- The bad news came with the death of an
elderly patient in Britain two years ago. While seemingly unremarkable,
this was automatically the subject of an autopsy because the patient had
a blood transfusion in 1999 from a donor who had died later from the human
form of mad cow disease: variant Creutzfeldt-Jakob disease (vCJD).
- In Britain, paranoia is rife about human-to-human
vCJD transmission via blood. This disease is the newest type of prion disease
in a group that includes bovine spongiform encephalopathy (BSE). This automatic
look-back policy on British blood product recipients proved a grim genetic
revelation, as well as the first solid indication of what experts had feared:
that the BSE epidemic that has wiped out millions of cows was entering
a new phase - secondary transmission through humans.
- Reported in 2004, elderly patients were
the second probable case of blood-borne vCJD transmitted between humans.
The first was identified months earlier, in December 2003, in a 62-year-old
man who died of vCJD six years after a blood transfusion. This man's blood
donor had been an apparently healthy young man who died of vCJD three years
after the donation.
- A third blood transfusion-related case
was identified in March this year. All three were in Britain, the epicentre
of the declining but continuing two-decades-old BSE epidemic in which more
than 184,000 cows have been diagnosed with BSE and millions more have been
slaughtered as a precaution.
- Although the patient died of unrelated
causes, the spleen in the second case was "loaded" with abnormal
prion protein, according to one expert. Prion protein is a Jekyll-and-Hyde
protein. In normal brains it helps create nerve cells. In diseased brains
it changes shape, misfolds and causes terminal damage.
- In vCJD, unlike other types of CJD, it
starts in the lymphoreticular tissue. This includes the spleen, appendix,
lymph nodes and tonsils, and takes years to reach the brain where the abnormal
prion creates tiny "spongy" holes.
- The second case marked a turning point
in the history of vCJD, which burst into the annals of disease just a decade
ago (March 20, 1996) with the announcement in the House of Commons that
a new disease had been identified in 10 young British people and was linked
to the BSE epidemic.
- Despite no symptoms of vCJD, the second
patient was carrying the infectious rogue prion and was a danger to anyone
who received that person's blood, organs or tissue, or whose surgery followed
any procedure performed in which the same metal instruments were used.
Most worrying was the genetic make-up in this case on one tiny point of
a gene all humans and other mammals carry - the prion protein gene (PRNP)
on chromosome 20.
- To date, all 191 victims of vCJD have
shared a genetic trait. They are MM at codon 129 of the PRNP gene. Forty
per cent of caucasians have the MM genotype. It had been hoped this was
the only susceptible population group.
- But the second case, sadly, had the most
common genetic type at the codon 129 position of the PRNP gene. It is known
as MV - a trait shared by half of all caucasians.
- This is the first identified vCJD-linked
human to have the MV genotype. The last 10 per cent of the population is
known as VV on codon 129, and until last month being VV was pretty good
news if you wanted to avoid vCJD.
- BEFORE vCJD, there was another orally
transmitted prion disease. Kuru (the "shivering" disease, named
after one symptom) probably originated with a single case of CJD around
1900, in the Fore tribe of the eastern highlands of Papua New Guinea. The
disease nearly wiped out the Fore, who ate the brains of dead relatives
in a mourning ritual.
- However, cannibalism was prohibited in
the 1950s and gradually the epidemic died. But with the odd case still
emerging, the longest incubation period for this disease is now more than
40 years and serves as a model for what might happen with vCJD.
- Recent genetic analysis of the scrupulously
preserved records and blood samples from the kuru epidemic show victims
with the MM genetic variation were younger when symptoms began (many were
children), probably had a shorter incubation period and a shorter illness.
Another study revealed most MV or VV individuals survived the epidemic
or developed kuru when older. The VV genotype - reassuringly for those
who might die of something else first - had the longest incubation period,
according to a 2001 study published in the Journal of Infectious Diseases.
- LAST month two papers provided additional
foundation for the kuru findings - that the MM genotype may affect merely
the shorter incubation victims of the human mad cow epidemic and that MV
or VV genotypes will live longer, but not necessarily escape the same fate.
- In the first, published in The Lancet
Neurology, mice whose PRNP gene had been replaced with the human counterpart
did not develop BSE when deliberately injected with it. However, when vCJD
was injected into MM and MV mice they were "equally susceptible"
to infection, although most of the MV mice did not develop symptoms before
the end of the 700-day experiment - their natural life span.
- The transmission rate of vCJD in the
VV transgenic mice was much less but indicated a rather grim scenario:
that all three genotypes on codon 129 showed subclinical or symptomless
infection. What differed was the incubation periods until symptoms either
appeared or the mice died. The mice were useful in showing that once BSE
has passed into humans in the form of vCJD, it was altered, which also
raised "concerns relevant to the possibility of secondary transmission
of vCJD through blood transfusion, fractionated blood products, or contaminated
surgical instruments", the authors warned.
- And if the news could get worse, it did.
A retrospective study published in the British Medical Journal analysed
the genotypes of the three positive samples of infected tissue found among
11,109 appendixes and 1565 tonsils removed in operations in Britain between
1995 and 2000 from anonymous patients aged between 20 and 29. With enough
DNA left in only two of the three positive appendixes, the researchers
found that is was "perhaps surprising" to find they were both
VV. This bad news is the first time that the VV population in humans -
the smallest population of the three genotypes at codon 129 on the PRNP
gene - has been found to be potentially susceptible to vCJD infection.
- Reaffirming earlier findings, the researchers
from the national CJD Surveillance Unit at the University of Edinburgh
stated: "Genetic studies of kuru, another orally transmitted human
prion disease, found that PRNP codon 129 MV and VV genotypes were associated
with longer incubation periods than the MM genotype."
- And the ramifications? With such a long
incubation period projected for VV genotypes, a potential risk for horizontal
transmission of vCJD infection by "blood transfusion, blood products
or contaminated surgical instruments" arises, underscoring the vital
need for continued surveillance of cases well into the future, they warned.
- Dr Andrew Hill, a molecular genetics
expert who heads a laboratory studying prion diseases at the Bio21 Institute
at the University of Melbourne, was one of the first to reveal through
mouse experiments reported in 2000 that there was a silent reservoir of
infection in symptomless prion disease carriers. The latest mice revelations
"confirm concerns we raised in our study", he says. "These
studies underlie the urgent need for a rapid, sensitive test for infectious
prions so we can identify potential asymptomatic carriers.
- "The blood bans [banning the donation
of blood from any Australian who has spent a cumulative six months or more
in Britain between 1980 and 1996 or who has ever had a blood transfusion]
still apply and people might question why."
- While Australia remains free of BSE "you
can't ignore this just because it's happening overseas", he says.
- Given Australia's historic migratory
and tourism ties with Britain in particular, Australian prion disease experts
think it inevitable that vCJD will emerge in Australia from someone infected
- "I suppose it all really underscores
the need for continuing CJD surveillance in Australia," Professor
James Ironside, from Edinburgh's CJD Surveillance Centre, told the Herald.
More silent carriers as well as symptomatic vCJD cases in the 25 BSE-affected
countries affected to date also loom.
- Any continuing pattern of change to the
genotypes of vCJD victims could mark the beginning of the next phase of
the human epidemic.
- THE TRAIL
- Prion diseases
- * Incurable, untreatable.
- * Definitive diagnosis only at autopsy.
- * Widely accepted cause is that abnormal
prion protein misfolds, replicates, causes spongy holes in the brain.
- * Prions stick to metal (cattle feed
bins, surgical instruments).
- * Resistant to standard surgical
- * In humans includes Kuru and Creutzfeldt-Jakob
disease which has four main types:
- 1. Sporadic (no known cause).
- 2. Familial (inherited).
- 3. Iatrogenic (medically acquired).
- 4. Variant, the only type linked
- Bovine Spongiform Encephalopathy (BSE)
- * First reported 1986 in England.
- * Spread to other countries via exports
of live carrier cattle and meat-and-bonemeal protein supplements (MBM).
- * Continuing cases in Britain believed
linked to MBM contamination of inadequately cleaned metal feed bins.
- * Never appeared in Australasia.
- Variant CJD
- * First reported 1996 in England.
- * 191 cases; Britain (161), France
(18), other countries (12); none in Australasia.
- * Looks and behaves differently to
other CJD types.
- * Only type to transmit between humans
- * Until now all cases are MM genotype;
BUT one carrier case is MV; two VV genotype cases in appendixes
- © 2006 Independent News and Media