Resumo das publicações mais relevantes de 2004

Projeto Cure SMA anuncia com satisfação a fase II do ensaio clínico (pesquisa com medicamento) para continuar a avaliação da combinação de ácido valpróico com carnitina em crianças com AME. Aprovado pelo FDA (órgão americano de controle de medicamentos semelhante a ANVISA no Brasil), esta pesquisa será multicêntrica nos Estados Unidos (em diversos hospitais) e financiada pela FSMA. Mais informação em inglês www.ProjectCureSMA.org

Project Cure SMA is pleased to announce a phase II clinical trial to further evaluate a combined regimen of valproic acid and carnitine in children with Spinal Muscular Atrophy (SMA). This phase II trial has been reviewed and approved by the FDA. This trial is a collaborative multi-center effort funded by Families of Spinal Muscular Atrophy. For complete information please see www.ProjectCureSMA.org

Ensaio clínico no Reino Unido começando este ano, irá utilizar o ácido valpróico em todas as 3 formas de AME. Será um estudo duplo cego com placebo (nem o médico nem o paciente sabem se está usando o ácido valpróico ou a substância inócua). Será realizado simultaneamente em diferentes hospitais da Europa. Mais informações em inglês www.jtsma.org.uk/research18feb05

February 18, 2005 – From the Jennifer Trust for SMA (UK): First UK Drugs Trials for SMA likely to start this year!

Following a meeting of the top clinicians from across Europe at ENMC in Holland on 11 -13th February it was agreed that the next step in our quest to find answers for Spinal Muscular Atrophy would be to perform a drugs trial using Valproic Acid (VPA) for all three types of childhood SMA. It is hoped that this trial will commence within the year. The trials will be double blind placebo controlled and will be run in parallel across Europe including Great Britain. This drug is not a cure – but it is hoped it may give functional improvement. For more information see http://www.jtsma.org.uk/research18feb05.html

NINDS; Bethesda, Maryland está recrutando pacientes e carreadores do gene (familiares não doentes) para testar o sangue com referência aos níveis de SMA. Mais informações em inglês Measuring Levels of SMN in Blood Samples of SMA Patients

NINDS; Bethesda, Maryland

The National Institute of Neurological Disease and Strokes (NINDS) is seeking patients and carriers for Blood Samples. For more information please see Measuring Levels of SMN in Blood Samples of SMA Patients

Stanford University Medical Center, Dr. Ching Wang, Palo Alto, California – Dois ensaios clínicos utilizando hidroxiuréia estão em curso. O primeiro teste em crianças tipo I com menos de 2 anos de idade e o segundo em pacientes com 2 a 8 anos de idade portando os tipos II e III.

Stanford University Medical Center, Dr. Ching Wang, Palo Alto, California

2 clinical trial studies using hydroxyurea are currently being conducted. The first study is targeted at children with Type I SMA and less than 2 years of age. The second study is targeted at patients 2 to 8 years of age with Type II or Type III. For more information please contact Tony Trela at 650-498-7658.

AmSMART (American Spinal Muscular Atrophy Randomized Trials) – O grupo AmSMART é uma organização que engloba 15 centros pediátricos e o Centro de Bioestatistica e Ciência Clínica. O grupo foi formado para fazer ensaios clínicos em crianças portadoras de AME. A AmSMART está atualmente recrutando crianças entre 0 e 2 anos para testar o Rilutek. Testes clínicos com o fenilbutirato está programado para ser realizado no final de 2004.

AmSMART (American Spinal Muscular Atrophy Randomized Trials)

The AmSMART group is an organization of 15 pediatric medical centers and the Center for Biostatistics and Clinical Science at UT Southwestern formed in order to perform clinical trials in children with SMA. AmSMART currently is enrolling children 0 through 2 years of age in an open label Rilutek clinical trial. A phenylbutyrate clinical trial is planned for late 2004. For more information and locations please see their website at www.amsmart.org

Resumo das publicações mais relevantes de 2003

Neste estudo, pretendia-se avaliar o efeito de uma medicação inibidora de uma substância chamada glutamato, o riluzole, em 30 crianças com AME tipo 1. Como apenas 10 crianças foram incluídas para participar, sendo 7 usando a medicação e 3 usando placebo, o estudo não foi capaz de avaliar o efeito da droga sobre a doença, mas observou-se que não houve efeitos colaterais.

Arch Neurol. 2003 Nov;60(11):1601-3.

A phase 1 trial of riluzole in spinal muscular atrophy.
Russman BS, Iannaccone ST, Samaha FJ.
Oregon Health Sciences University and Shriners Hospital for Children, Portland, OR 97201, USA. brussman@shrinenet.org
BACKGROUND: Severe spinal muscular atrophy (SMA) (Werdnig-Hoffmann disease, acute SMA, and SMA I) is a disease of the motor neuron characterized by onset before 6 months of age, failure ever to achieve sitting without support, and a life expectancy of 2 years or less. There is no known treatment for SMA, and, until recently, no therapeutic trials have been attempted. There is reason to believe that glutamate, an excitatory neurotransmitter, enhances programmed cell death of anterior horn cells. Riluzole, a glutamate inhibitor, has been shown to slow the rate of decline in patients with amyotrophic lateral sclerosis, another form of motor neuron disease. OBJECTIVES: To determine whether a glutamate inhibitor might be tolerated by infants with SMA and, furthermore, whether this medication could have a positive effect on life expectancy. DESIGN: Subjects with homozygous deletions of the survival motor neuron gene were recruited from pediatric neuromuscular clinics and randomized in a 2:1 ratio, 2 riluzole to 1 placebo. Neurologic examination was performed at the first visit by one of the investigators. Complete blood count, hepatic and renal screens, and urinalysis were performed at baseline, 2 weeks, 1 month, 2 months, 3 months, 6 months, and 9 months after drug or placebo was started. An electrocardiogram was done at baseline, 3 months, 6 months, and 12 months. Treatment was stopped after 9 months, and blood work was repeated at 12 months. Treatment was reinstituted at 1 year if requested by the parents. The enrollment goal was 30 patients; however, support from the pharmaceutical company was withdrawn when Rhone-Poulenc Rorer was taken over by Aventis. The investigational review boards of the participating centers approved the protocol and consent forms. RESULTS: Seven patients received riluzole and 3 received placebo medication. All 3 patients in the placebo group died (mean age, 9 months). Three of 7 who received active drug are still living at ages 513 years, 4 years, and 30 months. None of the 10 subjects experienced adverse effects or changes in laboratory test results. None showed any change in motor abilities. CONCLUSIONS: Riluzole appears to be safe in young children. This was a limited study with insufficient power to show a difference between the 2 groups. Because there is a suggestion of possible benefit in treated subjects, we recommend further study of riluzole in pediatric patients with SMA.


Usando células chamadas de fibroblastos de pacientes com Atrofia Muscular Espinhal, verificou-se que o ácido valpróico, um medicamento usado no controle de crises epilépticas, aumenta a produção da proteína de sobrevivência do neurônio motor.

Ann Neurol. 2003 Nov;54(5):647-54.

Valproic acid increases SMN levels in spinal muscular atrophy patient cells.
Sumner CJ, Huynh TN, Markowitz JA, Perhac JS, Hill B, Coovert DD, Schussler K, Chen X, Jarecki J, Burghes AH, Taylor JP, Fischbeck KH.
Neurogenetics Branch, National Institute of Neurologic Diseases and Stroke/NIH, Building 10, Room 3B-14, MSC 1250, 10 Center Drive, Bethesda, MD 20892, USA. sumnerc@ninds.nih.gov
Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by mutation of the telomeric copy of the survival motor neuron gene (SMN1). Although a centromeric copy of the survival motor neuron gene (SMN2) is retained in all patients with SMA, it differs from SMN1 at a critical nucleotide such that the majority of SMN2 transcripts lack exon 7 and encode an unstable, truncated protein. Here, we show that valproic acid increases levels of exon 7-containing SMN transcript and SMN protein in type I SMA patient-deriv ed fibroblast cell lines. Valproic acid may increase SMN levels both by activating the SMN promoter and by preventing exon 7 skipping in SMN transcripts. Valproic acid and related compounds warrant further investigation as potential treatment for SMA.


Este outro grupo na Alemanha também fez observações semelhantes com o ácido valpróico em fibroblastos de pacientes com Atrofia Muscular Espinhal.

Valproic acid increases the SMN2 protein level: a well-known drug as a potential therapy for spinal muscular atrophy.
Brichta L, Hofmann Y, Hahnen E, Siebzehnrubl FA, Raschke H, Blumcke I, Eyupoglu IY, Wirth B.
Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, 53111 Bonn, Germany.
Proximal spinal muscular atrophy (SMA) is a common neuromuscular disorder causing infant death in half of all patients. Homozygous absence of the survival motor neuron gene (SMN1) is the primary cause of SMA, while SMA severity is mainly determined by the number of SMN2 copies. One SMN2 copy produces only about 10% of full-length protein identical to SMN1, whereas the majority of SMN2 transcripts is aberrantly spliced due to a silent mutation within an exonic splicing enhancer in exon 7. However, correct splicing can be restored by over-expression of the SR-like splicing factor Htra2-beta 1. We show that in fibroblast cultures derived from SMA patients treated with therapeutic doses (0.5-500 microM) of valproic acid (VPA), the level of full-length SMN2 mRNA/protein increased 2- to 4-fold. Importantly, this up-regulation of SMN could be most likely attributed to increased levels of Htra2-beta 1 which facilitates the correct splicing of SMN2 RNA as well as to an SMN gene transcription activation. Especially at low VPA concentrations, the restored SMN level depended on the number of SMN2 copies. Moreover, VPA was able to increase SMN protein levels through transcription activation in organotypic hippocampal brain slices from rats. Finally, VPA also increased the expression of further SR proteins, which may have important implications for other disorders affected by alternative splicing. Since VPA is a drug highly successfully used in long-term epilepsy therapy, our findings open the exciting perspective for a first causal therapy of an inherited disease by elevating the SMN2 transcription level and restoring its correct splicing.


Estudo brasileiro que descreve a experiência com a cirurgia para correção de escoliose em 14 pacientes com Atrofia Muscular Espinhal. Como complicações da cirurgia observaram fístula liquórica (orifício de comunicação entre o meio externo e o meio interno onde circula o líquido espinhal), infecção e desprendimento de fixador da coluna. Os benefícios foram estéticos, na qualidade de vida e na função respiratória.

Arq Neuropsiquiatr. 2003 Sep;61(3A):631-8. Epub 2003 Sep 16.

[Surgical treatment of scoliosis in spinal muscular atrophy]
[Article in Portuguese]
Roso V, Bitu Sde O, Zanoteli E, Beteta JT, de Castro RC, Fernandes AC.
Clinicas de Escoliose e de Doencas Neuromusculares, Associacao de Assistencia Crianca Deficiente, Sao Paulo, SP, Brasil.
OBJECTIVE: To describe the early and late postoperative data from SMA patients with surgical procedure. METHOD: Clinical data and radiographic imaging from 14 SMA patients with surgical treatment of scoliosis were reviewed, and all were reassessed clinically with new spinal radiographs and a questionnaire. The mean follow-up were 22 months. The mean preoperative Cobb angle was 78.4 . All patients presented pelvic obliquity (mean 25.5 ) and 11 had cifosis. The mean age at time of surgery was 12 years and 3 months. All patients were treated with posterior spinal fusion with Luque-Galveston instrumentation in 12 and Cotrel-Dubousset instrumentation in 2. RESULTS: The average curve correction at the immediate postoperative was 64.3% for scoliosis and 36.4% for cifosis, with the pelvic obliquity correction of the 70.9%. The complications were liquoric fistula and infection earlier in one case, and lately wire looseness of T1 in 2 patients. It was detected mean lost of the correction at the final assessment of the 0.26 of the scoliosis and the 1.28 of the pelvic obliquity. Relatives and the patients related good improvement regarding to esthetic aspects, posture balance, body care, as well as respiratory problems. CONCLUSION: The spinal fusion for scoliosis in SMA patients has a satisfactory impact for esthetic, quality of life and respiratory function, with minimal lost of corrected deformities and few complications.


Foram estudados os efeitos de uma substância chamada gabapentina, que tem propriedades neuroprotetoras, em pacientes com Atrofia Muscular Espinhal do tipo 2 e 3. Não se observou diferença entre os pacientes tratados com os não tratados sobre as medidas de função respiratória. Houve uma melhora na força das pernas em 37,7 % dos tratados e 20,3% dos não tratados com a gabapentina.

J Child Neurol. 2003 Aug;18(8):537-41.

Role of gabapentin in spinal muscular atrophy: results of a multicenter, randomized Italian study.
Merlini L, Solari A, Vita G, Bertini E, Minetti C, Mongini T, Mazzoni E, Angelini C, Morandi L.
Neuromuscular Unit, Istituto Ortopedico Rizzoli, Bologna, Italy.
Recent studies suggest that gabapentin has a neuroprotective effect in experimental models of motoneuron disease. We carried out a multicenter, randomized, controlled trial of gabapentin versus no treatment in 120 patients with type II or III spinal muscular atrophy for 12 months. We assessed maximum voluntary isometric contraction with a handheld myometer and calculated an arm megascore (summing elbow flexion, hand grip, and three-point pinch scores), and a leg megascore (summing knee flexion, knee extension, and foot extension scores). Forced vital capacity and timed tasks were also evaluated. Arm megascore improved by at least 30% in 24.6% of treated and 16.9% of untreated patients (relative risk = 1.45; 95% confidence interval = 0.71-2.97). The leg megascore improved by at least 30% in 37.7% of treated and 20.3% of untreated patients (relative risk = 1.85; 95% confidence interval = 1.02-3.37). We conclude that gabapentin produced a significant improvement in leg megascore at 6 months, which was more evident at 12 months, with a trend for improvement in arm megascore at 12 months. The treatment had no effect on forced vital capacity or timed functional tests.


Um grupo tradicional de estudos de doenças neuromusculares desenvolveu uma escala para avaliar a evolução de pacientes com Atrofia Muscular Espinhal tipo 2 e 3.

Eur J Paediatr Neurol. 2003;7(4):155-9.

The Hammersmith functional motor scale for children with spinal muscular atrophy: a scale to test ability and monitor progress in children with limited ambulation.
Main M, Kairon H, Mercuri E, Muntoni F.
Department of Physiotherapy, Hammersmith Hospital, Du Cane Road, London W12 OHS, UK.
A functional motor scale was devised for use in children with spinal muscular atrophy type 2 and type 3, in particular those with limited mobility, to give objective information on motor ability and clinical progression. The scale, which has 20 scored activities, was designed to be self-explanatory, quick, easy to use, reproducible and reliable. In this paper we describe the development of the scale, reporting the criteria used to choose the items to be included, their application in a normal cohort and in a cohort of children with SMA and how we arrived to a final version of the scale in which the items are arranged in order of difficulty.The analysis of 120 assessments over 2 years from 51 children with type 2 and type 3 SMA also led to a more accurate profile of functional achievements in both type 2 and 3 SMA and to a more detailed sub-classification of type 2 SMA.


Este centro de pesquisa tradicional de doenças neuromusculares, mostrou que “em tubo de ensaio” e nos fibroblastos de pacientes com Atrofia Muscular Espinhal, oligonucleotídeos, substâncias que entram na composição do material genético, modificam o efeito do gene defeituoso da Atrofia Muscular Espinhal.

Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4114-9. Epub 2003 Mar 17.

Bifunctional antisense oligonucleotides provide a trans-acting splicing enhancer that stimulates SMN2 gene expression in patient fibroblasts.
Skordis LA, Dunckley MG, Yue B, Eperon IC, Muntoni F.
Dubowitz Neuromuscular Centre, Imperial College London, Hammersmith Hospital, London W12 0NN, United Kingdom.
The multiplicity of proteins compared with genes in mammals owes much to alternative splicing. Splicing signals are so subtle and complex that small perturbations may allow the production of new mRNA variants. However, the flexibility of splicing can also be a liability, and several genetic diseases result from single-base changes that cause exons to be skipped during splicing. Conventional oligonucleotide strategies can block reactions but cannot restore splicing. We describe here a method by which the use of a defective exon was restored. Spinal muscular atrophy (SMA) results from mutations of the Survival Motor Neuron (SMN) gene. Mutations of SMN1 cause SMA, whereas SMN2 acts as a modifying gene. The two genes undergo alternative splicing with SMN1, producing an abundance of full-length mRNA transcripts, whereas SMN2 predominantly produces exon 7-deleted transcripts. This discrepancy is because of a single nucleotide difference in SMN2 exon 7, which disrupts an exonic splicing enhancer containing an SF2ASF binding site. We have designed oligoribonucleotides that are complementary to exon 7 and contain exonic splicing enhancer motifs to provide trans-acting enhancers. These tailed oligoribonucleotides increased SMN2 exon 7 splicing in vitro and rescued the incorporation of SMN2 exon 7 in SMA patient fibroblasts. This treatment also resulted in the partial restoration of gems, intranuclear structures containing SMN protein that are severely r educed in patients with SMA. The use of tailed antisense oligonucleotides to recruit positively acting factors to stimulate a splicing reaction may have therapeutic applications for genetic disorders, such as SMA, in which splicing patterns are altered.


Usando um vírus manipulado em laboratório, para conter um gene sadio de sobrevivência do neurônio motor, este grupo de pesquisa conseguiu fazer com que cultura de fibroblastos de pacientes com Atrofia Muscular Espinhal, passasse a ter um melhor funcionamento do gene defeituoso.

Hum Gene Ther. 2003 Jan 20;14(2):179-88.

Development of a gene therapy strategy for the restoration of survival motor neuron protein expression: implications for spinal muscular atrophy therapy.
DiDonato CJ, Parks RJ, Kothary R.
Ottawa Health Research Institute, Molecular Medicine Program and University of Ottawa Center for Neuromuscular Disease, Ottawa, ON, K1N 8L6, Canada. cdidonato@ohri.ca
Spinal muscular atrophy (SMA) is a motor neuron degeneration disorder, and manifests itself in patients as muscle weakness and paralysis that ultimately leads to death. Currently, there is no effective treatment for this disease. As a first step in developing a treatment for SMA, we are examining whether delivery of the gene encoding survival motor neuron (SMN) protein to primary fibroblast ce ll lines derived from SMA patients can lead to restoration of nuclear-staining foci, called gems, which are absent in patients with severe SMA. Using adenovirus-mediated gene delivery, we show that SMN can be efficiently expressed in patient fibroblasts, and leads to restoration of nuclear gems, which are thought to be important for the functional rescue of the SMA phenotype. The number of gems per cell is equal to or greater than those found in fibroblasts of normal individuals. Furthermore, ectopic expression of SMN also caused relocalization of Gemin2, an SMN-interacting protein, to gems. Overall, this work is the first demonstration of the feasibility of virus-based delivery of the SMN-coding gene to restore the normal SMN expression pattern in SMA patient-derived cells, and holds promise for gene therapy of SMA, as a potential long-term therapy for this devastating childhood disease.


Este trabalho mostra que a visão que os cuidadores de pacientes com Atrofia Muscular Espinhal tem pode ser diferente daquela que os profissionais de saúde fazem a respeito dos pacientes. Os cuidadores atribuem aos pacientes com Atrofia Muscular Espinhal uma qualidade de vida superior aquela atribuída pelos profissionais de saúde.

Am J Phys Med Rehabil. 2003 Feb;82(2):137-42.

Spinal muscular atrophy type 1 quality of life.
Bach JR, Vega J, Majors J, Friedman A.
Department of Neuroscience, UMDNJ-New Jersey Medical School, Newark, 07103, USA.
OBJECTIVE: To compare healthcare professionals’ assessment of the quality of life of spinal muscular atrophy type 1 children with that of the care providers for the children. DESIGN: The care providers of all 53 surviving spinal muscular atrophy type 1 children managed in one neuromuscular disease clinic were sent Likert-scale surveys of six quality of life issues and ten polar-adjective pairs. The quality of life estimations were compared with those of 67 clinicians and with those of 30 parents considering their unaffected children. RESULTS: One h undred care providers from 46 out of the 53 families (87%) responded. Although the clinicians’ mean estimate of the children’s quality of life was 2.85 +/- 0.2/10, the care providers’ estimate was 7.81 +/- 0.2/10 (P < 0.0001). The care providers also found life with the children to be satisfying (6.0 +/- 0.2/7), interesting (6.6 +/- 0.1/7), friendly (6.1 +/- 0.1/7), enjoyable (6.3 +/- 0.1/7), worthwhile (6.7 +/- 0.1/7), full (6.6 +/- 0.1/7), hopeful (5.9 +/- 0.2/7), and rewarding (6.4 +/- 0.1/7), and they estimated the children to be happy (8.5 +/- 0.2/10) and their lives worth living (9.6 +/- 0.1/10). However, 69 of 104 felt that their lives were hard rather than easy, and 56 of 104 reported feeling tied down rather than free. Although the effort they felt for raising the child was high (8.3 +/- 0.3 by comparison with 5 for an unaffected child), the burden they felt in doing so was not (5.8 +/- 0.3/5). When asked whether they would or would not recommend ventilator use, 31 clinicians (45.5%) indicated they would, 24 (36.4%) would not, and 12 (18.2%) chose not to respond to this question. Care provider responses did not differ significantly from the responses of the parents of unaffected children except for the easy/hard semantic differential (care providers, 3.80 +/- 1.75 controls, 5.27 +/- 1.14, < 0.001). CONCLUSIONS: Although there is a widespread perception that spinal muscular atrophy type 1 children have a poor quality of life, this perception is not shared by their care providers.