Cingles Info

Blood Transfusions Could Transmit Variant Creutzfeldt-Jakob
By Neil Osterweil, Senior Associate Editor, MedPage Today
Reviewed by Robert Jasmer, MD; Assistant Professor of Medicine, University of
California, San Francisco
March 27, 2006
Also covered by: BBC News, Forbes
Review
EDINBURGH, Scotland, March 27 - Bovine spongiform encephalopathy (BSE), better
known as mad cow disease, is apparently not easily transmitted from cattle to
humans. That's the good news.
The bad news is that once BSE makes the jump into people in the form of variant
Creutzfeldt-Jakob disease, or vCJD, it may readily spread from one person to the
next through the British blood supply, reported researchers in an early online
release from The Lancet Neurology.
Studies of transgenic mice bred to express the human prion protein gene in its
most common human variants indicate that while there appears to be good
protection against BSE transmission to humans, human-to-human transmission of
vCJD may readily occur in all but about 10% of the population, according to Jean
C. Manson, Ph.D., and colleagues of the Institute for Animal Health here.
Variant CJD may also have a very long incubation period, and there may be a
significant level of subclinical disease, the investigators suggested.
"Although the cattle BSE epidemic in the United Kingdom has amounted to more
than 180,000 cases since the 1980s, the extent of the human vCJD epidemic has so
far remained limited, with the total number of cases worldwide currently at
190," Dr. Manson and colleagues wrote.
"One explanation for this apparent discrepancy is that there exists a
significant species barrier between cattle and human beings, which limits the
susceptibility of the human population to BSE.," they added. "However, once BSE
has passed through human beings in the form of vCJD, the transmissibility of
this transmissible spongiform encephalopathy strain is altered for the human
population."
A specific polymorphism, or variant, in the prion protein gene in humans has
been shown to be a major determinant of susceptibility to prion diseases. The
polymorphism, which occurs at codon 129 of the gene, determines whether the
amino acids methionine or valine are present at that location.
About 40% of Caucasians are homozygous for methionine, and an additional 50% of
Caucasians are heterozygous (i.e., have one valine and one methionine allele),
and another 10% are homozygous for valine.
"All cases of human vCJD have been in patients with the methionine-methionine
genotype, which suggests that the methionine-valine and valine-valine genotypes
are protective," wrote Corinne Ida Lasmezas, Ph.D., a professor of biomedical
research at the Scripps Research Institute in Jupiter, Fla., in an accompanying
editorial.
But as Dr. Manson and colleagues found in their study, "all individuals,
irrespective of codon-129 genotype, could be susceptible to secondary
transmission of vCJD through routes such as blood transfusion."
They determined this by using transgenic mice as surrogates for humans. The mice
were bred to express either the human or bovine forms of the prion protein gene.
For the mice with the human gene, the investigators bred three genetically
identical populations that expressed the gene in the three human variants
(methionine homozygous, heterozygous, or valine homozygous).
The mice were then inoculated with either BSE or vCJD delivered directly into
the brain, and all mice were assessed for clinical and pathological signs of
prion disease.
They found that while BSE was transmitted via inoculation to those mice
expressing the bovine form of the prion protein gene, the mice with the human
forms of the gene did not develop transmissible spongiform encephalopathies.
In contrast, vCJD was transmitted to all three mouse lines expressing the human
gene variants, with different pathological characteristics for each genotype.
For example, mice with the methionine-methionine polymorphism had evidence of
disease at a relatively early stage, 370 days after inoculation, whereas as the
heterozygous animals had evidence of disease that was restricted to only a few
brain areas beginning at around 581 days, and remained limited at least 700 days
after inoculation.
In addition, the authors found that there was a gradation of transmission
efficiency, with the methionine-methionine genotype being the most susceptible
(11 of 17 mice infected) to methionine-valine (11 or 16 infected) to
valine-valine (1 of 16 infected).
There findings suggest that "transmission of BSE to human beings is probably
restricted by the presence of a significant species barrier. However, there
seems to be a substantially reduced barrier for human-to-human transmission of
vCJD," the authors wrote.
"Moreover, all individuals, irrespective of codon-129 genotype, could be
susceptible to secondary transmission of vCJD through routes such as blood
transfusion. A lengthy preclinical disease is predicted by these models, which
may represent a risk for further disease transmission and thus a significant
public-health issue," they concluded.
http://www.medpagetoday.com/Neurology/GeneralNeurology/dh/2933