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Scientists identify the gene linked to autosomal recessive juvenile als
InfoFact RESEARCH UPDATE Reversible ALS-like Disorder in HIV infection
Two studies published in the September issue of the journal Neurology describe an ALS- like syndrome associated with HIV that is responsive to anti-retroviral therapy. A viral mechanism for ALS has long been hypothesized the results have rekindled an interest in understanding the possible link between viruses and ALS. The two studies report seven cases of ALS-like syndromes accompanying HIV infection. In one study led by Dr. Antoine Moulignier of Adolphe de Rothschild Foundation in Paris, six cases of ALS-like syndromes were identified among 1700 HIV patients with neurologic manifestations. All six of these patients either stabilized or partially recovered from the ALS-like syndromes after starting anti-retroviral therapy.
The other study was led by Daniel J.L. MacGowan, MD, MRCPI, Beth Israel MedicalCenter, New York. In the article, authored by McGowan, Stephen Scelsa, MD and M. Waldron, MD, the researchers describe a patient diagnosed with HIV with a progressiveALS-like disease. Antiviral therapy led to complete and sustained recovery from ALS-like symptoms. "These intriguing findings warrant further investigation of how virusesmay play a role in ALS. Determining how antiretroviral agents may be involved inreversing the ALS-like symptoms may lead to a better understanding of ALS," said LucieBruijn, PhD, Science Director of The ALS Association. ALSA-Funded Follow-up Study Being Conducted at Beth Israel
A study began October 1, it is a placebo-controlled investigation with 46 patients toassess whether Indinavir, a protease inhibitor used in the treatment of HIV infection,slows the progression of ALS in patients that are negative for HIV and to investigate thepossible mechanism of the compound. Indinavir is similar to one of the compounds in the
cocktail of drugs that showed reversal of symptoms in the HIV patients with ALS-likesymptoms.
These HIV-related cases of an ALS-like syndrome suggest that a viral mechanism mayunderlie some forms of ALS, however, there is currently no evidence that reversal ofsymptoms with treatment of these antiviral agents will be effective in ALS patients thatare negative for HIV. At this point HIV treatment for ALS patients is not recommended,as there are no animal or human studies to support their use in ALS patients who do nothave HIV infection. These medications, unfortunately, may have serious adverse effects. Scientists Identify the Gene Linked to Autosomal Recessive Juvenile ALS
Juvenile ALS is a rare form of ALS characterized by muscle atrophy, generalizedfasciculations, and bulbar and pseudobulbar signs with normal sensory findings. Thedisease has a mean age of onset of 12 years and progresses slowly for many years. Twomutations in the same gene have been identified, one in a Tunisian family (A261del) andone in an unrelated Kuwaiti family (AG1548del). The mutations shorten the proteinremoving the predicted regions important for protein function. As the disease isautosomal recessive (two copies of the mutant gene must be present), these mutations arelikely to result in a loss of function. The discovery of a new gene linked to ALS is extremely exciting and will open up newavenues for ALS research. ALS research needs new leads to find therapies for thedisease. Understanding the normal function of the gene product will provide newinformation about the disease mechanism and may shed new light on the role of theSOD1 mutations (the first ALS-linked mutations to be identified) in the disease process.”The gene designated ALS2CR6 encodes a 184 kD protein (with the suggested name“alsin”) of as yet unknown function. Due to structural similarity with other proteins, it isspeculated to act as a regulator/activator of particular proteins that modulate microtubuleassembly, membrane organization and trafficking in cells including neurones (importantfeatures of axonal transport and structural organization of the cell). The gene is found inneuronal cells throughout the brain and spinal cord, particularly in neurones in thehippocampus and dentate gyrus, cerebellar, Purkinje cells, neurones in the cerebral cortexand spinal gray matter including anterior horn cells. It is unclear why motor neuronespecific degeneration occurs and further studies to understand the function of the geneproduct is necessary. The discovery of a new gene for ALS is extremely important. Characterization of theprotein product and its function will open up new avenues to understand the pathology ofthe disease, not only in the juvenile form of the disease but in other familial and sporadicforms. Stem Cell therapy developments Results of an experiment where SOD1 mice were given bone marrow stem cells were presented at the MND Association Annual Conference. SOD1 mice develop a form of motor neurone degeneration and usually die 4-5 months after birth. Six mice were given an injection of bone marrow stem cells at 10 weeks of age and there was a significant delay in the onset of the disease. Indeed, in three of the mice the onset of symptoms has been delayed by over 50 days, which is a long time in ‘mouse years’. Preliminary results from a team in the United States, using another cell line also show that stem cells can slow down disease progression in SOD1 mice, although there is as yet no evidence that they can reverse damage once it has occurred. Dr Ray explained that his results are extremely preliminary and he won’t fully believe them himself until he has managed to reproduce the experiment in a larger number of animals. He also added that he doesn’t know why the mice are reacting in such a way, as the pathology has not yet been investigated. It could be that the stem cells are replacing dying motor neurones and connecting to the muscles, or it could be that the stem cells are helping the existing motor neurones to fight the disease, through the production of a cocktail of neuroprotective chemicals. It was an uplifting end to a fascinating presentation, but Dr Ray re-emphasised the very preliminary stage of the research. “It fills us with encouragement - albeit cautious encouragement. Now comes the hard work!” Creatine Trial A study conducted by Dr Jeff Rosenfeld (USA) focused on 30 patients with ALS, taking either creatine or placebo for nine months. He said, “Treatment with creatine appears to be safe and well tolerated, with no significant adverse events. Arm muscle strength showed an initial short-term improvement, followed by a slower rate of decline than those taking placebo”. Further studies will take place. New Research Avenues The discovery that Vascular Epithelial Growth Factor (VEGF) may be linked to motor neurone degeneration came as a complete surprise. VEGF is a family of growth factors involved in blood vessel development. It is highly regulated by oxygen levels. Development of mice with a deleted VEGF gene resulted in decreased levels of VEGF and a mouse with motor neurone degeneration. This study was the first indication that the factor may in some way be involved in motor neuron degeneration. Studies are on going. Antibiotic may help treat ALS An antibiotic commonly prescribed for acne may slow the development of ALS according to a study conducted at the McGill University Health Centre Research Institute. The study found that the antibiotic MINOCYCLINE delays the onset and
progression of disease in a mouse model of ALS. The research results will be publishedin the June issue of the journal Neurobiology of Disease.
The study compares the life span, muscle strength, neuronal loss and inflammatoryresponse in ALS-mice that were fed a regular diet with those given food containingminocycline. The mice fed the minocycline lived substantially longer, had a delayedonset of neuronal and muscle deterioration, and a noticeably reduced inflammation oftheir brains.
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The Scottish MND Association maintains a professionally administered MND/ALSlibrary and information centre at its head office in Glasgow. The library stocks a widerange of MND/ALS-related journals and textbooks containing detailed information onilson,76 Firhill Road, Glasgow, G20 7BA, Tel: 0141 945 1077 Fax: 0141 945 2578, Email: [email protected], Web page: www.scotmnd.org.uk
The information in this InfoFACT leaflet is believed to be accurate at the time of going to press. However, the Scottish MND Association cannot give detailed medical advice – and this InfoFACT leaflet should be regarded only as general background information.
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UNDERSTANDING YOUR MEDICINE The mainstay of treatment for those with severe mental illnesses is medication. This is not to undermine the value of psychotherapy, group therapy, case management, and other kinds of interventions. In fact, the evidence supporting the combination of psychotherapy with antidepressants as improving the outcome of depressive illnesses than either of the two treatments alo