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Item does not contain fulltext, BACKGROUND: Drug repurposing could provide novel treatment options for Duchenne muscular dystrophy. Because tamoxifen-an oestrogen receptor regulator-reduced signs of muscular pathology in a Duchenne muscular dystrophy mouse model, we aimed to assess the safety and efficacy of tamoxifen in humans as an adjunct to corticosteroid therapy over a period of 48 weeks. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 12 study centres in seven European countries. We enrolled ambulant boys aged 6·5-12·0 years with a genetically confirmed diagnosis of Duchenne muscular dystrophy and who were on stable corticosteroid treatment for more than 6 months. Exclusion criteria included ophthalmological disorders, including cataracts, and haematological disorders. We randomly assigned (1:1) participants using an online randomisation tool to either 20 mg tamoxifen orally per day or matched placebo, stratified by centre and corticosteroid intake. Participants, caregivers, and clinical investigators were masked to treatment assignments. Tamoxifen was taken in addition to standard care with corticosteroids, and participants attended study visits for examinations every 12 weeks. The primary efficacy outcome was the change from baseline to week 48 in scores on the D1 domain of the Motor Function Measure in the intention-to-treat population (defined as all patients who fulfilled the inclusion criteria and began treatment). This study is registered with ClinicalTrials.gov (NCT03354039) and is completed. FINDINGS: Between May 24, 2018, and Oct 14, 2020, 95 boys were screened for inclusion, and 82 met inclusion criteria and were initially enrolled into the study. Three boys were excluded after initial screening due to cataract diagnosis or revoked consent directly after screening, but before randomisation. A further boy assigned to the placebo group did not begin treatment. Therefore, 40 individuals assigned tamoxifen and 38 allocated placebo were inc

Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (median age at symptom onset 0.9 years, range: 0.0-2.0). Age of onset and age of death were significantly lower in patients who never acquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (median: 1.2 years, range: 0.8-4.0) and age of ambulation loss (median: 7 years, range: 1.2-38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype-phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confi

Cockayne syndrome (CS) is a multisystem degenerative disorder divided in 3 overlapping subtypes, with a continuous phenotypic spectrum: CS2 being the most severe form, CS1 the classical form and CS3 the late-onset form. Failure to thrive and growth difficulties are among the most consistent features of CS, leaving affected individuals vulnerable to numerous medical complications, including adverse effects of undernutrition, abrupt overhydration and overfeeding. There is thus a significant need for specific growth charts. We retrospectively collected growth parameters from genetically-confirmed CS1 and CS2 patients, used the GAMLSS package to construct specific CS growth charts compared to healthy children from WHO and CDC databases. Growth data were obtained from 88 CS patients with a total of 1626 individual growth data points. 49 patients were classified as CS1 and 39 as CS2 with confirmed mutations in CSB/ERCC6, CSA/ERCC8 or ERCC1 genes. Individuals with CS1 initially have normal growth parameters; microcephaly occurs from 2 months whereas onset of weight and height restrictions appear later, between 5 and 22 months. In CS2, growth parameters are already below standard references at birth or drop below the 5th percentile before 3 months. Microcephaly is the first parameter to show a delay, appearing around 2 months in CS1 and at birth in CS2. Height and head circumference are more severely affected in CS2 compared to CS1 whereas weight curves are similar in CS1 and CS2 patients. These new growth charts will serve as a practical tool to improve the nutritional management of children with CS.

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Item does not contain fulltext, Verheij syndrome, also called 8q24.3 microdeletion syndrome, is a rare condition characterized by ante- and postnatal growth retardation, microcephaly, vertebral anomalies, joint laxity/dislocation, developmental delay (DD), cardiac and renal defects and dysmorphic features. Recently, PUF60 (Poly-U Binding Splicing Factor 60 kDa), which encodes a component of the spliceosome, has been discussed as the best candidate gene for the Verheij syndrome phenotype, regarding the cardiac and short stature phenotype. To date, only one patient has been reported with a de novo variant in PUF60 that probably affects function (c.505C>T leading to p.(His169Tyr)) associated with DD, microcephaly, craniofacial and cardiac defects. Additional patients were required to confirm the pathogenesis of this association and further delineate the clinical spectrum. Here we report five patients with de novo heterozygous variants in PUF60 identified using whole exome sequencing. Variants included a splice-site variant (c.24+1G>C), a frameshift variant (p.(Ile136Thrfs*31)), two nonsense variants (p.(Arg448*) and p.(Lys301*)) and a missense change (p.(Val483Ala)). All six patients with a PUF60 variant (the five patients of the present study and the unique reported patient) have the same core facial gestalt as 8q24.3 microdeletions patients, associated with DD. Other findings include feeding difficulties (3/6), cardiac defects (5/6), short stature (5/6), joint laxity and/or dislocation (5/6), vertebral anomalies (3/6), bilateral microphthalmia and irido-retinal coloboma (1/6), bilateral optic nerve hypoplasia (2/6), renal anomalies (2/6) and branchial arch defects (2/6). These results confirm that PUF60 is a major driver for the developmental, craniofacial, skeletal and cardiac phenotypes associated with the 8q24.3 microdeletion.

Background: Exon skipping therapy is an emerging approach in Duchenne Muscular Dystrophy (DMD). Antisense oligonucleotides that induce skipping of exon 51, 44, 45, or 53 are currently being evaluated in clinical trials. These trials were designed on the basis of data available in general DMD population. Objectives: Our objective was to compare the clinical and functional statuses of non-ambulant DMD patients theoretically treatable by exon 53 skipping and of DMD patients with other mutations. Methods: We first compared fifteen non-ambulant DMD patients carrying deletions theoretically treatable by exon 53 skipping (DMD-53) with fifteen closely age-matched DMD patients with mutations not treatable by exon 53 skipping (DMD-all-non-53) then with fifteen DMD patients carrying deletions not treatable by exon 53 skipping (DMD-del-non-53). Results: We found that DMD-53 patients had a lower left ventricular ejection fraction, more contractures and they tend to have weaker grips and pinch strengths than other DMD patients. DMD-53 patients lost ambulation significantly younger than other DMD patients. This result was confirmed by comparing ages at loss of ambulation in all non-ambulant DMD patients of the DMD cohort identified in a molecular diagnostic lab. Conclusions: These prospective and retrospective data demonstrate that DMD-53 patients have clinically more severe phenotypes than other DMD patients.