Resumo das mais relevantes publicações de 2002

Este trabalho testou o uso da estimulação elétrica de músculos de pacientes com AME em comparação com a falta de estimulação. Verificou-se que, após 6 meses e 12 meses, não havia diferença na força dos músculos estimulados eletricamente e os não estimulados

Dev Med Child Neurol 2002 Nov;44(11):741-4
Evaluation of therapeutic electrical stimulation to improve muscle strength and function in children with types II/III spinal muscular atrophy.

Fehlings DL, Kirsch S, McComas A, Chipman M, Campbell K.

Department of Pediatrics, Bloorview MacMillan Children’s Centre, Hospital for Sick Children, University of Toronto, ON, Canada.

The study aimed to evaluate the effect of low-intensity night-time therapeutic electrical stimulation (TES) on arm strength and function in children with intermediate type spinal muscular atrophy (SMA). The design was a randomized controlled trial with a 6-month baseline control period. Children were evaluated at baseline, 6, and 12 months. TES was applied from 6 to 12 months to the deltoid and biceps muscle, of a randomly selected arm with the opposite arm receiving a placebo stimulator. Thirteen individuals with SMA between 5 to 19 years of age were recruited into the study and eight completed the 12-month assessment. No statistically significant differences between the treatment and control arm were found at baseline, 6, and 12 months for elbow flexors, or shoulder abductors on quantitative myometry or manual muscle testing. There was no significant change in excitable muscle mass assessed by M-wave amplitudes, nor function on the Pediatric Evaluation of Disability Inventory (self-care domain). Therefore, in this study there was no evidence that TES improved strength in children with SMA.

O autor fornece uma revisão sobre AME e perspectivas terapêuticas, baseado nas últimas publicações científicas. A gravidade da AME é relacionada, dentre outros, a quantidade de SMN2, que por sua vez depende da mutação do exon 7 deste gene. Algumas substâncias, como a Htra2-beta1, butirato de sódio e aclarubicina, são capazes de aumentar a quantidade de SMN2. Portanto são promissoras as estratégias de pesquisa, que envolvam substâncias como estas.

Amyotroph Lateral Scler Other Motor Neuron Disord 2002 Jun;3(2):87-95

Spinal muscular atrophy: state-of-the-art and therapeutic perspectives.

Wirth B.

Institute of Human Genetics, University of Bonn, Germany.

Proximal spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans caused by degeneration of alpha motor neurons in the anterior horns of the spinal cord. This affects voluntary movements, leading to muscle weakness and atrophy. SMA is caused by homozygous deletions/mutations in the survival motor neuron gene 1 (SMN1). The severity of the phenotype is modulated by the copy number of SMN2 and by other yet unknown factors. SMN2 is affected by a critical non-translational nucleotide exchange in exon 7 that disrupts an exonic splicing enhancer. In consequence SMN2 produces mainly alternatively spliced mRNA that lacks exon 7. Trans-activating factors such as Htra2-beta1, as well as various drugs like sodium butyrate or aclarubicin, are able to restore the full-length SMN2 RNA to large amounts. Since each SMA patient carries at least one SMN2 copy, reconstitution of full-length SMN2 protein is an exciting strategy for somatic gene therapy in SMA patients.

Os autores comparam dois grupos de pacientes com AME 1 (Werdnig-Hoffman). O grupo A que usou ventilação invasiva com traqueostomia e o grupo B que usou a ventilação não invasiva. Mostram que com cuidados respiratórios como estes as crianças com AME 1 sobrevivem os 2 anos de idade. O grupo B (ventilação não invasiva) apresentou um menor número de internações, estava livre de uso de ventilador durante o dia e era capaz de falar após os 5 anos de idade.

Pediatr Pulmonol 2002 Jul;34(1):16-22

Spinal muscular atrophy type 1: management and outcomes.

Bach JR, Baird JS, Plosky D, Navado J, Weaver B.

Department of Physical Medicine and Rehabilitation, UMDNJ-New Jersey Medical School, Newark, New Jersey 07103, USA.

Our objectives were to describe survival, hospitalization, speech, and outcomes related to respirator needs for spinal muscular atrophy type 1 (SMA1) patients, using noninvasive or tracheostomy ventilation. From 65 SMA patients referred to our clinic since 1996, we chose 56 SMA1 patients who developed respiratory failure before age 2 years. Patients either had tracheostomy tubes (group A), or used noninvasive ventilation and assisted coughing; a previously reported extubation protocol (group B) was used as needed. Sixteen patients underwent tracheostomy at 10.8 +/- 5.0 months of age, 33 were in group B, and 7 others died without life-support interventions. Compared to group B, group A patients had fewer hospitalizations until age 3 years, but more after age 5, and 15 of 16 lost all spontaneous breathing tolerance posttracheostomy and could not speak. One group A patient died at 16 months of age, and the others were 73.8 +/- 57 months of age (the oldest was 19 years old). Two group B patients died at 6 and 13 months, respectively, whereas the other 31 were 41.8 +/- 26.0 months (and up to 8.3 years) old. Three of 31 in group B required high-span positive inspiratory pressure plus positive end-expiratory pressure (PIP + PEEP) continuously with minimal tolerance for breathing on their own, and 4 could not communicate verbally. In conclusion, SMA type 1 children can survive beyond 2 years of age when offered tracheostomy or noninvasive respiratory support. The latter is associated with fewer hospitalizations after age 5 years, freedom from daytime ventilator use, and the ability to speak. Copyright 2002 Wiley-Liss, Inc.

Os autores criaram um método de laboratório capaz de monitorar a inclusão do exon 7 no gene SMN2. Esta prova de laboratório é importante para testar substâncias que estimulem a regulação desta porção do gene (exon 7 do SMN2), e que são potenciais candidatos para o tratamento da AME.

Gene Ther 2001 Oct;8(20):1532-8

An in vivo reporter system for measuring increased inclusion of exon 7 in SMN2 mRNA: potential therapy of SMA.

Zhang ML, Lorson CL, Androphy EJ, Zhou J.

Department of Dermatology, New England Medical Center and Tufts University School of Medicine, Boston, MA 02111, USA.

Spinal muscular atrophy (SMA) is a degenerative motor neuron disorder resulting from homozygous loss of the SMN1 gene. SMN2, a nearly identical copy gene, is preserved in SMA patients. A single nucleotide difference between SMN1 and SMN2 causes exon 7 skipping in the majority of SMN2 mRNA. Gene therapy through modulation of SMN2 gene transcription in SMA patients may be possible. We constructed a series of SMN mini-genes comprised of SMN exon 6 to exon 8 sequences fused to green fluorescence protein (GFP) or luciferase reporters, to monitor SMN exon 7 splicing. These reporters recapitulated the splicing patterns of the endogenous SMN gene in stable cell lines. The SMN1-luciferase reporter was approximately 3.5-fold more active than SMN2-luciferase and SMN1-GFP intensities were visually distinguishable from SMN2-GFP. We have screened chemical inducers and inhibitors of kinase pathways using stable SMN-reporter lines and found that the phosphatase inhibitor sodium vanadate specifically stimulated exon 7 inclusion within SMN2 mRNAs. This is the first compound identified that can stimulate exon 7 inclusion into transcripts derived from the endogenous SMN2 gene. These results demonstrate that this system can be utilized to identify small molecules that regulate the splicing of SMN exon 7.


Dra. Alexandra Prufer de Araújo – Neuropediatra e Pesquisadora de Atrofia Muscular Espinhal

Universidade Federal do Rio de Janeiro – UFRJ