Autosomal recessive -related disorder: comprehensive analysis of phenotypic variability and genetic mutations.

A newly identified subtype of hereditary axonal motor neuropathy, characterized by early proximal limb involvement, has been discovered in a cohort of 34 individuals with biallelic variants in von Willebrand factor A domain-containing 1 (). This study further delineates the disease characteristics in a cohort of 20 individuals diagnosed through genome or exome sequencing, incorporating neurophysiological, laboratory and imaging data, along with data from previously reported cases across three different studies. Newly reported clinical features include hypermobility/hyperlaxity, axial weakness, dysmorphic signs, asymmetric presentation, dystonic features and, notably, upper motor neuron signs.

Noncoding variants are a rare cause of recessive developmental disorders in trans with coding variants.

Purpose: Identifying pathogenic noncoding variants is challenging. A single protein-altering variant is often identified in a recessive gene in individuals with developmental disorders (DD), but the prevalence of pathogenic noncoding "second hits" in trans with these is unknown.

Methods: In 4073 genetically undiagnosed rare-disease trio probands from the 100,000 Genomes project, we identified rare heterozygous protein-altering variants in recessive DD-associated genes.

Therapeutic Role of Nusinersen on Respiratory Progression in Pediatric Patients With Spinal Muscular Atrophy Type 2 and Nonambulant Type 3.

Background And Objectives: Nusinersen has shown significant functional motor benefit in the milder types of spinal muscular atrophy (SMA). Less is known on the respiratory outcomes in patients with nusinersen-treated SMA. The aim of this study was to describe changes in respiratory function in pediatric patients with SMA type 2 and 3 on regular treatment with nusinersen within the iSMAc international cohort and to compare their trajectory with the natural history (NH) data published by the consortium in 2020.

Risdiplam in Spinal Muscular Atrophy: Safety Profile and Use Through The Early Access to Medicine Scheme for the Paediatric Cohort in Great Britain.

Background: Spinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by mutations in Survival motor neuron 1 (SMN1) gene, leading to reduction in survival motor neuron protein (SMN), key for motor neuron survival and function in the brainstem and spinal cord. Risdiplam is an orally administered SMN2-splicing modifier which increases production of functional SMN protein. Risdiplam was offered in the UK under early access to medicines scheme (EAMS) to SMA type 1 and 2 patients aged 2 months and older, not suitable for authorised treatments from September 2020 to December 2021.

Development of respiratory care guidelines for Duchenne muscular dystrophy in the UK: key recommendations for clinical practice.

Unlabelled: Significant inconsistencies in respiratory care provision for Duchenne muscular dystrophy (DMD) are reported across different specialist neuromuscular centres in the UK. The absence of robust clinical evidence and expert consensus is a barrier to the implementation of care recommendations in public healthcare systems as is the need to increase awareness of key aspects of care for those living with DMD. Here, we provide evidenced-based and/or consensus-based best practice for the respiratory care of children and adults living with DMD in the UK, both as part of routine care and in an emergency.

Safety and efficacy of tamoxifen in boys with Duchenne muscular dystrophy (TAMDMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

Background: Drug repurposing could provide novel treatment options for Duchenne muscular dystrophy. Because tamoxifen-an oestrogen receptor regulator-reduced signs of muscular pathology in a Duchenne muscular dystrophy mouse model, we aimed to assess the safety and efficacy of tamoxifen in humans as an adjunct to corticosteroid therapy over a period of 48 weeks.

Methods: We did a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 12 study centres in seven European countries.

Assessment of face validity of a disease model of nonsense mutation Duchenne muscular dystrophy: a multi-national Delphi panel study.

Objective: The objective of this study was to assess the face validity of a disease model evaluating the cost-effectiveness of ataluren for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD).

Methods: This was a Delphi panel study comprising of physicians with first-hand experience of ataluren for the treatment of nmDMD. Consensus was sought for previously unvalidated model data, including patient health status and quality of life measured using the Health Utility Index (HUI), mortality, informal caregiving, and the expected benefit of early ataluren treatment across four states: (1) ambulatory, (2) non-ambulatory, not yet requiring ventilation support, (3) non-ambulatory, night-time ventilation support, and (4) non-ambulatory, full-time ventilation support.

A recent surge of fulminant and early onset subacute sclerosing panencephalitis (SSPE) in the United Kingdom: An emergence in a time of measles.

Background: Subacute Sclerosing Panencephalitis (SSPE) is a fatal progressive neurological disorder following measles infection.

Methods: Cases were collated from Paediatric Neurology centres in the UK over 24 months from 2017 to 2019 and represent all cases referred to the National Viral Reference Department (VRD). Diagnosis was established with detection of a raised measles index, demonstrating intrathecal measles antibody production.

Prediagnosis pathway benchmarking audit in patients with Duchenne muscular dystrophy.

Objective: To describe age and time at key stages in the Duchenne muscular dystrophy (DMD) prediagnosis pathway at selected centres to identify opportunities for service improvement.

Design: A multicentre retrospective national audit.

Setting: Nine tertiary neuromuscular centres across the UK and Ireland.

Homozygous intronic variants in TPM2 cause recessively inherited Escobar variant of multiple pterygium syndrome and congenital myopathy.

Pathogenic variants in TPM2 have been associated with a variable clinical spectrum, including congenital myopathies and distal arthrogryposis, all but one with dominant inheritance. We report the second case of recessively inherited TPM2-related Escobar variant of multiple pterygium syndrome and congenital myopathy in a patient from a consanguineous family. Ultra-structural examination of the biopsy revealed few cores/mini-cores and sparse nemaline rods.

Respiratory Trajectories in Type 2 and 3 Spinal Muscular Atrophy in the iSMAC Cohort Study.

Objective: To describe the respiratory trajectories and their correlation with motor function in an international pediatric cohort of patients with type 2 and nonambulant type 3 spinal muscular atrophy (SMA).

Methods: This was an 8-year retrospective observational study of patients in the International SMA Consortium (iSMAc) natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC percent predicted (FVC%P), and noninvasive ventilation (NIV) requirement.

Outpatient appointment non-attendance and unplanned health care for children and young people with neurological conditions: a retrospective cohort study.

Aim: To test the hypothesis that children and young people with neurological conditions who missed outpatient appointments have more emergency inpatient admissions and Accident and Emergency centre (A&E) visits than those who missed none.

Method: Retrospective cohort of individuals aged up to 19 years with neurological conditions, identified from routine hospital data in England, UK from April 1st, 2003 to March 31st, 2015 using an International Statistical Classification of Diseases and Related Health Problems, coding framework. Counts of emergency inpatient admissions and A&E visits per person per year were modelled (random intercept negative binomial regression) with outpatient attendance the independent variable of interest.

A checklist for clinical trials in rare disease: obstacles and anticipatory actions-lessons learned from the FOR-DMD trial.

Background: Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011.

The impact of neurological disorders on hospital admissions for children and young people: a routine health data study.

Introduction: Neurological conditions are a major and increasing cause of hospitalisation among children and young people, but little is known about the impact of neurological conditions on hospital services in England, nor the factors that influence length of stay and bed days per year.

Objectives: To quantify the hospital usage in children and young people related to neurological conditions, trends over time and variation by ethnicity and deprivation status.

Methods: An ICD10 coding framework identified a cohort of individuals aged 0-19 years with neurological conditions from linked routinely collected healthcare data from England (The Hospital Episode Statistics Admitted Patient Care dataset), from 1 April 2003 to 31 March 2015.

Paediatric spinal cord infarction-a review of the literature and two case reports.

Ischemic spinal cord infarction is rare in the paediatric population, and when it does occur, it is usually associated with traumatic injury. Other potential causes include congenital cardiovascular malformations, cerebellar herniation, thromboembolic disease and infection. Magnetic resonance imaging (MRI) findings can be subtle in the early evaluation of such patients.

The clinical, biochemical and genetic features associated with -related mitochondrial disease.

Background: Mutations in the (Required for Meiotic Nuclear Division protein 1) gene have recently been linked to infantile onset mitochondrial disease characterised by multiple mitochondrial respiratory chain defects.

Methods: We summarised the clinical, biochemical and molecular genetic investigation of an international cohort of affected individuals with mutations. In addition, we reviewed all the previously published cases to determine the genotype-phenotype correlates and performed survival analysis to identify prognostic factors.