Phenotypic Variability of Childhood Charcot-Marie-Tooth Disease

IMPORTANCE: Disease severity of childhood Charcot-Marie-Tooth disease (CMT) has not been extensively characterized, either within or between types of CMT to date. OBJECTIVE: To assess the variability of disease severity in a large cohort of children and adolescents with CMT. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study was conducted among 520 children and adolescents aged 3 to 20 years at 8 universities and hospitals involved in the Inherited Neuropathies Consortium between August 6, 2009, and July 31, 2014, in Australia, Italy, the United Kingdom, and the United States. Data analysis was conducted from August 1, 2014, to December 1, 2015. MAIN OUTCOMES AND MEASURES: Scores on the Charcot-Marie-Tooth Disease Pediatric Scale (CMTPedS), a well-validated unidimensional clinical outcome measure to assess disease severity. This instrument includes 11 items assessing fine and gross motor function, sensation, and balance to produce a total score ranging from 0 (unaffected) to 44 (severely affected). RESULTS: Among the 520 participants (274 males) aged 3 to 20 years, CMT type 1A (CMT1A) was the most prevalent type (252 [48.5%]), followed by CMT2A (31 [6.0%]), CMT1B (15 [2.9%]), CMT4C (13 [2.5%]), and CMTX1 (10 [1.9%]). Disease severity ranged from 1 to 44 points on the CMTPedS (mean [SD], 21.5 [8.9]), with ankle dorsiflexion strength and functional hand dexterity test being most affected. Participants with CMT1B (mean [SD] CMTPedS score, 24.0 [7.4]), CMT2A (29.7 [7.1]), and CMT4C (29.8 [8.6]) were more severely affected than those with CMT1A (18.9 [7.7]) and CMTX1 (males: 15.3 [7.7]; females: 13.0 [3.6]) (P < .05). Scores on the CMTPedS tended to worsen principally during childhood (ages, 3-10 years) for participants with CMT4C and CMTX1 and predominantly during adolescence for those with CMT1B and CMT2A (ages, 11-20 years), while CMT1A worsened consistently throughout childhood and adolescence. For individual items, participants with CMT4C recorded more affected functional dexterity test scores than did those with all other types of CMT (P < .05). Participants with CMT1A and CMTX1 performed significantly better on the 9-hole peg test and balance test than did those with all other types of CMT (P < .05). Participants with CMT2A had the weakest grip strength (P < .05), while those with CMT2A and CMT4C exhibited the weakest ankle plantarflexion and dorsiflexion strength, as well as the lowest long jump and 6-minute walk test distances (P < .05). Multiple regression modeling identified increasing age (r = 0.356, β = 0.617, P < .001) height (r = 0.251, β = 0.309, P = .002), self-reported foot pain (r = 0.162, β = .114, P = .009), and self-reported hand weakness (r = 0.243, β = 0.203, P < .001) as independent predictors of disease severity. CONCLUSIONS AND RELEVANCE: These results highlight the phenotypic variability within CMT genotypes and mutation-specific manifestations between types. This study has identified distinct functional limitations and self-reported impairments to target in future therapeutic trials

Natural history of Charcot-Marie-Tooth disease during childhood

OBJECTIVE: To determine the rate of disease progression in a longitudinal natural history study of children with Charcot-Marie-Tooth disease (CMT). METHODS: 206 (103 female) participants aged 3-20 years enrolled in the Inherited Neuropathies Consortium were assessed at baseline and 2-years. Demographic, anthropometric, and diagnostic information were collected. Disease progression was assessed with the CMT Pediatric Scale (CMTPedS), a reliable Rasch-built linearly weighted disability scale evaluating fine and gross motor function, strength, sensation, and balance. RESULTS: On average CMTPedS Total scores progressed at a rate of 2.4±4.9 over 2-years (14% change from baseline, p<0.001). There was no difference between males and females (mean difference 0.5, 95%CI -0.9 to 1.9, p=0.49). The most responsive CMTPedS items were dorsiflexion strength (z-score change: -0.3, 95% CI -0.6 to -0.05, p=0.02), balance (z-score change: -1.0, 95% CI -1.9 to -0.09, p=0.03), and long jump (z-score change: -0.4, 95% CI -0.7 to -0.02, p=0.04). Of the most common genetic subtypes, 111 participants with CMT1A/PMP22 duplication progressed by 1.8±4.2 (12% change from baseline, p<0.001), nine participants with CMT1B/MPZ mutation progressed by 2.2±5.1 (11% change), six participants with CMT2A/MFN2 mutation progressed by 6.2±7.9 (23% change), and seven participants with CMT4C/SH3TC2 mutations progressed by 3.0±4.5 (12% change). Participants with CMT2A progressed faster than CMT1A (mean difference -4.4, 95%CI -8.1 to -0.8, p=0.02). Children with CMT1A progressed consistently through early childhood (3-10 years) and adolescence (11-20 years) (mean difference 1.1, 95%CI -0.6 to 2.7, p=0.19) while CMT2A appeared to progress faster during early childhood than adolescence (mean difference 10.0, 95%CI -2.2 to 22.2, p=0.08). INTERPRETATION: Using the CMTPedS as an outcome measure of disease severity, children with CMT progress at a significant rate over 2-years. Understanding the rate at which children with CMT deteriorate is essential for adequately powering trials of disease-modifying interventions. This article is protected by copyright. All rights reserved

The periodicity of sleep duration &amp;ndash; an infradian rhythm in spontaneous living

Shi Ngar Wong, Mark Halaki, Chin Moi ChowDiscipline of Exercise and Sport Science, University of Sydney, Sydney, NSW, AustraliaAbstract: The sleep&amp;ndash;wake cycle is a process not only dictated by homeostatic and circadian factors but also by social and environmental influences. Thus, the total sleep time partly reflects sleep need, which is integral to the dynamics of sleep loss recovery. This study explored the nature of the observed oscillations in total sleep time in healthy adults under spontaneous living conditions. Actigraph-measured sleep data for 13 healthy young male adults were collected over 14 consecutive days and analyzed for habitual sleep duration. The total sleep time periodicity was modeled using the cosinor method for each individual across the 14 days. The findings confirm the existence of periodicity in habitual sleep duration as there were clear periodic patterns in the majority of the participants. Although exclusive to each individual, the observed oscillations may be a resultant response of homeostatic sleep need, circadian timing, and/or social and environmental influences. These findings instigate further indepth studies into the periodicity of sleep duration in healthy individuals to provide a better understanding of sleep need in short versus long sleepers, in predicting work performance, and reducing sleepiness-related accidents following shift work, and how this periodicity may impact sleep treatment outcome in clinical populations.Keywords: sleep regulation, homeostasis, habitual sleep, spontaneous living, healthy male

Revision of the shoulder normalization tests is required to include rhomboid major and teres major

The four “Shoulder Normalization Tests” were found previously to be a parsimonious set of isometric tests that produce maximal voluntary isometric contractions (MVIC) in the supraspinatus, infraspinatus, subscapularis, trapezius, serratus anterior, deltoid, latissimus dorsi, and pectoralis major [Boettcher et al. (2008). J Orthop Res 26:1591–1597]. However, these tests have not been validated for rhomboid major and teres major. In the current study, these Shoulder Normalization Tests were evaluated and compared to three other tests that could possibly elicit maximum activity in rhomboid major and teres major: abduction/extension in 90° abduction; adduction at 90° abduction; and extension in 30° abduction. No statistical difference was found in the mean activation of rhomboid major and teres major in these additional MVIC tests compared to the Shoulder Normalization Tests. However, the extension MVIC test produced maxima for at least 50% of subjects in rhomboid major, teres major, and latissimus dorsi. We concluded that the original Shoulder Normalization Tests should be expanded to include the extension MVIC test. The EMG normalization reference value for any of the above muscles would be the maximum EMG level generated across these Revised Shoulder Normalization Tests

Positional Differences in External On-Field Load During Specific Drill Classifications Over a Professional Rugby League Preseason.

PURPOSE: To quantify the external training loads of positional groups in preseason training drills. METHODS: Thirty-three elite rugby league players were categorized into 1 of 4 positional groups: outside backs (n = 9), adjustables (n = 9), wide-running forwards (n = 9), and hit-up forwards (n = 6). Data for 8 preseason weeks were collected using microtechnology devices. Training drills were classified based on drill focus: speed and agility, conditioning, and generic and positional skills. RESULTS: Total, high-speed, and very-high-speed distance decreased across the preseason in speed and agility (moderate, small, and small, respectively), conditioning (large, large, and small) and generic skills (large, large, and large). The duration of speed and generic skills also decreased (77% and 48%, respectively). This was matched by a concomitant increase in total distance (small), high-speed running (small), very-high-speed running (moderate), and 2-dimensional (2D) BodyLoad (small) demands in positional skills. In positional skills, hit-up forwards (1240 ± 386 m) completed less very-high-speed running than outside backs (2570 ± 1331 m) and adjustables (2121 ± 1163 m). Hit-up forwards (674 ± 253 AU) experienced greater 2D BodyLoad demands than outside backs (432 ± 230 AU, P = .034). In positional drills, hit-up forwards experienced greater relative 2D BodyLoad demands than outside backs (P = .015). Conversely, outside backs experienced greater relative high- (P = .007) and very-high-speed-running (P < .001) demands than hit-up forwards. CONCLUSION: Significant differences were observed in training loads between positional groups during positional skills but not in speed and agility, conditioning, and generic skills. This work also highlights the importance of different external-load parameters to adequately quantify workload across different positional groups

The effects of fabric for sleepwear and bedding on sleep at ambient temperatures of 17&deg;C and 22&deg;C

Mirim Shin,1 Mark Halaki,1 Paul Swan,2 Angus Ireland,2 Chin Moi Chow1 1Exercise, Health and Performance Research Group, Faculty of Health Sciences, The University of Sydney, Lidcombe, 2Australian Wool Innovation Limited, The Woolmark Company, Sydney, NSW, Australia Abstract: The fibers used in clothing and bedding have different thermal properties. This study aimed to investigate the influences of textile fabrics on sleep under different ambient temperature (Ta) conditions. Seventeen healthy young participants (ten males) underwent nine nights of polysomnography testing including an adaptation night. Participants were randomized to each of the three binary factors: sleepwear (cotton vs wool), bedding (polyester vs wool), and Ta (17&deg;C vs 22&deg;C with relative humidity set at 60%). Skin temperature (Tsk) and core temperature (Tc) were monitored throughout the sleep period. Sleep onset latency (SOL) was significantly shortened when sleeping in wool with trends of increased total sleep time and sleep efficiency compared to cotton sleepwear. At 17&deg;C, the proportion of sleep stages 1 (%N1) and 3 (%N3) and rapid eye movement sleep was higher, but %N2 was lower than at 22&deg;C. Interaction effects (sleepwear &times; Ta) showed a significantly shorter SOL for wool than cotton at 17&deg;C but lower %N3 for wool than cotton at 22&deg;C. A significantly lower %N2 but higher %N3 was observed for wool at 17&deg;C than at 22&deg;C. There was no bedding effect on sleep. Several temperature variables predicted the sleep findings in a stepwise multiple regression analysis and explained 67.8% of the variance in SOL and to a lesser degree the %N2 and %N3. These findings suggest that sleepwear played a contributory role to sleep outcomes and participants slept better at 17&deg;C than at 22&deg;C.Keywords: cotton, polyester, wool, polysomnography, skin temperature, core body temperatur