteins/*genetics; Risk Factors; Support, Non-U.S. Gov't
AD Jean-Philippe Brandel (jean-philippe.brandel@psl.ap-hop-paris.fr), Yves Agid, National Reference Centre of Iatrogenic CJD, Salpêtrière Hospital, 75651 Paris Cedex 13, France; Annick Alpérovitch, Jean-Philippe Brandel (jean-philippe.brandel@psl.ap-hop-paris.fr), Institute Nationale de la Santé et de la Recherche Médicale U360, Salpêtrière Hospital, 75651 Paris Cedex 13, France; Michael Preece, Institute of Child Health, 30 Guilford Street, London, UK; Paul Brown, Laboratory of CNS Studies, National Institutes of Health, Bethesda, MD, USA; Esther Croes (eacroes@yahoo.com), Erasmus University Medical School, Rotterdam, Netherlands; Jean-Louis Laplanche, Central Laboratory of Biochemistry, Lariboisière Hospital, Paris, France; Robert Will, CJD Surveillance Unit, Western General Hospital, Edinburgh, UK
SP englisch
PO England