Notes and comments on an excellent 10 page expository article published 2 Dec 1996 in the New Yorker magazine from John Lanchester (UK journalist). This is a very good item to xerox and distribute to the off-line people in your life who need a very up-to-date and balanced introduction to what happened. [There are a few technical errors to be sure.] -- webmaster
"[I] heard in scientific circles [late October 96] that doctors are now monitoring another 60 cases [of suspected nv-CJD]" Lanchester, page 80
Secrecy surrounds the extent of the epidemic. Dr. Sheila Gore called for the Edinburgh CJD Unit to releasing monthly or quarterly figures on suspected nv-CJD cases to other scientists, but they refused. Because of increasing familiarity with nvCJD, false-positives are probably increasingly rare among the suspected category. If even half of the 60 new cases are nvCJD, this would reperesent a huge acceleration in the epidemic. -- webmaster
"The character of the animal changes. In fact, the symptoms of BSE vary accorig to what the original nature of the animal was. The mad cows have generally been pretty mad before they got BSE. If they're wild before they get it, they suffer much more exaggerated symptoms. The very quiet,subdued animals tend to show lmuchmilder early signs.. The farmers all notice it. cows are creatures of habit. They tend to come into the milking parlor in the same order each times -- but these cows hang back. They don't feed quite as well. they stop ruminating, they stopy cuddind, and that leds to digestive upsets. They lose condition and their milk production fallls. All those things show up before they ever show any nervousness, or madness."
'Shipley's cow video shows an animal looking "worried." The cow's head was hanging, and her movements had a quality that was sumultaneously jumpy and slowed down. She was frowning -- her brow was furrowed -- and her movements were somehow tentative, she seemed to be nervous about where to put her front feet.. When another cow came up behind her, she started and looked alarmed. There was a shaking movement across her shoulders. Later: the affected animals rubbed parts of their bodies against walls or fences. They began to shake and tremble, their sense of balance was impaired. After about six months, they could no longer get to their feet.'
"Because the dominant characteristics of the scrapie agent resemble those of a protein, an acronym is introduced to emphasize this feature....the term prion (pronounced ) is suggested. Prions are small proteinaceous infectious particle which are resistant to inactivation by most procedures that modify nucleic acids." Prusiner, Science, 1982 .
1952 kuru reported in New Guinea
1957-1975 2,500 deaths or 1% per year at peak, 5% men 1980 40 victims per year, still today. 1732 first clinical description of UK scrapie. First known BSE case on seen on farm: veterinary Colin Whitaker, April 1985, Ashford Kent. October 31, 1987 Veterinary Record, first account of BSE. 420 cases of BSE confirmed by December 31, 1987 7,137 in 1989 14,181 in 1990 25,032 in 1991 February 1989 Southward report:"From present evidence, it is likely that cattle will prove to be a 'dead-end host'13 November 1989 offal ban was issued. 1988-1991 merely 3 million pounds spent on research. March 20, 1996 Stephen Dorrell Sec State for Health
for the disease agent and most unlikely that BSE will have any implications for human health."
finally makes the announcement about cow-to-human transmission.
Symptoms started with difficulty sleeping, victim became very agitated, felt dizzy, short-tempered, fatigued, pains in the soles of his feet.
Initial diagnosis: stress; hard to keep up with his work; feeling tired;short-term memory problems. speech slurred; after work, immediatelyl laid down on couch, began to come home from work early.
June 1 30th birthday party: generally unwell, noticed and commented on by family members.
Couldn't react appropriately in conversation; impaired balance and slurred speech made people think he was drunk.
Halllucinations: woke wife in middle of night demanding to know where his wife was, shaved and dressed for work in early evening; thought New Zealand rugby team was upstairs, asked wife to check, unaware of what was happening to himeself.
CJD mentioned as possible diagnosis on August 1995 by neurologist Tom Esmonde [who told wife Clare Callaghan "you shouldn't mention BSE and CJD in the same breath."]
Martin Zeidler of CJD Surveillance unit arrives at house with lengthy questionaire, mostly on diet. Did he ever eat tongue or cow's brain? Did he ever eat sheep's brain, sheep's eyeball. Had he ever been on a farm, had he ever spent holidays on a farm as a kid?
Admitted to Royal Victoria hospital in July, 1995; develped aversion to sudden movement and seemed particularly disturbed by the sight of house flies; daily deterioration evident. Six weeks at home being 'fed, wiped, and washed.'
November 1, 1995 went into hospice; initial death certificate 'pneumonia and premature dementia."
Died November 4, 1995 at age 30.
November 13, 1995 wife Clare gives birth to their second daughter.
Funeral and wake issues: family gives permission for autopsy on condition that Catholic funeral rituals would not be affected. Next, priest tells family that authorities were insisting on cremation. Undertaker brought instructions for children to stay out of room in which the body was kept, nobody to touch body or even inside of open coffin.
At midnight, authorities sealed the coffin. At Belfast City Cemetary: Maurice's grave dug to double depth and heavily limed it, the hole "looked like a mineshaft" according to older brother Brendan.
Brain material from the November 5 autopsy did not reach Edinburgh until January because no courier in Belfast was willing to carry it. In the end, Martin Zeidler of CJD Unit came to Belfast to pick it up.
"Here, in the place where we don't want to be, we know that one of three things will happen. First, there's the theoretical possibility that there is no connection whatsoever between BSE and the new human disease. Unfortunately, scientists aren't looking anywhere other than at BSE for the cause of new-variant CJD, and a real consensus has solidified on the existence of a link (which may well be as difficult to 'prove' as the link between tobacco and lung cancer).
Second, there's the apocalyptic scenario--that all parts of the infected cow are infective and the species barrier is nonexistent. In that case, anyone who had eaten any part of the 729,000 infected cattle would come down with a fatal brain disease -- a disaster of Old Testament proportions. This, too, seems highly unlikely, since there is no evidence that muscle tissue is infective, and we already know, thanks to [John] Collinge's mice, that some form of species barrier is in place.
Third, it may turn out that BSE does cause a fatal human disease but that the species barrier is such that only a minority of those exposed to it succumb. This seems to be the most realistic prediction. It means that over the next several years--over the next decades, if kuru is any guide--the death toll will fall between the current total of 12 and some other, darker figure."
"From present evidence, it is likely that cattle will prove to be a 'dead-end host' for the disease agent and most unlikely that BSE will have any implications for human health."
Tuesday, Nov 26, contrasted the way in which risk information is brokered by scientists and the lay media. In the morning, the UK broadsheet newspaper The Independent had led its front page with an exclusive headlined "After the hype, the scientists' verdict: CJD to kill hundreds". In the afternoon, the Royal Statistical Society met in London to discuss the latest information about bovine spongiform encephalopathy (BSE) and its connection to Creutzfeldt-Jakob disease (CJD). The same data are in question: whether or not the 14 known cases of new-variant CJD (nvCJD) arise from eating BSE-infected cattle and are the vanguard of an epidemic.
The Independent reported Dr James Ironside from the CJD Surveillance Unit in Edinburgh, UK, as saying "It looks as though the total number of cases over the whole course of the disease will be in the hundreds, rather than the thousands". The sharp eye could discern in a dark and unidentified accompanying photograph an abattoir hook and a cloven hoof, which invited reinforcement of the suspected but unproven link between eating beef products and nvCJD. Dr Ironside told The Lancet that he had been quoted incorrectly. At the press conference after the statisticians' meeting, the expert panel was immediately pressed to predict the "size of the nvCJD epidemic". The answer was given by Prof Adrian Smith, the President of the society: zero to millions.
What makes that answer any more defensible than the previous estimates fed to the public by the media, which ranged from millions last April, to hundreds of thousands in the summer, to the latest "hundreds"? Zero to millions is correct because it is the best estimate available with the known information. In truth, a useful prediction is impossible. Crucial parts of the equation remain unknown, in particular the incubation period in human beings and the minimum infective dose of the prion organism. The only way to estimate either is by continuing observation. There will be no quick answer. At the current rate of finding new cases, 2-3 further years of observation will be needed, unless there is a rapid increase in finding new cases. Other unknown factors include the extent of the interspecies barrier between cow and human being, and the effectiveness of the 1989 UK offal ban. A new finding, which will restrict the population at risk, is that all the known cases are homozygous for methionine at position 129 of the prion. Only 38% of the total population carry this homozygosity. At the statistical meeting, Prof Smith reaffirmed that no predictions about nvCJD are possible from what is currently known. The same line was taken by another expert in epidemic modelling, Prof Roy Anderson, also on that Tuesday morning at a press conference held by veterinary experts (see Lancet, Nov 30, p 1505).
What a newspaper such as The Independent has done is to assume that its readers cannot cope with the uncertainty of an estimate that runs from none to several millions. It was assumed that the public wants high precision. Yet this belief has led to needless confusion. If the "epidemic" is in the hundreds, the argument goes, the public will be reassured, even though no-one can say for certain which individuals will be affected. If the estimate is in the millions, then the chance of being affected is too high for comfort. Until there is good evidence that such assumptions are valid, we all must strive to balance prudent journalism with impartial accuracy.
The public rightly wishes to know about risks they take. The background in this case is that the UK Government, initially at least, denied any danger from eating contaminated beef products. What is less clear is what the public needs to know: absolute risk estimates or a range reflecting current uncertainties? When "don't know" is the correct answer, then that is what should be printed. Anything else betrays people's trust.
Here's an odd editorial that just came out in tomorrow's Lancet. I say odd, because it focuses on bashing the Independent's article that quoted Ironside [on the supposed low side of eventual magnitude of the epidemic], rather than bashing Ironside for leaking to the media contents of an article submitted to Lancet but still out for peer review. But I doubt that we will ever see the article in print, given its bashing by Anderson and Adrian Smith. Indeed, the conclusions of the final paragraph are very much on target. English science has split cleanly down the middle, acoording to whether they are funded independently by Burroughs-Wellcome or by the internally conflicted MAFF. The later grantees, for whatever reason, anachronistically release a steady stream of face-saving analyses that don't sit well with the first group of scientists, who only recently got their hands on basic data (and samples!) after years of stonewalling (see Anderson Aug 29 Nature).
The truth of the matter is that from the moment BSE started to appear in other species it apparent that there was a very real risk to humans. However the implications of this risk to the UK dairy and beef industries was so horrendous that we have been desparately clinging to the absence of absolute proof despite all the circumstantial evidence. Lacey may have been one of the few scientists with the guts to put this in print but most scientists in the SCRs and coffee rooms recognised the risk a long time ago. People died unnecessarily because we gambled that on the unlikely chance that we would be immune.
There appears to be a pattern to these incidents. It starts with a suggestion of a new danger to human life or health that has economic consequences (BSE, HIV in Facter VIII). Even before we know the nature of the risk a government official denies (quoting unspecified scientific advisors) that there is any chance of humans being affected. The worried industry sighs with relief, the consumers are reassured and business continues as usual. The few people who publicly disagree are discredited. The evidence mounts until the facts can no longer be ignored. The government finally admits the problem but sactimoniously says that it could not have been predicted. Cost have been minimised, some additional people have died and everyone has kept their jobs (except possibly the Lacey s of this world).
The process works very well for everyone except the people who die or are injured but these people represent a very small % of the total population who are unlikely to be able to vote or claim compensation so they are not a problem. No true scientist would ever claim that there was no risk to humans simply because there was no proof of a risk to humans.
I assume that all so-called sporadic CJD can be put down to infections, by blood-transmissions (CJD-infected blood) for example, consumption of meat of cattle, sheep, and goat (BSE- and scrapie-infected), scratching and licking by cats (FSE), gutting of game (CWD) and so on.
A first piece of evidence is the results of a study by Goodbrand et al. (1995). They found out by immunostaining that a subset of the "sporadic" CJD-cases showed a very similar staining pattern to the growth hormone related cases. One could indeed assume that this subset was caused by an infection with blood of a CJD patient, whereas the patterns in other "sporadic" cases, very different from that one, could have been caused by infection with animal TSE.
It was in an article from the Bundesforschungsanstalt fuer Viruskrankheiten der Tiere, Tuebingen, where I found the statement that the lamb is mainly infected by the milk (O.C. Straub: Bovine spongiforme Ezephalopathie (BSE), Deutsches Tieraerzteblatt 5, 1990). This institution is _the_ leading German institute for virus diseases (ranked as a ministry); they do active research on scrapie.
Though in the German scientific literature, the paper has never been revised, I was told by telephone only two days ago about the statement not being necessarily true. I'll inform you as soon as I'll have got a comment on it from Tuebingen
Kindly provided byPhil Rogers, MRCVSDealler SF; Lacey RW (1990) TSEs: the threat of BSE to man. Food Microbiology 7(4);253-279. Dealler SF (1991) TSE agents as crystalline forms of PrP that multiply by allowing normal metabolic forms of PrP to join the crystal. Med Hypotheses 36(2);131-134. Dealler SF; Lacey RW (1991) Beef and BSE: the risk persists. Nutrition and Health 7(3);117-133. Dealler SF (1993) BSE: The potential effect of the epidemic on the human population. British Food Journal 95:22-34 Lacey RW (1993) BSE: the gathering crisis. British Food J 95(4);17-21. Dealler SF (1994) Alkaloidal Glycosidase Inhibitors (AGIs) as the Cause of Sporadic Scrapie, and the Potential Treatment of Both TSEs and Human-Immunodeficiency-Virus (HIV) Infection. Med Hypotheses FEB;42(2):69-75. Dealler SF; Lacey RW (1994) Suspected VT of BSE. [Correspondence]. Vet Rec FEB 5;134(6);151. Lacey RW; Dealler SF (1994) BSE: The Increasing Threat to the Human-Population. Rapid Methods and Automation in Microbiology and Immunology 291-303. Lacey RW; Dealler SF (1994) Vertical transfer of prion disease. Human Reproduction 9(10):1792-1800. Dealler SF; Kent J (1995) The added risk from BSE to a UK adult that continues to eat beef products is now less than 5% of the risk that has already been taken. Prion Meeting at Goettingen (Nov). Dealler SF (1995) If BSE infects humans, when will we start to see cases? Federation of Infection Societies, Manchester Symposium, November 29th. Dealler S; Kent J (1995) BSE: an update on the statistical evidence. British Food Journal 97:3-18. Dealler SF (1995) VT of BSE: epidemiological model. International Symposium on Prion diseases. Ed: Kretzschmar H. Gottingen, Germany Dealler SF (1995) National Food Alliance Meeting (April). Patterson WJ; Dealler S (1995) BSE and public health. J Public Health Medicine 17(3):261-268. Anon (1996) TSEs: Dealler advises beef ban for children. Adapted from the special coverage in April's Public Health News. MAFF Food Safety Info Bulletin, 1996, no70, February, pp1-2. Dealler S (1996) BSE: The ethics concerning decisions about whether to continue taking a risk with this disease. Editorial. Nurs Ethics 3(3):259-262. Dealler SF; Narang H (1996) Twenty eight asymptomatic adult dairy cattle from a UK abattoir in 1995 examined for BSE using two techniques. Submitted to the Internet Journal of Transmissible SE Dealler SF (1996) VT of BSE: epidemiological evidence. Symposium of the Society for Vet Epidemiology and Preventive Medicine. Glasgow. (Email: firstname.lastname@example.org). Dealler SF (1996) Scrapie in the UK. From WWW: Email: "Steve Dealler"
. Hornsby M (1996) Dealler: BSE deaths "could be two million". London Times 17th April. Lacey RW (1996) CJD and BSE: BSE Is Being Maintained by Vertical and Horizontal Transmission. BMJ 20 Jan 312(7024):180-181. Dealler SF; Lacey RW (1991) Beef and BSE: the risk persists. Nutrition and Health 7(3);117-133. Univ of Leeds Microbiol Dept, 1 Thoresby Place, Leeds LS2 9JT, UK. Anon (1992) Guidelines for minimizing the risk of transmitting agents causing SE via medicinal products. EU Commission, Committee for Proprietary Medicinal Products EEC Regulatory Document. Note for guidance. Biologicals 20(2);155-158. Permanent Office Biostandards, Case Postale 456, CH-1211 Geneva, Switzerland. Will RG. Is there a potential risk of transmission of BSE to the human population and how may this be assessed? In: Subacute SEs: Proceedings of a Seminar in the CEC Agric Res Programme held in Brussels, 12-14 November 1990. Eds: R. Bradley, M. Savey & B. Marchant. Published by Kluwer Academic Publishers 1991. Will RG; Ironside JW; Bell JE. BSE and risk to health. BMJ 1992; 305: 53. Danner K (1993) BSE: A Risk for Man Through Pharmaceutical Products: Position and Politics of the German Pharmaceutical- Industry. TSEs: Impact on A., 80:199-205. K Danner, Bundesverband Pharmazeut Ind, BSE Working Grp, Bundesfachverband Arzneimittelhersteller, Frankfurt, Germany. Discussion of policy on TSEs within the pharmaceutical industry. Davies PTG; Jahfar S; Ferguson IT; Windl O (1993) CJD in individual occupationally exposed to BSE. Lancet (British edition) 342(8872); 680. Dept Neurol, Frenchay Hospital, Bristol BS16 1LE, UK. Savey M; Belli P; Coudert M (1993) BSE in Europe: Present and Future. Vet Res 24(2):213-225. M Savey, CNEVA, Pathol Bovine Lab, 31 AV Tony Garnier, BP 7033, F-69342 Lyon 07, France. Savey M; Baron T (1994) BSE: A Risk for Public-Health. Rev Med Vet NOV;145(11):819-827. M Savey, CNEVA, Pathol Bovine Lab, 31 Ave Tony Garnier, BP 7033, F-69342 Lyon 07, France. Anon (1995) Govt Claims Challenged by Dr Stephen Dealler. Manchester Guardian Weekly, November 26. Baron T; Belli P; Coudert M; Savey M (1995) BSE. Pathol Biol FEB;43(2):73-79. T Baron, CNEVA, Pathol Bovine Lab, 31 Ave Tony Garnier, BP 7033, F-69342 Lyon 07, France. Dealler SF; Kent J (1995) The added risk from BSE to a UK adult that continues to eat beef products is now less than 5% of the risk that has already been taken. Prion Meeting at Goettingen (Nov). Dealler SF (1995) National Food Alliance Meeting (April). Dealler S; Kent J (1995) BSE: an update on the statistical evidence. British Food Journal 97:3-18. Med Microbiol, Burnley General Hospital, Burnley, UK and Professor of Statistics, Univ of Leeds, Leeds, UK. Groschup MH; Haas B (1995) BSE: Is It a Health Risk to Man. Fleischwirtschaft SEP;75(9):1087-1091. MH Groschup, Schickhardtstr 4, D-72072 Tubingen, Germany. Ranjchapel-Messai J (1995) A search for the identity of an infectious agent. Biofutur (141);23-27. Biofutur, 141 rue de Javel, 75747 Paris Cedex 15, France. Tyler K (1995) Risk of human exposure to BSE. BMJ 25th Nov 311(7017):1420-1421. Univ of Colorado, Health Sci Centre, Denver VA Med Centre, Denver. Baron T; Madec JY; Belli P; Savey M (1996) Natural Transmissibility of Animal SEs: Public-Health Risks. Med Mal Infec 26(BIS):275-280. CNEVA Lyon, 31 Ave Tony Garnier, BP 7033, F 69342 Lyon 07, France. Brown P (1996) BSE and CJD: The link is unproved, but no better explanation is presently forthcoming. Editorial. BMJ 312(7034):790- 791. Coquin Y (1996) What Problems Do Prion Diseases Pose for Public Authorities. Med Mal Infec 26(BIS):292-294. Minist Affaires Sociales Sante & Ville, 1 Pl Fontenoy, F 75007 Paris, France. Dealler S (1996) BSE: The ethics concerning decisions about whether to continue taking a risk with this disease. Editorial. Nurs Ethics 3(3):259-262. Burnley Gen Hosp, Burnley BB10 2PQ, Lancs, UK. Dnes AW (1996) An Economic Analysis of the BSE Scare. Scot J Polit Econ 43(3):343-348. Nottingham Trent Univ, Nottingham NG1 4BU, UK. The economic aspects of the outbreak of BSE in UK cattle are investigated. On balance, a non-interventionist approach is most likely to be the least-cost method of dealing with the BSE problem, where costs include the risks of humans contracting CJD. There is no case for compensating farmers for the historic cost of building up infected herds. Groschup MH; Haas B (1996) BSE: A Health Risk to Man. Fleischwirtschaft FEB;76(2):159-161. MH Groschup, Schickhardtstr 4, D-72072 Tubingen, Germany. Gunasekera KD; Hapgood AI; Harvey EL; Benjamin TRMH; Jachuck MSJ; Jackson ALN; Kronfeld NPA; Manikon MI; Mearns CJ; Mushtaq N; Adshead F (1996) CJD and BSE: Doctors and Scientists Must Be Able to Communicate Degree of Risk .. But Members of the Public Make-Up Their Own Minds About Risks. BMJ 312(7037):1038. St George Hosp, Sch Med, Dept Publ Hlth Sci, London SW17 0RE, UK. Letter. Harrison J (1996) CJD and BSE: Doctors and Scientists Must Be Able to Communicate Degree of Risk. BMJ 312(7037):1037-1038. Univ Newcastle, Sch Med, Dept Environm & Occupat Med, Newcastle Tyne NE2 4HH, Tyne & Wear, UK. Letter. Hawkes N (1996) Beef blamed for causing CJD deaths: John Collinge: warning after new laboratory tests. Science Editor, The Times: Britain: October 24. Hornsby M (1996) Dealler: BSE deaths "could be two million". London Times 17th April. Ironside JW (1996) CJD and health and safety in the autopsy suite. Royal College of Pathologists Symposia, 25th Jan. Univ of Edinburgh. MacKnight C; Rockwood K (1996) BSE and CJD: Implications for Physicians. Can Med Assn J 155(5):529-536. Rockwood K, Dalhousie Univ, Div Geriatr Med, Vet Mem Bldg, 5955 Jubilee Rd, Halifax, NS B3H 2E1, Canada. Narang HK (1996) Origin and implications of BSE. Proc Soc Exp Biol Med APR;211(4):306-322. H Narang, Ken Bell Int, 22-40 Brentwood Ave, Newcastle Tyne NE2 3DH, Tyne & Wear, UK. Michael Greger (6 May 1996).was one of the first scientists to speak out strongly about the presence of mad cow disease in the US cattle populations, the risk of transmissions to humans, and the on-going government and media cover-up. His influential 1994 Web page asserted that, as a public health risk, bovine-CJD was a "worse threat than AIDS," a seemingly radical view that was quickly affirmed upon reading his meticulously documented essay. Two years later, Greger's views are widely shared within the biomedical community. However, the media blackout continues as before. Wickham EA (1996) Potential transmission of BSE via medicinal products. BMJ 312, 20 April p988-9. Box 246, Canterbury CT4 5YY. Listserve 12.07.96
Clue from sporadic ALS?
Here is something remarkable that came up with another neurodegenerative disease that could have applicability to (some fraction) of sporadic CJD (that comprises 85% of all cases). That is, some sporadic CJD could be genetic after all (even though the coding region of the gene is normal).
The surprise with ALS is that a tissue-specific error (motor cortex and spinal cord) is being made in mRNA intron editing. Either some non-coding mutation is giving the cell's RNA-processing machinery the wrong directions for removing the introns, or a mutation is in the processing machinery itself (which would then have a component somewhat specific to this gene product), or some somatic process is causing the problem (if these are truly non-heritable).
The prion gene also has introns, but these are upstream of the coding region. Prion protein itself would not normally be sequenced in a case of sporadic CJD because it is so much faster and safer to work on DNA. And because of where the restriction endonuclease sites occur, only the ORF is generally examined. But perhaps the ALS study will encourage researchers to look at mature prion mRNA now. There is some talk that Collinge's group has indeed done this with interesting results. However, the introns are long tracts of DNA with little selective pressure, so expect a highly unfavorable signal to noise ratio of irrelevent polymorphisms, which will make it hard to isolate causative factors. Each such case of sporadic CJD might have its own separate genetic basis. There are a variaty of reasons why these might not show up as familial (penetrance only in conjunction with other factors, etc.).
Further, this mechanism might also only account for a fraction of sporadic CJD. The rest could be like nvCJD, e.g., from other strains of BSE or other species than cow.
Faulty Protein Linked to ALS
Science Volume 274, Number 5293, Issue of 6 December 1996, p. 1612
WASHINGTON, D.C.--Neuroscientists gathered here late last month for their largest annual meeting ever. The presentations covered a wide range of topics, from spinal cord injury and obesity (Science, 29 November, p. 1466) to learning and neurodegenerative disease.
When scientists found the gene at fault in some cases of the neurodegenerative disease amyotrophic lateral sclerosis a few years ago, the discovery was the first real clue to what might cause ALS. But mutations in the gene, which makes an enzyme called superoxide dismutase (SOD1), account for only about 1% of all cases of ALS--also known as Lou Gehrig's disease--which causes a gradual paralysis and usually results in death. And it is still unclear whether SOD1 defects contribute to unexplained "sporadic" cases, which are not inherited and which constitute 95% of all cases. Now a team led by Johns Hopkins University neurologist Jeffrey Rothstein has uncovered an abnormality that seems to be widespread in patients with sporadic ALS.
In a poster session here, Rothstein and his colleagues presented evidence that a brain protein called EAAT2 is improperly made in almost half of the patients they studied. If confirmed, Rothstein says, the finding would strengthen earlier suspicions that a deficiency of the protein, which deactivates and recycles the neurotransmitter glutamate, is a "potential cause or contributor" to the disease, because such a deficiency could lead to a glutamate buildup. Glutamate is toxic to cells in high concentrations, and some researchers have theorized that the paralysis of ALS might be caused by increased levels of the neurotransmitter and the resulting death of neurons that control the muscles.
Albert Ludolph, a neuroscientist at the University of Ulm in Germany, is cautious about the results, which are not yet published. "It's a promising finding that needs confirmation," he says. "It's another piece in the puzzle we're trying to solve." Rothstein agrees. "We don't believe there's only one cause" of ALS, he says, but if the defect does turn out to contribute to ALS development, the finding could someday lead to a useful diagnostic test and perhaps to improved treatments.
Rothstein, postdoctoral researcher Glen Lin, and research associate Lynn Bristol discovered the EAAT2 defects while following up on earlier observations that many ALS patients have abnormally low levels of the protein in areas affected by the disease: the motor cortex and spinal cord. To track down the cause of that deficit, the Hopkins team examined the messenger RNAs (mRNAs), which provide the direct instructions for making the protein, in brain and spinal cord tissue obtained at autopsy from ALS patients. They found that those mRNAs were often edited incorrectly in precisely the same tissues where the low protein levels were seen.
Most genes of higher organisms contain non-protein-coding sequences, called introns, that have to be removed from the mRNAs before the proteins themselves are synthesized. But the Hopkins workers found that the machinery that removes the introns from the EAAT2 mRNAs made mistakes in 11 of the 20 sporadic ALS patients they tested. It either failed to remove an unneeded intron, or it deleted an essential protein-coding sequence, called an exon. As a result, the mRNAs make no EAAT2 at all or make a faulty version. Rothstein and his colleagues did not find the abnormalities in brain tissue from 12 normal subjects or in 16 patients who died of other neurodegenerative diseases, including Alzheimer's and Huntington's. This suggests that the EAAT2 defect is specific to ALS and not just a general consequence of nerve cell death.
Many questions remain unanswered. The researchers do not yet know what causes the mistakes in the mRNAs. It may be that a mutation in the EAAT2 gene gives the cell's RNA-processing machinery the wrong directions for removing the introns. Or the fault may lie in the processing machinery itself. Also unexplained, Rothstein says, is how the defect could be restricted to the motor cortex and spinal cord.
Nevertheless, says neurologist Wim Robberecht of the University of Leuven in Belgium, the evidence for a common denominator in at least some sporadic ALS cases is exciting. Even if the primary cause is "something completely unrelated" to glutamate metabolism--for example, the buildup of damaging free radicals from a malfunctioning SOD1 protein--Rothstein's findings "would finally give very conclusive evidence that an abnormality of glutamate metabolism is indeed involved" in ALS, if only as an important secondary mechanism.
CJD in Oman - report of 2 casesScrimgeour,E.M.; Chand,P.R.; Kenny,K.; Brown,P.
Journal of the Neurological Sciences 1996; 142(N1-2): 148-50 1996
Sporadic Creutzfeldt-Jakob disease (CJD) was diagnosed in two Omani Arab men, aged 50 and 75 years respectively, both with a history of rapidly developing dementia and myoclonic jerks. Illness developed over a period of 3 months in the first case and over six months in the second. Electroencephalography in both subjects showed periodic triphasic sharp waves characteristic of CJD. In neither case was it possible to obtain a brain biopsy or perform autopsy (autopsy is contrary to Islamic practice in the Middle East), however, electrophoresis of cerebrospinal fluid from the second patient revealed the distinctive double protein spots characteristic of CJD. This is the first report of CJD from Oman.