Blood Transfusions Could Transmit Variant Creutzfeldt-Jakob

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.

Action Points

  • Explain to patients who ask that this study suggests that human-to-human transmission of the degenerative neurologic disease variant Creutzfeldt-Jakob (vCJD), caused by exposure to bovine spongiform encephalopathy (BSE), also known as mad cow disease, could occur if blood from infected individuals enters the blood supply.
  • Be aware that the incubation period for vCJD appears to be lengthy, and that many people infected with the disease-causing prion may have a subclinical illness for decades.
  • Reassure concerned patients that blood donors in the United States are carefully screened for possible exposure to BSE and for family history of CJD, significantly reducing the risk of human-to-human transmission.

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 BSEâ€¦," 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.