Barth syndrome with severe dilated cardiomyopathy and growth hormone resistance: a case report.

OBJECTIVES: To describe the metabolic and endocrine features of a patient with Barth syndrome who showed evidence of growth hormone resistance. CASE PRESENTATION: A male proband deteriorated rapidly with lactic acidosis after a circumcision at age three weeks and was found to have severe dilated cardiomyopathy. A cardiomyopathy gene panel led to the diagnosis of TAZ-deficiency Barth syndrome. He subsequently experienced hypotonia and gross motor delay, feeding difficulties for the first four years, constitutional growth delay and one episode of ketotic hypoglycaemia. Cardiomyopathy resolved on oral anti-failure therapy by age three years. He had a hormonal pattern of growth hormone resistance, and growth hormone treatment was considered, however height velocity improved spontaneously after age 3½ years. He also had biochemical primary hypothyroidism. CONCLUSIONS: With careful metabolic management with l-arginine supplementation, overnight corn starch, and a prescribed exercise program, our patient's strength, endurance, level of physical activity and body composition improved significantly by age six years.

Correction: Optimization of prophylaxis for hemophilia A.

[This corrects the article DOI: 10.1371/journal.pone.0192783.].

Exploring the Relationship Between Fundamental Motor Skill Interventions and Physical Activity Levels in Children: A Systematic Review and Meta-analysis.

BACKGROUND: Physical activity provides many health benefits, yet few children meet the physical activity recommendations. In school-age children, low proficiency in fundamental movement skills (FMS) is associated with low physical activity (PA). It is unknown if the same relationship exists in pre-schoolers (aged 3-5 years). OBJECTIVES: The aims of this review were to firstly evaluate interventions for improving FMS and PA levels in children aged 3-5 years and 5-12 years, and secondly to determine, where possible, if there is a similar relationship between change in FMS and change in PA across both age groups. METHODS: A systematic search of electronic databases was conducted up until 20 July 2017. Controlled trials that implemented an FMS/PA intervention and measured PA levels (objective/subjective) and FMS (objective) in healthy children between the ages of 3 and 12 years were included. Sub-analysis was conducted based on the type of intervention (teacher-led [TL] or teacher educated), sessions per week (< 3 or ≥ 3) and age group. RESULTS: Search terms yielded 17,553 articles, of which 18 met the inclusion criteria. There was significant improvement in FMS with TL interventions of three or more sessions per week (standardised mean difference = 0.23 [0.11-0.36]; p = 0.0002). In TL interventions, there was a strong negative correlation between moderate-vigorous physical activity (MVPA) and sedentary behaviour (SB) (r = - 0.969; p = 0.031). CONCLUSIONS: There are limited studies measuring both FMS and PA following an FMS intervention, especially in school-aged children. Results indicate that training pre-schoolers at least three times a week in FMS can improve proficiency, increase intensity of PA, and reduce SB, possibly helping to reduce the burden of childhood obesity and its associated health risks.

Optimization of prophylaxis for hemophilia A.

BACKGROUND & AIMS: Prophylactic injections of factor VIII reduce the incidence of bleeds and slow the development of joint damage in people with hemophilia. The aim of this study was to identify optimal person-specific prophylaxis regimens for children with hemophilia A. METHODS: Analytic and numerical methods were used to identify prophylaxis regimens which maximize the time for which plasma factor VIII concentrations exceed a threshold, maximize the lowest plasma factor VIII concentrations, and minimize risk of bleeds. RESULTS: It was demonstrated analytically that, for any injection schedule, the regimen that maximizes the lowest factor VIII concentration involves sharing doses between injections so that all of the trough concentrations in a prophylaxis cycle are equal. Numerical methods were used to identify optimal prophylaxis schedules and explore the trade-offs between efficacy and acceptability of different prophylaxis regimens. The prophylaxis regimen which minimizes risk of bleeds depends on the person's pattern of physical activity and may differ greatly from prophylaxis regimens that optimize pharmacokinetic parameters. Prophylaxis regimens which minimize risk of bleeds also differ from prophylaxis regimens that are typically prescribed. Predictions about which regimen is optimal are sensitive to estimates of the effects on risk of bleeds of factor VIII concentration and physical activity. CONCLUSION: The methods described here can be used to identify optimal, person-specific prophylaxis regimens for children with hemophilia A.

Compound heterozygous mutations in glycyl-tRNA synthetase (GARS) cause mitochondrial respiratory chain dysfunction.

Glycyl-tRNA synthetase (GARS; OMIM 600287) is one of thirty-seven tRNA-synthetase genes that catalyses the synthesis of glycyl-tRNA, which is required to insert glycine into proteins within the cytosol and mitochondria. To date, eighteen mutations in GARS have been reported in patients with autosomal-dominant Charcot-Marie-Tooth disease type 2D (CMT2D; OMIM 601472), and/or distal spinal muscular atrophy type V (dSMA-V; OMIM 600794). In this study, we report a patient with clinical and biochemical features suggestive of a mitochondrial respiratory chain (MRC) disorder including mild left ventricular posterior wall hypertrophy, exercise intolerance, and lactic acidosis. Using whole exome sequencing we identified compound heterozygous novel variants, c.803C>T; p.(Thr268Ile) and c.1234C>T; p.(Arg412Cys), in GARS in the proband. Spectrophotometric evaluation of the MRC complexes showed reduced activity of Complex I, III and IV in patient skeletal muscle and reduced Complex I and IV activity in the patient liver, with Complex IV being the most severely affected in both tissues. Immunoblot analysis of GARS protein and subunits of the MRC enzyme complexes in patient fibroblast extracts showed significant reduction in GARS protein levels and Complex IV. Together these studies provide evidence that the identified compound heterozygous GARS variants may be the cause of the mitochondrial dysfunction in our patient.

Interventions to improve fundamental motor skills in pre-school aged children: A systematic review and meta-analysis.

OBJECTIVES: Mastery in -fundamental motor skills (FMS) is associated with increased physical activity (PA) in school-aged children; however, there is limited research on pre-schoolers (3-5 years). We aimed to evaluate interventions for improving FMS as well as PA. DESIGN/METHODS: A search of electronic databases was conducted for controlled trials using PA interventions with FMS as outcomes in healthy pre-schoolers. Standardised mean difference (SMD), 95% confidence intervals and publication bias were calculated for each outcome using Revman 5.3. RESULTS: Twenty trials met inclusion criteria. In total, 4255 pre-schoolers were analysed with 854 completing a FMS intervention. Studies were categorised into three groups (i) Teacher-Led (TL)(n=13); (ii) Child-Centred (CC)(n=6) and (iii) Parent-Led (PL)(n=1). Mean age was 4.3±0.4 years, with equal gender distribution. Interventions ran for 21±17 weeks, 3±1 times per week for 35±17 minutes. TL interventions significantly improved overall FMS (SMD=0.14[0.06, 0.21]; p=0.0003), object control (SMD=0.47[0.15, 0.80]; p= 0.004), and locomotor skills (SMD=0.44[0.16, 0.73]; p=0.002), whereas CC interventions were not significant. There was a small, non-significant reduction in sedentary time (SMD=-0.35[-0.80, 0.10]; p= 0.12), and a large non-significant increase in PA (SMD=0.79[-0.83, 2.41]; p=0.34). CONCLUSION: PA interventions improve FMS in pre-schoolers; however, due to limited research, more study is needed on CC interventions. Targeting FMS development in pre-schoolers may promote higher PA levels and reduce sedentary time, however more study is needed.

Sustained improvements in fitness and exercise tolerance in obese adolescents after a 12 week exercise intervention.

A 12 week exercise program was evaluated for its effect on aerobic fitness, anaerobic threshold, physical activity and sedentary behavior levels in obese insulin resistant adolescents post intervention and at follow up. 111 obese insulin resistant 10-17 year olds were recruited to a 12 month lifestyle intervention, known as RESIST. From months 4 to 6, adolescents participated in supervised exercise sessions twice per week (45-60min/session). Aerobic fitness and anaerobic threshold were measured by gas analysis at baseline, 6 months (post intervention) and 12 months (follow up). Self-reported physical activity and sedentary behavior was measured using the CLASS questionnaire. At 6 months aerobic fitness and time to reach the anaerobic threshold had improved by 5.8% [95% CI: 0.8-11.3] and 19.7% [95% CI: 10.4-29.0], respectively compared with baseline. These improvements were maintained at 12 months. Compared to baseline, 6 month physical activity levels increased by 19min/day [95% CI: 5-33] and screen time decreased by 49min/day [95% CI: 23-74] but returned to baseline levels by 12 months. Improved fitness and anaerobic threshold can be sustained up to 6 months following completion of an exercise program possibly enhancing capacity to perform daily functional tasks.

Improved insulin sensitivity and body composition, irrespective of macronutrient intake, after a 12 month intervention in adolescents with pre-diabetes; RESIST a randomised control trial.

BACKGROUND: A higher protein to carbohydrate ratio in the diet may potentiate weight loss, improve body composition and cardiometabolic risk, including glucose homeostasis in adults. The aim of this randomised control trial was to determine the efficacy of two structured lifestyle interventions, differing in dietary macronutrient content, on insulin sensitivity and body composition in adolescents. We hypothesised that a moderate-carbohydrate (40-45% of energy), increased-protein (25-30%) diet would be more effective than a high-carbohydrate diet (55-60%), moderate-protein (15%) diet in improving outcomes in obese, insulin resistant adolescents. METHODS: Obese 10-17 year olds with either pre-diabetes and/or clinical features of insulin resistance were recruited at two hospitals in Sydney, Australia. At baseline adolescents were prescribed metformin and randomised to one of two energy restricted diets. The intervention included regular contact with the dietician and a supervised physical activity program. Outcomes included insulin sensitivity index measured by an oral glucose tolerance test and body composition measured by dual-energy x-ray absorptiometry at 12 months. RESULTS: Of the 111 adolescents recruited, 85 (77%) completed the intervention. BMI expressed as a percentage of the 95th percentile decreased by 6.8% [95% CI: -8.8 to -4.9], ISI increased by 0.2 [95% CI: 0.06 to 0.39] and percent body fat decreased by 2.4% [95% CI: -3.4 to -1.3]. There were no significant differences in outcomes between diet groups at any time. CONCLUSION: When treated with metformin and an exercise program, a structured, reduced energy diet, which is either high-carbohydrate or moderate-carbohydrate with increased-protein, can achieve clinically significant improvements in obese adolescents at risk of type 2 diabetes. TRIAL REGISTRATION: Australian New Zealand Clinical Trail Registry ACTRN12608000416392 . Registered 25 August 2008.

Optimal macronutrient content of the diet for adolescents with prediabetes; RESIST a randomised control trial.

CONTEXT: Prediabetes and clinical insulin resistance in adolescents are rapidly emerging clinical problems with serious health outcomes. OBJECTIVE: The objective of this study was to determine the efficacy of 2 structured lifestyle interventions, both differing in diet macronutrient composition, on insulin sensitivity. DESIGN: This study was a randomized controlled trial, known as Researching Effective Strategies to Improve Insulin Sensitivity in Children and Teenagers, in 2 hospitals in Sydney, Australia. PARTICIPANTS: Participants included overweight or obese 10- to 17-year-olds with either prediabetes and/or clinical features of insulin resistance. INTERVENTION: At baseline adolescents were prescribed metformin and randomized to a structured diet, which was either high carbohydrate or moderate carbohydrate with increased protein. The program commenced with a 3-month dietary intervention, with the addition of an exercise intervention in the next 3 months. OUTCOMES: The outcomes included an insulin sensitivity, anthropometry, and cardiometabolic profile at 6 months. RESULTS: One hundred eleven subjects (66 girls) were recruited and 98 subjects (58 girls) completed the 6-month intervention. After 3 months the mean insulin sensitivity index increased by 0.3 [95% confidence interval (CI) 0.2-0.4]. After 6 months the mean insulin (picomoles per liter) to glucose ratio (millimoles per liter) decreased by 7.2 [95%CI -12.0 to -2.3], body mass index, expressed as a percentage of the 95th centile, decreased by 9% (95% CI -3 to -15), but there was no significant change in the lipids. There were no significant differences in outcomes between the diet groups at any time point. CONCLUSIONS: These results are in contrast with our hypothesis that adolescents randomized to the increased protein diet would have better outcomes. Further strategies are required to better address prediabetes and clinical features of insulin resistance in adolescents.

Association between physical activity and risk of bleeding in children with hemophilia.

CONTEXT: Vigorous physical activity is thought to increase risk of bleeds in children with hemophilia, but the magnitude of the risk is unknown. OBJECTIVE: To quantify the transient increase in risk of bleeds associated with physical activity in children with hemophilia. DESIGN, SETTING, AND PARTICIPANTS: A case-crossover study nested within a prospective cohort study was conducted at 3 pediatric hemophilia centers in Australia between July 2008 and October 2010. A total of 104 children and adolescent boys aged 4 through 18 years with moderate or severe hemophilia A or B were monitored for bleeds for up to 1 year. Following each bleed, the child or parent was interviewed to ascertain exposures to physical activity preceding the bleed. Physical activity was categorized according to expected frequency and severity of collisions. The risk of bleeds associated with physical activity was estimated by contrasting exposure to physical activity in the 8 hours before the bleed with exposures in two 8-hour control windows, controlling for levels of clotting factor in the blood. MAIN OUTCOME MEASURES: Association of physical activity and factor level with risk of bleeding. RESULTS: The participants were observed for 4839 person-weeks during which time 436 bleeds occurred. Of these, 336 bleeds occurred more than 2 weeks after the preceding bleed and were used in the primary analysis of risk. Compared with inactivity and category 1 activities (eg, swimming), category 2 activities (eg, basketball) were associated with a transient increase in the risk of bleeding (30.6% of bleed windows vs 24.8% of first control windows; odds ratio, 2.7; 95% CI, 1.7-4.8, P < .001). Category 3 activities (eg, wrestling) were associated with a greater transient increase in risk (7.0% of bleed windows vs 3.4% of first control windows; odds ratio, 3.7; 95% CI, 2.3-7.3, P < .001). To illustrate absolute risk increase, for a child who bleeds 5 times annually and is exposed on average to category 2 activities twice weekly and to category 3 activities once weekly, exposure to these activities was associated with only 1 of the 5 annual bleeds. For every 1% increase in clotting factor level, bleeding incidence was lower by 2% (95% CI, 1%-3%; P = .004). CONCLUSIONS: In children and adolescents with hemophilia, vigorous physical activity was transiently associated with a moderate relative increase in risk of bleeding. Because the increased relative risk is transient, the absolute increase in risk of bleeds associated with physical activity is likely to be small.

Researching Effective Strategies to Improve Insulin Sensitivity in Children and Teenagers - RESIST. A randomised control trial investigating the effects of two different diets on insulin sensitivity in young people with insulin resistance and/or pre-diabetes.

BACKGROUND: Concomitant with the rise in childhood obesity there has been a significant increase in the number of adolescents with clinical features of insulin resistance and prediabetes. Clinical insulin resistance and prediabetes are likely to progress to type 2 diabetes and early atherosclerosis if not targeted for early intervention. There are no efficacy trials of lifestyle intervention in this group to inform clinical practice. The primary aim of this randomised control trial (RCT) is to determine the efficacy and effectiveness of two different structured lifestyle interventions differing in diet composition on insulin sensitivity, in adolescents with clinical insulin resistance and/or prediabetes treated with metformin. METHODS/DESIGN: This study protocol describes the design of an ongoing RCT. We are recruiting 108 (54 each treatment arm) 10 to 17 year olds with clinical features of insulin resistance and/or prediabetes, through physician referral, into a multi-centred RCT. All participants are prescribed metformin and participate in a diet and exercise program. The lifestyle program is the same for all participants except for diet composition. The diets are a high carbohydrate, low fat diet and a moderate carbohydrate, increased protein diet.The program commences with an intensive 3 month dietary intervention, implemented by trained dietitians, followed by a 3 month intensive gym and home based exercise program, supervised by certified physical trainers. To measure the longer term effectiveness, after the intensive intervention trial participants are managed by either their usual physician or study physician and followed up by the study dietitians for an additional 6 months. The primary outcome measure, change in insulin sensitivity, is measured at 3, 6 and 12 months. DISCUSSION: Clinical insulin resistance and prediabetes in the paediatric population are rapidly emerging clinical problems with serious health outcomes. With appropriate management these conditions are potentially reversible or at least their progression can be delayed. This research study is the first trial designed to provide much needed data on the effective dietary management for this cohort. This study will inform clinical practice guidelines for adolescents with clinical insulin resistance and may assist in preventing metabolic complications, type 2 diabetes and early cardiovascular disease. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registration Number ACTRN12608000416392.

Estimation of transient increases in bleeding risk associated with physical activity in children with haemophilia.

BACKGROUND: Although it is widely appreciated that vigorous physical activity can increase the risk of bleeding episodes in children with haemophilia, the magnitude of the increase in risk is not known. Accurate risk estimates could inform decisions made by children with haemophilia and their parents about participation in physical activity and aid the development of optimal prophylactic schedules. The aim of this study is to provide an accurate estimate of the risks of bleeding associated with vigorous physical activity in children with haemophilia. METHODS/DESIGN: The study will be a case-crossover study nested within a prospective cohort study. Children with moderate or severe haemophilia A or B, recruited from two paediatric haematology departments in Australia, will participate in the study. The child, or the child's parent or guardian, will report bleeding episodes experienced over a 12-month period. Following a bleeding episode, the participant will be interviewed by telephone about exposures to physical activity in the case period (8 hours before the bleed) and 2 control periods (an 8 hour period at the same time on the day preceding the bleed and an 8 hour period two days preceding the bleed). Conditional logistic regression will be used to estimate the risk of participating in vigorous physical activity from measures of exposure to physical activity in the case and control periods. DISCUSSION: This case-control study will provide estimates of the risk of participation in vigorous physical activity in children with haemophilia.

The effect of an exercise intervention on aerobic fitness, strength and quality of life in children with haemophilia (ACTRN012605000224628).

BACKGROUND: Children with haemophilia have lower levels of fitness and strength than their healthy peers. We present the protocol of a study designed to determine whether an exercise intervention improves quality of life, aerobic fitness and strength in children with haemophilia. METHODS/DESIGN: The study will be a randomised, assessor-blinded, controlled trial of exercise treatment. Seventy children aged between 6 and 18 years with haemophilia or von Willebrand disease will be recruited from two paediatric haemophilia clinics in NSW. Each participant will be allocated to an exercise group or a control group using a concealed allocation procedure. The control group will receive usual medical care while the intervention group will receive usual medical care plus an exercise program for 12 weeks. Outcomes (VO2peak, knee extensor strength and quality of life) will be measured at baseline and on completion of the exercise program by a blinded assessor. The primary analysis will be conducted on an intention to treat basis. The effects of the exercise intervention on each of the three primary outcomes will be estimated from between-group differences in the mean outcome adjusted for baseline scores. DISCUSSION: This study will be the first randomised controlled trial to examine the effects of a structured exercise program on fitness and quality of life in children with haemophilia.

7. Sport for special groups.

Sports participation among children is declining. Sport and physical activity are important in childhood for optimising bone mass and reducing obesity and insulin resistance. Physical activity reduces cardiovascular risk factors in adults, and can improve survival in patients with cardiac failure. Musculoskeletal injury is the most common complication of sports participation in adults - not cardiac events. Some of the decline in function which occurs with ageing can be positively affected by regular physical activity.