The GENESIS database and tools: A decade of discovery in Mendelian genomics.

In the past decade, human genetics research saw an acceleration of disease gene discovery and further dissection of the genetic architectures of many disorders. Much of this progress was enabled via data aggregation projects, collaborative data sharing among researchers, and the adoption of sophisticated and standardized bioinformatics analyses pipelines. In 2012, we launched the GENESIS platform, formerly known as GEM.app, with the aims to 1) empower clinical and basic researchers without bioinformatics expertise to analyze and explore genome level data and 2) facilitate the detection of novel pathogenic variation and novel disease genes by leveraging data aggregation and genetic matchmaking. The GENESIS database has grown to over 20,000 datasets from rare disease patients, which were provided by multiple academic research consortia and many individual investigators. Some of the largest global collections of genome-level data are available for Charcot-Marie-Tooth disease, hereditary spastic paraplegia, and cerebellar ataxia. A number of rare disease consortia and networks are archiving their data in this database. Over the past decade, more than 1500 scientists have registered and used this resource and published over 200 papers on gene and variant identifications, which garnered >6000 citations. GENESIS has supported >100 gene discoveries and contributed to approximately half of all gene identifications in the fields of inherited peripheral neuropathies and spastic paraplegia in this time frame. Many diagnostic odysseys of rare disease patients have been resolved. The concept of genomes-to-therapy has borne out for a number of such discoveries that let to rapid clinical trials and expedited natural history studies. This marks GENESIS as one of the most impactful data aggregation initiatives in rare monogenic diseases.

The cross-sectional area of the median nerve: An independent prognostic biomarker in amyotrophic lateral sclerosis.

INTRODUCTION: Ultrasound changes in the cross-sectional area of the median nerve (CSAmn) could be of interest as biomarkers in patients with amyotrophic lateral sclerosis (ALS). METHODS: Eighty-four ALS patients (51 men [60.7%]; mean 62.0 [SD 11.46] years old) and forty-six controls (27 men [58.7%]; mean 59.9 [SD 8.08] years old) of two different cohorts were recruited between September 2013 and February 2018. The CSAmn was measured bilaterally in each cohort, by two different examiners with two different ultrasound machines (one in each cohort). Its association with clinical variables (disease duration, muscle strength, disability, progression rate and tracheostomy-free survival) was assessed. RESULTS: The CSAmn was smaller in patients than in controls, and the study cohort did not influence its values. A mild correlation between the strength of the wrist flexor and the CSAmn was found. In the multivariable analysis, the probability of this association being true was 90%. In the cox regression, both a faster progression rate and a larger CSAmn independently predicted poor survival (HR=4.29, [Cr.I95%: 2.71-6.80], p<0.001; and HR=1.14, [Cr.I95%: 1.03-1.25], p=0.01), after adjusting by age, body mass index, bulbar onset, and diagnostic delay. CONCLUSIONS: The CSAmn is an easy to assess biomarker that seems reliable and reproducible. Our data also suggest that it could act as a progression and prognostic biomarker in ALS patients. Longitudinal studies with repeated measures are warranted to confirm its usefulness in the clinical practice.

Cascade testing in mitochondrial diseases: a cross-sectional retrospective study.

BACKGROUND: Cascade testing can offer improved surveillance and timely introduction of clinical management for the at-risk biological relatives. Data on cascade testing and costs in mitochondrial diseases are lacking. To address this gap, we performed a cross-sectional retrospective study to provide a framework for cascade testing in mitochondrial diseases, to estimate the eligibility versus real-time uptake of cascade testing and to evaluate the cost of the genetic diagnosis of index cases and the cost of predictive cascade testing. METHODS: Data was collected through retrospective chart review. The variant inheritance pattern guided the identification of eligible first-degree relatives: (i) Males with mitochondrial DNA (mtDNA) single nucleotide variants (SNVs) - siblings and mothers. (ii) Females with mtDNA SNVs - siblings, mothers and offspring. (iii) Autosomal Dominant (AD) nuclear DNA (nDNA) variants - siblings, offspring and both parents. (iv) Autosomal Recessive (AR) nDNA variants - siblings. RESULTS: We recruited 99 participants from the Adult Mitochondrial Disease Clinic in Sydney. The uptake of cascade testing was 55.2% in the mtDNA group, 55.8% in the AD nDNA group and 0% in AR nDNA group. Of the relatives in mtDNA group who underwent cascade testing, 65.4% were symptomatic, 20.5% were oligosymptomatic and 14.1% were asymptomatic. The mean cost of cascade testing for eligible first-degree relatives (mtDNA group: $694.7; AD nDNA group: $899.1) was lower than the corresponding index case (mtDNA group: $4578.4; AD nDNA group: $5715.1) (p < 0.001). CONCLUSION: The demand for cascade testing in mitochondrial diseases varies according to the genotype and inheritance pattern. The real-time uptake of cascade testing can be influenced by multiple factors. Early diagnosis of at-risk biological relatives of index cases through cascade testing, confirms the diagnosis in those who are symptomatic and facilitates implementation of surveillance strategies and clinical care at an early stage of the disease.

Feasibility and Reproducibility of Isokinetic Dynamometry in Children with Neuromuscular Diseases.

Background/Objectives: High-precision measurement tools are needed to measure relevant changes in strength and power in children with neuromuscular diseases. The aim of this study was to determine the feasibility (i), reproducibility (ii), and validity (iii) of isokinetic dynamometry in this population. Methods: Isometric and isokinetic knee and elbow flexion and extension were measured twice on the same day. Feasibility was based on completion rate and acceptability. Acceptability was measured with a 100 mm visual analog scale. We measured reproducibility as the intraclass correlation coefficient (ICC-agreement), standard error of measurement (SEM), and smallest detectable change (SDC). We investigated relationships between isometric strength and isokinetic power with Pearson's correlation coefficient. ROC curves were used to determine the cutoff of isometric strength to conduct isokinetic measurements. Results: Fifty children with NMDs participated with completion rates of 78-90% for isometric and 39-75% for isokinetic measurements. Acceptability was high (mean (SD) = 73 (19) mm). The ICCs for all measurements were over 0.9 (95% confidence interval (CI) = 0.932-0.998). The SEM% ranged from 5 to 14% and the SDC% from 14 to 28%. The correlations of strength and power were high (Pearson's correlation coefficient >0.9 (95% CI: 0.89-0.98)). The isometric strength needed to conduct isokinetic measurements ranged from 11.1 N in elbow flexors to 24.9 N in knee extensors. Conclusions: Isokinetic dynamometry is a feasible and reproducible method for measuring isometric strength in children with neuromuscular diseases with moderate weakness to normal strength, and isokinetic measurements are only feasible in knee extension for children with moderate weakness to normal strength. The convergent validity between isometric strength and power at low velocities is high.

Sero-Positive Isolated Ocular Myasthenia Gravis.

Ocular myasthenia gravis (OMG) is a neuromuscular disease characterized by the production of autoantibodies against post-synaptic proteins at the neuromuscular junction (NMJ). An 18-year-old male who had symptoms of drooping eyelids and double vision was diagnosed with ocular myasthenia gravis on investigations and examinations. Treatment was initiated with a tablet of pyridostigmine 60 mg twice daily per oral for two weeks, followed by three times daily for four weeks. The patient demonstrated significant improvement in ptosis and diplopia. There are still a considerable number of challenges in the diagnosis and treatment of ocular myasthenia gravis, with the typical treatment involving acetylcholinesterase inhibitors and immunosuppressants.

Interpretation of Sydney Swallow Questionnaire results using the oropharyngeal dysphagia risk matrix.

BACKGROUND: Oropharyngeal dysphagia (OD) commonly occurs in neuromuscular diseases (NMD). Appropriate management involves early detection, clinical evaluation, and tailored follow-up to minimize complications. Various assessment tools exist, including the Sydney Swallow Questionnaire (SSQ), a patient-reported outcome measure for assessing OD severity in adult patients. This paper proposes utilizing an innovative risk matrix (OD-Risk-Matrix) to enhance SSQ interpretation. This matrix categorizes OD risk for each SSQ question, offering valuable assistance to clinicians. METHODS: This study analyzes SSQ results from a cohort of individuals with NMD (n = 57). Patients filled in the SSQ during outpatient visits at our neuromuscular center. Subsequently, SSQ scores were grouped by NMD conditions and interpreted using the OD-Risk-Matrix categorizing each question's risk as low, moderate, or high. This matrix is based on the SSQ results by categorizing the risk of OD for each question, as well as the likelihood of occurrence of OD. KEY RESULTS: In light of the OD-Risk-Matrix, the interpretation of SSQ scores revealed various risk categories associated with each question, while also highlighting distinct OD characteristics and discrepancies among the different NMDs. CONCLUSION AND INFERENCES: In conclusion, the OD-Risk-Matrix offers a framework for interpreting the SSQ, revealing variations in the risks of OD among different questions in patients with NMD. This novel approach could be a valuable tool in SSQ interpretation to identify specific fields of OD and could lead to a tailored management plan, prioritizing interventions aimed at reducing the risk of aspiration, ensuring proper nutrition, and enhancing swallowing safety and efficiency.

[Neurophysiological substantiation and validity assessment of manual muscle testing in clinical practice. (A literature review)]. / Neirofiziologicheskoe obosnovanie i otsenka validnosti manual'nogo myshechnogo testirovaniya v klinicheskoi praktike. (Obzor literatury).

The relevance of the study of neuromuscular dysfunction's causes and mechanisms is undeniable, considering the large number of nosologies accompanied by malfunction of muscles. Adequate diagnosis and correction of these disorders is impossible without understanding of their pathogenetic mechanisms. Currently, manual muscle testing (MMT) is a widespread technique. MMT is an agile diagnostic tool used by physiatrists, doctors in sports medicine, osteopaths and rehabilitation physicians to assess the functional status of muscles. Unconditionally, this method attracts with its low cost, which will optimize the financial costs of hospital and the healthcare system as a whole. In addition, there is no clear substantiation of the objectivity and validity of the MMT to date. The article considers the issues of neurophysiological principles, classification of methods and approaches, assessment criteria of repeatability and accuracy of MMT. Understanding of the pathophysiological mechanisms of MMT effectiveness will allow to timely correct the therapy and improve the results of treatment and rehabilitation of patients with neuromuscular dysfunction.

Development of the Brazilian version of the Performance of Upper Limb scale for children and adolescents with Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) is one of the most common and disabling childhood genetic diseases. The course of DMD involves progressive muscular degeneration and weakness, leading to functional decline. The Performance of the Upper Limb scale (PUL) is a specific instrument designed to assess the upper limb function of patients with DMD. OBJECTIVE: To adapt the PUL cross-culturally to Brazilian Portuguese (PUL-Br) and assess the convergent validity, structural validity, inter-rater reliability, and internal consistency for Brazilian patients with DMD METHODS: The cross-cultural adaptation involved six steps: translation to Brazilian Portuguese, Brazilian Portuguese translation synthesis, back-translation to English, back-translation synthesis, an expert committee review, and a pre-final version test (n = 12). The convergent validity of the PUL-Br was evaluated by examining its correlation to the Motor Function Measure scale (MFM) using 30 patients with DMD. Confirmatory factor analysis was conducted to assess structural validity. Intraclass correlation coefficient (ICC) verified the PUL-Br interrater reliability. Cronbach's alpha was calculated to verify internal consistency. RESULTS: The PUL was cross-culturally adapted to Brazilian Portuguese. A strong and positive correlation was found between the PUL-Br total score and the total score on the MFM (r = 0.83; 95% CI: 0.67, 0.91). The PUL-Br showed a satisfactory fit of the data to the three-factor model, excellent inter-rater reliability (ICC: 0.94), and good internal consistency (Cronbach's: 0.91). CONCLUSION: The PUL-Br is valid and reliable for assessing the upper limb function of Brazilian patients with DMD.

Novel variants and genotype-phenotype correlation in a multicentre cohort of GNE myopathy in China.

BACKGROUND: GlcNAc2-epimerase (GNE) myopathy is a rare autosomal recessive disorder caused by pathogenic variants in the GNE gene, which is essential for the sialic acid biosynthesis pathway. OBJECTIVE: This multi-centre study aimed to delineate the clinical phenotype and GNE variant spectrum in Chinese patients, enhancing our understanding of the genetic diversity and clinical manifestation across different populations. METHODS: We retrospectively analysed GNE variants from 113 patients, integrating these data with external GNE variants from online databases for a global perspective, examining their consequences, distribution, ethnicity and severity. RESULTS: This study revealed 97 distinct GNE variants, including 35 (36.08%) novel variants. Two more patients with deep intronic variant c.862+870C>T were identified, while whole genome sequencing (WGS) uncovered another two novel intronic variants: c.52-8924G>T and c.1505-12G>A. Nanopore long reads sequencing (LRS) and further PCR analysis verified a 639 bp insertion at chr9:36249241. Missense variants predominantly located in the epimerase/kinase domain coding region, indicating the impairment of catalytic function as a key pathogenic consequence. Comparative studies with Japanese, Korean and Jewish, our cohorts showed later onset ages by 2 years. The high allele frequency of the non-catalytic GNE variant, c.620A>T, might underlie the milder phenotype of Chinese patients. CONCLUSIONS: Comprehensive techniques such as WGS and Nanopore LRS warrants the identifying of GNE variants. Patients with the non-catalytic GNE variant, c.620A>T, had a milder disease progression and later wheelchair use.

An Evaluation of an Australian Pediatric Neuromuscular Transition Model.

BACKGROUND: After receiving a diagnosis of a neuromuscular condition, patients have to make their way through a convoluted network of community and state resources as health care shifts from being family and child centered to adult focused. This study examined the barriers to successful transition from patient and clinician perspectives. METHODS: Adolescents with a primary diagnosis of a neuromuscular condition who were aged 16 years and over in Queensland, Australia, and who had started the transition process were eligible. Surveys were collected over six months and statistics used to characterize survey responses. RESULTS: There was a high degree of anxiety reported about the transition, with almost 50% of patients and families surveyed reporting concerns about moving across to the adult hospital system. The main barriers to effective transition identified by clinicians were limited time (84%), clinic space (58%), and a lack of an identified transition coordinator (79%). CONCLUSIONS: This study has provided a checklist to assist patients with neuromuscular disorders in transitioning from pediatric to adult care. A new model has been developed to enable a slow, personalized transition that is led by a multidisciplinary team.

Loss-of-function variants in JPH1 cause congenital myopathy with prominent facial and ocular involvement.

BACKGROUND: Weakness of facial, ocular and axial muscles is a common clinical presentation in congenital myopathies caused by pathogenic variants in genes encoding triad proteins. Abnormalities in triad structure and function resulting in disturbed excitation-contraction coupling and Ca2+ homeostasis can contribute to disease pathology. METHODS: We analysed exome and genome sequencing data from four unrelated individuals with congenital myopathy characterised by facial, ocular and bulbar involvement. We collected deep phenotypic data from the affected individuals. We analysed the RNA-sequencing (RNA-seq) data of F3-II.1 and performed gene expression outlier analysis in 129 samples. RESULTS: The four probands had a remarkably similar clinical presentation with prominent facial, ocular and bulbar features. Disease onset was in the neonatal period with hypotonia, poor feeding, cleft palate and talipes. Muscle weakness was generalised but prominent in the lower limbs with facial weakness also present. All patients had myopathic facies, bilateral ptosis, ophthalmoplegia and fatigability. Muscle biopsy on light microscopy showed type 1 myofiber predominance and ultrastructural analysis revealed slightly reduced triads, and structurally abnormal sarcoplasmic reticulum.DNA sequencing identified four unique homozygous loss-of-function variants in JPH1, encoding junctophilin-1 in the four families; one stop-gain (c.354C>A;p.Tyr118*) and three frameshift (c.373delG;p.Asp125Thrfs*30, c.1738delC;p.Leu580Trpfs*16 and c.1510delG;p. Glu504Serfs*3) variants. Muscle RNA-seq showed strong downregulation of JPH1 in the F3 proband. CONCLUSIONS: Junctophilin-1 is critical for the formation of skeletal muscle triad junctions by connecting the sarcoplasmic reticulum and T-tubules. Our findings suggest that loss of JPH1 results in a congenital myopathy with prominent facial, bulbar and ocular involvement.

Improving Clinical Documentation of Rare Neuromuscular Diseases: Development of a Standardised Information Model.

Rare neuromuscular diseases (NMDs) encompass various disorders of the nervous system and skeletal muscles, and present intricate challenges in diagnosis, treatment, and research due to their low prevalence and often diverse multisystemic manifestations. Leveraging collected patient data for secondary use and analysis holds promise for advancing medical understanding in this field. However, a certain level of data quality is a prerequisite for the methods that can be used to analyze data. The heterogeneous nature of NMDs poses a significant obstacle to the creation of standardized documentation, as there are still many challenges to accurate diagnosis and many discrepancies in the diagnostic process between different countries. This paper proposes the development of an information model tailored to NMDs, aiming to augment visibility, address deficiencies in documentation, and facilitate comprehensive analysis and research endeavors. By providing a structured framework, this model seeks to propel advancements in understanding and managing NMD, ultimately benefiting patients and healthcare providers worldwide.

Large TRAPPC11 gene deletions as a cause of muscular dystrophy and their estimated genesis.

BACKGROUND: Transport protein particle (TRAPP) is a multiprotein complex that functions in localising proteins to the Golgi compartment. The TRAPPC11 subunit has been implicated in diseases affecting muscle, brain, eye and to some extent liver. We present three patients who are compound heterozygotes for a missense variant and a structural variant in the TRAPPC11 gene. TRAPPC11 structural variants have not yet been described in association with a disease. In order to reveal the estimated genesis of identified structural variants, we performed sequencing of individual breakpoint junctions and analysed the extent of homology and the presence of repetitive elements in and around the breakpoints. METHODS: Biochemical methods including isoelectric focusing on serum transferrin and apolipoprotein C-III, as well as mitochondrial respiratory chain complex activity measurements, were used. Muscle biopsy samples underwent histochemical analysis. Next-generation sequencing was employed for identifying sequence variants associated with neuromuscular disorders, and Sanger sequencing was used to confirm findings. RESULTS: We suppose that non-homologous end joining is a possible mechanism of deletion origin in two patients and non-allelic homologous recombination in one patient. Analyses of mitochondrial function performed in patients' skeletal muscles revealed an imbalance of mitochondrial metabolism, which worsens with age and disease progression. CONCLUSION: Our results contribute to further knowledge in the field of neuromuscular diseases and mutational mechanisms. This knowledge is important for understanding the molecular nature of human diseases and allows us to improve strategies for identifying disease-causing mutations.

Improving Heckmatt muscle ultrasound grading scale through Rasch analysis.

The 4-point Heckmatt grading scale can easily be used to analyze muscle ultrasound images. The scale is used in an expanding set of muscles and neuromuscular disorders. This prompted the need for evaluation of the measurement properties of the scale in its current form. In this retrospective observational study we included muscle ultrasound images from patients who were undergoing an ultrasound exam for either clinical or research purposes. The primary outcome of this study was to investigate and improve the measurement properties of the Heckmatt scale using Rasch analysis. We investigated whether observers consistently used the 4 response categories. Data was available of 30.967 muscle ultrasound images from 1783 patients and 43 different individual muscles. In 8 of the 43 muscles, observers had difficulty to discriminate between the response categories, especially in bulbar muscles. After rescoring to a 3-point scale, the response categories were consistently used in all 43 muscles. In conclusion, a 3-point Heckmatt grading scale leads to improved accurate scoring compared to the original 4-point Heckmatt grading scale. Using the 3-point Heckmatt grading scale will not only simplify the use of the scale but also enhance its application in clinical practice and research purposes.

Nociceptive Pain in Patients with Neuromuscular Disorders: A Cross-Sectional Clinical Study.

Background: Muscle pain is a common symptom in patients with neuromuscular disorders (NMD) and accounts for severely reduced quality of life. OBJECTIVE: This clinical study aimed to observe possible differences in pain prevalence among distinct NMDs and to determine whether the patients' nociceptive pain is influenced by gender, muscle strength and psychological factors and to examine potential pain-associated alterations in muscle properties. Methods: The cross-sectional study on nociceptive pain in various NMDs involved patient-reported outcomes, muscle strength evaluations (dynamometry and quick motor function test (QMFT)), nociceptive pain evaluations (muscular pressure pain threshold (PPT)), and non-invasive measurement of muscle stiffness, frequency, decrement, relaxation, and creep (myotonometry). Results: Involving 81 NMD patients and a control group, the study found high variability in pain prevalence among the subgroups. Patients with DM2 and FSHD had significantly higher levels of pain prevalence compared to other examined NMD subgroups and the control group. Female gender, high fatigue levels (representing factors such as depression, anxiety, stress, and impairment of quality of life), and low QMFT scores (representing reduced muscle strength) showed an association with increased sensitivity to pressure pain in the arm and leg region. As assessed by myotonometry, less pain is experienced in neck muscles with a high muscle tone, high stiffness, and a short relaxation time highlighting the importance of intrinsic muscular tone for their pressure pain sensitivity. Conclusion: Individualized therapeutic concepts including psychological and physical approaches in the pain management of patients with NMDs, especially in women, should be considered. Further research in this field is necessary to gain a more detailed insight into the perception of muscle pain.

Longitudinal Assessment of Blood-Based Inflammatory, Neuromuscular, and Neurovascular Biomarker Profiles in Intensive Care Unit-Acquired Weakness: A Prospective Single-Center Cohort Study.

BACKGROUND: The diagnosis of intensive care unit (ICU)-acquired weakness (ICUAW) and critical illness neuromyopathy (CINM) is frequently hampered in the clinical routine. We evaluated a novel panel of blood-based inflammatory, neuromuscular, and neurovascular biomarkers as an alternative diagnostic approach for ICUAW and CINM. METHODS: Patients admitted to the ICU with a Sequential Organ Failure Assessment score of ≥ 8 on 3 consecutive days within the first 5 days as well as healthy controls were enrolled. The Medical Research Council Sum Score (MRCSS) was calculated, and motor and sensory electroneurography (ENG) for assessment of peripheral nerve function were performed at days 3 and 10. ICUAW was defined by an MRCSS < 48 and CINM by pathological ENG alterations, both at day 10. Blood samples were taken at days 3, 10, and 17 for quantitative analysis of 18 different biomarkers (white blood cell count, C-reactive protein, procalcitonin, C-terminal agrin filament, fatty-acid-binding protein 3, growth and differentiation factor 15, syndecan 1, troponin I, interferon-γ, tumor necrosis factor-α, interleukin-1α [IL-1α], IL-1ß, IL-4, IL-6, IL-8, IL-10, IL-13, and monocyte chemoattractant protein 1). Results of the biomarker analysis were categorized according to the ICUAW and CINM status. Clinical outcome was assessed after 3 months. RESULTS: Between October 2016 and December 2018, 38 critically ill patients, grouped into ICUAW (18 with and 20 without) and CINM (18 with and 17 without), as well as ten healthy volunteers were included. Biomarkers were significantly elevated in critically ill patients compared to healthy controls and correlated with disease severity and 3-month outcome parameters. However, none of the biomarkers enabled discrimination of patients with and without neuromuscular impairment, irrespective of applied classification. CONCLUSIONS: Blood-based biomarkers are generally elevated in ICU patients but do not identify patients with ICUAW or CINM. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02706314.

Enhancing respiratory function in neuromuscular disease: the role of non-invasive ventilation. A narrative review.

Neuromuscular diseases (NMDs) comprise a heterogeneous group of conditions characterized by extreme progressive muscle weakness leading to respiratory failure. Noninvasive mechanical ventilation (NIV) has emerged as a cornerstone in the management of respiratory complications associated with NMDs. This review aims to elucidate the role of NMV in respiratory function, improving quality of life, and prolonging survival in individuals with NMD. The physiological basis of respiratory impairment in NMDs, principles of NMV application, evidence supporting its efficacy, patient selection criteria, and potential challenges in its application are discussed.

Development of an initial training and evaluation programme for manual lower limb muscle MRI segmentation.

BACKGROUND: Magnetic resonance imaging (MRI) quantification of intramuscular fat accumulation is a responsive biomarker in neuromuscular diseases. Despite emergence of automated methods, manual muscle segmentation remains an essential foundation. We aimed to develop a training programme for new observers to demonstrate competence in lower limb muscle segmentation and establish reliability benchmarks for future human observers and machine learning segmentation packages. METHODS: The learning phase of the training programme comprised a training manual, direct instruction, and eight lower limb MRI scans with reference standard large and small regions of interest (ROIs). The assessment phase used test-retest scans from two patients and two healthy controls. Interscan and interobserver reliability metrics were calculated to identify underperforming outliers and to determine competency benchmarks. RESULTS: Three experienced observers undertook the assessment phase, whilst eight new observers completed the full training programme. Two of the new observers were identified as underperforming outliers, relating to variation in size or consistency of segmentations; six had interscan and interobserver reliability equivalent to those of experienced observers. The calculated benchmark for the Sørensen-Dice similarity coefficient between observers was greater than 0.87 and 0.92 for individual thigh and calf muscles, respectively. Interscan and interobserver reliability were significantly higher for large than small ROIs (all p < 0.001). CONCLUSIONS: We developed, implemented, and analysed the first formal training programme for manual lower limb muscle segmentation. Large ROI showed superior reliability to small ROI for fat fraction assessment. RELEVANCE STATEMENT: Observers competent in lower limb muscle segmentation are critical to application of quantitative muscle MRI biomarkers in neuromuscular diseases. This study has established competency benchmarks for future human observers or automated segmentation methods. KEY POINTS: • Observers competent in muscle segmentation are critical for quantitative muscle MRI biomarkers. • A training programme for muscle segmentation was undertaken by eight new observers. • We established competency benchmarks for future human observers or automated segmentation methods.

Reabilitação fisioterapêutica em pacientes com síndrome da pessoa rígida: revisão integrativa / Physiotherapy rehabilitation in patients with stiff person syndrome: integrative review

Introdução: A Síndrome da Pessoa Rígida é uma doença neuroimunológica rara do sistema nervoso central caracterizada por espasmos dolorosos e rigidez progressiva que envolvem os músculos proximais dos membros e axiais do tronco. A forma clássica tem início insidioso com piora gradual ao longo do tempo e muitas vezes leva à incapacidade permanente. Objetivo: Analisar os estudos publicados na literatura científica que utilizaram a reabilitação fisioterapêutica como proposta de tratamento dos sintomas motores na Síndrome da Pessoa Rígida. Método: Trata-se de uma revisão integrativa da literatura realizada no período de julho a dezembro de 2022 nas bases de dados PubMed, SciELO, LILACS e BVS. Resultados: Foram encontrados 12 artigos publicados entre o período de 2002 a 2021, que discorriam sobre o tratamento fisioterapêutico nesta população. O número escasso de estudos se dá pela raridade da patologia que dificulta a realização de ensaios clínicos robustos. Os artigos selecionados eram relatos de casos de um ou mais indivíduos, com enfoque nas intervenções realizadas de acordo com cada queixa funcional apresentada, sendo estas a dor, fraqueza muscular, hipomobilidade articular, rigidez, instabilidade postural, alterações na marcha e limitações nas atividades de vida diária. Conclusão: A reabilitação fisioterapêutica faz parte do tratamento sintomatológico e tem como finalidade, auxiliar na manutenção da funcionalidade e qualidade de vida, minimizando as repercussões motoras que são desencadeadas pela síndrome.

Introduction: Stiff Person Syndrome is a rare neuroimmunological disease of the central nervous system characterized by painful spasms and progressive rigidity involving the proximal muscles of the limbs and axial muscles of the trunk. The classic form has an insidious onset with gradual worsening over time and often leads to permanent disability. Objective: To analyze the studies published in the scientific literature that used hysiotherapeutic rehabilitation as a proposal for treating motor symptoms in Stiff Person Syndrome. Method: This is an integrative review of the literature carried out from July to December 2022 in the PubMed, SciELO, LILACS and VHL databases. Results: 12 articles published between 2002 and 2021 were found, which discussed physiotherapeutic treatment in this population. The scarce number of studies is due to the rarity of the pathology, which makes it difficult to carry out robust clinical trials. The selected articles were case reports of one or more individuals, focusing on interventions carried out according to each functional complaint presented, these being pain, muscle weakness, joint hypomobility, stiffness, postural instability, changes in gait and limitations in walking activities. daily life. Conclusion: Physiotherapy rehabilitation is part of symptomatological treatment and aims to help maintain functionality and quality of life, minimizing the motor repercussions that are triggered by the syndrome.