Guest guest Posted November 14, 2006 Report Share Posted November 14, 2006 has anyone any information on this? I received this email and was wondering if anyone else had heard anything. > Recent History Valproate may improve str... > [input] > > > > Valproate may improve strength and function in > patients with type III/IV spinal muscle atrophy > [brief Communications] > Weihl, Conrad C. MD, PhD; Connolly, Anne M. MD; > Pestronk, Alan MD > From the Department of Neurology, Washington > University School of Medicine, St. Louis, MO. > This article was previously published in > electronic format as an Expedited E-pub on June 14, > 2006, at www.neurology.org . > Disclosure: The authors report no conflicts of > interest. > Received January 31, 2006. Accepted in final form > March 27, 2006. > Address correspondence and reprint requests to Dr. > A. Pestronk, Department of Neurology, Washington > University School of Medicine, 660 South Euclid > Avenue, Box 8111, St. Louis, MO 63110; e-mail: > pestronka@... > > > Abstract†" > Spinal muscular atrophy (SMA) is a recessively > inherited motor neuron disease caused by deficient > survival motor neuron (SMN) protein. Valproate > increases SMN protein in vitro by increasing > transcription of SMN2 genes. The authors treated > seven adult patients with SMA type III/IV with > valproate for a mean duration of 8 months. The > treated patients with SMA had increased quantitative > muscle strength and subjective function. Further > trials of valproate treatment for SMA type III/IV > are warranted. > > --------------------------------- > > Spinal muscular atrophy (SMA) is a recessively > inherited motor neuron disease due to mutations in > the SMN1 gene located on chromosome 5q. SMN1 gene > mutations in SMA patients eliminate its expression > of survival motor neuron (SMN) protein. The SMN2 > gene is a nearly identical centromeric copy of SMN1 > that differs by one nucleic acid located in a splice > enhancer region. SMN2 generates only 10% of the > amount of full-length SMN protein vs SMN1. Recent in > vitro studies demonstrate that inhibitors of histone > deacetylase, such as valproate, can change SMN2 gene > transcription, resulting in increased production of > full-length SMN transcript and protein.1†" 3 It has > been proposed that increasing the amount of SMN > protein might benefit patients with SMA.4 Based on > this hypothesis, we treated seven SMA type III/IV > patients with valproate for up to 15 months. > Methods. > We retrospectively reviewed charts of seven > patients with SMA type III/IV (walked at some time) > who were evaluated in the Washington University > Neuromuscular Clinic and treated with valproate > (table). All patients had genetically confirmed > homozygous exon 7 and 8 deletions in the SMN1 gene. > Three female and four male SMA patients had a mean > age of 33 years (range 17 to 45 years). The decision > to begin valproate treatment was at the discretion > of the treating physician and the patient and was > offered to all patients with SMA type III/IV age 17 > years or older with a known homozygous SMN gene > deletion. Treatment was carried out for mean > duration of 8 months (range 1 to 15 months). > Patients were typically started on valproate at a > dose of 250 mg twice a day. If no adverse effects > were noticed, the dose was increased to 500 mg twice > a day after 3 months. All patients had a complete > blood cell count and comprehensive metabolic panel > before initiating and after 4 to 6 months of > therapy. Six patients were continuing the use of > valproate after the final clinic visit. One patient > (no. 3) discontinued valproate treatment after 1 > month due to concerns about weight gain. > Quantitative strength testing was performed using > hand-held dynamometry. Handheld dynamometry is a > valid and reliable measure of serial strength in > patients with muscle weakness due to motor neuron > disease and motor neuropathy.5†" 8 At each clinic > visit, quantitative measurements were obtained > bilaterally in all proximal muscle groups (deltoid, > biceps, triceps, iliopsoas, quadriceps, and > hamstrings) with measurable antigravity strength. > Patients 1, 2, 3, and 4 were ambulatory throughout > the study and had measurable strength in all 12 > tested muscle groups. Patient 5 had not walked for > 12 years and had measurable strength in all 12 > muscle groups. Patient 6 had not walked for 28 years > and had measurable strength in the biceps, triceps, > and hamstrings. Patient 7 had not walked for 19 > years > and had measurable strength in the biceps and > triceps. Serial measurements in each patient were > made by the same examiner. Examiners were blinded to > the results of prior testing. Results in individual > muscles were divided by the expected strength of an > adult of the same sex, multiplied by 100, and > averaged to derive a cumulative mean percentage of > normal at each time point. Changes in the strength > index in an individual of at least 12% of normal are > significant (p < 0.05).6 The mean percentage of > normal strength in all measurable proximal muscles > was determined for each patient at three time > points, 6 to 12 months prior to treatment, > immediately prior to treatment, and at the last > clinic visit. No muscle without measurable strength > became measurable at later time points. We analyzed > our group data in an “intent-to-treatâ€? fashion, > including the one patient who stopped treatment > after 1 month due to side effects. Data are > expressed as means ± SEM. Paired t tests were > used to calculate the significance of differences > between groups. > > > --------------------------------- > > [Help with image viewing] > [Email Jumpstart To Image] Table Results of > treatment > --------------------------------- > Results. > There was no change in strength in the group of > SMA type III/IV patients, comparing time points at 6 > to 12 months prior to treatment and at the onset of > treatment (table). No SMA type III/IV individual > showed improvement in strength of 12%. > Strength improved (p = 0.002) in the group of SMA > type III/IV patients by an absolute mean level of > 16% of normal strength and by 48% of initial levels, > comparing the time points immediately before > initiating valproate treatment and at the last > visit. Four of the six SMA type III/IV patients who > continued valproate treatment showed improvement in > strength of more than 12%. All six SMA type III/IV > patients who continued valproate treatment noted > subjective benefit at the last visit. A 45-year-old > wine-maker, who had not been able to pick grapes for > several years, was able to return to this activity. > A 17-year-old high school student was able to > participate in marching band after stopping 2 years > before. > The mean serum level of valproate after 4 to 6 > months of treatment was 87 µg/mL. The average > weight gain was 5 lbs (range †" 8 to 11 lbs). Two > patients initially reported drowsiness. These > symptoms were minimized by decreasing the dose of > valproate. There was no change in liver enzymes or > platelet levels in any patient throughout the > duration of treatment. > Discussion. > We found that valproate treatment was followed by > a sustained increase in function and strength in our > group of patients with SMA III/IV. In some patients, > treatment benefit persisted for more than 1 year. A > notable feature of valproate responders was the > relatively rapid onset of improvement. Most patients > reported benefit within a few months after beginning > treatment. In contrast, during the months prior to > treatment, there was no clear change in strength in > our patients, a course that is similar to prior > studies of the natural history of SMA III/IV.4 > The mechanisms underlying improvement in SMA > III/IV require further study. Increased levels of > SMN protein could allow recovery of some neurons, > axons, or terminal branches that were previously > marginally functioning, or inactive, but > anatomically intact. Alternatively, improvement > could occur with rapid growth of motor axon > terminals to reinnervate neighboring denervated > muscle fibers. There is some evidence that the SMN > protein may play a role in neurite outgrowth.8 > Large, controlled studies are planned to test the > effects of treatment with valproate and other > histone deacetylase inhibitors in younger, or more > severely affected, SMA patients.9 Our results > showing improvement in SMA III/IV patients indicate > that trials, with controls to rule out a placebo > effect, are also warranted in adults with milder > disease. Our findings, showing measurably improved > strength over a relatively short time, suggest that > large trials may not be necessary to demonstrate a > change in patients with SMA III/IV. > Valproate treatment may be more likely to be > efficacious in adult SMA III/IV patients than in > those with more severe phenotypes. Improvement in > our study was manifest in muscles with residual > strength at the time of treatment onset. Valproate > treatment is probably better tolerated in adults > than children.10 Further, we speculate that the > generally greater number of copies of the SMN2 gene > in patients with SMA III/IV 11 may multiply the > pharmacologic effects of valproate in increasing the > production of SMN protein. Measurements of SMN > protein in patient tissue before and after valproate > treatment may be useful. > References > 1. Sumner CJ, Huynh TN, Markowitz JA, et al. > Valproic acid increases SMN levels in spinal > muscular atrophy patient cells. Ann Neurol > 2003;54:647†" 654. Bibliographic Links [Context > Link] > 2. Brichta L, Hofmann Y, Hahnen E, et al. Valproic > acid increases the SMN2 protein level: a well-known > drug as a potential therapy for spinal muscular > atrophy. Hum Mol Genet 2003;12:2481†" 2489. > Bibliographic Links [Context Link] > 3. Kernochan LE, Russo ML, Woodling NS, et al. The > role of histone acetylation in SMN gene expression. > Hum Mol Genet 2005;14:1171†" 1182. Bibliographic > Links [Context Link] > 4. Swoboda KJ, Prior TW, CB, et al. Natural > history of denervation in SMA: relation to age, SMN2 > copy number, and function. Ann Neurol > 2005;57:704†" 712. Bibliographic Links [Context > Link] > 5. Beck M, Giess R, Wurffel W, Magnus T, Ochs G, > Toyka KV. Comparison of maximal voluntary isometric > contraction and Drachman's hand-held dynamometry in > evaluating patients with amyotrophic lateral > sclerosis. Muscle Nerve 1999;22:1265†" 1270. > Bibliographic Links [Context Link] > 6. Pestronk A, Lopate G, Kornberg AJ, et al. > Distal lower motor neuron syndrome with high-titer > serum IgM anti-GM1 antibodies: improvement following > immunotherapy with monthly plasma exchange and > intravenous cyclophosphamide. Neurology > 1994;44:2027†" 2031. [Context Link] > 7. Pestronk A, Florence J, T, Choksi R, > Al-Lozi MT, Levine TD. Treatment of IgM antibody > associated polyneuropathies using rituximab. J > Neurol Neurosurg Psychiatry 2003;74:485†" 489. > Bibliographic Links [Context Link] > 8. Fan L, Simard LR. Survival motor neuron (SMN) > protein: role in neurite outgrowth and neuromuscular > maturation during neuronal differentiation and > development. Hum Mol Genet 2002;11:1605†" 1614. > Bibliographic Links [Context Link] > 9. Hirtz D, Iannaccone S, Heemskerk J, Gwinn-Hardy > K, Moxley R III, Rowland LP. Challenges and > opportunities in clinical trials for spinal muscular > atrophy. Neurology 2005;65:1352†" 1357. Ovid Full > Text Bibliographic Links [Context Link] > 10. Coulter DL, Wu H, RJ. Valproic acid > therapy in childhood epilepsy. JAMA > 1980;244:785†" 788. Bibliographic Links [Context > Link] > 11. Gavrilov DK, Shi X, Das K, Gilliam TC, Wang > CH. Differential SMN2 expression associated with SMA > severity. Nat Genet 1998;20:230†" 231. [Context > Link] > > --------------------------------- > > Accession Number: 00006114-200608080-00032 > Copyright © 2000-2006 Ovid Technologies, Inc. > Version: rel10.4.0, SourceID 1.12596.1.117 Quote Link to comment Share on other sites More sharing options...
Guest guest Posted November 14, 2006 Report Share Posted November 14, 2006 If I'm not mistaken, I think that Valproate is just another name for Valproic acid which is the drug used in the current Carni-Val study for children which my son is currently participating in. I have not heard of the study involving adults, but the dosages, possible side effects and benefits mentioned in the article sound pretty much the same. The only difference is that the Carni-Val study is for children with type 2 and 3 SMA. -- In , " LBHJ " <lct1275@...> wrote: > > has anyone any information on this? I received this email and was > wondering if anyone else had heard anything. > > > > Recent History Valproate may improve str... > > [input] > > > > > > > > Valproate may improve strength and function in > > patients with type III/IV spinal muscle atrophy > > [brief Communications] > > Weihl, Conrad C. MD, PhD; Connolly, Anne M. MD; > > Pestronk, Alan MD > > From the Department of Neurology, Washington > > University School of Medicine, St. Louis, MO. > > This article was previously published in > > electronic format as an Expedited E-pub on June 14, > > 2006, at www.neurology.org . > > Disclosure: The authors report no conflicts of > > interest. > > Received January 31, 2006. Accepted in final form > > March 27, 2006. > > Address correspondence and reprint requests to Dr. > > A. Pestronk, Department of Neurology, Washington > > University School of Medicine, 660 South Euclid > > Avenue, Box 8111, St. Louis, MO 63110; e-mail: > > pestronka@... > > > > > > Abstract†" > > Spinal muscular atrophy (SMA) is a recessively > > inherited motor neuron disease caused by deficient > > survival motor neuron (SMN) protein. Valproate > > increases SMN protein in vitro by increasing > > transcription of SMN2 genes. The authors treated > > seven adult patients with SMA type III/IV with > > valproate for a mean duration of 8 months. The > > treated patients with SMA had increased quantitative > > muscle strength and subjective function. Further > > trials of valproate treatment for SMA type III/IV > > are warranted. > > > > --------------------------------- > > > > Spinal muscular atrophy (SMA) is a recessively > > inherited motor neuron disease due to mutations in > > the SMN1 gene located on chromosome 5q. SMN1 gene > > mutations in SMA patients eliminate its expression > > of survival motor neuron (SMN) protein. The SMN2 > > gene is a nearly identical centromeric copy of SMN1 > > that differs by one nucleic acid located in a splice > > enhancer region. SMN2 generates only 10% of the > > amount of full-length SMN protein vs SMN1. Recent in > > vitro studies demonstrate that inhibitors of histone > > deacetylase, such as valproate, can change SMN2 gene > > transcription, resulting in increased production of > > full-length SMN transcript and protein.1†" 3 It has > > been proposed that increasing the amount of SMN > > protein might benefit patients with SMA.4 Based on > > this hypothesis, we treated seven SMA type III/IV > > patients with valproate for up to 15 months. > > Methods. > > We retrospectively reviewed charts of seven > > patients with SMA type III/IV (walked at some time) > > who were evaluated in the Washington University > > Neuromuscular Clinic and treated with valproate > > (table). All patients had genetically confirmed > > homozygous exon 7 and 8 deletions in the SMN1 gene. > > Three female and four male SMA patients had a mean > > age of 33 years (range 17 to 45 years). The decision > > to begin valproate treatment was at the discretion > > of the treating physician and the patient and was > > offered to all patients with SMA type III/IV age 17 > > years or older with a known homozygous SMN gene > > deletion. Treatment was carried out for mean > > duration of 8 months (range 1 to 15 months). > > Patients were typically started on valproate at a > > dose of 250 mg twice a day. If no adverse effects > > were noticed, the dose was increased to 500 mg twice > > a day after 3 months. All patients had a complete > > blood cell count and comprehensive metabolic panel > > before initiating and after 4 to 6 months of > > therapy. Six patients were continuing the use of > > valproate after the final clinic visit. One patient > > (no. 3) discontinued valproate treatment after 1 > > month due to concerns about weight gain. > > Quantitative strength testing was performed using > > hand-held dynamometry. Handheld dynamometry is a > > valid and reliable measure of serial strength in > > patients with muscle weakness due to motor neuron > > disease and motor neuropathy.5†" 8 At each clinic > > visit, quantitative measurements were obtained > > bilaterally in all proximal muscle groups (deltoid, > > biceps, triceps, iliopsoas, quadriceps, and > > hamstrings) with measurable antigravity strength. > > Patients 1, 2, 3, and 4 were ambulatory throughout > > the study and had measurable strength in all 12 > > tested muscle groups. Patient 5 had not walked for > > 12 years and had measurable strength in all 12 > > muscle groups. Patient 6 had not walked for 28 years > > and had measurable strength in the biceps, triceps, > > and hamstrings. Patient 7 had not walked for 19 > > years > > and had measurable strength in the biceps and > > triceps. Serial measurements in each patient were > > made by the same examiner. Examiners were blinded to > > the results of prior testing. Results in individual > > muscles were divided by the expected strength of an > > adult of the same sex, multiplied by 100, and > > averaged to derive a cumulative mean percentage of > > normal at each time point. Changes in the strength > > index in an individual of at least 12% of normal are > > significant (p < 0.05).6 The mean percentage of > > normal strength in all measurable proximal muscles > > was determined for each patient at three time > > points, 6 to 12 months prior to treatment, > > immediately prior to treatment, and at the last > > clinic visit. No muscle without measurable strength > > became measurable at later time points. We analyzed > > our group data in an “intent-to-treatâ€? fashion, > > including the one patient who stopped treatment > > after 1 month due to side effects. Data are > > expressed as means ± SEM. Paired t tests were > > used to calculate the significance of differences > > between groups. > > > > > > --------------------------------- > > > > [Help with image viewing] > > [Email Jumpstart To Image] Table Results of > > treatment > > --------------------------------- > > Results. > > There was no change in strength in the group of > > SMA type III/IV patients, comparing time points at 6 > > to 12 months prior to treatment and at the onset of > > treatment (table). No SMA type III/IV individual > > showed improvement in strength of 12%. > > Strength improved (p = 0.002) in the group of SMA > > type III/IV patients by an absolute mean level of > > 16% of normal strength and by 48% of initial levels, > > comparing the time points immediately before > > initiating valproate treatment and at the last > > visit. Four of the six SMA type III/IV patients who > > continued valproate treatment showed improvement in > > strength of more than 12%. All six SMA type III/IV > > patients who continued valproate treatment noted > > subjective benefit at the last visit. A 45-year-old > > wine-maker, who had not been able to pick grapes for > > several years, was able to return to this activity. > > A 17-year-old high school student was able to > > participate in marching band after stopping 2 years > > before. > > The mean serum level of valproate after 4 to 6 > > months of treatment was 87 µg/mL. The average > > weight gain was 5 lbs (range †" 8 to 11 lbs). Two > > patients initially reported drowsiness. These > > symptoms were minimized by decreasing the dose of > > valproate. There was no change in liver enzymes or > > platelet levels in any patient throughout the > > duration of treatment. > > Discussion. > > We found that valproate treatment was followed by > > a sustained increase in function and strength in our > > group of patients with SMA III/IV. In some patients, > > treatment benefit persisted for more than 1 year. A > > notable feature of valproate responders was the > > relatively rapid onset of improvement. Most patients > > reported benefit within a few months after beginning > > treatment. In contrast, during the months prior to > > treatment, there was no clear change in strength in > > our patients, a course that is similar to prior > > studies of the natural history of SMA III/IV.4 > > The mechanisms underlying improvement in SMA > > III/IV require further study. Increased levels of > > SMN protein could allow recovery of some neurons, > > axons, or terminal branches that were previously > > marginally functioning, or inactive, but > > anatomically intact. Alternatively, improvement > > could occur with rapid growth of motor axon > > terminals to reinnervate neighboring denervated > > muscle fibers. There is some evidence that the SMN > > protein may play a role in neurite outgrowth.8 > > Large, controlled studies are planned to test the > > effects of treatment with valproate and other > > histone deacetylase inhibitors in younger, or more > > severely affected, SMA patients.9 Our results > > showing improvement in SMA III/IV patients indicate > > that trials, with controls to rule out a placebo > > effect, are also warranted in adults with milder > > disease. Our findings, showing measurably improved > > strength over a relatively short time, suggest that > > large trials may not be necessary to demonstrate a > > change in patients with SMA III/IV. > > Valproate treatment may be more likely to be > > efficacious in adult SMA III/IV patients than in > > those with more severe phenotypes. Improvement in > > our study was manifest in muscles with residual > > strength at the time of treatment onset. Valproate > > treatment is probably better tolerated in adults > > than children.10 Further, we speculate that the > > generally greater number of copies of the SMN2 gene > > in patients with SMA III/IV 11 may multiply the > > pharmacologic effects of valproate in increasing the > > production of SMN protein. Measurements of SMN > > protein in patient tissue before and after valproate > > treatment may be useful. > > References > > 1. Sumner CJ, Huynh TN, Markowitz JA, et al. > > Valproic acid increases SMN levels in spinal > > muscular atrophy patient cells. Ann Neurol > > 2003;54:647†" 654. Bibliographic Links [Context > > Link] > > 2. Brichta L, Hofmann Y, Hahnen E, et al. Valproic > > acid increases the SMN2 protein level: a well-known > > drug as a potential therapy for spinal muscular > > atrophy. Hum Mol Genet 2003;12:2481†" 2489. > > Bibliographic Links [Context Link] > > 3. Kernochan LE, Russo ML, Woodling NS, et al. The > > role of histone acetylation in SMN gene expression. > > Hum Mol Genet 2005;14:1171†" 1182. Bibliographic > > Links [Context Link] > > 4. Swoboda KJ, Prior TW, CB, et al. Natural > > history of denervation in SMA: relation to age, SMN2 > > copy number, and function. Ann Neurol > > 2005;57:704†" 712. Bibliographic Links [Context > > Link] > > 5. Beck M, Giess R, Wurffel W, Magnus T, Ochs G, > > Toyka KV. Comparison of maximal voluntary isometric > > contraction and Drachman's hand-held dynamometry in > > evaluating patients with amyotrophic lateral > > sclerosis. Muscle Nerve 1999;22:1265†" 1270. > > Bibliographic Links [Context Link] > > 6. Pestronk A, Lopate G, Kornberg AJ, et al. > > Distal lower motor neuron syndrome with high-titer > > serum IgM anti-GM1 antibodies: improvement following > > immunotherapy with monthly plasma exchange and > > intravenous cyclophosphamide. Neurology > > 1994;44:2027†" 2031. [Context Link] > > 7. Pestronk A, Florence J, T, Choksi R, > > Al-Lozi MT, Levine TD. Treatment of IgM antibody > > associated polyneuropathies using rituximab. J > > Neurol Neurosurg Psychiatry 2003;74:485†" 489. > > Bibliographic Links [Context Link] > > 8. Fan L, Simard LR. Survival motor neuron (SMN) > > protein: role in neurite outgrowth and neuromuscular > > maturation during neuronal differentiation and > > development. Hum Mol Genet 2002;11:1605†" 1614. > > Bibliographic Links [Context Link] > > 9. Hirtz D, Iannaccone S, Heemskerk J, Gwinn-Hardy > > K, Moxley R III, Rowland LP. Challenges and > > opportunities in clinical trials for spinal muscular > > atrophy. Neurology 2005;65:1352†" 1357. Ovid Full > > Text Bibliographic Links [Context Link] > > 10. Coulter DL, Wu H, RJ. Valproic acid > > therapy in childhood epilepsy. JAMA > > 1980;244:785†" 788. Bibliographic Links [Context > > Link] > > 11. Gavrilov DK, Shi X, Das K, Gilliam TC, Wang > > CH. Differential SMN2 expression associated with SMA > > severity. Nat Genet 1998;20:230†" 231. [Context > > Link] > > > > --------------------------------- > > > > Accession Number: 00006114-200608080-00032 > > Copyright © 2000-2006 Ovid Technologies, Inc. > > Version: rel10.4.0, SourceID 1.12596.1.117 > Quote Link to comment Share on other sites More sharing options...
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