The burden of mitochondrial disease with associated seizures: systematic literature reviews of health-related quality of life, utilities, costs and healthcare resource use data.

BACKGROUND: Mitochondrial disease is a degenerative, progressive, heterogeneous group of genetic disorders affecting children and adults. Mitochondrial disease is associated with morbidity and mortality, with predominantly neurological and neuromuscular symptoms including dystonia, weakness, encephalopathy, developmental delay and seizures. Seizures are one of the most common and severe manifestations of mitochondrial disease. These seizures are typically refractory to common anti-seizure therapies. There are no approved disease-modifying treatments for mitochondrial disease. Our objective was to conduct two systematic literature reviews to identify health-related quality of life (HRQoL), utilities, costs and healthcare resource use data in mitochondrial disease with associated seizures. METHODS: A range of databases and information sources were searched up to July 2022 to identify eligible studies. Search strategies included a range of variant terms for mitochondrial disease and HRQoL, utilities, cost and healthcare resource use outcomes. Two reviewers independently assessed articles against the eligibility criteria; studies were extracted by one reviewer and checked by a second. Risk of bias was assessed for studies reporting HRQoL data. Results were narratively assessed. RESULTS: Seven studies were eligible for the HRQoL and utilities review. The studies used different tools to report data, and despite the variability in methods, HRQoL scores across the studies showed moderate/severe disease in patients with mitochondrial disease with associated seizures. Parents of patients with mitochondrial disease with associated seizures were characterised by high total parenting stress. No studies reported utilities data. Two case reports and one retrospective review of medical records of children who died in hospital were eligible for the costs and resource use review. These provided limited information on the duration of hospital stay, in an intensive care unit (ICU), on mechanical ventilation. No studies reported costs data. CONCLUSION: These reviews highlight the limited HRQoL, utilities, costs and resource use data and the variability of instruments used in mitochondrial disease with associated seizures. However, the data available indicate that mitochondrial disease with associated seizures affects patients' and caregivers' HRQoL alike. No robust conclusion can be drawn on the impact of mitochondrial disease with associated seizures on hospital or ICU length of stay. Trial registration PROSPERO: CRD42022345005.

Whole genome sequencing diagnostic yield for paediatric patients with suspected genetic disorders: systematic review, meta-analysis, and GRADE assessment.

BACKGROUND: About 80% of the roughly 7,000 known rare diseases are single gene disorders, about 85% of which are ultra-rare, affecting less than one in one million individuals. NGS technologies, in particular whole genome sequencing (WGS) in paediatric patients suffering from severe disorders of likely genetic origin improve the diagnostic yield allowing targeted, effective care and management. The aim of this study is to perform a systematic review and meta-analysis to assess the effectiveness of WGS, with respect to whole exome sequencing (WES) and/or usual care, for the diagnosis of suspected genetic disorders among the paediatric population. METHODS: A systematic review of the literature was conducted querying relevant electronic databases, including MEDLINE, EMBASE, ISI Web of Science, and Scopus from January 2010 to June 2022. A random-effect meta-analysis was run to inspect the diagnostic yield of different techniques. A network meta-analysis was also performed to directly assess the comparison between WGS and WES. RESULTS: Of the 4,927 initially retrieved articles, thirty-nine met the inclusion criteria. Overall results highlighted a significantly higher pooled diagnostic yield for WGS, 38.6% (95% CI: [32.6 - 45.0]), in respect to WES, 37.8% (95% CI: [32.9 - 42.9]) and usual care, 7.8% (95% CI: [4.4 - 13.2]). The meta-regression output suggested a higher diagnostic yield of the WGS compared to WES after controlling for the type of disease (monogenic vs non-monogenic), with a tendency to better diagnostic performances for Mendelian diseases. The network meta-analysis showed a higher diagnostic yield for WGS compared to WES (OR = 1.54, 95%CI: [1.11 - 2.12]). CONCLUSIONS: Although whole genome sequencing for the paediatric population with suspected genetic disorders provided an accurate and early genetic diagnosis in a high proportion of cases, further research is needed for evaluating costs, effectiveness, and cost-effectiveness of WGS and achieving an informed decision-making process. TRIAL REGISTRATION: This systematic review has not been registered.

Incremental net benefit of whole genome sequencing for newborns and children with suspected genetic disorders: Systematic review and meta-analysis of cost-effectiveness evidence.

BACKGROUND: The introduction of massive parallel sequencing has contributed to a decline in sequencing costs. In recent years, whole-exome sequencing (WES) and whole-genome sequencing (WGS) have been increasingly adopted for diagnostic purposes in individuals with suspected genetic diseases. However, a debate is still ongoing in the scientific community about the superiority of WGS over WES in terms of cost-effectiveness. The aim of this study is to assess whether WGS, for the pediatric population with suspected genetic disorders, is cost-effective with respect to WES and chromosomal microarray (CMA) by pooling incremental net benefits. MATERIALS AND METHODS: Articles were retrieved from PubMed, Web of Science, Embase and Scopus from 2015 to 2021. The dominance ranking matrix (DRM) tool was adopted to provide a qualitative synthesis of all the included studies. Incremental net benefits (INBs) were estimated and meta-analysis was implemented to pool INBs across studies. RESULTS: The database search identified 1600 publications of which four articles were considered eligible for the meta-analysis. The pooled INB of WGS over WES was estimated at I$4073 (95% CI I$2426 - I$5720). The pooled INB of WGS over CMA amounted to I$6003 (95% CI I$2863 - I$9143). CONCLUSIONS: WGS could be cost-effective in the diagnostic workup of affected infants and children. Further economic evaluations however are needed for comparing WGS versus WES and confirm the present conclusions.

North Star Ambulatory Assessment changes in ambulant Duchenne boys amenable to skip exons 44, 45, 51, and 53: A 3 year follow up.

INTRODUCTION: The aim of this study was to report 36-month longitudinal changes using the North Star Ambulatory Assessment (NSAA) in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53. MATERIALS AND METHODS: We included 101 patients, 34 had deletions amenable to skip exon 44, 25 exon 45, 19 exon 51, and 28 exon 53, not recruited in any ongoing clinical trials. Five patients were counted to skip exon 51 and 53 since they had a single deletion of exon 52. RESULTS: The difference between subgroups (skip 44, 45, 51 and 53) was significant at 12 (p = 0.043), 24 (p = 0.005) and 36 months (p≤0.001). DISCUSSION: Mutations amenable to skip exons 53 and 51 had lower baseline values and more negative changes than the other subgroups while those amenable to skip exon 44 had higher scores both at baseline and at follow up. CONCLUSION: Our results confirm different progression of disease in subgroups of patients with deletions amenable to skip different exons. This information is relevant as current long term clinical trials are using the NSAA in these subgroups of mutations.

The Spinal Muscular Atrophy Health Index: Italian validation of a disease-specific outcome measure.

Patient report outcome measures in Spinal Muscular Atrophy (SMA) represent a potential complement to observer rated scales which can be used to better understand treatment response. We developed, translated and validated an Italian version of the Spinal Muscular Atrophy Health Index (SMAHI), a disease-specific, patient reported outcome measure questionnaire, designed to estimate the patients' perception of disease burden. Test-retest reliability was assessed in 37 patients (16 children aged 12-17 and 21 adults) and was excellent in both cohorts. Internal consistency in an additional 98 patients (24 children, 74 adults) was also excellent (Cronbach's alpha = 0.93 and 0.91 respectively). In children the highest level of disease burden was generated from lower limb dysfunction and fatigue as well as their perception of decreased performance in social situations. Most patients in the adult cohort were sitters and complained of problems with upper limb functions as well as of fatigue. The SMAHI-IT was also able to differentiate between SMA types according to diseases severity. The results of our study demonstrate that the SMAHI can be considered a marker of disease-specific burden in patients with SMA with a high test-retest reliability and internal validity in Italian patients aged 12 and older.

Estimating the impact of COVID-19 pandemic on services provided by Italian Neuromuscular Centers: an Italian Association of Myology survey of the acute phase.

INTRODUCTION: Since February 2020, the outbreak of COVID-19 in Italy has forced the health care system to undergo profound rearrangements in its services and facilities, especially in the worst-hit areas in Northern Italy. In this setting, inpatient and outpatient services had to rethink and reorganize their activities to meet the needs of patients during the "lockdown". The Italian Association of Myology developed a survey to estimate the impact of these changes on patients affected by neuromuscular disorders and on specialized neuromuscular centers during the acute phase of COVID-19 pandemic. METHODS: We developed an electronic survey that was sent to neuromuscular centers affiliated with the Italian Association of Myology, assessing changes in pharmacological therapies provision, outpatient clinical and instrumental services, support services (physiotherapy, nursing care, psychological support) and clinical trials. RESULTS: 40% of surveyed neuromuscular centers reported a reduction in outpatient visit and examinations (44.5% of centers in Northern regions; 25% of centers in Central regions; 50% of centers in Southern regions). Twenty-two% of centers postponed in-hospital administration of therapies for neuromuscular diseases (23.4% in Northern regions; 13.0% in Central regions; 20% in Southern regions). Diagnostic and support services (physiotherapy, nursing care, psychological support) were suspended in 57% of centers (66/43/44% in Northern, Central and Southern centers respectively) Overall, the most affected services were rehabilitative services and on-site outpatient visits, which were suspended in 93% of centers. Strategies adopted by neuromuscular centers to overcome these changes included maintaining urgent on-site visits, addressing patients to available services and promoting remote contact and telemedicine. CONCLUSIONS: Overall, COVID-19 pandemic resulted in a significant disruption of clinical and support services for patients with neuromuscular diseases. Despite the efforts to provide telemedicine consults to patients, this option could be promoted and improved further. A close collaboration between the different neuromuscular centers and service providers as well as further implementation of telehealth platforms are necessary to ensure quality care to NMD patients in the near future and in case of recurrent pandemic waves.

Speech and Language Disorders in Friedreich Ataxia: Highlights on Phenomenology, Assessment, and Therapy.

Speech and language disorders are prominent signs in Friedreich ataxia (FRDA), which significantly impact on patients' quality of life. Despite such relevance, several issues regarding phenomenology, assessment, and treatment are still unmet. In this short review, we thus analyzed the existing literature to summarize what is known about the features of speech and language disorders in FRDA, which methods are used for evaluation and rating, and what are the available therapeutic strategies and future direction of scientific research in this field, in order to highlight critical aspects for a better clinical approach to the problem. FRDA patients often present dysarthria, resulting from central and peripheral causes and additional primary language disorders. Speech disturbances have peculiar characteristics, although variable among patients, and progress along the disease course. Assessment relies on multiple but not specific clinical scales, some of which can also reflect the general severity of ataxia; classical instrumental investigations and novel technologies allow more accurate measurements of several speech parameters, which could found application as potential disease's biomarkers. No successful treatments exist for communication disorders of FRDA patients; however, the tailored speech training or the non-invasive neuromodulation appear as the most reliable therapeutic options to be validate in future trials.

Development of SaraHome: A novel, well-accepted, technology-based assessment tool for patients with ataxia.

BACKGROUND AND OBJECTIVE: Early onset ataxias (EOAs) are a heterogeneous group of neurological conditions, responsible for severe motor disability in paediatric age, which still lack reliable outcome measures. Available scales to assess ataxia, such as the Scale for Assessment and Rating of Ataxia (SARA), are based on subjective assessment of specific motor and language tasks by an examiner, and therefore is age dependent and lacks accuracy in detecting small variations in disease severity. In last years, novel technologies, including computer interfaces and videogames, have emerged for clinical applications and the advent of Internet of Medical Things and of Information Communication Technology have allowed the remote control of such technologies. This pilot study describes a newly developed tool (SaraHome) for the assessment at home of EOA evaluating its feasibility and acceptability on a small sample of children. METHODS: Ten EOA children and ten caregivers have been enrolled for a preliminary outpatient evaluation. The Microsoft Kinect 2.0 and Leap Motion Controller (LMC) connected to a personal computer with an ad hoc software have been set-up, for the acquisition of standardized motor tasks performed by the patients with the caregivers' assistance. Acceptance and practicability have been tested by QUEST 2.0 and IMI questionnaires in caregivers and patients respectively. RESULTS: The SaraHome software was developed, based on a collection of services provided by a complex architecture that consists of a Restful interface, which enables to access a series of plugins for the execution of different tasks. A graphical user interface allows the acquisition of the patient movements while performing a motor task. A protocol of standard tasks inspired by SARA was established, and a system of video-assisted instruction provided. The set-up for the optimal acquisition of such protocol by Kinect and LMC has been defined. Both patients and caregivers accomplished the SaraHome assessment with good feedback at the technology acceptance questionnaires. CONCLUSIONS: SaraHome represents a newly developed tool for the assessment of ataxia in patients, resulting from the integration of low-cost and easy-accessible technologies. This pilot application highlighted the feasibility and the acceptability of the system, suggesting the potential use in clinical practice.

Evaluation of gait in Duchenne Muscular Dystrophy: Relation of 3D gait analysis to clinical assessment.

Walking ability in Duchenne Muscular Dystrophy (DMD) deteriorates progressively until complete loss of the function. Interventions aimed at maintaining ambulatory ability relies on accurate clinical-based scores and evaluations of walking. This kind of assessment has intrinsic limitations. A 3D optoelectronic system could provide elements useful for the functional evaluation of patients with DMD. Nineteen boys with DMD were evaluated using the 6-Minutes Walking Test, North Star Ambulatory Assessment and 3D gait analysis. Participants' gait parameters were compared to those of an age-matched control group and correlated with standard clinical scores. Seventeen kinematic variables differed between DMD and control groups. Strong correlations with North Star Ambulatory Assessment were found for stride width, gait velocity and ankle angles on the sagittal plane. The 6-Minutes Walking test did not correlate with investigated kinematic variables but showed a correlation with North Star Ambulatory Assessment. Our data support the reported DMD gait pattern characterized by increased anterior pelvic tilt and ankle plantar flexion. The stride width and ankle kinematics emerged as the main representative gait parameters of DMD global ambulatory status. Although preliminary, our findings suggest that 3D gait analysis may provide useful objective and accurate parameters reflecting the functional ability of individuals with DMD.

Longitudinal gait assessment in a stiff person syndrome.

Stiff person syndrome (SPS) is an autoimmune disorder with multiple clinical presentations, all characterized by generalized or focal muscular stiffness leading to abnormal postures and movements. To date, no standardized treatments are available; also, the outcome measures are mainly clinical based and unstandardized, limiting the reliability of clinical trials. In this case study, we used the eight-camera motion capture system for gait analysis (GA) to outline the gait features and track the clinical evolution of a young patient with SPS receiving a personalized multimodal therapy. GA was accurate in reflecting clinical changes over a 7-week-long period, thus representing a potential source for objective biomarkers in SPS. Therefore, future studies focusing on either the natural history or the treatment of SPS could adopt GA for reliable outocome measures, confirming this preliminary observation.

Functional and Gait Assessment in Children and Adolescents Affected by Friedreich's Ataxia: A One-Year Longitudinal Study.

Friedreich's ataxia is the most common autosomal recessive form of neurodegenerative ataxia. We present a longitudinal study on the gait pattern of children and adolescents affected by Friedreich's ataxia using Gait Analysis and the Scale for the Assessment and Rating of Ataxia (SARA). We assessed the spectrum of changes over 12 months of the gait characteristics and the relationship between clinical and instrumental evaluations. We enrolled 11 genetically confirmed patients affected by Friedreich's ataxia in this study together with 13 normally developing age-matched subjects. Eight patients completed a 12-month follow-up under the same protocol. By comparing the gait parameters of Friedreich's ataxia with the control group, we found significant differences for some relevant indexes. In particular, the increased knee and ankle extension in stance revealed a peculiar biomechanical pattern, which correlated reliably with SARA Total, Gait and Sitting scores. The knee pattern showed its consistency also at the follow-up: Knee extension increased from 6.8±3.5° to -0.5±3.7° and was significantly correlated with the SARA total score. This feature anticipated the loss of the locomotor function in two patients. In conclusion, our findings demonstrate that the selective and segmental analysis of kinetic/kinematic features of ataxic gait, in particular the behavior of the knee, provides sensitive measures to detect specific longitudinal and functional alterations, more than the SARA scale, which however has proved to be a reliable and practical assessment tool. Functional outcomes measures integrated by instrumental evaluation increase their sensitivity, reliability and suitability for the follow-up of the disease progression and for the application in clinical trials and in rehabilitative programs.

Revised North Star Ambulatory Assessment for Young Boys with Duchenne Muscular Dystrophy.

The advent of therapeutic approaches for Duchenne muscular dystrophy (DMD) has highlighted the need to identify reliable outcome measures for young boys with DMD. The aim of this study was to develop a revised version of the North Star Ambulatory Assessment (NSAA) suitable for boys between the age of 3 and 5 years by identifying age appropriate items and revising the scoring system accordingly. Using the scale in 171 controls between the age of 2.9 and 4.8 years, we identified items that were appropriate at different age points. An item was defined as age appropriate if it was completed, achieving a full score, by at least 85% of the typically developing boys at that age. At 3 years (±3months) there were only 8 items that were age appropriate, at 3 years and 6 months there were 13 items while by the age of 4 years all 17 items were appropriate. A revised version of the scale was developed with items ordered according to the age when they could be reliably performed. The application of the revised version of the scale to data collected in young DMD boys showed that very few of the DMD boys were able to complete with a full score all the age appropriate items. In conclusion, our study suggests that a revised version of the NSAA can be used in boys from the age of 3 years to obtain information on how young DMD boys acquire new abilities and how this correlates with their peers.

Suitability of North Star Ambulatory Assessment in young boys with Duchenne muscular dystrophy.

The aim of this study was to establish the suitability of the North Star Ambulatory Assessment for use in young boys with Duchenne muscular dystrophy. We studied 147 typically developing and 144 boys affected by Duchenne muscular dystrophy between the ages of 3 and 5 years. More than 85% of the typically developing boys by the age of 4 years had full scores on all the items with total scores ≥33/34. Before the age of 4 years more than 15% of the typically developing boys did not achieve full scores on all the items. Some items, such as standing on one leg, showed significant improvement with age. In contrast, other activities were rarely achieved even in the older boys. Even if there was a progressive increase in scores with age, both total and individual item scores in Duchenne were still far from those obtained in the typically developing children of the same age. Our findings suggest that the North Star Ambulatory Assessment can be reliably used at least from the age of 4 years. Longitudinal natural history data studies are needed to assess possible changes over time and the possible effect of early steroids.

Reliability of the Performance of Upper Limb assessment in Duchenne muscular dystrophy.

The Performance of Upper Limb was specifically designed to assess upper limb function in Duchenne muscular dystrophy. The aim of this study was to assess (1) a cohort of typically developing children from the age of 3years onwards in order to identify the age when the activities assessed in the individual items are consistently achieved, and (2) a cohort of 322 Duchenne children and young adults to establish the range of findings at different ages. We collected normative data for the scale validation on 277 typically developing subjects from 3 to 25years old. A full score was consistently achieved by the age of 5years. In the Duchenne cohort there was early involvement of the proximal muscles and a proximal to distal progressive involvement. The scale was capable of measuring small distal movements, related to activities of daily living, even in the oldest and weakest patients. Our data suggest that the assessment can be reliably used in both ambulant and non ambulant Duchenne patients in a multicentric setting and could therefore be considered as an outcome measure for future trials.

Early neurodevelopmental assessment in Duchenne muscular dystrophy.

The aim of this study was to assess neurodevelopmental profile in young boys affected by Duchenne muscular dystrophy and to establish the correlation between neurodevelopmental findings, and the type and site of mutations. A structured neurodevelopmental assessment (Griffiths Scale of Mental Development) was performed in 81 DMD boys before the age of four years (range: 7-47 months). The mean total DQ was 87 (SD 15.3). Borderline DQ (between 70 and 84) was found in 32% and DQ below 70 in 12.3% of the patients. Children with mutations upstream or in exon 44 had higher DQ than those with mutations downstream exon 44 which are associated with involvement of dystrophin isoforms expressed at high levels in brain. The difference was significant for total and individual subscale DQ with the exception of the locomotor subscale. Items, such as ability to run fast, or getting up from the floor consistently failed in all children, irrespective of the age or of the site of mutation. Our results help to understand the possible different mechanisms underlying the various aspects of neurodevelopmental delay, suggesting that the involvement of brain dystrophin isoforms may cause a delay in the maturation of coordination and dexterity.

North Star Ambulatory Assessment, 6-minute walk test and timed items in ambulant boys with Duchenne muscular dystrophy.

The North Star Ambulatory Assessment is a functional scale specifically designed for ambulant boys affected by Duchenne muscular dystrophy (DMD). Recently the 6-minute walk test has also been used as an outcome measure in trials in DMD. The aim of our study was to assess a large cohort of ambulant boys affected by DMD using both North Star Assessment and 6-minute walk test. More specifically, we wished to establish the spectrum of findings for each measure and their correlation. This is a prospective multicentric study involving 10 centers. The cohort included 112 ambulant DMD boys of age ranging between 4.10 and 17 years (mean 8.18±2.3 DS). Ninety-one of the 112 were on steroids: 37/91 on intermittent and 54/91 on daily regimen. The scores on the North Star assessment ranged from 6/34 to 34/34. The distance on the 6-minute walk test ranged from 127 to 560.6 m. The time to walk 10 m was between 3 and 15 s. The time to rise from the floor ranged from 1 to 27.5 s. Some patients were unable to rise from the floor. As expected the results changed with age and were overall better in children treated with daily steroids. The North Star assessment had a moderate to good correlation with 6-minute walk test and with timed rising from floor but less with 10 m timed walk/run test. The 6-minute walk test in contrast had better correlation with 10 m timed walk/run test than with timed rising from floor. These findings suggest that a combination of these outcome measures can be effectively used in ambulant DMD boys and will provide information on different aspects of motor function, that may not be captured using a single measure.