Wednesday, December 30, 2009

Is there evidence of vertical transmission of variant CJD ?

J Neurol Neurosurg Psychiatry doi:10.1136/jnnp.2009.172148

Is there evidence of vertical transmission of variant CJD?

Katy Murray ( + Author Affiliations

NationalCJD Surveillance Unit, United Kingdom James Peters ( + Author Affiliations

NationalCJD Surveillance Unit, United Kingdom Lesley Stellitano ( + Author Affiliations

Addenbrooke's Hospital, United Kingdom Annemarie Winstone ( + Author Affiliations

Addenbrooke's Hospital, United Kingdom Christopher Verity ( + Author Affiliations

Addenbrooke's Hospital, United Kingdom Robert Will ( + Author Affiliations

NationalCJD Surveillance Unit, United Kingdom Published Online First 27 April 2009 Abstract Objectives: The possibility of vertical transmission of variant CJD (vCJD) has been raised, because of the widespread distribution of infectivity in vCJD and the demonstration that this condition can be transmitted through blood transfusion. The aim is to search for evidence of this type of transmission of vCJD.

Methods: A national surveillance system for CJD has been established in the UK since 1990. Through this register details were extracted of all children born to vCJD cases up to March 2009. This list was checked against the CJD register and cases identified through the UK study of progressive intellectual and neurological deterioration in children (PIND) to determine whether any of the children of vCJD cases had themselves developed a progressive neurological disorder or vCJD.

Results: 125 children have been born to parents with a diagnosis of vCJD. Nine of these children were born to females with vCJD who were symptomatic at conception, birth or within a year of clinical onset. Only one woman was known to have breast fed her child. None of the children of vCJD cases have been referred to the NCJDSU as suspected vCJD and none have been classified as suffering from a progressive neurodegenerative disorder through the PIND study. One of the children has been investigated by the National Prion Unit (see accompanying case report).

Interpretation: To date there is no evidence of vertical transmission of vCJD. However, the incubation period through this mechanism might be prolonged and it will be many years before observational data can exclude this possibility.

PLoS One. 2009; 4(9): e6929. Published online 2009 September 7. doi: 10.1371/journal.pone.0006929. PMCID: PMC2732902

Copyright Bencsik et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Possible Case of Maternal Transmission of Feline Spongiform Encephalopathy in a Captive Cheetah

Anna Bencsik,1* Sabine Debeer,1¤ Thierry Petit,2 and Thierry Baron1 1Unité ATNC, Agence Française de Sécurité Sanitaire des Aliments (AFSSA), Lyon, France 2Zoo de La Palmyre, Les Mathes, France Neil Mabbott, Editor University of Edinburgh, United Kingdom * E-mail: Conceived and designed the experiments: AAB. Performed the experiments: AAB SOD. Analyzed the data: AAB SOD TB. Contributed reagents/materials/analysis tools: AAB TP. Wrote the paper: AAB SOD TP TB. ¤Current address: INSERM Unité 851, Immunité Infection Vaccination, Tour CERVI, Lyon, France Received May 27, 2009; Accepted August 12, 2009.


Feline spongiform encephalopathy (FSE) is considered to be related to bovine spongiform encephalopathy (BSE) and has been reported in domestic cats as well as in captive wild cats including cheetahs, first in the United Kingdom (UK) and then in other European countries. In France, several cases were described in cheetahs either imported from UK or born in France. Here we report details of two other FSE cases in captive cheetah including a 2nd case of FSE in a cheetah born in France, most likely due to maternal transmission. Complete prion protein immunohistochemical study on both brains and peripheral organs showed the close likeness between the two cases. In addition, transmission studies to the TgOvPrP4 mouse line were also performed, for comparison with the transmission of cattle BSE. The TgOvPrP4 mouse brains infected with cattle BSE and cheetah FSE revealed similar vacuolar lesion profiles, PrPd brain mapping with occurrence of typical florid plaques. Collectively, these data indicate that they harbor the same strain of agent as the cattle BSE agent. This new observation may have some impact on our knowledge of vertical transmission of BSE agent-linked TSEs such as in housecat FSE, or vCJD.



Here are reports of two cases of feline spongiform encephalopathy (FSE) in 2 female cheetahs, one imported from Great Britain, the other born in France, that most likely constitute the first description of a possible maternal transmission of this disease in that species. FSE is a transmissible spongiform encephalopathy (TSE) of the felidae, identified for several years now, in domestic and in captive wild felids, for the most part in cheetahs [21], [22]. In captivity, all these felidae could have been exposed to infected tissues from cattle from early in their lives and the most probable explanation of the occurrence of FSE is consequently a contamination by oral route with the infectious agent of the bovine spongiform encephalopathy (BSE). For FSE cases in domestic cats only, a link between BSE and FSE agent was demonstrated by the similarity of mean incubation periods and lesion profiles in FSE and BSE cases transmitted to wild-type mice [3], [23]. Here we report the transmission of the FSE case 1 (the mother of case 2) into the Tg(OvPrP4) mouse model that has been demonstrated as sensitive to and efficient at detecting the BSE strain of agent [2], [15], [16]. When BSE agent is transmitted in this model, at first passage the mean incubation periods may vary depending on the species of the host harboring the BSE agent (cattle, sheep etc.), and was reported to be from 300 d.p.i. +/-50 (mean +/- standard error) to 475 +/-69 d.p.i. (and even up to 500 d.p.i. +/-110 for an experimental ovine BSE in an ARR/ARR genotype sheep) [2], [15], [17].

For both passages reported in the present study, the mean incubation periods of FSE are totally in accordance with this previously reported range of data obtained in BSE agent transmission studies in TgOvPrP4 mice. It is likely that the slight differences between the incubation periods reported here in BSE and FSE transmissions resulted from the different species and different titre of infectious agent present in the inoculum. This was also suggested in other BSE transmission studies in RIII or C57Bl mouse lines, for which quite a wide range of mean incubation times has also been reported (range 393–909 days in BSE transmissions to C57Bl mice) [24]. At second passage, the incubation period for FSE appeared slightly longer, but this was not statistically different from the mean incubation period of the first passage experiment. The reason for this tendency is unclear but it had already been reported for ovine BSE transmitted to this model (296 d.p.i at first passage to 365 d.p.i at 2nd passage) [17]. However, it remained within the range of expected duration for BSE agent transmitted to this transgenic mouse model.

The comparison of FSE and BSE lesion profiles indicates clear resemblance in the shape and severity of vacuolation of the nine referential gray matter sites, consistent with the hypothesis of similarity between the infectious agents responsible for these TSE cases. In the same way, the systematic assessment of PrPd-accumulation sites and type revealed additional supportive arguments: PrPd depositions were also found in the cortex, septum, hippocampus, thalamus, hypothalamus, midbrain and brain stem, in structures all previously identified as accumulation sites in past experiments using different BSE sources [2], [15]–[17]. More characteristically in this transgenic mouse model, the typical amyloid florid plaques detected in each group indicated that the infectious agent present in the case of the mother cheetah was similar to the one responsible for the BSE in cattle. Collectively, these transmission data therefore clearly signified that the FSE case 1 was linked to the classical BSE agent.

As established for other species such as mink affected with transmissible mink encephalopathy [25], oral contamination appeared as the most obvious cause in that case. It is likely that this case, born in 1989 in a UK zoo, like other previously-described FSE cases in cheetah (born before 1986 and fed with cattle carcasses) [10]), was exposed to a BSE risk mainly during the first year of her life, before being exported in 1993 to Peaugres Safari Park in France. Contamination with another TSE source such as scrapie appears less likely, since scrapie is not transmittable to domestic cats, at least via the intracerebral route [26].

The occurrence of the second case reported here is of great interest since for this female cheetah the meat source was exclusively from rabbits and hens freshly killed or beef (minced steak fit for human consumption), every effort being made to avoid any possible risk of oral contamination with the BSE agent. In April 1996, immediately after the identification of the first cases of vCJD in the UK and France, essential precautionary measures were implemented, with a ban on the introduction of specified risk materials (SRM), including bovine brain and spinal cord, into the human and animal food chain. In addition, cheetahs are threatened with extinction and the species is classified as Vulnerable on the IUCN Red List, with subspecies venaticus and hecki classified as Critically Endangered. They appear on Annex I of the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). Captive specimens are managed in the context of breeding and conservation programs (EEP in Europe) where participating zoos including La Palmyre and Peaugres work in cooperation.

Moreover, lack of genetic diversity and the difficulty of breeding them in captivity make these animals very precious in zoological collections and they receive special care from the staff, including their diet which is evaluated for nutritional and sanitary risks. In addition, this female cheetah was not in contact with any other identified FSE-affected cheetah, except her mother. It therefore seems most likely that this female cheetah was contaminated through the vertical transmission of a prion agent related to BSE. The mother started to express the first clinical symptoms of FSE about 2 months before giving birth, suggesting that during the gestation as well as the suckling periods the little cheetah could have been exposed to the infectious agent from the mother. At the very least, these critical periods were those when the mother accumulated a maximum of PrPd. It is not possible to determine the precise way (in utero, via placenta, at birth, after birth via colostrums/milk) by which the infectious agent may have contaminated the young female cheetah. Anatomically, in the cheetah as in other carnivores, there is an endothelio-chorial placenta, a type of placenta facilitating exchanges between the mother and the fetus, in particular thanks to the proximity of their vascular elements. This is not the case of ruminants, which have an epithelio-chorial placenta and for which the risk of this type of transmission is thus very low. The mother gave birth to 5 individuals and 2 little cheetahs died in the first days after birth. At present, the 2 brothers of the FSE case 2 are still alive and healthy, living in 2 other, different French zoos, suggesting that the dose of infectious agent must not have been very high. In that context, the hypothesis of transmission of the disease via colostrums or milk is also credible, first because cellular as well as pathological forms of PrP have been detected in ruminant mammary glands [27], [28], second because PrPc (the acknowledged protein substrate for PrPd conversion) exists in the milk of domestic ruminants [27] and third because the possibility of transmitting the disease through milk and colostrums has recently been shown in the sheep species [29], [30]. In that hypothesis, the fact that PrPd was detectable in the lymph nodes of this cheetah is also remarkable because the lymphoreticular system seems to play a substantial role in facilitating neuroinvasion in the event of low doses of infective agent as demonstrated in a scrapie infection model of hamsters [31]. The age for onset of the disease (between 6 and 7 years) as well as the clinical symptoms seem to be comparable for the two FSE cases, and the fact that the incubation period was not shortened in the daughter is in accordance with the hypothesis of a low dose infection.

The comparison of PrPd brain mapping and type of deposition does not reveal obvious differences either in the brain structures affected or in the intensity of PrPd accumulation. The thalamo-cortical PrPd labeling might explain the sensorial dysfunctions observed in both cases, and the strong PrPd accumulation seen in the cerebellum may be at least a contributor to the loss of equilibrium. Finally the transmission studies of this second FSE case to TgOvPrP4 should make it possible to establish whether or not the parameters of the BSE strain reported here for the mother are stable.

In summary, although oral contamination by the BSE agent could not be totally excluded, the elements reported in the present article indicate collectively that the 2nd case of cheetah FSE, concerning an animal born in France, is most likely due to maternal transmission from a cheetah harboring the same strain of agent as the cattle BSE agent. Beside the epidemiological significance of this finding (and this may have some impact on our knowledge of FSE cases in domestic cats in which the possibility of a maternal transmission should be taken into account) it may have some incidence on the question of vertical transmission of other TSEs, especially those linked to the BSE agent. In the case of BSE in sheep, it appears that maternal transmission can occur [32], [33]. In cattle, there is no evidence of vertical transmission of either natural or experimental BSE even though the risk has been analyzed [34], but the peripheral pathogenesis of the BSE agent is also much more restricted, compared to the case of sheep or humans. Prion protein immunostaining and infectivity have been reported in lymphoreticular tissues in vCJD cases, as in the present FSE cases. Despite this, vertical transmission had not been found until now in vCJD cases. This question is still a current issue and a recent article underlines the caveats and difficulties in excluding this possibility, principally due to the limited availability of data concerning children in vCJD cases and a relatively short period of observation [35]. In this context, our article should bring additional elements for consideration in the hypothesis of a vertical transmission of the human disease linked to the BSE agent.

Journal of Virology, July 2005, p. 8665-8668, Vol. 79, No. 13 0022-538X/05/$08.00+0 doi:10.1128/JVI.79.13.8665-8668.2005 Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Vertical Transmission of Bovine Spongiform Encephalopathy Prions Evaluated in a Transgenic Mouse Model

J. Castilla,1 A. Brun,1 F. Díaz-San Segundo,1 F. J. Salguero,1 A. Gutiérrez-Adán,2 B. Pintado,2 M. A. Ramírez,2 L. del Riego,1 and J. M. Torres1* Centro de Investigación en Sanidad Animal (CISA-INIA), Ctra. de Valdeolmos a El Casar, Valdeolmos, 28130 Madrid, Spain,1 Departamento de Reproducción Animal y Conservación de Recursos Zoogenéticos (INIA), Avda. Puerta de Hierro s/n, Madrid 28040, Spain2

Received 4 November 2004/ Accepted 3 March 2005

In this work we show evidence of mother-to-offspring transmission in a transgenic mouse line expressing bovine PrP (boTg) experimentally infected by intracerebral administration of bovine spongiform encephalopathy (BSE) prions. PrPres was detected in brains of newborns from infected mothers only when mating was allowed near to the clinical stage of disease, when brain PrPres deposition could be detected by Western blot analysis. Attempts to detect infectivity in milk after intracerebral inoculation in boTg mice were unsuccessful, suggesting the involvement of other tissues as carriers of prion dissemination. The results shown here prove the ability of BSE prions to spread centrifugally from the central nervous system to peripheral tissues and to offspring in a mouse model. Also, these results may complement previous epidemiological data supporting the occurrence of vertical BSE transmission in cattle.


* Corresponding author. Mailing address: Centro de Investigación en Sanidad Animal INIA, Valdeolmos, 28130 Madrid, Spain. Phone: 34 91 620 23 00. Fax: 34 91 620 22 47. E-mail: .


Journal of Virology, July 2005, p. 8665-8668, Vol. 79, No. 13 0022-538X/05/$08.00+0 doi:10.1128/JVI.79.13.8665-8668.2005 Copyright © 2005, American Society for Microbiology. All Rights Reserved.


Public Health and European CJD Surveillance Professor Robert Will University of Edinburgh, UK

Continuing public health concerns

•Prevalence of human BSE infection

•?Surgical transmission of vCJD

•?Vertical transmission of vCJD

•?Novel forms of human BSE infection (MV/VV)

•Atypical BSE/scrapie

•Chronic wasting disease of deer (North America)

•Countries exposed to BSE with inadequate animal or human surveillance

NEUROLOGY 1998;50:684-688 © 1998 American Academy of Neurology

Creutzfeldt-Jakob disease in a husband and wife

P. Brown, MD, L. Cervenáková, MD, L. McShane, PhD, L. G. Goldfarb, MD, K. Bishop, BS, F. Bastian, MD, J. Kirkpatrick, MD, P. Piccardo, MD, B. Ghetti, MD and D. C. Gajdusek, MD From the Laboratory of CNS Studies (Drs. Brown, Cervenáková, Goldfarb, and Gajdusek), NINDS, and Biometric Research Branch (Dr. McShane), NCI, National Institutes of Health, Bethesda, MD; the Department of Obstetrics (K. Bishop), Gynecology and Reproductive Sciences, University of Texas Houston Health Science Center, Houston, TX; the Department of Pathology (Dr. Bastian), University of South Alabama Medical Center, Mobile, AL; the Department of Pathology (Dr. Kirkpatrick), The Methodist Hospital, Houston, TX; and the Department of Pathology (Drs. Piccardo and Ghetti), Indiana University School of Medicine, Indianapolis, IN.

Address correspondence and reprint requests to Dr. Paul Brown, Building 36, Room 5B21, National Institutes of Health, Bethesda, MD 20892.

A 53-year-old man died of sporadic Creutzfeldt-Jakob disease (CJD) after a 1.5-year clinical course. Four and a half years later, his then 55-year-old widow died from CJD after a 1-month illness. Both patients had typical clinical and neuropathologic features of the disease, and pathognomonic proteinase-resistant amyloid protein ("prion" protein, or PrP) was present in both brains. Neither patient had a family history of neurologic disease, and molecular genetic analysis of their PrP genes was normal. No medical, surgical, or dietary antecedent of CJD was identified; therefore, we are left with the unanswerable alternatives of human-to-human transmission or the chance occurrence of sporadic CJD in a husband and wife.


Received May 5, 1997. Accepted in final form September 10, 1997.

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