The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed ...clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them.
We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES).
997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported.
Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT.
ID number NCT01193075.
Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this ...STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US.
STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes vg/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed).
From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p<0·0001). 31 (97%, 95% CI 91–100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8–44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 67% of 33), upper respiratory infection (11 33%), and increased alanine aminotransferase (nine 27%). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study.
STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline.
Novartis Gene Therapies.
Background
Family‐centred care (FCC) is recognized as the model of best practice for the provision of services for children who have physical disabilities and their families.
Objective
To assess the ...overall perception of FCC provided in an Italian network of 17 rehabilitation services, as perceived by parents of children with cerebral palsy and professionals, and to explore whether children, families, service providers and service‐related characteristics influence parent satisfaction regarding service provision in an FCC practice.
Methods
The Measure of Processes of Care (MPOC‐20) for parents/caregivers and the Measure of Processes of Care for Service Providers (MPOC‐SP) for healthcare providers were used. For the purposes of the study, an ad hoc information form was developed to collect information concerning children, families, service providers and services.
Results
A total of 382 parents/caregivers and 269 healthcare providers completed the MPOC questionnaires. Parents and service providers both identified the domains for enabling partnerships and interpersonal sensitivity as a strength, while the domain relating to general information was always scored the lowest. An advanced maternal age, being a single parent, being unemployed and having lower socio‐economic status were factors identified as individually predictive of lower FCC scores on the MPOC‐20. Higher intensity treatment, inpatient services, primary healthcare settings and settings identified with limited financial resources and reduced space/time for each family were other variables significantly associated with less favourable MPOC‐20 ratings.
Conclusions
The perception of FCC provided was fairly positive, with some areas of improvement, such as the domain of provision of information. Professionals should, therefore, provide better communication and take more time in giving information and attention to parents. Potential sources of variation in parent perceptions of FCC based on family characteristics and the organization of services highlight the importance the need to support services through the provision of greater financial and human resources.
Abstract Gait pattern classification may assist in clinical decision making and cluster analysis (CA) has been often adopted to this aim. The goal of this study was to identify, through CA, typical ...walking patterns in a group of 21 young subjects with CMT1A, a hereditary progressive neuropathy, and to study possible correlation with the disease's clinical status. The protocol included kinematic/kinetic analysis of natural walking and more demanding locomotor tasks, i.e. toe- and heel-walking. Hierarchical cluster analysis was carried out on parameters related to primary signs (foot-drop and push-off deficit) and, separately, to compensatory mechanisms at proximal (pelvis, hip and knee) or distal (ankle) level. CA on primary signs during natural walking identified three clusters: (1) pseudo-normal patients (PN), not significantly different from controls; (2) patients showing only foot-drop (FD); (3) patients with foot-drop and push-off deficit (FD&POD). Patients belonging to the PN subgroup showed distal abnormalities during heel-walking. The FD&POD subgroup was associated to a significantly worse clinical score (CMTES, p < 0.05). The main compensatory strategies, which occurred independently from primary clusterization, included augmented hip/knee flexion in swing (steppage) and early ankle plantarflexion at mid stance (vaulting). We concluded that, although a number of young CMT1A patients do not show typical primary deviations during natural walking, they do show significant abnormalities in more demanding locomotor tasks that should be therefore considered. It is also hypothesized that progression of this degenerative condition may be associated to the migration of patients to more severe clusters, with possible appearance of compensatory strategies.
Triethyloxonium tetrafluoroborate derivatization combined with direct headspace (HS) or SPME-gas chromatography-mass spectrometry (GC-MS) is proposed here for the simultaneous determination of ...nitrite and nitrate in seawater at micromolar level after conversion to their corresponding volatile ethyl-esters (EtO-NO and EtO-NO(2)). Isotopically enriched nitrite (15)N and nitrate (15)N are employed as internal standards and for quantification purposes. HS-GC-MS provided instrumental detection limits of 0.07 μM NO(2)(-) and 2 μM NO(3)(-). Validation of the methodology was achieved by determination of nitrite and nitrate in MOOS-1 (Seawater Certified Reference Material for Nutrients, NRC Canada), yielding results in excellent agreement with certified values. All critical aspects connected with the potential inter-conversion between nitrite and nitrate (less than 10%) were evaluated and corrected for by the use of the isotopically enriched internal standard.
Abstract Some neurodegenerative diseases at early stage may not drastically affect basic gait ability, whereas more demanding locomotor tasks are more prone to disease-induced abnormalities. In this ...study, we evaluated the interday test–retest reliability, 4–6 weeks apart, of instrumented movement analysis on a group of 20 subjects with Charcot–Marie–Tooth (CMT) disease considering a set of kinematic and kinetic curves and related parameters obtained during natural walking (NW) and faster walking, heel and toe-walking, step ascending and descending. Results showed that the reliability was good for NW, with the exception of trunk curves, pelvic tilt and EMG profiles (moderate reliability), and trunk ROM in sagittal/transverse plane (poor reliability). Comparing our results with literature, CMT patients did not present a greater variability during NW than healthy subjects or patients with diseases of CNS. Additional locomotor tasks showed a slight reduction of reliability, although the moderate-to-good level shown in NW was almost never reduced to poor. Most of SEM values (absolute measurement errors) were smaller than 5°, a clinically acceptable threshold. In particular THS, an ankle joint related parameter computed across heel and toe-walking tasks, showed an optimal reliability (ICC = 0.95, SEM = 2.7°) and correlation with CMT clinical scores. Toe and heel-walking and step ascending tasks maximised the number of parameters with a moderate-to-good correlation with patients’ clinical status. We concluded that, in addition to natural walking, more challenging locomotor tasks are good candidates to provide reliable and sensitive outcome measures for CMT patients.
In hemiplegic children, the recognition of the activity limitation pattern and the possibility of grading its severity are relevant for clinicians while planning interventions, monitoring results, ...predicting outcomes.
Aim of the study is to examine the reliability and validity of Besta Scale, an instrument used to measure in hemiplegic children from 18 months to 12 years of age both grasp on request (capacity) and spontaneous use of upper limb (performance) in bimanual play activities and in ADL.
Psychometric analysis of reliability and of validity of the Besta scale was performed.
Outpatient study sample
Reliability study: A sample of 39 patients was enrolled. The administration of Besta scale was video-recorded in a standardized manner. All videos were scored by 20 independent raters on subsequent viewing. 3 raters randomly selected from the 20-raters group rescored the same video two years later for intra-rater reliability. Intra and inter-rater reliability were calculated using Intraclass Correlation Coefficient (ICC) and Kendall's coefficient (K), respectively. Internal consistency reliability was assessed using Alpha's Chronbach coefficient. Validity study: a sample of 105 children was assessed 5 times (at t0 and 2, 3, 6 and 12 months later) by 20 independent raters. Each patient underwent at the same time to QUEST and Besta scale administration and assessment. Criterion validity was calculated using rho-Pearson coefficient.
Reliability study: The inter-rater reliability calculated with Kendall's coefficient resulted moderate K=0.47. The intra-rater (or test-retest) reliability for 3 raters was excellent (ICC=0.927). The Cronbach's alpha for internal consistency was 0.972. Validity study: Besta scale showed a good criterion validity compared to QUEST increasing by age and severity of impairment. Rho Pearson's correlation coefficient r was 0.81 (P<0.0001). Limitations. Besta scales in infants finds hard to distinguish between mild to moderately impaired hand function.
Besta scale scoring system is a valid and reliable tool, utilizable in a clinical setting to monitor evolution of unimanual and bimanual manipulation and to distinguish hand's capacity from performance.
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