Ataluren treatment of patients with nonsense mutation dystrophinopathy

Introduction: Dystrophinopathy is a rare, severe muscle disorder, and nonsense mutations are found in 13% of cases. Ataluren was developed to enable ribosomal readthrough of premature stop codons in nonsense mutation (nm) genetic disorders. Methods: Randomized, double-blind, placebo-controlled study; males ≥5 years with nm-dystrophinopathy received study drug orally 3 times daily, ataluren 10, 10, 20 mg/kg (N=57); ataluren 20, 20, 40 mg/kg (N=60); or placebo (N=57) for 48 weeks. The primary endpoint was change in 6-Minute Walk Distance (6MWD) at Week 48. Results: Ataluren was generally well tolerated. The primary endpoint favored ataluren 10, 10, 20 mg/kg versus placebo; the week 48 6MWD Δ=31.3 meters, post hoc P=0.056. Secondary endpoints (timed function tests) showed meaningful differences between ataluren 10, 10, 20 mg/kg, and placebo. Conclusions: As the first investigational new drug targeting the underlying cause of nm-dystrophinopathy, ataluren offers promise as a treatment for this orphan genetic disorder with high unmet medical need

Solution structure of the inner DysF domain of myoferlin and implications for limb girdle muscular dystrophy type 2b

Mutations in the protein dysferlin, a member of the ferlin family, lead to limb girdle muscular dystrophy type 2B and Myoshi myopathy. The ferlins are large proteins characterised by multiple C2 domains and a single C-terminal membrane-spanning helix. However, there is sequence conservation in some of the ferlin family in regions outside the C2 domains. In one annotation of the domain structure of these proteins, an unusual internal duplication event has been noted where a putative domain is inserted in between the N- and C-terminal parts of a homologous domain. This domain is known as the DysF domain. Here, we present the solution structure of the inner DysF domain of the dysferlin paralogue myoferlin, which has a unique fold held together by stacking of arginine and tryptophans, mutations that lead to clinical disease in dysferlin

Multiplex SSCP and heteroduplex analysis with southern hybridization for large-scale mutation detection

We have developed a modification of the singlestrand conformational analysis and heteroduplex analysis methods of mutation detection, with the intention of applying them to genetic diseases involving large genes or multiple genes producing a similar phenotype. The technique involves electrophoresing up to 10 or more DNA fragments on a polyacrylamide gel, followed by bidirectional Southern blotting and individual examination by hybridization. This can reduce the time involved in mutation detection by more than 50%. We confirmed the validity of our approach by detecting 90% of mutations in a blind study of previously characterized mutations in the adenomatous polyposis coli (APC) gene that underlies familial adenomatous polyposis

Mortality cost of Duchenne muscular dystrophy

BackgroundDespite advances in management and care, Duchenne muscular dystrophy (DMD) remains universally fatal. The objective of this study was to estimate the mortality cost of DMD.MethodsWe estimated the mean total national annual mortality cost associated with DMD by simulating the mean number of patients who would have been alive in 2012 in the absence of DMD using data on the mean DMD incidence, mean number of live male births, mean life expectancy at birth in DMD and the male general population, and a societal willingness-to-pay (WTP) for a life-year. We attributed each patient who would have been alive in 2012 a lost life-year. Finally, to estimate the mean mortality cost of DMD, we multiplied the estimated mean number of life-years lost with a societal WTP for a life-year of €75,000.ResultsThe mean total number of patients who would have been alive in 2012 in the absence of DMD was estimated at 4470 (95% bootstrapped CI: 4449-4492) in Germany, 3313 (3297-3329) in Italy, 3564 (3547-3581) in the UK, and 16,105 (16,029-16,186) in the USA. The corresponding mean mortality cost (in millions) was estimated at €335 (€334-€337) for Germany, €248 (€247-€250) for Italy, €267 (€266-€269) for the UK, and €1,208 (€1,202-€1,214) for the USA.ConclusionsWe show that DMD is associated with a considerable mortality cost and a substantial total economic burden to society. Our findings serve as important intelligence input to health economic policy decisions, allocation of funds for research, and cost-effective care delivery systems

The Burden of Duchenne Muscular Dystrophy: An International, Cross-sectional Study

Objective: The objective of this study was to estimate the total cost of illness and economic burden of Duchenne muscular dystrophy (DMD). Methods: Patients with DMD from Germany, Italy, United Kingdom, and United States were identified through Translational Research in Europe?Assessment & Treatment of Neuromuscular Diseases registries and invited to complete a questionnaire online together with a caregiver. Data on health care use, quality of life, work status, informal care, and household expenses were collected to estimate costs of DMD from the perspective of society and caregiver households. Results: A total of 770 patients (173 German, 122 Italian, 191 from the United Kingdom, and 284 from the United States) completed the questionnaire. Mean per-patient annual direct cost of illness was estimated at between $23,920 and$54,270 (2012 international dollars), 7 to 16 times higher than the mean per-capita health expenditure in these countries. Indirect and informal care costs were substantial, each constituting between 18% and 43% of total costs. The total societal burden was estimated at between $80,120 and$120,910 per patient and annum, and increased markedly with disease progression. The corresponding household burden was estimated at between $58,440 and$71,900. Conclusions: We show that DMD is associated with a substantial economic burden. Our results underscore the many different costs accompanying a rare condition such as DMD and the considerable economic burden carried by affected families. Our description of the previously unknown economic context of a rare disease serves as important intelligence input to health policy evaluations of intervention programs and novel therapies, financial support schemes for patients and their families, and the design of future cost studies

Psychometric properties of the Zarit Caregiver Burden Interview administered to caregivers to patients with Duchenne muscular dystrophy: a Rasch analysis

<p><b>Purpose:</b> To explore the psychometric properties of the full 22-item English (UK and US) version of the Zarit Caregiver Burden Interview administered to caregivers to patients with Duchenne muscular dystrophy.</p> <p><b>Materials and methods:</b> Caregivers to patients with Duchenne muscular dystrophy from the United Kingdom and the United States, recruited through the TREAT-NMD network, completed the Zarit Caregiver Burden Interview online. The psychometric properties of the Zarit Caregiver Burden Interview were examined using Rasch analysis.</p> <p><b>Results:</b> A total of 475 caregivers completed the Zarit Caregiver Burden Interview. Model misfit was identified for 9 of 22 items (mean item fit residual 0.061, SD: 2.736) and 13 of 22 items displayed disordered thresholds. The overall item-trait interaction chi-square value was 499 (198 degrees of freedom, <i>p</i> < 0.001). The mean person fit residual was estimated at −0.213 (SD: 1.235). The Person Separation Index and Cronbach’s α were estimated at 0.902 and 0.914, respectively. Item dependency was low and we found no significant differential item functioning by country or sex.</p> <p><b>Conclusion:</b> Our Rasch analysis shows that the Zarit Caregiver Burden Interview fails to fully operationalize a quantitative conceptualization of caregiver burden among caregivers to patients with Duchenne muscular dystrophy from the United Kingdom and the United States. Further research is needed to understand the psychometric properties of the Zarit Caregiver Burden Interview in other populations and settings.Implications for Rehabilitation</p><p>Duchenne muscular dystrophy is a terminal disease characterized by progressive muscle degeneration resulting in substantial disability and a significant burden on family caregivers.</p><p>The Zarit Caregiver Burden Interview is one of the most widely applied measures of caregiver burden.</p><p>Our Rasch analysis suggests that the Zarit Caregiver Burden Interview is not fit for purpose to measure burden in UK and US caregivers to patients with Duchenne muscular dystrophy.</p><p>Clinicians and decision-makers should interpret Zarit Caregiver Burden Interview data from these populations with caution.</p><p></p> <p>Duchenne muscular dystrophy is a terminal disease characterized by progressive muscle degeneration resulting in substantial disability and a significant burden on family caregivers.</p> <p>The Zarit Caregiver Burden Interview is one of the most widely applied measures of caregiver burden.</p> <p>Our Rasch analysis suggests that the Zarit Caregiver Burden Interview is not fit for purpose to measure burden in UK and US caregivers to patients with Duchenne muscular dystrophy.</p> <p>Clinicians and decision-makers should interpret Zarit Caregiver Burden Interview data from these populations with caution.</p