RESUMO
Newborn screening for 5qSMA offers the potential for early, ideally pre-symptomatic, therapeutic intervention. However, limited data exist on the outcomes of individuals with 4 copies of SMN2, and there is no consensus within the SMA treatment community regarding early treatment initiation in this subgroup. To provide evidence-based insights into disease progression, we performed a retrospective analysis of 268 patients with 4 copies of SMN2 from the SMArtCARE registry in Germany, Austria and Switzerland. Inclusion criteria required comprehensive baseline data and diagnosis outside of newborn screening. Only data prior to initiation of disease-modifying treatment were included. The median age at disease onset was 3.0 years, with a mean of 6.4 years. Significantly, 55% of patients experienced symptoms before the age of 36 months. 3% never learned to sit unaided, a further 13% never gained the ability to walk independently and 33% of ambulatory patients lost this ability during the course of the disease. 43% developed scoliosis, 6.3% required non-invasive ventilation and 1.1% required tube feeding. In conclusion, our study, in line with previous observations, highlights the substantial phenotypic heterogeneity in SMA. Importantly, this study provides novel insights: the median age of disease onset in patients with 4 SMN2 copies typically occurs before school age, and in half of the patients even before the age of three years. These findings support a proactive approach, particularly early treatment initiation, in this subset of SMA patients diagnosed pre-symptomatically. However, it is important to recognize that the register will not include asymptomatic individuals.
Assuntos
Atrofia Muscular Espinal , Proteína 2 de Sobrevivência do Neurônio Motor , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Idade de Início , Áustria/epidemiologia , Progressão da Doença , Alemanha , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/diagnóstico , Triagem Neonatal , Sistema de Registros , Estudos Retrospectivos , Proteína 2 de Sobrevivência do Neurônio Motor/genética , SuíçaRESUMO
BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease that, in most cases, involves homozygous deletion of the SMN1 gene. This causes a deficiency in survival motor neuron (SMN) protein, which plays a critical role in motor neuron development. SMA has a range of phenotype expression resulting in variable age of symptom onset, maximum motor strength achieved, and survival. Without intervention, infants with a more severe form of the disease (type 1 SMA) die before 2 years of age. Although it is rare, SMA is the most common fatal inherited disease of infancy, and until recently, treatment was primarily supportive. In 2016, a new agent, nusinersen, was approved by the FDA. Other treatments are in development, including a gene therapy, AVXS-101. These treatments are not only improving the lives of patients with SMA and their families, they are changing the disease phenotype. They have the greatest benefit when given early in the disease course. OBJECTIVES: To discuss current knowledge about SMA, provide clinical evidence for available and emerging treatment options, and present approaches for adding new therapies to hospital/health system formularies to ensure timely access to newly approved therapies for SMA. SUMMARY: Advances in clinical care have significantly extended the lives of individuals with SMA, and research into the genetic mechanisms leading to disease have revealed strategies for intervention that target the underlying cause of SMA. Nusinersen is now on the market, and other treatment options, such as AVXS-101, may soon be approved. This article provides an overview of SMA and the genetic mechanisms leading to SMN deficiency, then describes how new and emerging treatments work to overcome this deficiency and prevent associated nerve damage and disability. In addition, we discuss steps for incorporating AVXS-101 into hospital/health system formularies, along with barriers and concerns that may delay access, based in part on lessons learned with nusinersen.
Assuntos
Terapia Genética/métodos , Atrofia Muscular Espinal/terapia , Oligonucleotídeos/uso terapêutico , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Ensaios Clínicos como Assunto , Dependovirus/genética , Aprovação de Drogas , Éxons/efeitos dos fármacos , Éxons/genética , Deleção de Genes , Terapia Genética/economia , Terapia Genética/legislação & jurisprudência , Terapia Genética/tendências , Vetores Genéticos/genética , Vetores Genéticos/uso terapêutico , Necessidades e Demandas de Serviços de Saúde/tendências , Humanos , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/mortalidade , Oligonucleotídeos/economia , Oligonucleotídeos/farmacologia , Sarcômeros/efeitos dos fármacos , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Estados Unidos , United States Food and Drug AdministrationRESUMO
BACKGROUND: Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder with neuronal degeneration leading to muscular atrophy and respiratory failure. SMA is frequently caused by homozygous deletions that include exon 7 of the survival motor neuron gene SMN1, and its clinical course is influenced by the copy number of a nearby 5q SMN1 paralog, SMN2. Multiple ligation probe amplification (MLPA) and real-time quantitative PCR (qPCR) can detect SMN1 deletions. Yet, qPCR needs normalization or standard curves, and MLPA demands DNA concentrations above those obtainable from dried blood spots (DBSs). We developed a multiplex, droplet digital PCR (ddPCR) method for the simultaneous detection of SMN1 deletions and SMN2 copy number variation in DBS and other tissues. An SMN1 Sanger sequencing process for DBS was also developed. METHODS: SMN1, SMN2, and RPP30 concentrations were simultaneously measured with a Bio-Rad AutoDG and QX200 ddPCR system. A total of 1530 DBSs and 12 SMA patients were tested. RESULTS: Population studies confirmed 1 to 5 SMN1 exon 7 copies detected in unaffected specimens, whereas patients with SMA revealed 0 SMN1 copies. Intraassay and interassay imprecisions were <7.1% CV for individuals with ≥1 SMN1 copies. Testing 12 SMA-positive samples resulted in 100% sensitivity and specificity. CONCLUSIONS: This ddPCR method is sensitive, specific, and applicable to newborn screening and carrier status determination for SMA. It can also be incorporated with a parallel ddPCR T-cell excision circles assay for severe combined immunodeficiencies.
Assuntos
Reação em Cadeia da Polimerase Multiplex/métodos , Atrofia Muscular Espinal/genética , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Autoantígenos/genética , Teste em Amostras de Sangue Seco , Éxons , Feminino , Triagem de Portadores Genéticos/métodos , Humanos , Recém-Nascido , Masculino , Triagem Neonatal/métodos , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase em Tempo Real/métodos , Valores de Referência , Reprodutibilidade dos Testes , Ribonuclease P/genética , Proteína 2 de Sobrevivência do Neurônio Motor/genéticaAssuntos
Atrofia Muscular Espinal/tratamento farmacológico , Oligonucleotídeos/uso terapêutico , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Criança , Aprovação de Drogas/economia , Humanos , Atrofia Muscular Espinal/economia , Atrofia Muscular Espinal/genética , Mutação , Oligonucleotídeos/economia , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Estados Unidos , United States Food and Drug AdministrationAssuntos
Processamento Alternativo/efeitos dos fármacos , Aprovação de Drogas , Atrofia Muscular Espinal/tratamento farmacológico , Oligonucleotídeos Antissenso/uso terapêutico , Oligonucleotídeos/uso terapêutico , Adolescente , Adulto , Animais , Criança , Pré-Escolar , Humanos , Lactente , Modelos Animais , Morfolinos/uso terapêutico , Atrofia Muscular Espinal/economia , Oligonucleotídeos/economia , Oligonucleotídeos/farmacologia , Oligonucleotídeos Antissenso/economia , Oligonucleotídeos Antissenso/farmacologia , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Estados Unidos , United States Food and Drug AdministrationAssuntos
Ensaios Clínicos como Assunto , Neurônios Motores/metabolismo , Atrofia Muscular Espinal/tratamento farmacológico , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Indústria Farmacêutica , Dosagem de Genes , Genoma Humano , Heterozigoto , Inibidores de Histona Desacetilases/uso terapêutico , Histona Desacetilases/administração & dosagem , Humanos , Recém-Nascido , Terapia de Alvo Molecular , Neurônios Motores/efeitos dos fármacos , Mutação , Proteína 1 de Sobrevivência do Neurônio Motor/uso terapêutico , Proteína 2 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/uso terapêuticoRESUMO
BACKGROUND & OBJECTIVES: Genetic diagnosis of spinal muscular atrophy (SMA) is complicated by the presence of SMN2 gene as majority of SMA patients show absence or deletion of SMN1 gene. PCR may amplify both the genes non selectively in presence of high amount of DNA. We evaluated whether allele-specific PCR for diagnostic screening of SMA is reliable in the presence of high amount of genomic DNA, which is commonly used when performing diagnostic screening using restriction enzymes. METHODS: A total of 126 blood DNA samples were tested in amounts ranging 80-200 ng, referred for the genetic diagnosis of SMA using both conventional PCR-RFLP and allele-specific PCR. RESULTS: The results from both methods showed agreement. Further, allele-specific PCR was found to be a time-efficient and cost-effective method. INTERPRETATION & CONCLUSIONS: Our study demonstrated the accuracy of our allele-specific PCR and the results were comparable compatible with that of PCR-RFLP, indicating its practical application in SMA diagnostic screening.
Assuntos
Atrofia Muscular Espinal/diagnóstico , Reação em Cadeia da Polimerase/métodos , Proteína 1 de Sobrevivência do Neurônio Motor/sangue , Adolescente , Alelos , Criança , Éxons , Feminino , Custos de Cuidados de Saúde , Humanos , Masculino , Atrofia Muscular Espinal/patologia , Deleção de Sequência , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 2 de Sobrevivência do Neurônio Motor/sangue , Proteína 2 de Sobrevivência do Neurônio Motor/genéticaRESUMO
With the detection of a homozygous deletion of the survival motor neuron 1 gene (SMN1), prenatal and preimplantation genetic diagnosis (PGD) for spinal muscular atrophy has become feasible and widely applied. The finding of a de novo rearrangement, resulting in the loss of the SMN1 gene, reduces the recurrence risk from 25% to a lower percentage, the residual risk arising from recurrent de novo mutation or germline mosaicism. In a couple referred to our PGD center because their first child was affected with SMA, the male partner was shown to carry two SMN1 copies. An analysis of the SMN1 gene and two flanking markers was performed on 12 single spermatozoa, to determine whether the father carried a CIS duplication of the SMN1 gene on one chromosome and was a carrier, or if the deletion has occurred de novo. We showed that all spermatozoa that were carriers of the 'at-risk haplotype' were deleted for the SMN1 gene, confirming the carrier status of the father. We provide an original application of single germ cell studies to recessive disorders using coamplification of the gene and its linked markers. This efficient and easy procedure might be useful to elucidate complex genetic situations when samples from other family members are not available.