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- Campbell, C., et al.
(author)
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Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy
- 2020
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In: Journal of Comparative Effectiveness Research. - : Becaris Publishing Limited. - 2042-6305 .- 2042-6313. ; 9:14
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Journal article (peer-reviewed)abstract
- Aim:Assess the totality of efficacy evidence for ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD).Materials & methods:Data from the two completed randomized controlled trials (ClinicalTrials.gov: NCT00592553; NCT01826487) of ataluren in nmDMD were combined to examine the intent-to-treat (ITT) populations and two patient subgroups (baseline 6-min walk distance [6MWD] >= 300-<400 or <400 m). Meta-analyses examined 6MWD change from baseline to week 48.Results:Statistically significant differences in 6MWD change with ataluren versus placebo were observed across all three meta-analyses. Least-squares mean difference (95% CI): ITT (n = 342), +17.2 (0.2-34.1) m, p = 0.0473; >= 300-<400 m (n = 143), +43.9 (18.2-69.6) m, p = 0.0008; <400 m (n = 216), +27.7 (6.4-49.0) m, p = 0.0109.Conclusion:These meta-analyses support previous evidence for ataluren in slowing disease progression versus placebo in patients with nmDMD over 48 weeks. Treatment benefit was most evident in patients with a baseline 6MWD >= 300-<400 m (the ambulatory transition phase), thereby informing future trial design.
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- Vershinina, T, et al.
(author)
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Genetic Spectrum of Left Ventricular Non-Compaction in Paediatric Patients
- 2020
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In: Cardiology. - : S. Karger AG. - 1421-9751 .- 0008-6312. ; 145:11, s. 746-755
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Journal article (peer-reviewed)abstract
- <b><i>Introduction:</i></b> Left ventricular non-compaction (LVNC) represents a genetically heterogeneous cardiomyopathy which occurs in both children and adults. Its genetic spectrum overlaps with other types of cardiomyopathy. However, LVNC phenotypes in different age groups can have distinct genetic aetiologies. The aim of the study was to decipher the genetic spectrum of LVNC presented in childhood. <b><i>Patient Group and Methods:</i></b> Twenty patients under the age of 18 years diagnosed with LVNC were enrolled in the study. Target sequencing and whole-exome sequencing were performed using a panel of 108 cardiomyopathy-associated genes. Pathogenic, likely pathogenic, and variants of unknown significance found in genes highly expressed in cardiomyocytes were considered as variants of interest for further analysis. <b><i>Results:</i></b> The median age at presentation was 8.0 (0.1–17) years, with 6 patients presenting before 1 year of age. Twelve (60%) patients demonstrated reduced ejection fraction. Right ventricular (RV) dilation was registered in 6 (30%), often in combination with reduced RV contractility (25%). Almost half (45%) of the patients demonstrated biventricular involvement already at disease presentation. For pathogenic and likely pathogenic variants, the positive genotyping rate was 45%, and these variants were found mainly in non-contractile structural sarcomeric genes (<i>ACTN2</i>, <i>MYPN</i>, and <i>TTN</i>) or in metabolic and signal transduction genes (<i>BRAF</i> and <i>TAZ</i>). Likely pathogenic <i>TAZ</i> variants were detected in all 5 patients suspected of having Barth syndrome. No pathogenic or likely pathogenic variants were found in genes encoding for sarcomeric contractile proteins, but variants of unknown significance were detected in 3 out of 20 patients (<i>MYH6</i>, <i>MYH7</i>, and <i>MYLK2</i>). In 4 patients, variants of unknown significance in ion-channel genes were detected. <b><i>Conclusion:</i></b> We detected a low burden of contractile sarcomeric variants in LVNC patients presenting below the age of 18 years, with the major number of variants residing in non-contractile structural sarcomeric genes. The identification of the variants in ion-channel and related genes not previously associated with LVNC in paediatric patients requires further examination of their functional role.
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- Jorholt, J, et al.
(author)
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Two New Cases of Hypertrophic Cardiomyopathy and Skeletal Muscle Features Associated with ALPK3 Homozygous and Compound Heterozygous Variants
- 2020
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In: Genes. - : MDPI AG. - 2073-4425. ; 11:10
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Journal article (peer-reviewed)abstract
- Hypertrophic cardiomyopathy associated with damaging variants in the ALPK3 gene is a fairly recent discovery, and only a small number of patients have been described thus far. Here we present two additional patients with hypertrophic cardiomyopathy caused by biallelic variants in ALPK3. Genetic investigation was performed using a targeted gene panel consisting of known cardiomyopathy-associated genes and whole exome sequencing. The patients showed a large difference in the age of onset, and both presented with extracardiac features that are often seen in ALPK3 patients. The patient with the later onset showed milder extracardiac symptoms, such as decreased muscle tone and distal muscular dystrophy, but had fast progression of cardiac complications leading to the need of heart transplantation. This study further elucidates the variability of both symptoms and age of onset among these patients.
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- Landfeldt, E., et al.
(author)
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Assessment of face validity of a disease model of nonsense mutation Duchenne muscular dystrophy: a multi-national Delphi panel study
- 2022
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In: Journal of Medical Economics. - : Informa UK Limited. - 1369-6998 .- 1941-837X. ; 25:1, s. 808-816
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Journal article (peer-reviewed)abstract
- Objective The objective of this study was to assess the face validity of a disease model evaluating the cost-effectiveness of ataluren for the treatment of nonsense mutation Duchenne muscular dystrophy (nmDMD). Methods This was a Delphi panel study comprising of physicians with first-hand experience of ataluren for the treatment of nmDMD. Consensus was sought for previously unvalidated model data, including patient health status and quality of life measured using the Health Utility Index (HUI), mortality, informal caregiving, and the expected benefit of early ataluren treatment across four states: (1) ambulatory, (2) non-ambulatory, not yet requiring ventilation support, (3) non-ambulatory, night-time ventilation support, and (4) non-ambulatory, full-time ventilation support. Results Nine experts from five countries participated in the Delphi panel. Consensus was obtained for all questions after three panel rounds (except for two HUI-questions concerning hand function [dexterity]). Consensus HUI-derived utilities for state (1) were 1.0000 for ataluren on top of best supportive care (BSC) and 0.7337 for BSC alone. Corresponding estimates for state (2) were 0.3179 and 0.2672, for state (3) 0.1643 and 0.0913, and for state (4) -0.0732 and -0.1163. Consensus mortality rates for states (1), (2), and (3) were 4%, 13%, and 33%, and life expectancy in state (4) was agreed to be 3 years. Panelists further agreed that two informal caregivers typically provide day-to-day care/support to patients with nmDMD, and that starting treatment with ataluren at 2 versus 5 years of age would be expected to delay loss of ambulation by an additional 2 years, and initiation of night-time and full-time ventilation support by an additional 3 years, respectively. Limitations The main limitation concerns the size of the Delphi panel, govern primarily by the rarity of the disease. Conclusion This study confirms the face validity of key clinical parameters and assumptions underlying the ataluren cost-effectiveness model.
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