Date: Thu, 17 Nov 94 01:40:49 -0500 From: Bob Broedel To: als@huey.met.fsu.edu Subject: ALSD#149 ALS-ON-LINE =============================================================== == == == ----------- ALS Interest Group ----------- == == ALS Digest (#149, 17 November 1994) == == == == ------ Amyotrophic Lateral Sclerosis (ALS) == == ------ Motor Neurone Disease (MND) == == ------ Lou Gehrig's disease == == ----- == == This e-mail list has been set up to serve the world-wide == == ALS community. That is, ALS patients, ALS researchers, == == ALS support/discussion groups, ALS clinics, etc. Others == == are welcome (and invited) to join. The ALS Digest is == == published (approximately) weekly. Currently there are == == 400+ subscribers. == == == == To subscribe, to unsubscribe, to contribute notes, == == etc. to ALS Digest, please send e-mail to: == == bro@huey.met.fsu.edu (Bob Broedel) == == Sorry, but this is *not* a LISTSERV setup. == == == == Bob Broedel; P.O. Box 20049; Tallahassee, FL 32316 USA == =============================================================== CONTENTS OF THIS ISSUE: 1 .. FDA trouble 2 .. Enterovirus and ALS 3 .. MDA Research Report #53 (1) ===== FDA trouble ========== Date : Wed, 16 Nov 1994 21:01:21 -0800 (PST) >From : Alexander Volokh Subject: ALS Interest Group List ______________________________________________________________ Hello; I'm looking for people who have run into "FDA trouble." If you: (1) Have yourself needed, or know someone who needed, a treatment that was available in another country but wasn't approved by the FDA; or, (2) Could have been helped, or know someone who could have been helped, by a treatment that was approved too late by the FDA, please drop me a line via private e-mail. - Thanks, Alexander "Sasha" Volokh (2) ===== Enterovirus and ALS ========== Date : Wed, 16 Nov 1994 16:20:08 >From : Stuart.Neilson@brunel.ac.uk (hssrsdn) Subject: Enterovirus and ALS I recently received a letter from Dr M.E. Westarp (Head of Motor Neuron Research Group, Ulm University Medical School, Germany) drawing my attention to his recent publications (see below). The SOD-1/SOD-C research output is prolific at the moment and is pulling in many, often contradictory, directions. His argument is cohesive, and I would appreciate any responses: --- START QUOTE --- Most German, Dutch and French ALS/MND patients do not have SOD-1 mutations, but polymorphism is to be expected. The animal models of ALS, such as Gurney's transgenic mice (which exhibit MND-like symptoms despite elevated SOD activity) and transgenic mice expressing a human suma retroviral gene fragment (Bothe et al, 1991) point to GENOMIC FACTOR(S) IN SPORADIC ALS. This could be a defective viral or retroviral element, optionally pathogenic, and silent if not demethylated by solvents or freed from the action of suppressor genes by alpha radiation interference. Whether it is neurotrophic or detoxification deficits in sporadic ALS, an impact spreading from cell to cell in the central nervous system would explain the oligofocal, segmental spread of paresis over the body - sometimes affecting only one side for years. --- END QUOTE --- I understand this to mean that susceptibility to ALS/MND may be either inherited (the small proportion of familial cases) or acquired by infection with ubiquitous pathogens. However, progression to symptoms is multifactorial and requires a further insult (solvents or radiation) to initiate clinical signs. This would explain the difficulty in locating replicable risk-factors for ALS/MND. Stuart Neilson, CSHSD, Brunel (stuart.neilson@brunel.ac.uk) REFERENCES Bothe K, Aguzzi A, Lassman H, Rethwilm A and Horak I. Progressive encephalopathy and myopathy in transgenic mice expressing human foamy virus genes. Science 1991;253:555-559 Westarp ME, Westphal KP, Kolde G, Wollinsky KH, Westarp MP and Kornhuber HH. Dermal, serological and CSF changes in ALS with and without intrathecal interferon beta treatment. Int J Clin Pharmacol Ther Toxicol 1992;30:81-93 Westarp ME, Westphal KP, Clausen J, Rasmussen HB, Hoff-Jorgensen R, Foehring B and Kornhuber HH. Retroviral interference with neuronotrophic signalling in human MND. Clin Physiol Biochem 1993;10:1-7 Westarp ME, Foehring B, Rasmussen H, Schraff S, Mertens T and Kornhuber HH. Retroviral synthetic peptide serum antibodies in human sporadic ALS. Peptides 1994;15:207-214 Westarp ME, Ferrante P, Perron H, Schraff S, Westarp MP and Kornhuber HH. Antiretroviral seroreactivity in sporadic adult ALS. Neurol Psychiat Brain Res 1994;3:1-6 (3) ===== MDA Research Report #53 ========== Date : 16 Nov 94 16:17:49 EST >From : Barry Goldberg <71154.330@compuserve.com> Subject: MDA Research Report #53 Here's the latest research report to come out of the Muscular Dystrophy Association's workshops and research efforts: November 7, 1994 TO : MDA Clinic Directors : >FROM: Norine Stirpe, Ph.D. : Director of Research Development : RE : MDA Research Update #53 MDA-SPONSORED GENETICS WORKSHOP REPORTS Myotonic dystrophy The myotonic dystrophy protein kinase (DMPK) is being analyzed to determine how the unstable repetitive DNA defect in its gene, discovered by MDA researchers in 1992, might be responsible for the disease. The scientists participating in the Myotonic Dystrophy (DM) Working Group met to discuss their latest findings regarding the gene defect and the function of this new protein kinase. Apparently DMPK has unusual characteristics in terms of its structure and function. The role of protein kinases in general is to interact with and thus modify the activity of other compounds. DMPK belongs to a particular class of protein kinases known to perform certain functions, however, DMPK may be much more specialized in its interactions compared to other members of the class. Results of studies of DMPK so far have been somewhat confusing for the researchers. Different labs are obtaining contrasting information which is most likely due to the fact that protein kinases are known to be difficult to study. It is common for them to exist in different forms and this can complicate the experiments designed to study their functions as well as studies of their genetic expression. At the workshop the scientists agreed that they need to obtain verification to determine which data is providing solid information about DMPK. The tools that each group has developed to study DMPK need to be evaluated as to how they differ since this may be the source of the conflicting information that the scientists are obtaining. When DMPK is overexpressed in mice the effects mimic, in some ways, features of DM. Although the study of these mice may be useful, they cannot yet be considered animal models of the disease. The pattern of DMPK expression in the various tissues of the body matches that of the tissues that are affected in DM. However, several questions still remain. Is altered function of DMPK a cause of DM? Do the unstable DNA repeats in the DMPK gene cause the disease through other effects not related to DMPK function? Can the disease be controlled by controlling the expansion of the unstable DNA? Spinal Muscular Atrophy The Spinal Muscular Atrophy (SMA) Working Group met to discuss the latest advances toward the identification of the SMA gene defect. As reported previously, the researchers are faced with difficulties looking for the SMA disease gene as the area where the defective gene is located is particularly rich in repeated DNA sequences and pseudogenes that can create confusing results. Pseudogenes appear to be nonfunctional, unexpressed genes that resemble a similar functional version of the gene which is expressed. The belief is that pseudogenes eventually get eliminated from the pool of genes that each species has, however, their existence is still not fully understood. Nevertheless, when researchers initially isolate a gene from the SMA area their analysis can be complicated if it is actually a pseudogene. The scientists are isolating and identifying individual genes in the region and analyzing them for signs that they contain defects such as deletions of genetic material that would indicate their involvement in SMA. Several genes have been examined and no association with SMA has been found at this time. Based on analyses of how the various types of SMA are inherited, a hypothesis was presented that two copies of the disease gene may be involved. For example, if two copies of the gene that is defective in SMA exist on each chromosome 5 inherited from the parents, several scenarios can be considered to explain the existence of the different forms of the disease. For example, SMA type I is most severe and an individual who has this form of the disease may have deletions of both versions of the SMA gene that are on each of their copies of chromosome 5. For the milder form of SMA, moderate defects in only one of two copies of the SMA gene on each chromosome 5 could result in SMA type III. In the latter case there would be one normal gene on each chromosome that would be expressed and partially provide the necessary activity. The hypothesis presented at the workshop cannot be proved until the SMA gene and the defect are identified, however, the idea of multiple genes possibly being involved in the inherited disorder will be considered by the scientists in future analyses. The SMA research group also discussed in detail the new tools that they have developed to track down the SMA gene and the DNA sequences or genes that they have analyzed. For the purpose of comparing their DNA sequence data more efficiently the group is working on establishing a central computer database to store and compare their results. The system would be accessible to each of the SMA research groups and would enhance their progress. Facioscapulohumeral muscular dystrophy The facioscapulohumeral muscular dystrophy (FSHD) genetics researchers met to exchange data and to discuss the genetic effects that might occur as a result of a gene being located near the tip - - the telomere - of a chromosome. DNA in the telomere is apparently inactivated. The gene that is defective in FSHD appears to be located near the tip of chromosome 4 and it has been proposed that expression of the FSHD gene could be altered as a result of a deletion that would move the gene too close to the telomere. Experts on the structure and function of the unique telomere sequence at the end of chromosomes were invited to participate in the meeting in hopes they could enlighten the working group. The work of the invited scientists appears to show that expressed genes that are moved adjacent to telomeres are not affected in terms of their ability to be expressed. However, telomere DNA has been shown to be unstable and this could have effects on the expression of the FSHD gene. The invited guests had several suggestions for future experiments that might assist the group in defining the FSHD gene defect. In addition, how the position of a gene within the nucleus -- where the chromosomal DNA is kept -- could influence gene expression was addressed. Suggestions were made as to what microscopic analyses could locate the FSHD gene within a cell nucleus in order to examine whether features of its location could affect its expression. Recent paper of interest: Bengtsson, U. et al. Human Molecular Genetics 1994; 3:1801-1805. The FSHD group has established a computer database for the exchange of information to compare their data on the sequence of DNA in the FSHD gene region. This system is allowing the scientists to be able to immediately compare their results which can save time and in that way enhance the progress toward isolating the disease gene. *** The mechanisms of motor neuron death in FALS due to defective SOD1 have yet to be determined. Alterations in SOD1 may result in reduced activity of the enzyme, however, this may not be the primary cause of motor neuron death. For instance, the defects may lead to the development of a new activity that is particularly harmful to motor neurons. One recent research paper presents results of a study to test the effects of defective SOD1 in nonhuman cells that are not motor neurons. The conditions for FALS were mimicked by co-expressing defective and normal SOD1 genes. No deleterious effects in cell growth or resistance to free radical damage was measured. (Nishida, C.R. et al. Proceedings National Academy of Science USA 1994; 91:9906-9910). Another recent report concluded that the neurons affected in ALS may be more dependent upon SOD1 than other neurons. (Tsuda, T. et al. Neuron 1994; 13:727-736). *** Methods to analyze the distribution and frequency of occurrence of amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and dementia were used to assess whether relatives of individuals affected by ALS share genetic susceptibility to these disorders. Clinical researchers found that the risk for having dementia was higher in relatives of individuals with ALS than that of the general population. The analysis concerning PD yielded results determined to not be statistically significant, however, the data obtained appeared to show that the risk of PD was higher in relatives of individuals affected by familial ALS than in relatives of those with sporadic cases of the disorder. The study results suggest that ALS and dementia, and possibly PD, occur together in a family more often than would be expected in the general population. (Majoor-Krakauer, D. et al. Neurology 1994; 44:1872-1877). *** Altered human adenovirus is a promising vehicle to deliver the dystrophin gene to cells that lack a fully functional version of the gene, as is the case in Duchenne and Becker muscular dystrophies (DMD/BMD). An altered virus was found to carry the dystrophin gene into muscle cells as a result of the ability of the virus to latch onto a structure called a receptor which is on the muscle cell's surface. Once attached, the viral vector is then brought inside the cell where the gene that it is carrying can be expressed. Researchers have found that myoblasts -- individual muscle cells -- have almost three times the amount of these receptors as myotubes -- fused myoblasts present in muscle that is developing into mature tissue. The researchers conclude that for efficient transfer of the dystrophin gene using adenovirus vectors modifications may be necessary to make the receptor more available in mature muscle. (Acsadi, G., et al. Gene Therapy 1994; 1:338- 340). *** Within the group of disorders classified as congenital muscular dystrophy (CMD) there are various forms of the disease. All are autosomal recessive and the most common form is Fukuyama CMD (FCMD). The disease gene for FCMD has been localized to chromosome 9 and another type of CMD was recently determined by MDA researchers to be a result of a lack of merosin whose gene is on chromosome 6. Merosin is an important component of the membranes surrounding muscle fibers. Individuals affected by CMD who test positive for merosin have also been identified and, as reported by scientists from France, the disease gene cannot be found on either chromosome 9 or 6. Therefore, merosin-positive and merosin- negative CMD are distinct genetic diseases. These studies to define the various forms of the CMD are leading the way toward determining the causes of these devastating disorders. (Hillaire, D. et al. Human Molecular Genetics 1994; 3:1657-1661). *** The retrovirus HTLV-1 has been found associated with polymyositis in individuals within the United States as well as in specific regions throughout the world. However, in certain individuals with polymyositis retrovirus has not been successfully identified in muscle. Researchers recently analyzed how inflammatory myopathy may arise in individuals infected by HTLV-1. In muscle biopsies from people with HTLV-1-associated polymyositis the virus was not detected in the muscle fiber but was found in certain macrophages -- cells of the immune system that can engulf foreign particles. The findings indicate that polymyositis associated with HTLV-1 is not due to direct infection of the muscle fiber but can be mediated through immune system cells or processes. The researchers suggest that due to the similarities between sporadic polymyositis and polymyositis associated with HTLV-1 and HIV, retroviruses are the main candidates for causing inflammatory myopathies. (Leon-Monzon, M. et al. Annals of Neurology 1994; 36:643-649). END*****11/14/94*Research Update #53 --- MDA -- Working to find the cure for neuromuscular disease --- === end of als 149 ===