The Growing Role of Telerehabilitation and Teleassessment in the Management of Movement Disorders in Rare Neurological Diseases: A Scoping Review.

Background: People with rare neurological diseases (RNDs) often experience symptoms related to movement disorders, requiring a multidisciplinary approach, including rehabilitation. Telemedicine applied to rehabilitation and symptom monitoring may be suitable to ensure treatment consistency and personalized intervention. The objective of this scoping review aimed to emphasize the potential role of telerehabilitation and teleassessment in managing movement disorders within RNDs. By providing a systematic overview of the available literature, we sought to highlight potential interventions, outcomes, and critical issues. Methods: A literature search was conducted on PubMed, Google Scholar, IEEE, and Scopus up to March 2024. Two inclusion criteria were followed: (1) papers focusing on telerehabilitation and teleassessment and (2) papers dealing with movement disorders in RNDs. Results: Eighteen papers fulfilled the inclusion criteria. The main interventions were home-based software and training programs, exergames, wearable sensors, smartphone applications, virtual reality and digital music players for telerehabilitation; wearable sensors, mobile applications, and patient home video for teleassessment. Key findings revealed positive outcomes in gait, balance, limb disability, and in remote monitoring. Limitations include small sample sizes, short intervention durations, and the lack of standardized protocols. Conclusion: This review highlighted the potential of telerehabilitation and teleassessment in addressing movement disorders within RNDs. Data indicate that these modalities may play a major role in supporting conventional programs. Addressing limitations through multicenter studies, longer-term follow-ups, and standardized protocols is essential. These measures are essential for improving remote rehabilitation and assessment, contributing to an improved quality of life for people with RNDs.

Improving paediatric movement disorders care: Insights on rating scales utilization and clinical practice.

AIM: This exploratory study evaluates rating scale usage by experts from the European Reference Network for Rare Neurological Diseases (ERN-RND) for paediatric MD, considering factors like diagnosis, intellectual disability, age, and transition to adult care. The aim is to propose a preliminary framework for consistent application. METHODS: A multicentre survey among 25 ERN-RND experts from 10 European countries examined rating scale usage in paediatric MD, categorizing MD into acute, non-progressive, and neurodegenerative types. Factors influencing scale choice and the transition to adult care practices were analysed. A comprehensive literature search was conducted to identify the earliest age of application of these scales in paediatric patients. RESULTS: The study identifies various rating scales and establishes their usage frequencies for different MDs. Experts highlighted the need for standardized scales and proposed preliminary evaluation strategies based on clinical contexts. Challenges in applying scales to young, non-cooperative patients were acknowledged. INTERPRETATION: The study recommends developing standardized rating scales for paediatric MDs to improve evaluations and data collection. It suggests potential scales for specific clinical scenarios to better evaluate disease progression. Comprehensive, patient-centred care remains crucial during the transition to adult care, despite the identified challenges. This exploratory approach aims to enhance patient outcomes and care.

Sitting Postural Management to Prevent Migration Percentage Progression in Non-Ambulatory Children with Cerebral Palsy: Randomized Controlled Trial Preliminary Data.

Background/Objectives: To determine whether a sitting position with the femoral heads centered into the acetabulum is more effective than the usual sitting position in preventing migration percentage progression in non-ambulatory children with bilateral cerebral palsy. Methods: This was a multicenter, randomized controlled trial. INCLUSION CRITERIA: spastic or dyskinetic cerebral palsy, Gross Motor Function Classification System level IV-V, age 1-6 years, migration percentage <41%, and informed consent. EXCLUSION CRITERIA: contractures affecting the hip, anterior luxation, previous hip surgery, and lumbar scoliosis. The treatment group sat with their hips significantly abducted to reduce the head into the acetabulum in a customized system for at least five hours/day for two years. Controls sat with the pelvis and lower limbs aligned but the hips less abducted in an adaptive seating system. The primary outcome was migration percentage (MP) progression. Health-related quality of life and family satisfaction were among the secondary outcomes. The study was approved by the local ethics board and conducted in accordance with CONSORT reporting guidelines. CLINICALTRIALS: gov ID: NCT04603625. RESULTS: Overall median MP progression was 1.6 after the first year and 2.5 after the second year. No significant differences were observed between the groups. MP exceeded 40% and 50% in 1.8% and 0% of the experimental group and 5.4% and 3.6% of controls in years 1 and 2, respectively. Both groups expressed satisfaction with the postural system and stable health-related quality of life. Conclusions: MP remained stable over the two-year period in both groups. Considering outliers which progressed over 50%, a more protective trend of the hip-centering sitting approach emerged, but this needs to be confirmed in a final, larger dataset.

Quality of life, functioning and participation of children and adolescents with visual impairment: A scoping review.

BACKGROUND: Vision has a key role in children's neuromotor, cognitive and social development. Children with visual impairment attain developmental milestones at later stages and are at higher risk of developing psychological disorders and social withdrawn. AIMS: We performed a scoping review to summarize the mostly used instruments assessing the impact of visual impairment on quality of life, functioning and participation of children and adolescents. In addition, the main findings of the included studies are discussed. METHODS AND PROCEDURES: We searched for papers assessing quality of life, functioning and participation of children and adolescents with visual impairment from 0 to 18 years old conducted between 2000 and 2023. OUTCOMES AND RESULTS: In total, 69 studies met the inclusion criteria and were included in the review. Child self-report, caregivers-proxy and self-report questionnaires as well as interviews were used. The results showed that quality of life, functioning and participation are significantly reduced in children and adolescents with visual impairment, and that the impact depends on different factors (e.g., severity of the impairment, age). CONCLUSIONS AND IMPLICATIONS: Considering the significant impact of visual impairment on quality of life, functioning and participation on this population, it is fundamental to develop integrated and multi-dimensional assessment programs that evaluate the impact of visual impairment on those dimensions considering different contexts of life (e.g., family, school, leisure time). WHAT THIS PAPER ADDS?: The present review aims to give an overview of what is known about the impact of visual impairment on quality of life, functioning and participation of children and adolescents. We assumed a biopsychosocial perspective which, in line with the definition of health by the International Classification of Functioning, Disability and Health (WHO, 2001), considered how body functions and structures, functioning, participation and environmental factors dynamically interact to define the health, or the disease, status of a person at a certain moment of life. We reported the most used instruments for the assessment of quality of life, participation, and functioning, with a specific interest on Patient-Reported Outcome Measures and self-report measures. By reporting the different instruments used, we gave a broad overview about the available tools that can be used in clinical as well as in research field to assess quality of life, functioning and participation in this population. Additionally, the review of the existing literature allowed us to demonstrate that those dimensions are negatively impacted by visual impairment and thus they should be considered in the assessment programs. Specifically, there is the need to provide more integrated assessment programs that investigate the impact of visual impairment on children and adolescents' social and emotional wellbeing, everyday functioning and social relationship, considering their subjective experience together with the one of caregivers, teachers, health care professionals, and other relevant adults involved in their life. Additionally, it is essential to plan and implement multidimensional assessment programs that consider how all areas of life are differently impacted by visual impairment.

Parent-proxy pediatric CMT quality of life outcome measure: Validation of the Italian version.

BACKGROUND AND AIMS: The parent-proxy reports can offer complementary informations or be the only source of Quality of Life measurement in young children. The aim of this study was to provide and validate the Italian version of the recently published parent-proxy pCMT-QOL for patients aged 8-18 years old, making it available for possible trials in Italian speaking children. METHODS: The English-language instrument was translated and adapted into the Italian language using standard procedures: translation, transcultural adaptation, and back-translation. Parent-proxy pCMT-QOL was administered to parents of patients with a genetic diagnosis of CMT, aged 8-18 years old. All parents were retested 2 weeks later to assess reliability. RESULTS: A total of 21 parents of CMT patients (18 CMT1A, 2 CMT2A, 1 CMT2K) were assessed during their children clinical appointments. The Italian-pCMT-QOL showed a high test-retest reliability; none of the parents had any difficulties with the completion of the questionnaire and no further revisions were necessary after completion. INTERPRETATION: The Italian parent-proxy pCMT-QOL is a reliable, culturally adapted, and comparable version of the original English instrument. This questionnaire will improve the quality of the follow-up and will make it possible to monitor more accurately the severity of the disease in Italian-speaking families.

Development of a Play-Based Motor Learning Approach (A.MO.GIOCO) in Children with Bilateral Cerebral Palsy: Theoretical Framework and Intervention Methodology.

The early intervention of motor training based on specific tasks and parent empowerment represents the new paradigm for the rehabilitation of children with Cerebral Palsy (CP). However, most published studies address the problem of the effectiveness of rehabilitation intervention without describing the treatment methodology or briefly mentioning it. The purpose of the study is to illustrate the development of a play-based motor learning approach titled A.MO.GIOCO (Apprendimento MOtorio nel GIOCO) and its systematization. Fifteen children aged between 2 and 6 years with bilateral CP will be enrolled and treated for 6-8 weeks (48 h). Motor Teaching methods applied by senior therapists have been extensively described, starting from rehabilitation goals and proposed therapeutic play activities, tailored to the functional profile of each child. This child-friendly rehabilitative approach (A.MO.GIOCO) refers to the systemic cognitive model of learning and movement control and is implemented in the context of spontaneous play activities and in the therapist-child-family interaction. In this study the theoretical framework of the approach and the process followed by the therapists to transfer it into rehabilitative practice are highlighted. As a result, an operational guide has been created. Further studies will explore the efficacy of the proposed standardized approach.

Evidence-based management and motor rehabilitation of cerebral palsy children and adolescents: a systematic review.

Background: Evidence regarding the management of several aspects of cerebral palsy improved in recent years. Still, discrepancies are reported in clinical practice. Italian professionals and stakeholders expressed the need of setting up updated, evidenced-based, shared statements, to address clinical practice in cerebral palsy rehabilitation. The objective of the present study was to provide an updated overview of the state of knowledge, regarding the management and motor rehabilitation of children and young people with cerebral palsy, as the framework to develop evidence-based recommendations on this topic. Methods: Guidelines and systematic reviews were searched, relative to evidence-based management and motor treatment, aimed at improving gross motor and manual function and activities, in subjects with cerebral palsy, aged 2-18 years. A systematic search according to the Patients Intervention Control Outcome framework was executed on multiple sites. Independent evaluators provided selection and quality assessment of the studies and extraction of data. Results: Four guidelines, 43 systematic reviews, and three primary studies were included. Agreement among guidelines was reported relative to the general requirements of management and motor treatment. Considering the subject's multidimensional profile, age and developmentally appropriate activities were recommended to set individual goals and interventions. Only a few approaches were supported by high-level evidence (i.e., bimanual therapy and constraint-induced movement therapy to enhance manual performance). Several task-specific active approaches, to improve gross motor function and gait, were reported (mobility and gait training, cycling, backward gait, and treadmill), based on low-level evidence. Increasing daily physical activity and countering sedentary behavior were advised. Based on the available evidence, non-invasive brain stimulation, virtual reality, action-observation therapy, hydrotherapy, and hippotherapy might be complementary to task or goal-oriented physical therapy programs. Conclusion: A multiple-disciplinary family-centered evidence-based management is recommended. All motor rehabilitation approaches to minors affected by cerebral palsy must share the following fundamental characteristics: engaging active involvement of the subject, individualized, age and developmentally appropriate, goal-directed, skill-based, and preferably intensive and time-limited, but suitable for the needs and preferences of the child or young person and their family, and feasible considering the implications for themselves and possible contextual limitations.

Clinical spectrum and frequency of Charcot-Marie-Tooth disease in Italy: Data from the National CMT Registry.

BACKGROUND AND PURPOSE: Data are reported from the Italian CMT Registry. METHODS: The Italian CMT Registry is a dual registry where the patient registers and chooses a reference center where the attending clinician collects a minimal dataset of information and administers the Charcot-Marie-Tooth (CMT) Examination/Neuropathy Score. Entered data are encrypted. RESULTS: Overall, 1012 patients had registered (535 females) and 711 had received a genetic diagnosis. Demyelinating CMT (65.3%) was more common than axonal CMT2 (24.6%) and intermediate CMT (9.0%). The PMP22 duplication was the most frequent mutation (45.2%), followed by variants in GJB1 and MPZ (both ~10%) and MFN2 (3.3%) genes. A relatively high mutation rate in some "rare" genes (HSPB1 1.6%, NEFL 1.5%, SH3TC2 1.5%) and the presence of multiple mutation clusters across Italy was observed. CMT4A was the most disabling type, followed by CMT4C and CMT1E. Disease progression rate differed depending on the CMT subtype. Foot deformities and walking difficulties were the main features. Shoe inserts and orthotic aids were used by almost one-half of all patients. Scoliosis was present in 20% of patients, especially in CMT4C. Recessive forms had more frequently walking delay, walking support need and wheelchair use. Hip dysplasia occurred in early-onset CMT. CONCLUSIONS: The Italian CMT Registry has proven to be a powerful data source to collect information about epidemiology and genetic distribution, clinical features and disease progression of CMT in Italy and is a useful tool for recruiting patients in forthcoming clinical trials.

Disease Progression in Charcot-Marie-Tooth Disease Related to MPZ Mutations: A Longitudinal Study.

OBJECTIVE: The paucity of longitudinal natural history studies in MPZ neuropathy remains a barrier to clinical trials. We have completed a longitudinal natural history study in patients with MPZ neuropathies across 13 sites of the Inherited Neuropathies Consortium. METHODS: Change in Charcot-Marie-Tooth Examination Score (CMTES) and Rasch modified CMTES (CMTES-R) were evaluated using longitudinal regression over a 5-year period in subjects with MPZ neuropathy. Data from 139 patients with MPZ neuropathy were examined. RESULTS: The average baseline CMTES and CMTES-R were 10.84 (standard deviation [SD] = 6.0, range = 0-28) and 14.60 (SD = 7.56, range = 0-32), respectively. A mixed regression model showed significant change in CMTES at years 2-5 (mean change from baseline of 0.87 points at 2 years, p = 0.008). Subgroup analysis revealed greater change in CMTES at 2 years in subjects with axonal as compared to demyelinating neuropathy (mean change of 1.30 points [p = 0.016] vs 0.06 points [p = 0.889]). Patients with a moderate baseline neuropathy severity also showed more notable change, by estimate, than those with mild or severe neuropathy (mean 2-year change of 1.14 for baseline CMTES 8-14 [p = 0.025] vs -0.03 for baseline CMTES 0-7 [p = 0.958] and 0.25 for baseline CMTES ≥ 15 [p = 0.6897]). The progression in patients harboring specific MPZ mutations was highly variable. INTERPRETATION: CMTES is sensitive to change over time in adult patients with axonal but not demyelinating forms of MPZ neuropathy. Change in CMTES was greatest in patients with moderate baseline disease severity. These findings will inform future clinical trials of MPZ neuropathies. ANN NEUROL 2023;93:563-576.

Validation of the Italian version of the pediatric CMT quality of life outcome measure.

The pediatric Charcot-Marie-Tooth (CMT) specific quality of life (QOL) outcome measure (pCMT-QOL) is a recently developed and validated patient-reported measure of health QOL for children with CMT. The aim of this study was to provide and validate an Italian version of the pCMT-QOL. The original English version was translated and adapted into Italian using standard procedures. pCMT-QOL was administered to patients genetically diagnosed with CMT, aged 8 to 18 years. A retest was given 2 weeks later to assess reliability in all patients. A total of 22 patients (median age 14 years, DS 2.5; M:F 1:1) affected with CMT (19 CMT1A, 2 CMT2A, 1 CMT2K) were assessed as part of their clinical visit. The Italian-pCMT-QOL demonstrate a high test-retest reliability. None of the patients experienced difficulty in completing the questionnaire, no further corrections were needed after administration in patients. The Italian-pCMT-QOL is a reliable, culturally adapted and comparable version of the original English pCMT-QOL. This questionnaire is expected to be valuable in monitoring disease progression and useful for future clinical trials in Italian-speaking children with CMT.

Design and custom fabrication of specialized orthoses for the upper-limb stabilization in childhood dyskinesia.

BACKGROUND: Childhood dyskinesia (CD) is a complex movement disorder with components of dystonic and hyperkinetic nature, characterized by involuntary, sometimes stereotypical postures and gestures that are often impossible to control and hinder the execution of willful motion. The standard orthoses for the treatment of neurological diseases, including CD, are generally poorly differentiated for functional characteristics. The application of similar devices for movement disorders is far less generalized because of the very different symptoms, including the incapacity to control rather than initiate movement. OBJECTIVES: This article aims to describe an innovative method to fabricate personalized orthoses for the elbow-wrist joints in CD, taking into account anatomical and functional diversities. It also proposes functional elements to implement the required dynamic postural control. METHODS: Wearable custom-made upper-limb orthoses have been fabricated and preliminarily tested on five patients with CD. Optoelectronic stereophotogrammetry was used as an innovative tool for all-in-one-frame acquisition of limb geometry. A new process for the functional personalization of the orthoses has been developed using shape memory alloys. CONCLUSIONS: The innovative method presented, encompassing data acquisition, virtual design, fabrication, and assembling, overcomes the problems due to the involuntary movements of the patients, which cannot be avoided during the fitting operations, providing comfortable and useful orthoses with minimal nuisance for the patients. Initial tests show that the orthoses were well tolerated by all the subjects; the promising comments of caregivers, together with improvements, were observed by the clinicians using specific clinical scales.

Telerehabilitation and Wellbeing Experience in Children with Special Needs during the COVID-19 Pandemic.

Social distancing due to the COVID-19 pandemic represented a golden opportunity to implement telerehabilitation for clinical groups of children. The present study aims to show the impact that telerehabilitation had on the experience of well-being of children with special needs being treated at the Foundation IRCCS Neurological Institute 'C. Besta' in Milan (Specific Learning Disorders and Cerebral Palsy diagnosis); it aims to do so by comparing it with experiences of those who did not undertake telerehabilitation despite the diagnosis during the pandemic, and with typically developing children. Results show that the three groups differed in the Support, Respect and Learning dimensions of well-being experience. Post hoc comparisons revealed that children with Specific Learning Disorders and Cerebral Palsy scored higher than normotypical children in Support and in Respect scales. Furthermore, children who experienced telerehabilitation showed the highest scores on the Learning scale in comparison with the other two groups. These results support the importance of reorganizing care and assistance by integrating telemedicine, which seems to have fostered a positive experience of well-being in people with special needs, particularly in the perception of a supportive environment that respects psychological needs.

Association Between Body Mass Index and Disability in Children With Charcot-Marie-Tooth Disease.

BACKGROUND AND OBJECTIVES: This study examined the association between body mass index (BMI) and disability in children with Charcot-Marie-Tooth disease (CMT). METHODS: We conducted a cross-sectional analysis of 477 patients with CMT who were 3 to 20 years of age from the Inherited Neuropathy Consortium and 316 age- and sex-matched healthy children from the 1,000 Norms Project. BMI was categorized according to the International Obesity Task Force (IOTF) criteria, and BMI categorization was compared with healthy children. IOTF categories (adult equivalent BMI cut points) were severely underweight (BMI <17 kg/m2), underweight (BMI ≥17-<18.5 kg/m2), healthy weight (BMI ≥18.5-<25 kg/m2), overweight (BMI ≥25-<30 kg/m2), and obese (BMI ≥30 kg/m2). Scores on the 0 to 44-point CMT Pediatric Scale (CMTPedS), a well-validated measure of disability, were examined in relation to BMI. RESULTS: There was a higher proportion of children with CMT categorized as severely underweight (5.7% vs 0.3%), underweight (10.3% vs 5.1%), and obese (7.3% vs 3.8%) (p < 0.05). Fewer children with CMT were categorized as healthy weight (61.8% vs 74.4%) (p < 0.05), and the proportion of overweight (14.9% vs 16.5%) between groups was similar. CMTPedS scores (mean ± SD) for weight categories were as follows: severely underweight 27 ± 9, underweight 20 ± 8, healthy weight 17 ± 9, overweight 17 ± 9, and obese 22 ± 10. Compared to children with a healthy weight with CMT, being severely underweight was associated with being more disabled (p < 0.001), as was being obese (p = 0.015). DISCUSSION: The proportion of children with CMT who are underweight or obese is higher compared to age- and sex-matched healthy children. In children with CMT, being underweight or obese is associated with greater disability, when compared to children with CMT of healthy weight.

Neuro-telehealth for fragile patients in a tertiary referral neurological institute during the COVID-19 pandemic in Milan, Lombardy.

BACKGROUND: Lombardy was severely hit by the COVID-19 pandemic since February 2020 and the Health System underwent rapid reorganization. Outpatient clinics were stopped for non-urgent patients: it became a priority to manage hundreds of fragile neurological patients who suddenly had less reference points. In Italy, before the pandemic, Televisits were neither recognized nor priced. METHODS: At the Fondazione IRCCS Istituto Neurologico C. Besta, we reorganized outpatient clinics to deliver Neuro-telemedicine services, including Televisits and Teleneurorehabilitation, since March 2020. A dedicated Working Group prepared the procedure, tested the system, and designed satisfaction questionnaires for adults and children. RESULTS: After a pilot phase, we prepared a procedure for Telemedicine outpatient clinics which was approved by hospital directions. It included prescription, booking, consenting, privacy and data protection, secure connection with patients (Teams Microsoft 365), electronic report preparation and delivery, reporting, and accountability of the services. During the March-September 2020 period, we delivered 3167 Telemedicine services, including 1618 Televisits, to 1694 patients (972 adults, 722 children) with a wide range of chronic neurological disorders. We successfully administered different clinical assessment and scales. Satisfaction among patients and caregivers was very high. CONCLUSIONS: During the dramatic emergency, we were able to take care of more than 1600 patients by organizing Neuro-telehealth in a few weeks, lessening the impact of the pandemic on fragile patients with chronic neurological disorders; this strategy is now stably embedded in our care pathways. In Italy, Telehealth is at present recognized and priced and is becoming a stable pillar of the health system.

A Retrospective Longitudinal Study in a Cohort of Children With Dyskinetic Cerebral Palsy Treated With Tetrabenazine.

Tetrabenazine has been studied with a variety of hyperkinetic movement disorders, but there is limited and empirical literature on the potential efficacy of tetrabenazine in children with dyskinetic cerebral palsy (DCP). The purpose of this study was to evaluate the efficacy of tetrabenazine in a sample of children with DCP using the Movement Disorders-Childhood Rating Scale 4-18 Revised (MD-CRS 4-18 R). The study is a multicenter retrospective longitudinal study in which the participants were selected from the databases of each Center involved, according to detailed inclusion criteria. The study was performed on 23 children and adolescents (19 male and 4 females; mean age 8.28 years, SD 3.59) with DCP having been evaluated before starting the treatment (baseline), after 6 and 12 months of treatment and in a sub-cohort after >2 years follow-up. A linear mixed model was used to evaluate the effects of the different timings on each MD-CRS 4-18 R Index (Index I, Index II, and Global Index) adding age and type of movement disorder as random effect. A significant clinical improvement related to a reduction of MD-CRS 4-18 R Indexes was detected between the baseline and after 6 and 12 months of treatment. Findings support the efficacy of tetrabenazine in children with DCP through a standardized outcome measure (MD-CRS 4-18 R) and confirm the use of this scale as a suitable tool to detect changes in further randomized clinical trials.

Being adults with cerebral palsy: results of a multicenter Italian study on quality of life and participation.

Cerebral palsy (CP) is still the most common cause of disability developing in infancy. How such a complex disorder affects adult life raises important questions on the critical issues to consider and the most appropriate care pathway right from early childhood. We conducted a multicenter study on a sample of 109 individuals with CP followed up from infancy and recalled for an assessment at ages ranging between 18 and 50 years (mean age 26 years). Semi-structured interviews and specific questionnaires (SF36, LIFE-H and Hollingshead Index) were conducted to assess general psychological state, quality of life, and socio-economic conditions. Our findings showed a globally positive perception of quality of life, albeit with lower scores for physical than for mental health. Our cases generally showed good scores on participation scales, though those with more severe forms scored lower on parameters such as mobility, autonomy, and self-care. These findings were investigated in more depth in interviews, in which our participants painted a picture showing that gradual improvements have been made in several aspects over the years, in the academic attainment and employment, for instance. On the downside, our sample reported persistent limitations on autonomy in daily life. As for the more profound psychological domain, there was evidence of suffering due to isolation and relational difficulties in most cases that had not emerged from the questionnaires. Our data have possible implications for the management of CP during childhood, suggesting the need to avoid an exclusive focus on motor function goals, and to promote strategies to facilitate communication, participation, autonomy, and social relations.

Expanding the phenotypic spectrum of TRIM2-associated Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of distal symmetric polyneuropathies due to progressive and length-dependent degeneration of peripheral nerves. Cranial nerve involvement has been described in association with various CMT-genes mutations, such as GDAP1, TRPV4, MFN2, MTMR2 and EGR2. Compound heterozygous mutations in the TRIM2 gene, encoding an E3 ubiquitin ligase, were previously identified in two patients with early-onset axonal CMT (CMT2). One of them also had bilateral vocal cord paralysis. The aim of this study is to further delineate the phenotypic and molecular genetic features of TRIM2-related CMT. We studied clinical, genetic and neurophysiological aspects of two unrelated CMT2 patients. Genetic analysis was performed by next generation sequencing of a multigene CMT panel. Patients presented with congenital hypotonia and bilateral clubfoot, delayed motor milestones, and severely progressive axonal neuropathy. Interestingly, along with vocal cord paralysis, they exhibited clinical features secondary to the involvement of several other cranial nerves, such as facial weakness, dysphagia, dyspnoea and acoustic impairment. Genetic analysis revealed two novel TRIM2 mutations in each patient. Our results expand the genotypic and phenotypic spectrum of TRIM2 deficiency showing that cranial nerves involvement is a core feature in this CMT2-subtype. Its finding should prompt physicians to suspect TRIM2 neuropathy. Conversely, patients carrying TRIM2 variants should be carefully evaluated for the presence of cranial nerve dysfunction in order to prevent and manage its impact on auditory and respiratory function and nutrition.

Refining clinical trial inclusion criteria to optimize the standardized response mean of the CMTPedS.

The CMT Pediatric Scale (CMTPedS) is a reliable, valid, and responsive clinical outcome measure of disability in children with CMT. The aim of this study was to identify the most responsive patient subset(s), based on the standardized response mean (SRM), to optimize the CMTPedS as a primary outcome measure for upcoming clinical trials. Analysis was based on a 2-year natural history data from 187 children aged 3-20 years with a range of CMT genetic subtypes. Subsets based on age (3-8 years), disability level (CMTPedS score 0-14), and CMT type (CMT1A) increased the SRM of the CMTPedS considerably. Refining the inclusion criteria in clinical trials to younger, mildly affected cases of CMT1A optimizes the responsiveness of the CMTPedS.

Validation of the Italian version of the Charcot-Marie-Tooth disease Pediatric Scale.

The Charcot-Marie-Tooth disease Pediatric Scale (CMTPedS) is a Rasch-built clinical outcome measure of disease severity. It is valid, reliable, and responsive to change for children and adolescents aged 3 to 20 years. The aim of this study was to translate and validate an Italian version of the CMTPedS using a validated framework of transcultural adaptation. The CMTPedS (Italian) was translated and culturally adapted from source into Italian by two experts in CMT with good English language proficiency. The two translations were reviewed by a panel of experts in CMT. The agreed provisional version was back translated into English by a professional translator. The definitive Italian version was developed during a consensus teleconference by the same panel. CMT patients were assessed with the final version of the outcome measure and a subset had a second assessment after 2 weeks to evaluate test-retest reliability. Seventeen patients with CMT aged 5 to 20 years (eight female) were evaluated with the CMTPedS (Italian), and test-retest was performed in three patients. The CMTPedS (Italian) showed a high test-retest reliability. No patient had difficulty in completing the scale. The instructions for the different items were clearly understood by clinicians and therefore the administration of the outcome measure was straight forward and easily understood by the children assessed. The CMTPedS (Italian) will be used for clinical follow-up and in clinical research studies in the Italian population. The data is fully comparable to that obtained from the English language version.

A longitudinal study of CMT1A using Rasch analysis based CMT neuropathy and examination scores.

OBJECTIVE: To evaluate the sensitivity of Rasch analysis-based, weighted Charcot-Marie-Tooth Neuropathy and Examination Scores (CMTNS-R and CMTES-R) to clinical progression in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). METHODS: Patients with CMT1A from 18 sites of the Inherited Neuropathies Consortium were evaluated between 2009 and 2018. Weighted CMTNS and CMTES modified category responses were developed with Rasch analysis of the standard scores. Change from baseline for CMTNS-R and CMTES-R was estimated with longitudinal regression models. RESULTS: Baseline CMTNS-R and CMTES-R scores were available for 517 and 1,177 participants, respectively. Mean ± SD age of participants with available CMTES-R scores was 41 ± 18 (range 4-87) years, and 56% were female. Follow-up CMTES-R assessments at 1, 2, and 3 years were available for 377, 321, and 244 patients. A mixed regression model showed significant change in CMTES-R score at years 2 through 6 compared to baseline (mean change from baseline 0.59 points at 2 years, p = 0.0004, n = 321). Compared to the original CMTES, the CMTES-R revealed a 55% improvement in the standardized response mean (mean change/SD change) at 2 years (0.17 vs 0.11). Change in CMTES-R at 2 years was greatest in mildly to moderately affected patients (1.48-point mean change, 95% confidence interval 0.99-1.97, p < 0.0001, for baseline CMTES-R score 0-9). CONCLUSION: The CMTES-R demonstrates change over time in patients with CMT1A and is more sensitive than the original CMTES. The CMTES-R was most sensitive to change in patients with mild to moderate baseline disease severity and failed to capture progression in patients with severe CMT1A. CLINICALTRIALSGOV IDENTIFIER: NCT01193075.