BACKGROUND AND OBJECTIVES:Spinal and bulbar muscular atrophy (SBMA) is a rare, slowly progressive, and debilitating disease without effective treatments available. Lack of reliable biomarkers and sensitive outcome measures makes clinical research conduct challenging. The primary objective of this study was to identify clinically meaningful and statistically sensitive outcome measures enabling the evaluation of therapeutic interventions in late-stage clinical trials. METHODS:This study was a meta-analysis of SBMA patient-level data from 6 observational studies conducted in Italy, South Korea, Denmark, United Kingdom, Japan, and United States. Patients with confirmed SBMA genetic diagnosis and differing severity were enrolled following individual site protocols. Routine assessments were performed longitudinally for approximately 3 years, including one or more clinical outcomes, such as SBMA functional rating scale (SBMAFRS), 6-minute walk test (6MWT), quantitative muscle testing (QMT), and Adult Myopathy Assessment Tool (AMAT). A modified scale, m-SBMAFRS, was derived by including only lower limb and trunk subscales having lower variability and larger effect size compared with the others. Changes from baseline at follow-up time points were calculated for all measures, and percent changes using random slope models were calculated to compare clinical measure performances. A survey conducted on 196 patients by the Coordination of Rare Diseases at Sanford (CoRDS), elucidating the impact of specific disease aspects on patients' lives, was also evaluated to corroborate these research outcomes. RESULTS:This global SBMA dataset analyzed data from 278 men (mean age = 59.7 ± 10.8 years, mean disease duration = 17.7 ± 11.9 years). Patients progressed on SBMAFRS (-4.7 ± 6.2 points after 38 months with 1-year standard response mean [SRM] = 0.6) and 6MWT (distance walked decreased by -53.2 ± 87.0 meters after 26 months with 1-year SRM = 0.5). These measures showed lower variability and larger effect size than AMAT and QMT (1-year SRM = 0.1 and -0.2, respectively) and confirmed SBMA linear progression across a range of disease stages. The m-SBMAFRS also showed a significant yearly decline of 0.9 ± 1.5 points (SRM = 0.6) and more consistent performance with less variability across clinical sites. The CoRDS survey confirmed the relevance of lower limb strength and mobility, which correlated with higher quality-of-life metrics and were reported by patients as predominant disease issues. DISCUSSION:We generated a comprehensive global SBMA dataset, enabling the identification of sensitive functional end points for clinical trials. Possible limitations relate to data collection nuances across sites that a single study protocol could override.

Background We aimed to investigate the clinical features of a large cohort of patients with myelin protein zero (MPZ)-related neuropathy, focusing on the five main mutation clusters across Italy. Methods We retrospectively gathered a minimal data set of clinical information in a series of patients with these frequent mutations recruited among Italian Charcot-Marie-Tooth (CMT) registry centres, including disease onset/severity (CMTES-CMT Examination Score), motor/sensory symptoms and use of orthotics/aids. Results We collected data from 186 patients: 60 had the p.Ser78Leu variant ('classical' CMT1B; from Eastern Sicily), 42 the p.Pro70Ser (CMT2I; mainly from Lombardy), 38 the p.Thr124Met (CMT2J; from Veneto), 25 the p.Ser44Phe (CMT2I; from Sardinia) and 21 the p.Asp104ThrfsX13 (mild CMT1B; from Apulia) mutation. Disease severity (CMTES) was higher (p<0.001) in late-onset axonal forms (p.Thr124Met=9.26.6; p.Ser44Phe=7.8 +/- 5.7; p.Pro70Ser=7.6 +/- 4.8) compared with p.Ser78Leu (6.1 +/- 3.5) patients. Disease progression (Delta CMTES/year) was faster in the p.Pro70Ser cohort (0.8 +/- 1.0), followed by p.Ser44Phe (0.7 +/- 0.4), p.Thr124Met (0.4 +/- 0.5) and p.Ser78Leu (0.2 +/- 0.4) patients. Disease severity (CMTES=1.2 +/- 1.5), progression (Delta CMTES/year=0.1 +/- 0.4) and motor involvement were almost negligible in p.Asp104ThrfsX13 patients, who, however, frequently (78%, p<0.001) complained of neuropathic pain. In the other four clusters, walking difficulties were reported by 69-85% of patients, while orthotic and walking aids use ranged between 40-62%and 16-28%, respectively. Conclusions This is the largest MPZ (and late-onset CMT2) cohort ever collected, reporting clinical features and disease progression of 186 patients from five different clusters across Italy. Our findings corroborate the importance of differentiating between 'classical' childhood-onset demyelinating, late-onset axonal and mild MPZ-related neuropathy, characterised by different pathomechanisms, in view of different therapeutic targets.

Background Shoe inserts, orthopaedic shoes, ankle-foot orthoses (AFOs) are important devices in Charcot-Marie-Tooth disease (CMT) management, but data about use, benefits and tolerance are scanty.Methods We administered to Italian CMT Registry patients an online ad hoc questionnaire investigating use, complications and perceived benefit/tolerability/emotional distress of shoe inserts, orthopaedic shoes, AFOs and other orthoses/aids. Patients were also asked to fill in the Quebec User Evaluation of Satisfaction with assistive Technology questionnaire, rating satisfaction with currently used AFO and related services.Results We analysed answers from 266 CMT patients. Seventy per cent of subjects were prescribed lower limb orthoses, but 19% did not used them. Overall, 39% of subjects wore shoe inserts, 18% orthopaedic shoes and 23% AFOs. Frequency of abandonment was high: 24% for shoe inserts, 28% for orthopaedic shoes and 31% for AFOs. Complications were reported by 59% of patients and were more frequently related to AFOs (69%). AFO users experienced greater emotional distress and reduced tolerability as compared with shoe inserts (p<0.001) and orthopaedic shoes (p=0.003 and p=0.045, respectively). Disease severity, degree of foot weakness, customisation and timing for customisation were determinant factors in AFOs' tolerability. Quality of professional and follow-up services were perceived issues.Conclusions The majority of CMT patients is prescribed shoe inserts, orthopaedic shoes and/or AFOs. Although perceived benefits and tolerability are rather good, there is a high rate of complications, potentially inappropriate prescriptions and considerable emotional distress, which reduce the use of AFOs. A rational, patient-oriented and multidisciplinary approach to orthoses prescription must be encouraged.

Sleep abnormalities have been reported in Charcot–Marie–Tooth disease (CMT), but data are scanty. We investigated their presence and correlation in a large CMT patients’ series. Epworth Sleepiness Scale (ESS) and Pittsburgh Sleep Quality Index (PSQI) were administered to CMT patients of the Italian registry and controls. ESS score > 10 indicated abnormal daytime somnolence, PSQI score > 5 bad sleep quality. We analyzed correlation with disease severity and characteristics, Hospital Anxiety and Depression Scale (HADS), Modified Fatigue Impact Scale (MFIS), Body Mass Index, drug use. ESS and PSQI questionnaires were filled by 257 and 253 CMT patients, respectively, and 58 controls. Median PSQI score was higher in CMT patients than controls (6 vs 4, p = 0.006), with no difference for ESS score. Abnormal somnolence and poor sleep quality occurred in 23