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Objectives: The objective of this study is to analyse retrospective, observational, longitudinal growth (weight, height and BMI) data in ambulatory boys aged 5-12 years with Duchenne muscular dystrophy (DMD).Background: We considered glucocorticoids (GC) use, dystrophin isoforms and amenability to exon 8, 44, 45, 51 and 53 skipping drug subgroups, and the impact of growth on loss of ambulation. We analysed 598 boys, with 2604 observations. This analysis considered patients from the UK NorthStar database (2003-2020) on one of five regimes: "GC naïve", "deflazacort daily" (DD), "deflazacort intermittent" (DI), "prednisolone daily" (PD) and "prednisolone intermittent" (PI). A random slope model was used to model the weight, height and BMI SD scores (using the UK90).Results: The daily regime subgroups had significant yearly height stunting compared to the GC naïve subgroup. Notably, the average height change for the DD subgroup was 0.25 SD (95% CI - 0.30, - 0.21) less than reference values. Those with affected expression of Dp427, Dp140 and Dp71 isoforms were 0.77 (95% CI 0.3, 1.24) and 0.82 (95% CI 1.28, 0.36) SD shorter than those with Dp427 and/or Dp140 expression affected respectively. Increased weight was not associated with earlier loss of ambulation, but taller boys still ambulant between the age of 10 and 11 years were more at risk of losing ambulation.Conclusion: These findings may provide further guidance to clinicians when counselling and discussing GCs commencement with patients and their carers and may represent a benchmark set of data to evaluate the effects of new generations of GC. [ABSTRACT FROM AUTHOR]

Objective GNE myopathy is a rare recessive myopathy associated with inclusion bodies on muscle biopsy. The clinical phenotype is associated with distal muscle weakness with quadriceps sparing. Most of the current information on GNE myopathy has been obtained through studies of Jewish and Japanese patient cohorts carrying founder mutations in the GNE gene. However, little is known about GNE myopathy in Europe where the prevalence is thought to be very low. Methods Patients were referred through the National Specialist Commissioning Team service for limb-girdle muscular dystrophies at Newcastle (UK). All patients harbouring mutations in the GNE gene were recruited for our study. Detailed clinical and genetic data as well as muscle MRIs and muscle biopsies were reviewed. Results We identified 26 patients harbouring mutations in the GNE gene. Two previously reported mutations (c.1985C>T, p.Ala662Val and c.1225G>T, p.Asp409Tyr) were prevalent in the Scottish, Northern Irish and Northern English populations; with 90% of these patients carrying at least one of the two mutations. Clinically, we confirmed the homogenous pattern of selective quadriceps sparing but noted additional features like asymmetry of weakness at disease onset. Conclusions GNE myopathy is an important diagnosis to consider in patients presenting with distal leg muscle weakness. We report, for the first time, two common mutations in the north of Britain and highlight the broader spectrum of clinical phenotypes. We also propose that the prevalence of GNE myopathy may be underestimated due to the frequent absence of rimmed vacuoles in the muscle biopsy. [ABSTRACT FROM AUTHOR]

Mutations in the four-and-a-half LIM domain 1 (FHL1) gene, which encodes a 280-amino-acid protein containing four LIM domains and a single zinc-finger domain in the N-terminal region, have been associated with a broad clinical spectrum of X-linked muscle diseases encompassing a variety of different phenotypes. Patients might present with a scapuloperoneal myopathy, a myopathy with postural muscle atrophy and generalized hypertrophy, an Emery-Dreifuss muscular dystrophy, or an early onset myopathy with reducing bodies. It has been proposed that the phenotypic variability is related to the position of the mutation within the FHL1 gene. Here, we report on three British families with a heterogeneous clinical presentation segregating a single FHL1 gene mutation and haplotype, suggesting that this represents a founder mutation. The underlying FHL1 gene mutation was detected by direct sequencing and the founder effect was verified by haplotype analysis of the FHL1 gene locus. A 3-bp insertion mutation (p.Phe127_Thr128insIle) within the second LIM domain of the FHL1 gene was identified in all available affected family members of the three families. Haplotype analysis of the FHL1 region on Xq26 revealed that the families shared a common haplotype. The p.Phe127_Thr128insIle mutation in the FHL1 gene therefore appears to be a British founder mutation and FHL1 gene screening, in particular of exon 6, should therefore be indicated in British patients with a broad phenotypic spectrum of X-linked muscle diseases. [ABSTRACT FROM AUTHOR]

Congenital muscular dystrophies (CMD) are a highly heterogeneous group of conditions clinically characterized by muscle weakness from birth, or shortly after, and variable involvement of eyes, heart and central nervous system. Some of these disorders are fatal in the first year of life, whereas others have a milder course and are compatible with survival into adulthood. The Dubowitz Neuromuscular Centre (DNC) is the National Specialist Commissioning Team (NSCT) referral centre for CMD in the UK. A few years ago we reported the relative frequency of CMD subtypes referred for clinical assessment to the DNC, with collagen VI related disorders being the most common diagnosis. This study reports the relative frequency and clinical and genetic spectrum of CMD in the entire cohort of UK patients in whom the genetic analysis for the CMD genes was requested between 2001 and 2013, including recently identified dystroglycanopathy genes. A total of 700 DNA samples were referred during this time interval and genetic diagnosis was reached in 366 of them. Detailed clinical information was available for 340 patients; 234 fulfilled a clinical diagnosis of CMD while the others had milder forms, such as LGMD. The most common type of genetically confirmed CMD was laminin α2 related dystrophy (MDC1A) accounting for about 44 % of cases, followed by dystroglycanopathies (26 %), Ullrich CMD (16 %) and Rigid Spine muscular dystrophy associated with SEPN1 gene mutations (14 %). Fifteen patients carried pathogenic mutations in the newly discovered ISPD, GMPPB and B3GALNT2 genes responsible for glycosylation defects in alpha-dystroglycan and here we also describe the associated phenotypes. Our results indicate MDC1A as the most common subtype of CMD in the UK and further expand the clinical and genetic spectrum of CMDs. [ABSTRACT FROM AUTHOR]

• Feeding difficulties are reported in 60% of children and adolescents with SMA type 2. • Underweight and weight gain problems are a major issue in up to 23–57% of patients. • There is an urgent need for guidelines on how to assess and anticipate on feeding problems. Disease course of feeding difficulties in spinal muscular atrophy type 2 is not well documented. Disease-modifying therapies rapidly change the trajectory of motor function and survival in spinal muscular atrophy, but effects on co-morbidities like bulbar function are unknown. We analysed data concerning feeding problems and their standard of care treatment in 146 patients with spinal muscular atrophy type 2. Data were collected from two separate cohorts: one single-centre retrospective chart review study from the United Kingdom (London), and one prospective questionnaire-based multicentre study from Italy. Cumulatively feeding difficulties were present in 88 patients (60%) in these 2 cohorts. Median age at onset of problems was 6.5years (range 0–16.5 years). Eighty-two patients (60%) showed periods of underweight according to age adjusted body mass index, and thirty-six patients (25%) showed malnourishment with a significant drop on their weight curves. Enteral feeding was indicated in 23 out of 72 patients in the UK cohort (32%) because of weight loss, oropharyngeal dysphagia or aspiration. Gastrostomy and its placement was generally well tolerated, uncomplicated in 96%, never reversed and performed without Nissen fundoplication in 66% of patients. After gastrostomy chest infections improved in 80% and nutritional status (e.g., Body Mass Index) in 84% of patients. These results show that feeding difficulties are a common problem in spinal muscular atrophy type 2. Treatment strategies should be tailor-made on the symptoms and needs of the individual patient. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy is a rapidly progressive X-linked neuromuscular disorder. The majority of boys, with and without treatments, lose ambulation by late teenage years. The North Star Ambulatory Assessment (NSAA) and the Performance of Upper Limb Module (PUL 2.0) are validated outcome measures used to assess change over time. The NSAA assesses gross motor function in ambulant boys (maximum score 34) while currently in the UK the PUL 2 is used predominantly to assess upper limb function in non-ambulant boys. The study aims to ascertain whether upper limb function starts to deteriorate in the ambulant population by applying both scales, and to assess which upper limb activities are most difficult in the younger age group. The PUL, which has a mixture of proximal and distal activities, has 22 items with a maximum achievable score of 42. It uses the Brook scale as an entry point. The boys engage well with this scale, finding it less challenging than some NSAA items (e.g standing from the floor, hopping). Cross sectional data was collected from 100 ambulant boys or those who recently lost ambulation (within 6 months of assessment) seen regularly in our neuromuscular service. Ages range from 4y 5m to 15y 2m for the ambulant boys. Ages for recently non-ambulant were 9y 7m to 13y 5m. In both ambulant and recently non-ambulant boys, scores for the North Star ambulatory assessment reduced with age. The corresponding scores for the PUL did not deteriorate with age and the majority of boys scored 35 or above. 20% scored maximum of 42, the youngest being 6y 4m. Four boys scored below 30 with NSAA below 6. Hardest items are lifting 1kg and 500g weights above shoulder level. This data shows that the majority of ambulant boys and recently non-ambulant boys with DMD maintain their upper limb function. Studies on older boys show a reduction in PUL 2.0. Further longitudinal studies are projected to show how function changes with loss of walking. [ABSTRACT FROM AUTHOR]

Through the DMD care UK project, a collaborative initiative between clinicians and patients, we have established an extensive, methodologically robust consultation process across all aspects of Duchenne muscular dystrophy (DMD) care. Initial benchmarking of current clinical care in the UK [against international recommendations (SoC)] and surveys of patient experience have been followed by a review of evidence and expert opinion by a series of specialist working groups. These groups were established to focus on different aspects of care but are all interlinked to ensure a multidisciplinary approach to the care of DMD. Each group includes patients or patient representatives and clinical experts from the UK North Star Clinical Network of specialist neuromuscular centres. This has led to consensus-building across different centres in all areas of care. Results from the first phases, including guidance from the endocrine and cardiac working groups, will be presented as a powerful illustration of the benefits of this approach. This highly successful model means that DMD Care UK has already effected change. We demonstrate examples of this through: endorsement of the first groups' consensus-built recommendations by UK professional bodies; tangible awareness-raising amongst clinicians by facilitation of group to group cross-talk; increased patient-community engagement in SoC development and dissemination; increased clinician engagement and network-building; securing of funding for clinical psychology and neuropsychiatry posts to address the identified gaps in psychosocial support for DMD; the release of an emergency care app to ensure that people with DMD get prompt and appropriate care in an emergency. We propose that this model of consensus building, awareness raising and collaboration improves the SoC for patients and empowers them to become active participants in their care. This model could be extended to other disease areas and other health systems. [ABSTRACT FROM AUTHOR]

Background Boys with Duchenne Muscular Dystrophy (DMD) display heterogeneous motor function trajectory in clinics, which represents a significant obstacle to monitoring., Objective: In this paper, we present the UK centiles for the North Star Ambulatory Assessment (NSAA), the 10 m walk/run time (10MWR) and velocity (10MWRV), and the rise from floor time (RFF) and velocity (RFFV) created from a cohort of glucocorticoid treated DMD boys between the age of 5 and 16 years., Methods: Participants were included from the UK NorthStar registry if they had initiated steroids (primarily deflazacorts/prednisolone, intermittent/daily) and were not enrolled in an interventional trial. Assessments were included if the participant had a complete NSAA, the timed tests had been completed or the corresponding items were 0, or the participant was recorded as non-ambulant, in which case the NSAA was assumed 0., Results: We analysed 3987 assessments of the NSAA collected from 826 participants. Of these, 1080, 1849 and 1199 were imputed as 0 for the NSAA, RFFV and 10MWRV respectively. The 10th, 25th, 50th, 75th and 90th centiles were presented. The NSAA centiles showed a peak score of 14, 20, 26, 30 and 32 respectively, with loss of ambulation at 10.7, 12.2 and 14.3 years for the 25th, 50th and 75th centiles, respectively. The centiles showed loss of rise from floor at 8.6, 10.1 and 11.9 years and a loss of 10MWR of 0 at 8.9, 10.3 and 13.8 years for the 25th, 50th and 75th centiles, respectively. The centiles were pairwise less correlated than the raw scores, suggesting an increased ability to detect variability in the DMD cohort., Conclusions: The NSAA, 10MWR and RFF centiles may provide insights for clinical monitoring of DMD boys, particularly in late ambulatory participants who are uniformly declining. Future work will validate the centiles in national and international natural history cohorts.

Congenital muscular dystrophies (CMDs) are clinically and genetically heterogeneous conditions; some fatal in the first few years of life and with central nervous system involvement, whereas others present a milder course. We provide a comprehensive report of the relative frequency and clinical and genetic spectrum of CMD in the UK. Genetic analysis of CMD genes in the UK is centralised in London and Newcastle. Between 2001 and 2013, a genetically confirmed diagnosis of CMD was obtained for 249 unrelated individuals referred to these services. The most common CMD subtype was laminin-α2 related CMD (also known as MDC1A, 37.4%), followed by dystroglycanopathies (26.5%), Ullrich-CMD (15.7%), SEPN1 (11.65%) and LMNA (8.8%) gene related CMDs. The most common dystroglycanopathy phenotype was muscle-eye-brain-like disease. Fifteen patients carried mutations in the recently discovered ISPD, GMPPB and B3GALNT2 genes. Pathogenic allelic mutations in one of the CMD genes were also found in 169 unrelated patients with milder phenotypes, such as limb girdle muscular dystrophy and Bethlem myopathy. In all, we identified 362 mutations, 160 of which were novel. Our results provide one of the most comprehensive reports on genetics and clinical features of CMD subtypes and should help diagnosis and counselling of families with this group of conditions., (Copyright © 2017 Elsevier B.V. All rights reserved.)