Genetic therapies for inherited neuromuscular disorders

Inherited neuromuscular disorders encompass a broad group of genetic conditions, and the discovery of these underlying genes has expanded greatly in the past three decades. The discovery of such genes has enabled more precise diagnosis of these disorders and the development of specific therapeutic approaches that target the genetic basis and pathophysiological pathways. Such translational research has led to the approval of two genetic therapies by the US Food and Drug Administration: eteplirsen for Duchenne muscular dystrophy and nusinersen for spinal muscular atrophy, which are both antisense oligonucleotides that modify pre-mRNA splicing. In this Review we aim to discuss new genetic therapies and ongoing clinical trials for Duchenne muscular dystrophy, spinal muscular atrophy, and other less common childhood neuromuscular disorders

Brain, cognition, and language development in spinal muscular atrophy type 1: a scoping review

Aim: To summarize the current knowledge on brain involvement in spinal muscular atrophy (SMA) type 1, focusing on brain pathology, cognition, and speech/language development. / Method: A scoping review was performed using the methodology of the Joanna Briggs Institute. Five databases and references from relevant articles were searched up to December 2019. Articles were screened on the basis of titles and abstracts. Full‐text papers published in peer‐reviewed journals in English were selected. / Results: Nineteen articles met eligibility criteria. Eight case series/reports on brain pathology showed abnormalities in few SMA type 0/1 cases, supported by findings in three post‐mortem examinations in mice. Four studies (three case–control, one cross‐sectional) on cognition reported contradictory results, with impaired cognitive performances in recent, small groups with SMA type 1. Four studies (three cross‐sectional, one observational) on speech/language showed that untreated SMA type 1 patients rarely achieve functional and intelligible speech, with data limited to parent reports/non‐formal evaluations. / Interpretation: Brain involvement is an under‐investigated aspect of SMA type 1, requiring further exploration in longitudinal studies. A deeper knowledge of brain involvement would improve the interpretation of clinical phenotypes and the personalization of rehabilitation programmes supporting patients' autonomies and quality of life. Additionally, it may help to define further outcome measures testing the efficacy of current and new developing drugs on this domain

Screening of Neonatal UK Dried Blood Spots Using a Duplex SMN1 Screening Assay

Spinal muscular atrophy (SMA) is an autosomal inherited neuromuscular genetic disease caused, in 95% of cases, by homozygous deletions involving the SMN1 gene exon 7. It remains the leading cause of death in children under 2 years of age. New treatments have been developed and adopted for use in many countries, including the UK. Success of these treatments depends on early diagnosis and intervention in newborn babies, and many countries have implemented a newborn screening (NBS) or pilot NBS program to detect SMN1 exon 7 deletions on dried blood spots. In the UK, there is no current NBS program for SMA, and no pilot studies have commenced. For consideration of adoption of NBS for a new condition, numerous criteria must be satisfied, including critical assessment of a working methodology. This study uses a commercially available real-time PCR assay to simultaneously detect two different DNA segments (SMN1 exon 7 and control gene RPP30) using DNA extracted from a dried blood spot. This study was carried out in a routine clinical laboratory to determine the specificity, sensitivity, and feasibility of SMA screening in a UK NBS lab setting. Just under 5000 normal DBSs were used alongside 43 known SMA positive DBSs. Study results demonstrate that NBS for SMA using real-time PCR is feasible within the current UK NBS Laboratory infrastructure using the proposed algorithm

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Traumatic brain injury: A forensic approach: A literature review

Traumatic brain injury (TBI) is the principal cause of invalidity and death in the population under 45 years of age worldwide. This mini-review aims to systematize the forensic approach in neuropathological studies, highlighting the proper elements to be noted during external, radiological, autoptical, and histological examinations with particular attention paid to immunohistochemistry and molecular biology. In the light of the results of this mini-review, an accurate forensic approach can be considered mandatory in the examination of suspected TBI with medico-legal importance, in order to gather all the possible evidence to corroborate the diagnosis of a lesion that may have caused, or contributed to, death. From this point of view, only the use of an evidence-based protocol can reach a suitable diagnosis, especially in those cases in which there are other neuropathological conditions (ischemia, neurodegeneration, neuro-inflammation, dementia) that may have played a role in death. This is even more relevant when corpses, in an advanced state of decomposition, are studied, where the radiological, macroscopic and histological analyses fail to give meaningful answers. In these cases, immune-histochemical and molecular biology diagnostics are of fundamental importance and a forensic neuropathologist has to know them. Particularly, MiRNAs are promising biomarkers for TBI both for brain damage identification and for medico-legal aspects, even if further investigations are required to validate the first experimental studies. In the same way, the genetic substrate should be examined during any forensic examination, considering its importance in the outcome of TBI

Longitudinal changes in respiratory and upper limb function in a pediatric type III spinal muscular atrophy cohort after loss of ambulation

Introduction/Aims: Spinal muscular atrophy (SMA) type III is a relatively mild form of SMA. Few studies have investigated the changes in both respiratory and upper limb function within this population after loss of ambulation. The aim of this study was to assess change in percentage of predicted forced vital capacity (FVC% predicted) and change in the Revised Upper Limb Module (RULM) score in these patients throughout a 24-month period after loss of ambulation. Effect of scoliosis and its surgical correction, disease duration since loss of ambulation, weight, and height were also investigated. / Methods: Retrospective analyses were performed on 24 nonambulant SMA III patients from data collected at two centers in the United Kingdom. / Results: The FVC% predicted score showed a significant progressive deterioration of 17% over the 24-month period. Respiratory deterioration correlated significantly with age, weight, disease duration since loss of ambulation, and spinal correctional surgery. Longitudinal RULM data were available for 16 patients; a significant deterioration was observed with a mean decrease in score of 3 over 24 months. Age correlated negatively with RULM score, as did height and time since loss of ambulation. A significant positive correlation between FVC% predicted and RULM was demonstrated. / Discussion: This study highlights how SMA type III patients have progressive deterioration of respiratory and upper limb function after loss of ambulation. Combining data from these assessments could provide insight into clinical progression, inform clinical trials, and provide assistance in managing disease progression expectations for patients

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Novel mutations expand the clinical spectrum of DYNC1H1-associated spinal muscular atrophy

OBJECTIVE To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. METHODS Patients with a phenotype suggestive of a motor, non-length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1. RESULTS We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anterior-medial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features. CONCLUSION Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions

Age and baseline values predict 12 and 24-month functional changes in type 2 SMA

The aim of this retrospective study was to establish the range of functional changes at 12 and 24-month in 267 type 2 Spinal Muscular Atrophy (SMA) patients with multiple assessments. We included 652 Hammersmith Functional Motor Scale Expanded (HFMSE) assessments at 12 month- and 305 at 24 month- intervals. The cohort was subdivided by functional level, Survival of Motor Neuron copy number and age. Stable scores (± 2 points) were found in 68% at 12 months and in 55% at 24 months. A decrease ≥2 points was found in 21% at 12 months and in 35% at 24 months. An increase ≥2 points was found in 11% at 12 months and 9.5% at 24 months. The risk of losing ≥2 points increased with age and HFMSE score at baseline both at 12 and 24-month. For each additional HFMSE point at baseline, the relative risk of a >2 point decline at 12 months increases by 5% before age 5 years (p = 0.023), by 8% between 5 and 13 (p<0.001) and by 26% after 13 years (p = 0.003). The combination of age and HFMSE scores at baseline increased the ability to predict progression in type 2 SMA

Long-term follow-up of patients with type 2 and non-ambulant type 3 spinal muscular atrophy (SMA) treated with olesoxime in the OLEOS trial

In a previous Phase 2 study, olesoxime had a favorable safety profile. Although the primary endpoint was not met, analyses suggested that olesoxime might help in the maintenance of motor function in patients with Types 2/3 SMA. This open-label extension study (OLEOS) further characterizes the safety, tolerability and efficacy of olesoxime over longer therapy durations. In OLEOS, no new safety risks were identified. Compared to matched natural history data, patients treated with olesoxime demonstrated small, non-significant changes in motor function over 52 weeks. Motor function scores were stable for 52 weeks but declined over the remainder of the study. The greatest decline in motor function was seen in patients ≤15 years old, and those with Type 2 SMA had faster motor function decline versus those with Type 3 SMA. Previous treatment with olesoxime in the Phase 2 study was not protective of motor function in OLEOS. Respiratory outcomes were stable in patients with Type 3 SMA >15 years old but declined in patients with Type 2 SMA and in patients with Type 3 SMA ≤15 years old. Overall, with no stabilization of functional measures observed over 130 weeks, OLEOS did not support significant benefit of olesoxime in patients with SMA