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From: TSS ()
Young-onset CJD: age and disease phenotype in variant and sporadic forms Manuel Coratoa,b,c Cristina Ceredaa Emanuela Covaa Carlo Ferraresec,d Mauro Ceronia,b,e a Laboratory of Experimental Neurobiology, IRCCS “C. Mondino Institute of Neurology” Foundation, Pavia, Italy b Department of Neurology, Policlinico di Monza, Monza, Italy c Department of Neuroscience and Biomedical Technologies, University of Milan-Bicocca, Milan, Italy d Department of Neurology, University of Milan-Bicocca, S. Gerardo Hospital, Monza, Italy e Department of Neurological Sciences, University of Pavia, Italy Reprint requests to: Prof. Mauro Ceroni Department of Neurological Sciences, University of Pavia Via Mondino, 2 - 27100 Pavia - Italy E-mail: mauro.ceroni@unipv.it Accepted for publication: December 28, 2006 Summary Since 1996, there have been over 140 reports of a Creutzfeldt-Jakob disease variant (vCJD), with a striking prevalence of these cases in the UK. The main peculiarity of vCJD is its onset in young people, but other features also distinguish it from sporadic CJD. Despite epidemiological data suggesting a link with bovine spongiform encephalopathy, the origin of vCJD is not completely understood. We hypothesized that the onset of vCJD at a young age might contribute to the disease phenotype. We searched the Medline/PubMed database for all case reports of CJD in the under-30s and selected 20 sporadic CJD patients with a median age at onset of 25.5 years. Our series displays a long disease duration and other vCJD-like features, suggesting that CJD in young people is different from classic CJD and that the vCJD phenotype may be partly related to young age. KEY WORDS: CJD, sporadic CJD, survival, variant CJD, young. snip... Discussion We analyzed a small sample of CJD patients, whose disease was characterized by young age at onset. The cases included in our series came from different countries and were reported at different times. The series was found to present several atypical features showing that CJD in young people is different from the classic form of CJD occurring in middle age. Yet it must be emphasized that all the reports analyzed were found to concern sCJD and that none of the cases described fulfilled all the clinical and pathological criteria for a diagnosis of vCJD. The most interesting finding in our CJD patient series was the prolonged survival time compared to the mean survival duration observed in the classic form of CJD. Until a few years ago, there were no available studies examining the duration of CJD in different age groups. In a recent paper by Boesenberg et al. (24), the authors Young-onset CJD Functional Neurology 2006; 21(4): 211-215 213 Table III - Clinical, laboratory and pathological features of sCJD in young patients. Reference Sex Age Survival Presenting Periodic Amyloid Codon PrP (years) (months) symptom(s) EEG plaques 129 type (25) M 25 18 Ataxia n.r. No n.r. n.r. (26) F 29 51 Ataxia Yes Yes n.r. n.r. (27) M 16 28 Dementia Yes No n.r. n.r. (28) F 26 34 Ataxia No No n.r. n.r. (29) F 19 4 Psychiatric Yes No n.r. n.r. (30) F 14 24 Dementia No No n.r. n.r. (31) M 27 24 Ataxia No Yes n.r. n.r. (18) F 19 10 Dementia No No n.r. n.r. (18) M 23 3 Dementia No No n.r. n.r. (18) F 27 3 Dementia No No n.r. n.r. (32) F 21 4 Ataxia No No n.r. n.r. (33) F 28 4 Dementia + ataxia Yes No MM n.r. (33) M 29 10 Dementia No No VV 1 (33) M 27 15 Dementia No No MV 1 (34) M 27 21 Dementia No No VV 1 (35) F 30 73 Altered vision + ataxia Yes Yes MM 2 (36) M 24 19 n.r. No n.r. VV 1 (36) M 27 18 n.r. No n.r. VV 1 (36) F 19 17 n.r. No n.r. VV 1 (37) F 19 24 Psychiatric + sensory No No VV 1 11F/9M 25.5 18 5/19 3/17 (median) (median) n.r: not reported. analyzed the clinical syndrome in a series of 52 sCJD patients aged 50 years or younger at disease onset, and found that they had a prolonged mean disease duration compared with patients older than 50 years. Our analysis also suggests that younger CJD patients survive longer than older ones and this observation is supported by several other findings both in sporadic reports (17, 23,38) and in studies of long-duration CJD cases (39). A recent article has also shown that young age at disease onset is one of the major factors influencing survival in CJD (40). In addition, the only late-onset vCJD case reported had a disease duration of just 7 months (41), whereas the mean survival in vCJD is around 14 months. Factors possibly contributing to an age-related disease duration may include the more protracted palliative treatments in young people and the increased frailty of elderly people. In our series, molecular analysis was available in nine cases; six of these were found to belong to the VV1 CJD subtype. However, the study of Boesenberg et al. confirms that the difference between young and older patients does not depend on the codon 129 genotype. They also found a similar proportion of type 1 and type 2 glycotypes in young compared to older sCJD patients (24). In addition to prolonged survival time, our series presented other features atypical of classic CJD, but resembling vCJD. For example, in 41% of cases the disease presented with a cerebellar syndrome and in 73% of patients the EEG recording did not show the periodic discharges typical of classic CJD. We have no useful data regarding the presence of the 14.3.3 protein in the cerebrospinal fluid in our series, since detection of 14.3.3 was performed in only four patients. Nevertheless, Boesenberg et al. report a similar proportion of positive 14.3.3 testing in young and older sCJD patients (24). Contrary to our expectations, we did not find an increased number of cases presenting amyloid plaques. Many researchers have hypothesized a correlation between the presence of amyloid plaques and the disease duration in CJD, since neuropathological lesions like amyloid plaques may take several years to develop, as suggested by the presence of PrP plaques in Gerstmann- Straussler-Scheinker disease (42). In a Japanese study, neuropathological examination in 45 patients affected by sCJD revealed that PrP plaques were preferentially found in cases with a long disease duration (43). Since amyloid plaques were reported in only 3 out of 17 patients, we think that further studies are needed to verify this hypothesis. Our observations demonstrate that some peculiarities of vCJD may be present in sCJD cases and may be very common in young CJD patients, thus emphasizing the need for more caution when diagnosing vCJD on the basis of single atypical features. The hypothesis that the long duration of vCJD depends on the patient’s young age at onset is supported by the finding that many young patients affected by sCJD also have prolonged survival. Our findings do not modify the view that vCJD cases are related to the BSE epidemic, because, as we stated earlier, the possibility that vCJD had been present, but undiagnosed, before the onset of BSE has been completely ruled out. Nevertheless, if our hypothesis of a relationship between age and survival is confirmed, the possibility that BSE may be transmitted to elderly people with a clinical pattern that differs in part from that of vCJD should be reconsidered. In our opinion, this is a very important issue, since the prevalence of vCJD in young people remains the most obscure point in current understanding of the vCJD epidemic. snip...see full text ; http://www.functionalneurology.it/materiale_cic/198_XXI_4/1889_young/article.pdf 18 January 2007 - Draft minutes of the SEAC 95 meeting (426 KB) held on 7 64. A member noted that at the recent Neuroprion meeting, a study was Other work presented suggested that BSE and bovine amyloidotic spongiform http://www.seac.gov.uk/minutes/95.pdf Models Qingzhong Kong, Ph.D., Assistant Professor, Pathology, Case Western Reserve Bovine Amyloid Spongiform Encephalopathy (BASE) is an atypical BSE strain ***These results indicate that BASE is transmissible to humans and suggest that BASE is more virulent than There is a growing number of human CJD cases, and they were presented last He estimates that it may be up to 14 or 15 persons which display selectively disease in the United States I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc? Full Text Diagnosis and Reporting of Creutzfeldt-Jakob Disease Singeltary, Sr et al. JAMA.2001; 285: 733-734. http://jama.ama-assn.org/cgi/content/full/285/6/733?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&fulltext=dignosing+and+reporting+creutzfeldt+jakob+disease&searchid=1048865596978_1528&stored_search=&FIRSTINDEX=0&journalcode=jama BRITISH MEDICAL JOURNAL SOMETHING TO CHEW ON BMJ http://www.bmj.com/cgi/eletters/319/7220/1312/b#EL2 BMJ http://www.bmj.com/cgi/eletters/320/7226/8/b#EL1
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