Kristy J. Rose

Consensus statement on standard of care for congenital myopathies.

Recent progress in scientific research has facilitated accurate genetic and neuropathological diagnosis of congenital myopathies. However, given their relatively low incidence, congenital myopathies remain unfamiliar to the majority of care providers, and the levels of patient care are extremely variable. This consensus statement aims to provide care guidelines for congenital myopathies. The International Standard of Care Committee for Congenital Myopathies worked through frequent e-mail correspondences, periodic conference calls, 2 rounds of online surveys, and a 3-day workshop to achieve a consensus for diagnostic and clinical care recommendations. The committee includes 59 members from 10 medical disciplines. They are organized into 5 working groups: genetics/diagnosis, neurology, pulmonology, gastroenterology/nutrition/speech/oral care, and orthopedics/rehabilitation. In each care area the authors summarize the committee’s recommendations for symptom assessments and therapeutic interventions. It is the committee’s goal that through these recommendations, patients with congenital myopathies will receive optimal care and improve their disease outcome.

Neuromuscular junction abnormalities in DNM2-related centronuclear myopathy

Dynamin-2-related centronuclear myopathy (DNM2-CNM) is a clinically heterogeneous muscle disorder characterized by muscle weakness and centralized nuclei on biopsy. There is little known about the muscle dysfunction underlying this disorder, and there are currently no treatments. In this study, we establish a novel zebrafish model for DNM2-CNM by transiently overexpressing a mutant version of DNM2 (DNM2-S619L) during development. We show that overexpression of DNM2-S619L leads to pathological changes in muscle and a severe motor phenotype. We further demonstrate that the muscle weakness seen in these animals can be significantly alleviated by treatment with an acetylcholinesterase inhibitor. Based on these results, we reviewed the clinical history of five patients with two different DNM2-CNM mutations (S619L and E368K) and found electrophysiological evidence of abnormal neuromuscular transmission in two of the individuals. All five patients showed improved muscle strength and motor function, and/or reduced fatigability following acetylcholinesterase inhibitor treatment. Together, our results suggest that deficits at the neuromuscular junction may play an important role in the pathogenesis of DNM2-CNM and that treatments targeting this dysfunction can provide an effective therapy for patients with this disorder.

Ataluren in patients with nonsense mutation Duchenne muscular dystrophy (ACT DMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND Duchenne muscular dystrophy (DMD) is a severe, progressive, and rare neuromuscular, X-linked recessive disease. Dystrophin deficiency is the underlying cause of disease; therefore, mutation-specific therapies aimed at restoring dystrophin protein production are being explored. We aimed to assess the efficacy and safety of ataluren in ambulatory boys with nonsense mutation DMD. METHODS We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 54 sites in 18 countries located in North America, Europe, the Asia-Pacific region, and Latin America. Boys aged 7-16 years with nonsense mutation DMD and a baseline 6-minute walk distance (6MWD) of 150 m or more and 80% or less of the predicted normal value for age and height were randomly assigned (1:1), via permuted block randomisation (block size of four) using an interactive voice-response or web-response system, to receive ataluren orally three times daily (40 mg/kg per day) or matching placebo. Randomisation was stratified by age (<9 years vs ≥9 years), duration of previous corticosteroid use (6 months to <12 months vs ≥12 months), and baseline 6MWD (<350 m vs ≥350 m). Patients, parents and caregivers, investigational site personnel, PTC Therapeutics employees, and all other study personnel were masked to group allocation until after database lock. The primary endpoint was change in 6MWD from baseline to week 48. We additionally did a prespecified subgroup analysis of the primary endpoint, based on baseline 6MWD, which is reflective of anticipated rates of disease progression over 1 year. The primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01826487. FINDINGS Between March 26, 2013, and Aug 26, 2014, we randomly assigned 230 patients to receive ataluren (n=115) or placebo (n=115); 228 patients comprised the intention-to-treat population. The least-squares mean change in 6MWD from baseline to week 48 was -47·7 m (SE 9·3) for ataluren-treated patients and -60·7 m (9·3) for placebo-treated patients (difference 13·0 m [SE 10·4], 95% CI -7·4 to 33·4; p=0·213). The least-squares mean change for ataluren versus placebo in the prespecified subgroups was -7·7 m (SE 24·1, 95% CI -54·9 to 39·5; p=0·749) in the group with a 6MWD of less than 300 m, 42·9 m (15·9, 11·8-74·0; p=0·007) in the group with a 6MWD of 300 m or more to less than 400 m, and -9·5 m (17·2, -43·2 to 24·2; p=0·580) in the group with a 6MWD of 400 m or more. Ataluren was generally well tolerated and most treatment-emergent adverse events were mild to moderate in severity. Eight (3%) patients (n=4 per group) reported serious adverse events; all except one event in the placebo group (abnormal hepatic function deemed possibly related to treatment) were deemed unrelated to treatment. INTERPRETATION Change in 6MWD did not differ significantly between patients in the ataluren group and those in the placebo group, neither in the intention-to-treat population nor in the prespecified subgroups with a baseline 6MWD of less than 300 m or 400 m or more. However, we recorded a significant effect of ataluren in the prespecified subgroup of patients with a baseline 6MWD of 300 m or more to less than 400 m. Baseline 6MWD values within this range were associated with a more predictable rate of decline over 1 year; this finding has implications for the design of future DMD trials with the 6-minute walk test as the endpoint. FUNDING PTC Therapeutics.

RELIABILITY OF QUANTIFYING FOOT AND ANKLE MUSCLE STRENGTH IN VERY YOUNG CHILDREN

Preschool‐age children with neuromuscular disorders are often excluded from clinical trials due to the lack of reliable and objective strength measures. We evaluated the reliability of measuring foot and ankle muscle strength in 60 healthy children age 2–4 years. The strength of foot inversion and eversion, ankle plantarflexion, and dorsiflexion was measured using a hand‐held dynamometer. Intrarater and interrater reliability of two assessors was determined for each muscle group using intraclass correlation coefficients (ICCs), 95% confidence intervals (CIs), and standard error of measurement (SEM). For all muscle groups intrarater (ICC2,2 = 0.85‐0.94, 95% CI = 0.75–0.96, SEM = 1.5–4.7 N) and interrater (ICC2,1 = 0.88–0.96, 95% CI = 0.81–0.98, SEM = 1.2–4.6 N) reliability was high for all children. As expected, reliability was generally highest in 3‐ and 4‐year‐old children and lowest in 2‐year‐old children. Hand‐held dynamometry can reliably measure foot and ankle strength in very young children and may help aid in diagnosis and in characterizing disease progression in disorders affecting the foot and ankle. Muscle Nerve, 2008

Serial night casting increases ankle dorsiflexion range in children and young adults with Charcot-Marie-Tooth disease: a randomised trial

QUESTION Does 4 weeks of serial night casting followed by 4 weeks of stretching of the gastrocnemius and soleus improve ankle dorsiflexion range and other outcomes compared with no intervention in children and young adults with Charcot-Marie-Tooth disease? DESIGN Randomised trial with concealed allocation, assessor blinding, and intention-to-treat analysis. PARTICIPANTS 30 children and young adults with Charcot-Marie-Tooth disease and restricted ankle dorsiflexion range. INTERVENTION The experimental group received 4 weeks of serial night casting followed by 4 weeks of weightbearing stretches. The control group received no intervention. OUTCOME MEASURES Primary outcome was ankle dorsiflexion range; secondary outcomes included foot deformity, mobility, balance, falls, and self-reported activity limitations. Outcomes were measured at baseline, 4, and 8 weeks. RESULTS By 4 weeks, serial night casting had increased ankle dorsiflexion range by a mean of 4 deg (95% CI 2 to 6) more in the experimental group than the control group. After a further 4 weeks of weightbearing stretches, the experimental group still had a mean of 3 deg (95% CI 0 to 5) more ankle dorsiflexion range than the control group. Other than reduced time to walk 10 metres at self-selected pace favouring night casting at 4 weeks, outcomes did not differ between groups at any time point. Two minor adverse events were reported in the experimental group. CONCLUSION 4 weeks of serial night casting increased ankle dorsiflexion range compared with no intervention, but at 8 weeks there was no significant difference between groups.

Factors Associated With Foot and Ankle Strength in Healthy Preschool-Age Children and Age-Matched Cases of Charcot-Marie-Tooth Disease Type 1A

Charcot-Marie-Tooth disease affects foot and ankle strength from the earliest stages of the disease; however, little is known about factors influencing normal strength development or the pathogenesis of foot weakness and deformity in Charcot-Marie-Tooth disease. The authors investigated factors associated with foot and ankle strength in healthy preschool-age children and compared to age-matched cases of Charcot-Marie-Tooth disease type 1A. In healthy children, ankle dorsiflexion range of motion was one of the strongest independent correlates of foot and ankle strength. Compared with healthy children, those with Charcot-Marie-Tooth disease type 1A had significantly less dorsiflexion strength and range as well as imbalance in inversion-to-eversion and plantarflexion-to-dorsiflexion strength ratios. Given the association between ankle dorsiflexion strength and range in the healthy children, and the abnormality of these parameters in Charcot-Marie-Tooth disease, investigation of the cause-effect relationship is warranted to identify more targeted therapy and further understand the pathogenesis of foot deformity in Charcot-Marie-Tooth disease.

Diagnosis and management of spinal muscular atrophy: Part 1: Recommendations for diagnosis, rehabilitation, orthopedic and nutritional care

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder due to a defect in the survival motor neuron 1 (SMN1) gene. Its incidence is approximately 1 in 11,000 live births. In 2007, an International Conference on the Standard of Care for SMA published a consensus statement on SMA standard of care that has been widely used throughout the world. Here we report a two-part update of the topics covered in the previous recommendations. In part 1 we present the methods used to achieve these recommendations, and an update on diagnosis, rehabilitation, orthopedic and spinal management; and nutritional, swallowing and gastrointestinal management. Pulmonary management, acute care, other organ involvement, ethical issues, medications, and the impact of new treatments for SMA are discussed in part 2.

Relationship between cognitive dysfunction, gait, and motor impairment in children and adolescents with neurofibromatosis type 1

Motor skill impairment and cognitive dysfunction are commonly reported features of neurofibromatosis type 1 (NF1). We characterized and determined the relationship between motor impairment, gait variables, and cognitive function in children and adolescents with NF1.

Effect of Oral Curcumin on Déjérine-Sottas Disease

Curcumin is the newest therapeutic agent for ameliorating the clinical and neuropathologic phenotype of a mouse model of Déjérine-Sottas disease. We undertook a 12-month dose-escalation safety trial of oral curcumin in a 15-year-old Caucasian girl with Déjérine-Sottas disease (point mutation, Ser72Leu) complicated by severe weakness, scoliosis, and respiratory impairment. The patient received 50 mg/kg/day oral curcumin for the first 4 months and 75 mg/kg/day thereafter, to complete a 12-month trial. Outcome measures included muscle strength, pulmonary function, upper/lower extremity disability, neurophysiologic studies, and health-related quality of life. After 12 months, the patient experienced no adverse events, and reported good compliance. There was little improvement in objective outcome measures. Knee flexion and foot strength increased slightly, but hand and elbow strength decreased. Pulmonary function, hand function, and measures of upper/lower extremity disability were stable or reduced. Her neurophysiologic findings were unchanged. Parent-reported quality of life improved for most domains, especially self-esteem, during the 12 months of treatment. Child-reported quality of life, assessed at the final visit, mirrored these results, with overall feelings of happiness and contentment. Further studies are required to explore the efficacy and safety of curcumin for severe demyelinating neuropathies of infancy and early childhood.

Results of a two-year pilot study of clinical outcome measures in collagen VI- and laminin alpha2-related congenital muscular dystrophies

Potential therapies are currently under development for two congenital muscular dystrophy (CMD) subtypes: collagen VI-related muscular dystrophy (COL6-RD) and laminin alpha 2-related dystrophy (LAMA2-RD). However, appropriate clinical outcome measures to be used in clinical trials have not been validated in CMDs. We conducted a two-year pilot study to evaluate feasibility, reliability, and validity of various outcome measures, particularly the Motor Function Measure 32, in 33 subjects with COL6-RD and LAMA2-RD. In the first year, outcome measures tested included: Motor Function Measure 32 (MFM32), forced vital capacity (FVC) percent predicted sitting, myometry, goniometry, 10-meter walk, Egen Klassification 2, and PedsQL(TM) Generic and Neuromuscular Cores. In the second year, we added the North Star Ambulatory Assessment (NSAA), Hammersmith Functional Motor Scale (HFMS), timed functional tests, Measure of Activity Limitations (ACTIVLIM), Quality of Upper Extremity Skills Test (QUEST), and Patient-Reported Outcomes Measurement Information System (PROMIS) fatigue subscale. The MFM32 showed strong inter-rater (0.92) and internal consistency (0.96) reliabilities. Concurrent validity for the MFM32 was supported by large correlations (range 0.623-0.936) with the following: FVC, NSAA, HFMS, timed functional tests, ACTIVLIM, and QUEST. Significant correlations of the MFM32 were also found with select myometry measurements, mainly of the proximal extremities and domains of the PedsQL(TM) scales focusing on physical health and neuromuscular disease. Goniometry measurements were less reliable. The Motor Function Measure is reliable and valid in the two specific subtypes of CMD evaluated, COL6-RD and LAMA2-RD. The NSAA is useful as a complementary outcome measure in ambulatory individuals. Preliminary concurrent validity of several other clinical outcome measures was also demonstrated for these subtypes.