Future uncertain for variant Creutzfeldt-Jakob disease
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For personal use. Only reproduce with permission from The Lancet Publishing Group. THE LANCET Neurology Vol 1 September 2002 http://neurology.thelancet.com 271 Newsdesk Eight years after the first case of variant Creutzfeldt-Jakob disease (vCJD) was identified, disease onsets and deaths are still increasing by over 20% per year on average, according to the UK National CJD Surveillance Unit’s tenth annual report (www.cjd.ed.ac.uk). The Edinburgh unit was set up in 1990, in the wake of the bovine spongiform encephalopathy (BSE) epidemic in cattle, to identify any changes in CJD that could be linked to BSE. Up to December 31, 2001, there were 104 deaths from definite or probable vCJD in the UK, of which 89 were confirmed neuropathologically, the report notes. The latest figures (as of June 28, 2002) show that the number of deaths have risen to 115 [92 confirmed]—a rise of 10·6% over the previous 6 months. According to Paul Brown (National Institutes of Health, Bethesda, MD, USA), all predictions about the future course of the UK epidemic of vCJD are “well- intentioned wheel spinning.” He adds, “if I had to add my own prediction, it would be that the outbreak should be peaking just about now and that there will be a dwindling number of cases over many years to come.” By his own admission, Brown is a ‘voice in the wilderness’. “But then again, I have no funding interest in predicting the worst!” Robert Will (National CJD Surveillance Unit) concedes that “predictions are less pessimistic than 2 to 3 years ago” but thinks there are too many unknowns— incubation times, the infective dose of the aberrant prion protein in man, how much infective material the population has been exposed to, and variations in susceptibility to the disease—to allow a meaningful prediction. However, “we are now thinking in terms of a few hundred or thousands of cases rather than tens of thousands or more”, he says. Roy Anderson (Imperial College, London, UK) notes that all vCJD patients so far have been homozygous for methionine at codon 129 of the prion protein gene, “but it is possible that heterozygotes might become susceptible later in the epidemic, just as kuru affects both homozygotes and heterozygotes”. The incubation period could be longer in heterozygotes, he adds. Anderson estimates a worst-case scenario of 150 000 vCJD deaths, assuming another unknown—that BSE was also transmitted to sheep via feed supplements and is still present (Nature 2002; 415: 420–24). So far, there is no evidence of vCJD transmission via blood or surgical instruments, says Will, “but the period of observation is short, and the incubation period could be long”. Dorothy Bonn Future uncertain for variant Creutzfeldt-Jakob disease Muscle weakness and “cobblestone lissencephaly” are characteristic of two types of congenital muscular dystrophy (CMD)—muscle-eye-brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD). Two reports in the July 25 issue of Nature suggest that -dystroglycan, a subunit of the protein dystroglycan, may not bind properly to the extracellular matrix of the cell. It is the lack of binding that causes the two symptoms. According to Kevin Campbell (University of Iowa, USA), who is the senior author of both papers, this research “demonstrates that dystroglycan is critical for normal brain development and that the lack of functional dystroglycan plays a major role in the pathogenesis of MEB and FCMD”. In the first paper (Nature 2002; 418: 417–22) the researchers took muscle biopsies from patients with MEB and FCMD and found that -dystroglycan was not glycosylated in these samples. In healthy people, -dystroglycan is glycosylated and is able to bind to proteins like laminin in the extracellular matrix. A naturally occurring mouse mutant, the myodystrophy mouse (myd)—which has a mutation in the LARGE gene that is thought to encode a glycosyl- transferase—was shown to have similar biochemical abnormalities. In the second paper (Nature 2002; 418: 422–25), Campbell’s team studied brain development and synaptic function in dystroglycan knockout mice that lacked the dystroglycan gene in glia and brain neurons, but nowhere else. The conditional knockout mice had neuronal migration abnormalities similar to those seen in MEB and FCMD patients. In addition, electrophysiological experiments showed that some mice had a reduced long-term potentiation, which is though to underlie learning and memory in human beings. The authors suggest that this is because of impaired dystroglycan in the post-synaptic mechanisms of neurotransmission. “This work beautifully proves three things”, says Francesco Muntoni, (Imperial College School of Medicine, London, UK). “Firstly, there’s a low molecular weight of -dystroglycan in MEB and FCMD; secondly, abnormally processed -dystroglycan does not bind to a variety of proteins of the extracellular matrix; and finally, dystroglycan is very important for the neuronal migration disorder associated with both conditions.” It also raises two questions, he adds. “Why does processing of -dystroglycan result in identical molecular weight product in FCMD, MEB and myd? And, are we sure that -dystroglycan’s abnormal processing accounts for all differences observed in brain and muscle of these patients?” According to Christina Gurnett and Anne Connolly (Washington University School of Medicine, Missouri, USA), “the work suggests new ways to make specific diagnoses in these progressive, multisystem disorders. While there is no immediate translation to better therapy, understanding the basic mechanism underlying these diseases is a critical first step.” Kate Nelson Faulty glycosylation causes two CMDs
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Transcript of Future uncertain for variant Creutzfeldt-Jakob disease
For personal use. Only reproduce with permission from The Lancet Publishing Group.
THE LANCET Neurology Vol 1 September 2002 http://neurology.thelancet.com 271
Newsdesk
Eight years after the first case ofvariant Creutzfeldt-Jakob disease(vCJD) was identified, disease onsetsand deaths are still increasing by over20% per year on average, according tothe UK National CJD SurveillanceUnit’s tenth annual report(www.cjd.ed.ac.uk). The Edinburghunit was set up in 1990, in the wake of the bovine spongiformencephalopathy (BSE) epidemic incattle, to identify any changes in CJDthat could be linked to BSE.
Up to December 31, 2001, therewere 104 deaths from definite orprobable vCJD in the UK, of which 89were confirmed neuropathologically,the report notes. The latest figures (asof June 28, 2002) show that thenumber of deaths have risen to 115[92 confirmed]—a rise of 10·6% overthe previous 6 months.
According to Paul Brown(National Institutes of Health,Bethesda, MD, USA), all predictionsabout the future course of the UKepidemic of vCJD are “well-intentioned wheel spinning.” Headds, “if I had to add my ownprediction, it would be that theoutbreak should be peaking justabout now and that there will be adwindling number of cases over manyyears to come.” By his ownadmission, Brown is a ‘voice in thewilderness’. “But then again, I haveno funding interest in predicting theworst!”
Robert Will (National CJDSurveillance Unit) concedes that“predictions are less pessimistic than2 to 3 years ago” but thinks there are too many unknowns—incubation times, the infective dose ofthe aberrant prion protein in man,how much infective material thepopulation has been exposed to, andvariations in susceptibility to thedisease—to allow a meaningfulprediction. However, “we are now thinking in terms of a fewhundred or thousands of cases ratherthan tens of thousands or more”, hesays.
Roy Anderson (Imperial College,London, UK) notes that all vCJDpatients so far have been homozygous
for methionine at codon 129 of theprion protein gene, “but it is possiblethat heterozygotes might becomesusceptible later in the epidemic, justas kuru affects both homozygotes andheterozygotes”. The incubationperiod could be longer inheterozygotes, he adds. Andersonestimates a worst-case scenario of150 000 vCJD deaths, assuming
another unknown—that BSE was alsotransmitted to sheep via feedsupplements and is still present(Nature 2002; 415: 420–24). So far,there is no evidence of vCJDtransmission via blood or surgicalinstruments, says Will, “but theperiod of observation is short, and theincubation period could be long”.Dorothy Bonn
Future uncertain for variant Creutzfeldt-Jakob disease
Muscle weakness and “cobblestonelissencephaly” are characteristic of twotypes of congenital musculardystrophy (CMD)—muscle-eye-braindisease (MEB) and Fukuyamacongenital muscular dystrophy(FCMD). Two reports in the July 25issue of Nature suggest that �-dystroglycan, a subunit of theprotein dystroglycan, may not bindproperly to the extracellular matrix ofthe cell. It is the lack of binding thatcauses the two symptoms. Accordingto Kevin Campbell (University ofIowa, USA), who is the senior authorof both papers, this research“demonstrates that dystroglycan iscritical for normal brain developmentand that the lack of functionaldystroglycan plays a major role in thepathogenesis of MEB and FCMD”.
In the first paper (Nature 2002;418: 417–22) the researchers tookmuscle biopsies from patients withMEB and FCMD and found that �-dystroglycan was not glycosylated inthese samples. In healthy people, �-dystroglycan is glycosylated and isable to bind to proteins like laminin inthe extracellular matrix. A naturallyoccurring mouse mutant, themyodystrophy mouse (myd)—whichhas a mutation in the LARGE gene thatis thought to encode a glycosyl-transferase—was shown to havesimilar biochemical abnormalities.
In the second paper (Nature 2002;418: 422–25), Campbell’s team studiedbrain development and synapticfunction in dystroglycan knockoutmice that lacked the dystroglycan genein glia and brain neurons, but nowhereelse. The conditional knockout micehad neuronal migration abnormalities
similar to those seen in MEB andFCMD patients. In addition,electrophysiological experimentsshowed that some mice had a reducedlong-term potentiation, which isthough to underlie learning andmemory in human beings. Theauthors suggest that this is because of impaired dystroglycan in the post-synaptic mechanisms ofneurotransmission.
“This work beautifully provesthree things”, says Francesco Muntoni,(Imperial College School of Medicine,London, UK). “Firstly, there’s a lowmolecular weight of �-dystroglycanin MEB and FCMD; secondly,abnormally processed �-dystroglycandoes not bind to a variety of proteinsof the extracellular matrix; and finally,dystroglycan is very important for theneuronal migration disorderassociated with both conditions.” It also raises two questions, he adds. “Why does processing of �-dystroglycan result in identicalmolecular weight product in FCMD,MEB and myd? And, are we sure that �-dystroglycan’s abnormalprocessing accounts for all differencesobserved in brain and muscle of thesepatients?”
According to Christina Gurnettand Anne Connolly (WashingtonUniversity School of Medicine,Missouri, USA), “the work suggestsnew ways to make specific diagnoses inthese progressive, multisystemdisorders. While there is no immediatetranslation to better therapy,understanding the basic mechanismunderlying these diseases is a criticalfirst step.”Kate Nelson
Faulty glycosylation causes two CMDs
