Joshua Burns

Ascorbic acid for Charcot-Marie-Tooth disease type 1A in children: a randomised, double-blind, placebo-controlled, safety and efficacy trial.

BACKGROUND Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common inherited nerve disorder. CMT1A is characterised by peripheral nerve demyelination, weakness, and impaired motor function and is caused by the duplication of PMP22, the gene that encodes peripheral myelin protein 22. High-dose ascorbic acid has been shown to have remyelinating potential and to correct the phenotype of a transgenic mouse model of CMT1A by decreasing expression of PMP22. We tested the efficacy and safety of ascorbic acid supplementation in children with CMT1A. METHODS This 12-month, randomised, double-blind, placebo-controlled trial undertaken between June, 2007, and December, 2008, assessed high-dose oral ascorbic acid (about 30 mg/kg/day) in 81 children with CMT1A (2-16 years). Randomisation was done on a 1:1 ratio by a computer-generated algorithm. All investigators and participants were blinded to treatment allocation with the exception of the trial pharmacist. The primary efficacy outcome was median nerve motor conduction velocity (m/s) at 12 months. Secondary outcomes were foot and hand strength, motor function, walking ability, and quality of life. Compliance was measured by plasma ascorbic acid concentration, pill count, and medication diary entries. Analysis was by intention to treat. This trial is registered with the Australian New Zealand Clinical Trials Registry, Number 12606000481572. FINDINGS 81 children were randomly assigned to receive high-dose ascorbic acid (n=42) or placebo (n=39). 80 children completed 12 months of treatment. The ascorbic acid group had a small, non-significant increase in median nerve motor conduction velocity compared with the placebo group (adjusted mean difference 1.7 m/s, 95% CI -0.1 to 3.4; p=0.06). There was no measurable effect of ascorbic acid on neurophysiological, strength, function, or quality of life outcomes. Two children in the ascorbic acid group and four children in the placebo group reported gastrointestinal symptoms. There were no serious adverse events. INTERPRETATION 12 months of treatment with high-dose ascorbic acid was safe and well tolerated but none of the expected efficacy endpoints were reached.

Foot Type and Overuse Injury in Triathletes

Abnormal foot morphology has been suggested to contribute to overuse injuries in athletes. This study investigated the relationship between foot type and injury incidence in a large sample of competitive triathletes not wearing foot orthoses during a 6-month retrospective analysis and a 10-week prospective cohort study. Foot alignment was measured using the Foot Posture Index and the Valgus Index, and participants were assigned to supinated, pronated, and normal foot-type groups. Overall, 131 triathletes sustained 155 injuries during the study. Generally, foot type was not a major risk factor for injury; however, there was a fourfold increased risk of overuse injury during the competition season in athletes with a supinated foot type. The results of this study show that triathletes with a supinated foot type are more likely to sustain an overuse injury.

Does stretching increase ankle dorsiflexion range of motion? A systematic review

Background: Many lower limb disorders are related to calf muscle tightness and reduced dorsiflexion of the ankle. To treat such disorders, stretches of the calf muscles are commonly prescribed to increase available dorsiflexion of the ankle joint. Hypothesis: To determine the effect of static calf muscle stretching on ankle joint dorsiflexion range of motion. Study design: A systematic review with meta-analyses. Methods: A systematic review of randomised trials examining static calf muscle stretches compared with no stretching. Trials were identified by searching Cinahl, Embase, Medline, SportDiscus, and Central and by recursive checking of bibliographies. Data were extracted from trial publications, and meta-analyses performed that calculated a weighted mean difference (WMD) for the continuous outcome of ankle dorsiflexion. Sensitivity analyses excluded poorer quality trials. Statistical heterogeneity was assessed using the quantity I2. Results: Five trials met inclusion criteria and reported sufficient data on ankle dorsiflexion to be included in the meta-analyses. The meta-analyses showed that calf muscle stretching increases ankle dorsiflexion after stretching for ⩽15 minutes (WMD 2.07°; 95% confidence interval 0.86 to 3.27), >15–30 minutes (WMD 3.03°; 95% confidence interval 0.31 to 5.75), and >30 minutes (WMD 2.49°; 95% confidence interval 0.16 to 4.82). There was a very low to moderate statistical heterogeneity between trials. The meta-analysis results for ⩽15 minutes and >15–30 minutes of stretching were considered robust when compared with sensitivity analyses that excluded lower quality trials. Conclusions: Calf muscle stretching provides a small and statistically significant increase in ankle dorsiflexion. However, it is unclear whether the change is clinically important.

Effective orthotic therapy for the painful cavus foot : a randomized controlled trial

Patients with a cavus or high-arched foot frequently experience foot pain, which can lead to significant limitation in function. Custom foot orthoses are widely prescribed to treat cavus foot pain. However, no clear guidelines for their construction exist, and there is limited evidence of their efficacy. In a randomized, single-blind, sham-controlled trial, the effect of custom foot orthoses on foot pain, function, quality of life, and plantar pressure loading in people with a cavus foot type was investigated. One hundred fifty-four participants with chronic musculoskeletal foot pain and bilateral cavus feet were randomly assigned to a treatment group receiving custom foot orthoses (n = 75) or to a control group receiving simple sham insoles (n = 79). At 3 months, 99% of the participants provided follow-up data using the Foot Health Status Questionnaire. Foot pain scores improved more with custom foot orthoses than with the control (difference, 8.3 points; 95% confidence interval [CI], 1.2 to 15.3 points; P = .022). Function scores also improved more with custom foot orthoses than with the control (difference, 9.5 points; 95% CI, 2.9 to 16.1 points; P = .005). Quality-of-life data favored custom foot orthoses, although differences reached statistical significance only for physical functioning (difference, 7.0 points; 95% CI, 1.9 to 12.1 points; P = .008). Plantar pressure improved considerably more with custom foot orthoses than with the control for all regions of the foot (difference, ‐3.0 N . s/cm 2 ; 95% CI, ‐3.7 to ‐2.4 N . s/cm 2 ; P < .001). In conclusion, custom foot orthoses are more effective than a control for the treatment of cavus foot pain and its associated limitation in function. (J Am Podiatr Med Assoc 96(3): 205-211, 2006)

CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: a cross-sectional analysis.

Background The international Inherited Neuropathy Consortium (INC) was created with the goal of obtaining much needed natural history data for patients with Charcot-Marie-Tooth (CMT) disease. We analysed clinical and genetic data from patients in the INC to determine the distribution of CMT subtypes and the clinical impairment associated with them. Methods We analysed data from 1652 patients evaluated at 13 INC centres. The distribution of CMT subtypes and pathogenic genetic mutations were determined. The disease burden of all the mutations was assessed by the CMT Neuropathy Score (CMTNS) and CMT Examination Score (CMTES). Results 997 of the 1652 patients (60.4%) received a genetic diagnosis. The most common CMT subtypes were CMT1A/PMP22 duplication, CMT1X/GJB1 mutation, CMT2A/MFN2 mutation, CMT1B/MPZ mutation, and hereditary neuropathy with liability to pressure palsy/PMP22 deletion. These five subtypes of CMT accounted for 89.2% of all genetically confirmed mutations. Mean CMTNS for some but not all subtypes were similar to those previously reported. Conclusions Our findings confirm that large numbers of patients with a representative variety of CMT subtypes have been enrolled and that the frequency of achieving a molecular diagnosis and distribution of the CMT subtypes reflects those previously reported. Measures of severity are similar, though not identical, to results from smaller series. This study confirms that it is possible to assess patients in a uniform way between international centres, which is critical for the planned natural history study and future clinical trials. These data will provide a representative baseline for longitudinal studies of CMT. Clinical trial registration ID number NCT01193075.

Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2

Childhood onset motor neuron diseases or neuronopathies are a clinically heterogeneous group of disorders. A particularly severe subgroup first described in 1894, and subsequently called Brown-Vialetto-Van Laere syndrome, is characterized by progressive pontobulbar palsy, sensorineural hearing loss and respiratory insufficiency. There has been no treatment for this progressive neurodegenerative disorder, which leads to respiratory failure and usually death during childhood. We recently reported the identification of SLC52A2, encoding riboflavin transporter RFVT2, as a new causative gene for Brown-Vialetto-Van Laere syndrome. We used both exome and Sanger sequencing to identify SLC52A2 mutations in patients presenting with cranial neuropathies and sensorimotor neuropathy with or without respiratory insufficiency. We undertook clinical, neurophysiological and biochemical characterization of patients with mutations in SLC52A2, functionally analysed the most prevalent mutations and initiated a regimen of high-dose oral riboflavin. We identified 18 patients from 13 families with compound heterozygous or homozygous mutations in SLC52A2. Affected individuals share a core phenotype of rapidly progressive axonal sensorimotor neuropathy (manifesting with sensory ataxia, severe weakness of the upper limbs and axial muscles with distinctly preserved strength of the lower limbs), hearing loss, optic atrophy and respiratory insufficiency. We demonstrate that SLC52A2 mutations cause reduced riboflavin uptake and reduced riboflavin transporter protein expression, and we report the response to high-dose oral riboflavin therapy in patients with SLC52A2 mutations, including significant and sustained clinical and biochemical improvements in two patients and preliminary clinical response data in 13 patients with associated biochemical improvements in 10 patients. The clinical and biochemical responses of this SLC52A2-specific cohort suggest that riboflavin supplementation can ameliorate the progression of this neurodegenerative condition, particularly when initiated soon after the onset of symptoms.

Understanding the nature and mechanism of foot pain

Approximately one-quarter of the population are affected by foot pain at any given time. It is often disabling and can impair mood, behaviour, self-care ability and overall quality of life. Currently, the nature and mechanism underlying many types of foot pain is not clearly understood. Here we comprehensively review the literature on foot pain, with specific reference to its definition, prevalence, aetiology and predictors, classification, measurement and impact. We also discuss the complexities of foot pain as a sensory, emotional and psychosocial experience in the context of clinical practice, therapeutic trials and the placebo effect. A deeper understanding of foot pain is needed to identify causal pathways, classify diagnoses, quantify severity, evaluate long term implications and better target clinical intervention.

EVOLUTION OF FOOT AND ANKLE MANIFESTATIONS IN CHILDREN WITH CMT1A

We studied the timing and progression of foot and ankle changes in 81 children with genetically confirmed Charcot–Marie–Tooth disease type 1A (CMT1A) and determined their impact on motor function and walking ability. Foot deformity, weakness, pain, cramps, and instability were a common feature of CMT1A. Foot structure evolved toward pes cavus from early childhood to adolescence, although a subgroup with normal and planus feet remained. Foot strength increased with age, although compared to age‐equivalent norms it declined from 4 years. Factors associated with evolving foot deformity included muscle weakness/imbalance, restricted ankle flexibility, and joint hypermobility. Regression modeling identified dorsiflexion weakness, global foot weakness, and difficulty toe‐walking as independent predictors of motor dysfunction, while pes cavus and difficulty heel‐walking were predictors of poor walking ability. Foot problems are present from the earliest stages of the disease and can have a negative impact on function. Early foot and ankle intervention may prevent long‐term disability and morbidity in CMT1A. Muscle Nerve 39: 158–166, 2009

Validation of the Charcot–Marie–Tooth disease pediatric scale as an outcome measure of disability

Charcot–Marie–Tooth disease (CMT) is a common heritable peripheral neuropathy. There is no treatment for any form of CMT, although clinical trials are increasingly occurring. Patients usually develop symptoms during the first 2 decades of life, but there are no established outcome measures of disease severity or response to treatment. We identified a set of items that represent a range of impairment levels and conducted a series of validation studies to build a patient‐centered multi‐item rating scale of disability for children with CMT.

Prevalence and impact of chronic musculoskeletal ankle disorders in the community.

OBJECTIVE To determine the point prevalence of chronic musculoskeletal ankle disorders in the community. DESIGN Cross-sectional stratified (metropolitan vs regional) random sample. SETTING General community. PARTICIPANTS Population-based computer-aided telephone survey of people (N=2078) aged 18 to 65 years in New South Wales, Australia. Of those contacted, 751 participants provided data. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Point prevalence for no history of ankle injury or chronic ankle problems (no ankle problems), history of ankle injury without residual problems, and chronic ankle disorders. Chronic musculoskeletal ankle disorders due to ankle sprain, fracture, arthritis, or other disorder compared by chi-square test for the presence of pain, weakness, giving way, swelling and instability, activity limitation, and health care use in the past year. RESULTS There were 231 (30.8%) participants with no ankle problems, 342 (45.5%) with a history of ankle injury but no chronic problems, and 178 (23.7%) with chronic ankle disorders. The major component of chronic ankle disorders was musculoskeletal disorders (n=147, 19.6% of the total sample), most of which were due to ankle injury (n=117, 15.6% of the total). There was no difference among the arthritis, fracture, sprain, and other groups in the prevalence of the specific complaints, or health care use. Significantly more participants with arthritis had to limit activity than in the sprain group (Chi-square test, P=.035). CONCLUSIONS Chronic musculoskeletal ankle disorders affected almost 20% of the Australian community. The majority were due to a previous ankle injury, and most people had to limit or change their physical activity because of the ankle disorder.