TY - JOUR
T1 - Distinct pathological phenotypes of Creutzfeldt-Jakob disease in recipients of prion-contaminated growth hormone
AU - Cali, Ignazio
AU - Miller, Cathleen J.
AU - Parisi, Joseph E.
AU - Geschwind, Michael D.
AU - Gambetti, Pierluigi
AU - Schonberger, Lawrence B.
N1 - Funding Information:
We thank the Public Health Service Interagency Coordinating Committee on Human Growth Hormone (hGH) and Creutzfeldt-Jakob Disease (CJD) as well as Westat Inc. Study Coordinator Lesa Houser, Washington State Health Officer Kathy Lofy, M.D. and CDC Epidemiologist Ryan Maddox, Ph.D. for help in ascertaining CJD cases and obtaining case information. We are also grateful for the essential cooperation of the CJD patients’ families that made this study possible. We thank Tetsuyuki Kitamoto, M.D. for kindly providing the Tohoku-2 antibody. We also thank the National Prion Disease Pathology Surveillance Center (NPDPSC), Diane Kofskey and Miriam Warren for their invaluable technical help; Janis Blevins, Allen Szegedy and Katie Glisic for obtaining case information; the pathologists Randall Woltjer M.D. Ph.D (Oregon Health & Science University) for performing brain biopsy on the index case and Alexander O. Vortmey, M.D., Ph.D. (Yale New Haven Hospital) for performing the autopsy of one GH-CJDMM1 patient; Mark L. Cohen, M.D. for helpful discussion. This study was supported by National Institutes of Health awards NIH/NIADS NS083687, NIH/NIADS 1AI106705-01A1, Centers for Disease Control and Prevention award 1U51CK000100 to PG. MDG was supported by NIH/NIA R01-AG031189 and the Michael J. Homer Family Fund.
PY - 2015/6/25
Y1 - 2015/6/25
N2 - INTRODUCTION: The present study compares the clinical, pathological and molecular features of a United States (US) case of growth hormone (GH)-associated Creutzfeldt-Jakob disease (GH-CJD) (index case) to those of two earlier referred US cases of GH-CJD and one case of dura mater (d)-associated CJD (dCJD). All iatrogenic CJD (iCJD) subjects were methionine (M) homozygous at codon 129 (129MM) of the prion protein (PrP) gene and had scrapie prion protein (PrP(Sc)) type 1 (iCJDMM1).RESULTS: The index subject presented with ataxia, weight loss and changes in the sleep pattern about 38 years after the midpoint of GH treatment. Autopsy examination revealed a neuropathological phenotype reminiscent of both sCJDMV2-K (a sporadic CJD subtype in subjects methionine/valine heterozygous at codon 129 with PrP(Sc) type 2 and the presence of kuru plaques) and variant CJD (vCJD). The two earlier cases of GH-CJDMM1 and the one of dCJDMM1 were associated with neuropathological phenotypes that differed from that of the index case mainly because they lacked PrP plaques. The phenotype of the earlier GH-CJDMM1 cases shared several, but not all, characteristics with sCJDMM1, whereas dCJDMM1 was phenotypically indistinguishable from sCJDMM1. Two distinct groups of dCJDMM1 have also been described in Japan based on clinical features, the presence or absence of PrP plaques and distinct PK-resistant PrP(Sc) (resPrP(Sc)) electrophoretic mobilities. The resPrP(Sc) electrophoretic mobility was, however, identical in our GH-CJDMM1 and dCJDMM1 cases, and matched that of sCJDMM1.CONCLUSIONS: Our study shows that receipt of prion-contaminated GH can lead to a prion disease with molecular features (129MM and PrP(Sc) type 2) and phenotypic characteristics that differ from those of sporadic prion disease (sCJDMM1), a difference that may reflect adaptation of "heterologous" prion strains to the 129MM background.
AB - INTRODUCTION: The present study compares the clinical, pathological and molecular features of a United States (US) case of growth hormone (GH)-associated Creutzfeldt-Jakob disease (GH-CJD) (index case) to those of two earlier referred US cases of GH-CJD and one case of dura mater (d)-associated CJD (dCJD). All iatrogenic CJD (iCJD) subjects were methionine (M) homozygous at codon 129 (129MM) of the prion protein (PrP) gene and had scrapie prion protein (PrP(Sc)) type 1 (iCJDMM1).RESULTS: The index subject presented with ataxia, weight loss and changes in the sleep pattern about 38 years after the midpoint of GH treatment. Autopsy examination revealed a neuropathological phenotype reminiscent of both sCJDMV2-K (a sporadic CJD subtype in subjects methionine/valine heterozygous at codon 129 with PrP(Sc) type 2 and the presence of kuru plaques) and variant CJD (vCJD). The two earlier cases of GH-CJDMM1 and the one of dCJDMM1 were associated with neuropathological phenotypes that differed from that of the index case mainly because they lacked PrP plaques. The phenotype of the earlier GH-CJDMM1 cases shared several, but not all, characteristics with sCJDMM1, whereas dCJDMM1 was phenotypically indistinguishable from sCJDMM1. Two distinct groups of dCJDMM1 have also been described in Japan based on clinical features, the presence or absence of PrP plaques and distinct PK-resistant PrP(Sc) (resPrP(Sc)) electrophoretic mobilities. The resPrP(Sc) electrophoretic mobility was, however, identical in our GH-CJDMM1 and dCJDMM1 cases, and matched that of sCJDMM1.CONCLUSIONS: Our study shows that receipt of prion-contaminated GH can lead to a prion disease with molecular features (129MM and PrP(Sc) type 2) and phenotypic characteristics that differ from those of sporadic prion disease (sCJDMM1), a difference that may reflect adaptation of "heterologous" prion strains to the 129MM background.
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U2 - 10.1186/s40478-015-0214-2
DO - 10.1186/s40478-015-0214-2
M3 - Article
C2 - 26108478
AN - SCOPUS:85018198530
SN - 2051-5960
VL - 3
SP - 37
JO - Acta Neuropathologica Communications
JF - Acta Neuropathologica Communications
ER -