Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease caused by deletion or mutation of SMN1. Four subtypes exist, characterized by different clinical severities. New ...therapeutic approaches have become available in the past few years, dramatically changing the natural history of all SMA subtypes, including substantial clinical improvement with the severe and advanced SMA type 1 variant. Trials have now demonstrated that phenotypic rescue is even more dramatic when pre-symptomatic patients are treated, and emerging real-world data are demonstrating the benefits of intervention even in the chronic phase of the condition. Here, we critically review how the field is rapidly evolving in response to the new therapies and questions that the new treatments have posed, including the effects of treatment at different ages and stages of disease, new phenotypes and long-term outcomes in patients who would not have survived without treatment, and decisions of who to treat and when. We also discuss how the outcomes associated with different timing of therapeutic intervention are contributing to our understanding of the biology and pathogenesis of SMA.
Summary Muscular dystrophies are a heterogeneous group of inherited disorders that share similar clinical features and dystrophic changes on muscle biopsy. An improved understanding of their ...molecular bases has led to more accurate definitions of the clinical features associated with known subtypes. Knowledge of disease-specific complications, implementation of anticipatory care, and medical advances have changed the standard of care, with an overall improvement in the clinical course, survival, and quality of life of affected people. A better understanding of the mechanisms underlying the molecular pathogenesis of several disorders and the availability of preclinical models are leading to several new experimental approaches, some of which are already in clinical trials. In this Seminar, we provide a comprehensive review that integrates clinical manifestations, molecular pathogenesis, diagnostic strategy, and therapeutic developments.
Risdiplam in Type 1 Spinal Muscular Atrophy Baranello, Giovanni; Darras, Basil T; Day, John W ...
The New England journal of medicine,
03/2021, Letnik:
384, Številka:
10
Journal Article, Web Resource
Recenzirano
Odprti dostop
The small molecule risdiplam increased the expression of SMN protein in blood in 21 infants with type 1 spinal muscular atrophy. Post hoc clinical features of sitting ability and respiratory status ...were reported.
Summary Spinal muscular atrophy is an autosomal recessive disorder characterised by degeneration of motor neurons in the spinal cord and is caused by mutations of the survival of motor neuron 1 gene ...SMN1 . The severity of spinal muscular atrophy is highly variable and no cure is available at present. Consensus has been reached on several aspects of care, the availability of which can have a substantial effect on prognosis, but controversies remain. The development of standards of care for children with the disorder and the identification of promising treatment strategies have changed the natural history of spinal muscular atrophy, and the prospects are good for further improvements in function, quality of life, and survival. A long-term benefit for patients will be the development of effective interventions (such as antisense oligonucleotides), some of which are in clinical trials. The need to be prepared for clinical trials has been the impetus for a remarkable and unprecedented cooperation between clinicians, scientists, industry, government, and volunteer organisations on an international scale.
Congenital muscular dystrophies are a highly heterogeneous group of conditions. In the last few years the identification of several new genes encoding for both glycosyltransferases and structural ...proteins has expanded the spectrum of the known forms. New classifications based on combined clinical, genetic and pathological data include all the recently discovered genes and allow an easier identification of the different forms and insight on pathogenetic mechanisms. The aim of this review is to discuss the most recent advances in this field, providing a conceptual framework to help the understanding of the responsible mechanisms and, when available, an update on the therapeutic perspectives.ANN NEUROL 2012;72:9–17
Spinal muscular atrophy D'Amico, Adele; Mercuri, Eugenio; Tiziano, Francesco D ...
Orphanet journal of rare diseases,
11/2011, Letnik:
6, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration of alpha motor neurons in the spinal cord, resulting in progressive proximal muscle ...weakness and paralysis. Estimated incidence is 1 in 6,000 to 1 in 10,000 live births and carrier frequency of 1/40-1/60. This disease is characterized by generalized muscle weakness and atrophy predominating in proximal limb muscles, and phenotype is classified into four grades of severity (SMA I, SMAII, SMAIII, SMA IV) based on age of onset and motor function achieved. This disease is caused by homozygous mutations of the survival motor neuron 1 (SMN1) gene, and the diagnostic test demonstrates in most patients the homozygous deletion of the SMN1 gene, generally showing the absence of SMN1 exon 7. The test achieves up to 95% sensitivity and nearly 100% specificity. Differential diagnosis should be considered with other neuromuscular disorders which are not associated with increased CK manifesting as infantile hypotonia or as limb girdle weakness starting later in life. Considering the high carrier frequency, carrier testing is requested by siblings of patients or of parents of SMA children and are aimed at gaining information that may help with reproductive planning. Individuals at risk should be tested first and, in case of testing positive, the partner should be then analyzed. It is recommended that in case of a request on carrier testing on siblings of an affected SMA infant, a detailed neurological examination should be done and consideration given doing the direct test to exclude SMA. Prenatal diagnosis should be offered to couples who have previously had a child affected with SMA (recurrence risk 25%). The role of follow-up coordination has to be managed by an expert in neuromuscular disorders and in SMA who is able to plan a multidisciplinary intervention that includes pulmonary, gastroenterology/nutrition, and orthopedic care. Prognosis depends on the phenotypic severity going from high mortality within the first year for SMA type 1 to no mortality for the chronic and later onset forms.
Highlights • An updated classification for SMA is presented. • The utility and limitations of animal models in SMA is discussed. • Biomarkers that are potentially useful in a clinical trial setting ...are reviewed. • A detailed review of clinical outcome measures for use in a clinical trial is tabulated.
There is an increasing number of papers reporting the real world use of Nusinersen in different cohorts of SMA patients. Our review suggests that Nusinersen provides a favorable benefit in motor ...function across a wide range of SMA type 2 and 3 patients over a 10-14 month observation period. Although a direct comparison with studies reporting data from untreated patients cannot be made, the longitudinal changes in the treated cohorts (consistently positive) are divergent from those observed in the untreated cohorts (consistently negative). The difference could be observed both in the global cohorts and in smaller groups subdivided according to age, type or functional status.
Objective
To continue evaluation of the long‐term efficacy and safety of eteplirsen, a phosphorodiamidate morpholino oligomer designed to skip DMD exon 51 in patients with Duchenne muscular dystrophy ...(DMD). Three‐year progression of eteplirsen‐treated patients was compared to matched historical controls (HC).
Methods
Ambulatory DMD patients who were ≥7 years old and amenable to exon 51 skipping were randomized to eteplirsen (30/50mg/kg) or placebo for 24 weeks. Thereafter, all received eteplirsen on an open‐label basis. The primary functional assessment in this study was the 6‐Minute Walk Test (6MWT). Respiratory muscle function was assessed by pulmonary function testing (PFT). Longitudinal natural history data were used for comparative analysis of 6MWT performance at baseline and months 12, 24, and 36. Patients were matched to the eteplirsen group based on age, corticosteroid use, and genotype.
Results
At 36 months, eteplirsen‐treated patients (n = 12) demonstrated a statistically significant advantage of 151m (p < 0.01) on 6MWT and experienced a lower incidence of loss of ambulation in comparison to matched HC (n = 13) amenable to exon 51 skipping. PFT results remained relatively stable in eteplirsen‐treated patients. Eteplirsen was well tolerated. Analysis of HC confirmed the previously observed change in disease trajectory at age 7 years, and more severe progression was observed in patients with mutations amenable to exon skipping than in those not amenable. The subset of patients amenable to exon 51 skipping showed a more severe disease course than those amenable to any exon skipping.
Interpretation
Over 3 years of follow‐up, eteplirsen‐treated patients showed a slower rate of decline in ambulation assessed by 6MWT compared to untreated matched HC. Ann Neurol 2016;79:257–271
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