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

The Impact of the COVID-19 Pandemic on the Practice of Forensic Medicine: An Overview

During the COVID-19 pandemic, forensic sciences, on the one hand, contributed to gaining knowledge about different aspects of the pandemic, while on the other hand, forensic professionals were called on to quickly adapt their activities to respond adequately to the changes imposed by the pandemic. This review aims to clarify the state of the art in forensic medicine at the time of COVID-19, discussing the following: the influence of external factors on forensic activities, the impact of autopsy practice on COVID-19 and vice-versa, the persistence of SARS-CoV-2 RNA in post-mortem samples, forensic personnel activities during the SARS-CoV-2 pandemic, the global vaccination program and forensic sciences, forensic undergraduate education during and after the imposed COVID-19 lockdown, and the medico-legal implications in medical malpractice claims during the COVID-19 pandemic. The COVID-19 pandemic has greatly influenced different aspects of human life, and, accordingly, the practical activities of forensic sciences that are defined as multidisciplinary, involving different expertise. Indeed, the activities are very different, including crime scene investigation (CSI), external examination, autopsy, and genetic and toxicological examinations of tissues and/or biological fluids. At the same time, forensic professionals may have direct contact with subjects in life, such as in the case of abuse victims (in some cases involving children), collecting biological samples from suspects, or visiting subjects in the case of physical examinations. In this scenario, forensic professionals are called on to implement methods to prevent the SARS-CoV-2 infection risk, wearing adequate PPE, and working in environments with a reduced risk of infection. Consequently, in the pandemic era, the costs involved for forensic sciences were substantially increased

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

The role of anxiety symptoms in school performance in a community sample of children and adolescents

Anxiety symptoms are relatively common among children and adolescents and can interfere with functioning. The prevalence of anxiety and the relationship between anxiety and school performance were examined among elementary, middle, and high school students

Chemicals of Emerging Arctic Concern in north-western Spitsbergen snow: Distribution and sources

Personal care products contain chemicals that are considered of emerging concern in the Arctic. In this study, a selected group of personal care products was investigated in the snowpack on north-western Spitsbergen. We report a preliminary study on the spatial and seasonal distribution of 13 ingredients commonly found in personal care products, including fragrance materials, UV filters, BHT and BPA. Possible sources and deposition processes are discussed. Experimental analyses utilizing GC–MS/MS, were complemented with outputs from the HYSPLIT transport and dispersion model. The results reveal the presence of all selected compounds in the snow, both in proximity to and distant from the research village of Ny-Ålesund. For some of these chemicals this is the first time their presence is reported in snow in Svalbard. These chemicals show different partitioning behaviours between the particulate and dissolved phases, affecting their transport and deposition processes. Additionally, concentrations of certain compounds vary across different altitudes. It is observed the relevance of long-range atmospheric transport during winter at most sites, and, regardless of the proximity to human settlements, snow concentrations can be influenced by long-distance sources. This study highlights the need for detailed information on CEACs' physical-chemical properties, considering their potential impact on fresh and marine waters during the snowmelt under climate change

Development of the forward parachute reaction and the age of walking in near term infants: a longitudinal observational study

<p>Abstract</p> <p>Background</p> <p>Near term infants are a main part of preterms. They are at higher risk for mortality and morbidity than term infants and could show a quite different development of tone and reflexes from them. The aim of the present study was to describe longitudinally, in a large sample of healthy near term infants, the development of the forward parachute reaction (FPR) and its correlation with the age of acquisition of independent walking.</p> <p>Methods</p> <p>The assessment of FPR (as absent, incomplete or complete) was performed at 3, 6, 9, 12 months of corrected age in 484 infants, with a gestational age between 35.0 and 36.9 weeks. The age of acquisition of independent walking was monitored until its appearance. A correlation analysis was done between the age of walking and the acquisition of a complete or incomplete FPR, using the Spearman Rank correlation. The Mann-Withney U test was used to identify significant gestational age differences for the age of FPR appearance.</p> <p>Results</p> <p>Most of infants had a two-step development pattern. In fact, they showed at first an incomplete and then a complete FPR, which was observed more frequently at 9 months. An incomplete FPR only, without a successive maturation to a complete FPR, was present in the 21% of the whole sample. Infants with a complete FPR walked at a median age of 13 months, whereas those with an incomplete FPR only walked at a median age of 14 months.</p> <p>Conclusion</p> <p>We identified two groups within our sample of near term infants. The first group showed a progressive maturation of FPR, whereas the second one was characterised by the inability to get a complete pattern, within the one year observation's period. Furthermore, we observed a trend toward a delayed acquisition of independent walking in the latter group of infants.</p

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

Evolution of bulbar function in spinal muscular atrophy type 1 treated with nusinersen

Aim: To assess the evolution of bulbar function in nusinersen-treated spinal muscular atrophy type 1 (SMA1). Method: This single-centre retrospective study identified 24 patients (14 females and 10 males) with SMA1, treated with nusinersen between 2017 and 2020. We adapted and validated the Paediatric Functional Oral Intake Scale (p-FOIS), which is an outcome measure to assess bulbar function. Analysis considered SMA1 subtype, nutritional support, and Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and p-FOIS scores at initiation of nusinersen treatment (baseline) and at 6, 12, and 24 months after initiation. Results: The median age at baseline was 11 months (range 1 month–7 years 6 months). Median age at initiation of tube feeding was 8 months (range 0–2 years 2 months). Fourteen patients were tube fed at baseline. The median p-FOIS score was 3 at baseline and 2 at 12 and 24 months. Four patients, all with type 1c SMA, remained orally fed at 24 months. Median CHOP INTEND scores increased from 32 at baseline to 42 at 12 and 24 months. Interpretation: Impaired bulbar function persisted as a significant complication in most nusinersen-treated patients with SMA1, in contrast to the improvement in motor abilities demonstrated in the majority. p-FOIS allows for tracking of bulbar function progression and treatment response. Larger, prospective studies investigating the longer-term impacts of nusinersen on bulbar function are warranted