Study Suggests New Human Genotype May Be Prone To Variant Creutzfeldt-Jakob Disease

A small study in this week's British Medical Journal suggests a new human genotype may be prone to variant Creutzfeldt-Jakob disease (vCJD).

Although this new evidence may rekindle fears of a larger epidemic, others warn that it is important to be cautious in interpreting these results.

Since the initial discovery of vCJD in the United Kingdom a decade ago, there has been concern about the ultimate extent of the epidemic. Fortunately the magnitude of the epidemic at present seems to match the lower limit of the early estimates, with 161 definite or probable cases in the UK.

Researchers at the University of Edinburgh analysed DNA from two tissue samples that harboured prion proteins (a marker for vCJD infection) to identify the genetic make-up (genotype) of the patients.

So far, all clinical cases of vCJD have occurred in individuals with the homozygous methionine (MM) genotype, and it was hoped that this was the only susceptible population group. But both these samples carried the homozygous valine (VV) genotype, suggesting that individuals with the VV genotype may also be susceptible to vCJD infection.

The fear is that individuals with this genotype may be at risk of developing the condition, possibly with longer incubation periods, say the authors. Alternatively, these people may be asymptomatic carriers who might transmit the condition to other susceptible individuals by blood transfusion or surgery.

Though they warn against over-interpreting data from only two positive cases, they conclude that these uncertainties further underline the need for continued surveillance of vCJD in the UK.

It is important to be cautious in interpreting the results of this study, warn experts from Canada in an accompanying editorial. The study shows the existence of the prion protein in two tissue samples, not clinical evidence of vCJD in two patients. The study also provides no evidence to suggest that tissue from these two people could transmit vCJD to others.

"Studies such as this are essential to the continuing effort to control the extent of the epidemic and highlight the urgent need for ongoing surveillance for vCJD," they add. "They also pose challenges to health officials who have to formulate policies comprising difficult trade-offs based on uncertain evidence."

Can Dementia Spread From Mother To Offspring?

Researchers have demonstrated spread of senile amyloidosis from affected mice to their nursing offspring. The paper by Korenaga et al., "Transmission of amyloidosis in offspring of mice with AApoAII amyloidosis," appears in the March issue of The American Journal of Pathology and is highlighted on the cover of the Journal.

Dementia can result from several disease mechanisms, including amyloidosis. Amyloidosis occurs when cellular proteins that normally float freely in the body form organized, nonfunctional aggregates, or fibrils, that cause cellular damage. This injury can lead to such disorders as Alzheimer's disease and Creutzfeld-Jakob disease, depending on the protein involved and where the fibrils accumulate.

Genetics are known to be involved in these disorders, but researchers have also shown that injecting fibrils into susceptible mice accelerates disease onset. That led researchers guided by Dr. Xiaoying Fu to ask whether pups born to affected mothers also display accelerated disease.

Using a mouse strain that carries a mutation for senile amyloidosis, Dr. Fu's group injected female mice with amyloid fibrils, to accelerate their disease, and then allowed the mice to mate and produce offspring. The mouse pups born to these mothers exhibited elevated levels of amyloid fibrils that increased with age. These fibrils were first seen in the intestines, spreading later to liver, spleen and other organs.

Interestingly, when mice born to injected mothers were nursed by control mothers (no fibrils injected), only one of nine pups had amyloid fibrils at 6 months. However, pups born to control mothers but nursed by injected mothers had amyloidosis at levels similar to that of pups born/nursed by injected mothers. The presence of fibrils in the milk of injected mothers was confirmed by protein assay and electron microscopy, and spread via the milk was demonstrated by injecting affected milk into naïve mice (fibrils were found at 3 months).

These authors use traditional "infectivity" concepts to show that ingestion of fibrils by nursing mouse pups, and not by events occurring in utero, transmits amyloid fibrils to their offspring, thus accelerating amyloidosis. Such events have not been observed in human amyloidosis but have been suggested in sheep scrapie, a prion disease related to Creutzfeld-Jakob disease.

Prion diseases, such as scrapie and bovine spongiform encephalopathy (mad cow), are known to be transmissible, with spread among susceptible hosts demonstrated in the laboratory and in the real world. Non-prion amyloidosis, however, has not been shown to spread in such a way until now.

Though provocative, the implications for such laboratory findings in human disease, such as Alzheimer's disease, are not clear. The study does, however, suggest interesting new areas for study of amyloidosis.

This work involved collaborators at the Institute on Aging and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto; the Institute for Frontier Medical Science, Kyoto University, Kyoto; Fukui Medical University, Matsuoka; the Institute for Developmental Research, Aichi Human Service Center, Kasugai; and The Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Tokyo, Japan.

Korenaga T, Yan J, Sawashita J, Matsushita T, Naiki H, Hosokawa M, Mori M, Higuchi K, Fu X: Transmission of amyloidosis in offspring of mice with AApoAII amyloidosis. Am J Pathol 2006 168:898-906