Martin B. Delatycki

Description:The reference 25 is incorrect. The correct reference is: De Leener B, Levy S, Dupont SM, Fonov VS, Stikov N, Louis Collins D, Callot V, Cohen-Adad J. SCT: Spinal Cord Toolbox, an open-source software for processing spinal cord MRI data. Neuroimage 2017. In the Author Contribution, Adam J. Schwarz should be credited for the Investigation and Project administration.

Description:Objective: Variants in the homeostatic iron regulator (HFE) gene are prevalent among individuals of European ancestry and have been linked to an increased risk of dementia. This study aimed to evaluate the effects of HFE p.Cys282Tyr and p.His63Asp variants on serum ferritin levels and the incidence of dementia in a cohort of initially healthy older adults. Methods: This prospective longitudinal study used data from the Aspirin in Reducing Events in the Elderly trial. Participants had no history of cardiovascular disease, dementia, or cognitive decline at enrollment. Genotyping for HFE p.Cys282Tyr and p.His63Asp variants was conducted using microarrays, and baseline serum ferritin concentrations were measured in peripheral blood samples. Dementia diagnoses were confirmed by an adjudication committee over a median follow-up of 6.4 years. Associations were evaluated using Cox proportional hazards models adjusted for related covariates. Results: The study included 12,174 unrelated, healthy participants of European ancestry aged 70 years or older, comprising 5,583 men (45.9%) and 6,591 women (54.1%). The median age was 73.7 years (interquartile range [IQR]: 71.6-76.9) for men and 73.9 years (IQR: 71.7-77.5) for women. Compared with the wild-type group, men with p.Cys282Tyr+/+ (p = 0.048) and p.Cys282Tyr+/p.His63Asp + genotypes (p < 0.001) had significantly higher baseline ferritin levels. Women with p.His63Asp+/+ (p = 0.015) and p.Cys282Tyr+/p.His63Asp+ (p < 0.001) genotypes also exhibited elevated ferritin levels. No significant association was observed between baseline serum ferritin levels and dementia risk. However, men with p.His63Asp+/+ genotype had a significantly higher risk of incident dementia (adjusted hazard ratio = 2.39, 95% CI 1.25-4.57, p = 0.009) compared with those without HFE variations. This association was not observed in women. Conclusions: Among initially healthy older adults, HFE p.His63Asp homozygosity was associated with a higher risk of incident dementia in men but not women. These findings highlight a potential sex-specific genetic risk factor for dementia and warrant further research into the underlying mechanisms linking p.His63Asp and dementia.

Description:Friedreich ataxia (FRDA) is a rare multisystem, life-limiting disease and is the most common early-onset inherited ataxia in populations of European, Arab and Indian descent. In recent years, substantial progress has been made in dissecting the pathogenesis and natural history of FRDA, and several clinical trials have been initiated. A particularly notable recent achievement was the approval of the nuclear factor erythroid 2-related factor 2 activator omaveloxolone as the first disease-specific therapy for FRDA. In light of these developments, we review milestones in FRDA translational and clinical research over the past 10 years, as well as the various therapeutic strategies currently in the pipeline. We also consider the lessons that have been learned from failed trials and other setbacks. We conclude by presenting a global roadmap for future research, as outlined by the recently established Friedreich's Ataxia Global Clinical Consortium, which covers North and South America, Europe, India, Australia and New Zealand.

Description:Background and Objectives: The Royal Australian College of General Practice recommends that all women contemplating pregnancy or in early pregnancy should be offered reproductive genetic carrier screening (RGCS). In November 2023, a new Medicare item number was introduced for RGCS to detect cystic fibrosis (CF), spinal muscular atrophy (SMA) and fragile X syndrome (FXS) carrier status. The role of general practice in offering RGCS is recognised as being of crucial importance, but only a minority of general practitioners (GPs) are offering such screening. This study investigates the facilitators and barriers to offering RGCS in general practice. Method: Fifteen Victorian GPs who had offered RGCS for CF, SMA and FXS participated in semi-structured telephone interviews. A behavioural change framework was used for this study. Results: Barriers to offering screening (eg out-of-pocket costs, low frequency of preconception care and lack of GP education) mapped predominantly onto the 'opportunity' domain of the behaviour change framework. Discussion: Reducing out-of-pocket costs and increasing the provision of preconception care and GP education will provide more people with the opportunity to make informed choices about participation in RGCS.

Description:Background: Facioscapulohumeral muscular dystrophy (FSHD) is a rare, progressive muscle disease with no available disease-modifying therapy. Creatine monohydrate (CrM) has been shown to improve muscle strength in individuals with muscular dystrophies but has not been tested in young people with FSHD. This study aimed to explore the efficacy of CrM on motor function in children with FSHD. Methods: In a randomized placebo-controlled double-blind crossover trial, powdered CrM at a dose of 100 mg/kg/day (maximum 10 g daily) was compared with placebo in two 12-week treatment periods with a 6-week washout between crossover arms. The primary outcome measure was the Motor Function Measure for Neuromuscular Disease (MFM-32) with secondary outcomes assessing safety, endurance, strength, patient-reported outcome measures, and muscle morphology measurements as assessed by whole-body magnetic resonance imaging (MRI). Results: Thirteen children were enrolled (mean (standard deviation, SD) 12.2 (2.67) years of age) and 11 patients completed both trial treatment periods. In an intention-to-treat analysis, no clinically meaningful difference was seen between treatment groups as measured by the mean difference in MFM-32 (0.19, 95% confidence interval (CI) -0.71 to 1.08). However, there was an improvement in 6-minute walk distance of 27.74 m (95% CI -1.41 to 56.88) and trends to improvement in the FSHD-Composite Outcome Measure for Pediatrics (FSHD-COM Peds), 10 meter walk/run, and in MRI measures. There were no serious adverse events. Serum creatinine increased by a mean 12.63 μmol/L (95% CI 1.14 to 24.12) post-CrM treatment, though this was presumed to reflect increased creatinine production. No participants discontinued CrM due to adverse events. Conclusions: CrM is safe and well tolerated in children with FSHD. Although CrM had no effect on motor function as measured by the MFM-32 compared with placebo, there were trends toward improvement in the 6-minute walk distance and other secondary outcome measures. This study confirms the feasibility of conducting clinical trials in children with FSHD. Further assessment of the efficacy of CrM in pediatric FSHD is warranted in a larger randomized controlled clinical trial. Future studies may benefit from stratifying population cohorts according to functional ability or by MRI fat infiltration measurements.