Estão sendo desenvolvidas pesquisas objetivando o
tratamento da AME em diversos países, tais como, Estados
Unidos, Canadá, Inglaterra, França, Alemanha.
Essas pesquisas são tanto no campo da genética
(clonagem terapêutica e terapia genética) quanto
no da farmacologia.
Num esforço mundial para se achar a cura da Atrofia
Muscular Espinhal, foi lançada a International
Alliance for SMA IASMA, que tem como estratégia
financiar pesquisas e disseminar informações
A esperança de contarmos no futuro com um tratamento
para estas doenças deve ficar acesa com os resumos
das pesquisas publicadas aqui selecionadas. No entanto cabe
o alerta de que não há no presente momento nenhuma
terapia comprovada e liberada para o tratamento. Para que
isto ocorra é necessário que a terapia se mostre
viável em tubo de ensaio e em testes com
animais de laboratório. Depois, estas mesmas terapias
são testadas em seres humanos, e, apenas quando comprovadamente
não causarem danos e se mostrarem eficazes, o que depende
de testes em muitos seres vivos é que estas terapias
são liberadas como forma de tratamento para uma doença.
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
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
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
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. email@example.com
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
Sumner CJ, Huynh TN, Markowitz JA, Perhac JS, Hill B, Coovert
DD, Schussler K, Chen X, Jarecki J, Burghes AH, Taylor JP,
Neurogenetics Branch, National Institute of Neurologic Diseases
and Stroke/NIH, Building 10, Room 3B-14, MSC 1250, 10 Center
Drive, Bethesda, MD 20892, USA. firstname.lastname@example.org
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
Arq Neuropsiquiatr. 2003 Sep;61(3A):631-8. Epub 2003 Sep
[Surgical treatment of scoliosis in spinal muscular atrophy]
[Article in Portuguese]
Roso V, Bitu Sde O, Zanoteli E, Beteta JT, de Castro RC, Fernandes
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,
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
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
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. email@example.com
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.
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,
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
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