Disease Trajectories in the Revised Hammersmith Scale in a Cohort of Untreated Patients with Spinal Muscular Atrophy types 2 and 3.

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS). Objective: In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019). Methods: We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient. Results: RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a's than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex. Conclusions: This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes.

Quantifying Variability in Motor Function in Duchenne Muscular Dystrophy: UK Centiles for the NorthStar Ambulatory Assessment, 10 m Walk Run Velocity and Rise from Floor Velocity in GC Treated Boys.

Background Boys with Duchenne Muscular Dystrophy (DMD) display heterogeneous motor function trajectory in clinics, which represents a significant obstacle to monitoring. OBJECTIVE: In this paper, we present the UK centiles for the North Star Ambulatory Assessment (NSAA), the 10 m walk/run time (10MWR) and velocity (10MWRV), and the rise from floor time (RFF) and velocity (RFFV) created from a cohort of glucocorticoid treated DMD boys between the age of 5 and 16 years. METHODS: Participants were included from the UK NorthStar registry if they had initiated steroids (primarily deflazacorts/prednisolone, intermittent/daily) and were not enrolled in an interventional trial. Assessments were included if the participant had a complete NSAA, the timed tests had been completed or the corresponding items were 0, or the participant was recorded as non-ambulant, in which case the NSAA was assumed 0. RESULTS: We analysed 3987 assessments of the NSAA collected from 826 participants. Of these, 1080, 1849 and 1199 were imputed as 0 for the NSAA, RFFV and 10MWRV respectively. The 10th, 25th, 50th, 75th and 90th centiles were presented. The NSAA centiles showed a peak score of 14, 20, 26, 30 and 32 respectively, with loss of ambulation at 10.7, 12.2 and 14.3 years for the 25th, 50th and 75th centiles, respectively. The centiles showed loss of rise from floor at 8.6, 10.1 and 11.9 years and a loss of 10MWR of 0 at 8.9, 10.3 and 13.8 years for the 25th, 50th and 75th centiles, respectively. The centiles were pairwise less correlated than the raw scores, suggesting an increased ability to detect variability in the DMD cohort. CONCLUSIONS: The NSAA, 10MWR and RFF centiles may provide insights for clinical monitoring of DMD boys, particularly in late ambulatory participants who are uniformly declining. Future work will validate the centiles in national and international natural history cohorts.

Starting the conversation on gene therapy for phenylketonuria: Current perspectives of patients, caregivers, and advocates.

Phenylketonuria (PKU) is a rare genetic condition caused by inborn error(s) in the gene for the enzyme phenylalanine hydroxylase. Resulting loss of phenylalanine (Phe) metabolism requires strict dietary therapy and/or medication to prevent toxic accumulation of Phe. Novel investigational therapies, including gene therapies that aim to address underlying causes of PKU, are now entering clinical trials. However, perceptions of this technology in the PKU community have not been assessed. We conducted a qualitative survey recruiting adult patients, caregivers, and patient advocates from the US and 3 EU countries to assess the impact of living with PKU and the perceptions of gene therapy. Telephone interviews were conducted for up to 60 min following a standardized discussion guide. Interviewers classified each participant by their level of knowledge regarding gene therapy as either: low (little or no prior awareness); moderate (awareness of gene therapy as a concept in PKU); or high (working knowledge of gene therapy, e.g., vectors). In total, 33 participants were recruited (patients, n = 24; caregivers, n = 5; advocates, n = 4). The patient sample was well balanced among age groups, sex, and US/EU geographies. The participants' experiences and burden of living with PKU were largely negative, characterized by frustrations with current management consistent with prior reports. Most participants (n = 18/33) were identified as displaying moderate gene-therapy knowledge, 10/33 as displaying high knowledge, and 5/33 as displaying low knowledge. Both positive and negative perceptions were observed; positive perceptions were often linked to "hope" that gene therapy may represent a cure, whereas negative perceptions were linked to the "uncertainty" of outcomes. High knowledge of gene therapy appeared to trend with negative perceptions; 7/10 participants from this group reported high levels of concern over gene therapy. In contrast, participants who displayed low knowledge reported low (n = 3/5) or moderate (n = 2/5) concern, with predominantly positive perceptions. These data highlight the need for education around the theoretical risk:benefit profile of gene therapy. Despite current unknowns around gene therapy, our study demonstrates the important role of healthcare providers as educators who can use available data to provide balanced information to patients and caregivers.

Dietary intake of four artificial sweeteners by Irish pre-school children.

In spite of rigorous pre- and post-market reviews of safety, there remains a high level of debate regarding the use of artificial sweeteners in foods. Young children are of particular interest when assessing food chemical exposure as a result of their unique food consumption patterns and comparatively higher exposure to food chemicals on a body weight basis when compared with the general population. The present study examined the intakes of four intense sweeteners (acesulfame K, aspartame, saccharin, sucralose) in the diets of children aged 1-4 years using food consumption and sweetener presence data from the Irish National Pre-school Nutrition Survey (2010-11) and analytical data for sweetener concentration in foods obtained from a national testing programme. Four exposure assessment scenarios were conducted using the available data on sweetener occurrence and concentration. The results demonstrated that the mean daily intakes for all four sweeteners were below the acceptable daily intake (ADI) (17-31%), even considering the most conservative assumptions regarding sweetener presence and concentration. High consumer intakes (P95) were also below the ADI for the four sweeteners when more realistic estimates of exposure were considered. Both sweetener occurrence and concentration data had a considerable effect on reducing the estimated intake values, with a combined reduction in intakes of 95% when expressed as a proportion of the ADI. Flavoured drinks were deemed to be a key contributor to artificial sweetener intakes in this population cohort. It was concluded that there is no health risk to Irish pre-school children at current dietary intake levels of the sweeteners studied.