Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this ...STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US.
STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes vg/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed).
From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p<0·0001). 31 (97%, 95% CI 91–100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8–44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 67% of 33), upper respiratory infection (11 33%), and increased alanine aminotransferase (nine 27%). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study.
STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline.
Novartis Gene Therapies.
•A multi-objective multi-parametric optimization study of a Brayton multi-step thermosolar plant is presented.•Each subsystem is modelled (solar collector, gas turbine) including the main ...irreversibility sources in this kind of plants.•The Pareto Fronts are obtained by using a genetic algorithm and also from exact calculations.•Two objective functions are simultaneously optimized: the overall plant efficiency and the power output.
A multi-objective and multi-parametric optimization analysis is presented for a recuperative multi-step solar-driven Brayton thermosolar plant. The analysis is done over a thermodynamic analytical model that incorporates all the losses observed in real plants, from the heat engine itself and from the solar subsystem. The model allows to consider several compression–expansion stages. The overall system efficiency and the power output were taken as objective functions. The Pareto Front of the system is obtained by considering possible fluctuations in all the involved parameters. This study allows to discern the significant design variables. Then, the exact Pareto Fronts were calculated, by taking as variables only those parameters, and building an appropriate grid. Several configurations (ideal and realistic, with single stage or multi-step compression–expansion processes) were analyzed and multi-criteria decision making procedures applied in order to obtain physical insights from the results. It was shown the importance of electing an appropriate conducting gas, and adequate values of the global pressure and temperature ratios. This study could constitute an interesting guideline for the design of future generations of plants of this type, that are now at the research and developing stage.
Myosin heavy chain 7 (MYH7)-related myopathies are emerging as an important group of muscle diseases of childhood and adulthood, with variable clinical and histopathological expression depending on ...the type and location of the mutation. Mutations in the head and neck domains are a well-established cause of hypertrophic cardiomyopathy whereas mutation in the distal regions have been associated with a range of skeletal myopathies with or without cardiac involvement, including Laing distal myopathy and Myosin storage myopathy. Recently the spectrum of clinical phenotypes associated with mutations in MYH7 has increased, blurring this scheme and adding further phenotypes to the list. A broader disease spectrum could lead to misdiagnosis of different congenital myopathies, neurogenic atrophy and other neuromuscular conditions.
As a result of a multicenter Italian study we collected clinical, histopathological and imaging data from a population of 21 cases from 15 families, carrying reported or novel mutations in MYH7. Patients displayed a variable phenotype including atypical pictures, as dropped head and bent spine, which cannot be classified in previously described groups. Half of the patients showed congenital or early infantile weakness with predominant distal weakness. Conversely, patients with later onset present prevalent proximal weakness. Seven patients were also affected by cardiomyopathy mostly in the form of non-compacted left ventricle. Muscle biopsy was consistent with minicores myopathy in numerous cases. Muscle MRI was meaningful in delineating a shared pattern of selective involvement of tibialis anterior muscles, with relative sparing of quadriceps.
This work adds to the genotype-phenotype correlation of MYH7-relatedmyopathies confirming the complexity of the disorder.
Background and purpose
Following the commercial availability of nusinersen, there have been a number of new referrals of adults with spinal muscular atrophy (SMA) not regularly followed in ...tertiary‐care centers or enrolled in any disease registry.
Methods
We compared demographics and disease characteristics, including assessment of motor and respiratory function, in regularly followed patients and newcomers subdivided according to the SMA type.
Results
The cohort included 166 adult patients (mean age: 37.09 years): one type I, 65 type II, 99 type III, and one type IV. Of these 166, there were 67 newcomers. There was no significant difference between newcomers and regularly followed patients in relation to age and disease duration. The Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module scores were higher in the regularly followed patients compared to newcomers in the whole cohort and in both SMA II and II. A difference was also found on ventilatory status (p = 0.013) and Cobb’s angle >50° (p = 0.039) between the two subgroups. No difference was found in scoliosis surgery prevalence (p > 0.05).
Conclusions
Our results showed differences between the two subgroups, even if less marked in the type III patients. In the type II patients, there was a higher proportion of newcomers who were in the severe end of the spectrum. Of the newcomers, only approximately a third initiated treatment, as opposed to the 51% in the regularly followed patients. The identification of patients who were not part of the registries will help to redefine the overall prevalence of SMA and the occurrence of different phenotypes.
Percentages of regularly followed patients and newcomers.
Complex I (CI) is the largest component of the mitochondrial respiratory chain (MRC) and it is made up of 7 mitochondrial DNA (mtDNA)-encoded and at least 38 nuclear DNA-encoded subunits. Isolated CI ...deficiency is the most common single enzyme deficiency in the heterogeneous group of MRC disorders and it is a relatively common etiology of Leigh-like syndrome (LS).
With a few exceptions, descriptions of the clinical spectrum of specific mutations in CI are scarce. We here present three unrelated Italian children who harbored the homoplasmic m.10197G>A mutation in MT-ND3 associated with reduced enzyme activity of CI in muscle. Compared with the spectrum of phenotypes seen in 13 previously described families with the same mutation, these children showed some novel clinical features. Two of the boys presented with subacute onset of dystonia, which showed a remitting-relapsing clinical course in one of them. The third boy presented acute symptoms consisting of speech impairment, progressive left-sided hemiparesis, and also vertebral and arterial malformations. In all the children, molecular studies identified a similar mutation load in tissues, and neuroimaging findings were consistent with the features seen in LS. Functional investigations in cultured skin fibroblasts suggested low ATP production in homoplasmic cells. Our results confirm that the m.10197G>A mutation is relevant to these patients' clinical and biochemical phenotypes, which thus expand the array of phenotypes associated with this variant.
•We present three new children harboring the m. 10197G>A mtDNA mutation.•Atypical features were associated with similar mutant load and impaired OXPHOS.•Remitting-relapsing dystonia in one case correlates with brain MRI changes.
Congenital myopathies (CMs) caused by mutation in cofilin‐2 gene (CFL2) show phenotypic heterogeneity ranging from early‐onset and rapid progressive forms to milder myopathy. Muscle histology is also ...heterogeneous showing rods and/or myofibrillar changes. Here, we report on three new cases, from two unrelated families, of severe CM related to novel homozygous or compound heterozygous loss‐of‐function mutations in CFL2. Peculiar histopathological changes showed nemaline bodies and thin filaments accumulations together to myofibrillar changes, which were evocative of the muscle findings observed in Cfl2−/− knockout mouse model.
To evaluate if duration of distal compound muscle action potential duration (DCMAPD) could represent a sensitive parameter in clinical practice to add to established electrophysiological diagnostic ...criteria in paediatric chronic inflammatory demyelinating polyneuropathy (CIDP) and its rule in patient’s follow-up. We retrospectively reviewed records of 8 children affected by CIDP (6/8 possible CIDP, 2/8 confirmed CIDP) according to established diagnostic criteria of the 88th ENMC International Workshop (2000), before consideration of DCMAPD prolongation. Patients were studied with EMG equipment with low-cut filter settings ⩽10 Hz. Using adult cut-offs to define DCMAPD prolongation it was present in 8/8 patients for peroneal nerve, in 6/8 for median nerve and in all five patients in which we recorded tibial nerve. During follow-up time clinical worsening corresponded always to a greater DCMAPD prolongation compared with other electrophysiological parameters (amplitude, distal latency and nerve conduction velocity). Appropriate evaluation of DCMAPD appears an essential criterion to consider in assessing suspected CIDP and to support clinical worsening in follow-up, which may be helpful in limiting extensiveness and duration of electrophysiological testing, thereby reducing patient discomfort, especially in children.
Combining great performances with high standards of safety and efficiency is the challenge for most aircraft manufacturers. Aircraft are subjected to extraordinary loads, repeated for millions of ...cycles also in extreme environmental conditions, hence every component must be designed and manufactured to maximize its fatigue resistance.
Friction Stir Welding of aluminium alloys and surface finishing process as might be a good solution to reach this goal.
The high performances reached in this field with the use of this technique could be further increased reducing the welded surface irregularity, which might promote the development of a dangerous fatigue failure mechanism.
In this work, the effect of the welded surface finishing treatment on the fatigue behavior of AA8090 FSW butt joints was assessed. The results obtained from the dynamic tests highlighted the higher fatigue resistance of finished specimens, with respect to the as-welded joints.
Introduction
This study aims to report on serial magnetic resonance imaging (MRI) studies and clinical features in a cohort of children with chronic inflammatory demyelinating polyneuropathy (CIDP).
...Methods
Clinical, neuroradiological, and statistical investigations performed on nine children with CIDP were retrospectively reviewed. Pathological nerve root enhancement was categorized according to severity, extension, and morphology. A MRI score was thus obtained, and correlations with the clinical picture and disease course were explored.
Results
Intrathecal nerve root enhancement (NRE) of varying degrees was seen in a high percentage of patients. There was no significant correlation between the total MRI score at the first MRI study and either severity or course of the disease. However, we found a significant difference (
p
= 0.002) in NRE of patients with improving CIDP with respect to those with stable or progressing disease at the time of follow-up MRI.
Conclusion
Contrast-enhanced MRI plays a pivotal role in children with CIDP, both for the initial diagnosis as well as a biomarker of clinical evolution, and should be performed in all children with suspected CIDP both at initial presentation and during follow-up. Further multicenter studies on larger cohorts are awaited to determine the ideal timing for follow-up MRI.
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