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The advent of clinical trials in myotonic dystrophy type 1 (DM1) necessitates the identification of reliable outcome measures to quantify different disease manifestations using minimal number of assessments. In this study, clinical correlations of mean masseter volume (mMV) were explored to evaluate its potential as a marker of muscle involvement in adult-onset DM1 patients. We utilised data from a preceding study, pertaining to 39 DM1 patients and 20 age-matched control participants. In this study participants had undergone MRI of the brain, completed various clinical outcome measures and had CTG repeats measured by small-pool PCR. Manual segmentation of masseter muscles was performed by a single rater to estimate mMV. The masseter muscle was atrophied in DM1 patients when compared to controls (p<0.001). Significant correlations were found between mMV and estimated progenitor allele length (p = 0.001), modal allele length (p = 0.003), disease duration (p = 0.009) and and the Muscle Impairment Rating Scale (p = 0.008). After correction for lean body mass, mMV was also inversely correlated with self-reported myotonia (p = 0.014). This study demonstrates that changes in mMV are sensitive in reflecting the underlying disease process. Quantitative MRI methods demonstrate that data concerning both central and peripheral disease could be acquired from MR brain imaging studies in DM1 patients., Competing Interests: Declaration of Competing Interest AO, CH, MJH, JMcL, SC, BB, RJ, CL and MEF declare no conflict of interest. DGM: Within the last three years Professor Monckton has been a scientific consultant and/or received an honoraria/stock options from AMO Pharma, LoQus23, Triplet Therapeutics and Vertex Pharmaceuticals. Professor Monckton has also had research contracts with AMO Pharma and Vertex Pharmaceuticals., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Abnormalities of sleep are common in myotonic dystrophy type 1 (DM1), but few previous studies have combined polysomnography with detailed clinical measures and brain imaging. In the present study, domiciliary polysomnography, symptom questionnaires and cognitive evaluation were undertaken in 39 DM1-affected individuals. Structural brain MRI was completed in those without contra-indication (n = 32). Polysomnograms were adequate for analysis in 36 participants. Sleep efficiency was reduced, and sleep architecture altered in keeping with previous studies. Twenty participants (56%) had moderate or severe sleep-disordered breathing (apnoea-hypopnoea index [AHI] ≥ 15). In linear modelling, apnoeas were positively associated with increasing age and male sex. AHI ≥ 15 was further associated with greater daytime pCO 2 and self-reported physical impairment, somnolence and fatigue. Percentage REM sleep was inversely associated with cerebral grey matter volume, stage 1 sleep was positively associated with occipital lobe volume and stage 2 sleep with amygdala volume. Hippocampus volume was positively correlated with self-reported fatigue and somnolence. Linear relationships were also observed between measures of sleep architecture and cognitive performance. Findings broadly support the hypothesis that changes in sleep architecture and excessive somnolence in DM1 reflect the primary disease process in the central nervous system., Competing Interests: Conflicts of interest Within the last five years Professor Monckton has been a scientific consultant and/or received an honoraria/stock options/grants from AMO Pharma, Charles River, LoQus23, Small Molecule RNA, Triplet Therapeutics and Vertex Pharmaceuticals. Professor Monckton also had research contracts with AMO Pharma and Vertex Pharmaceuticals. Professor Monckton has received research grants/contracts from the European Union, CHDI, European Huntington Disease Network, Huntington Disease Society of America, National Institute of Health, Muscular Dystrophy UK and the Myotonic Dystrophy Support Group. Professor Monckton is on the Scientific Advisory Board of Myotonic (formerly the Myotonic Dystrophy Foundation) and EuroDyMA (European Dystrophia Myotonica Association), is a scientific advisor to the Myotonic Dystrophy Support Group and is a vice president of Muscular Dystrophy UK.; The remaining authors have no conflicts to declare., (Copyright © 2022 Elsevier B.V. All rights reserved.)

This retrospective study evaluated the phenotypic and genotypic features of 14 patients with McArdle disease attending the West of Scotland adult muscle clinic. Although all patients experienced exercise-induced cramps, exercise intolerance and hyperCKaemia, only 71% (n = 10) experienced the second wind phenomenon, rhabdomyolysis and/or myoglobinuria. We observed a high rate of fixed muscle weakness (50%; n = 7), coronary artery disease (36%; n = 5), and psychological comorbidity (50%; n = 7). Although 79% had symptom onset in the first decade of life, the mean age at presentation and at genetic diagnosis was 43.8 years and 47.7 years, respectively. 93% had at least one copy of the common PYGM pathogenic variant, c.148C > T, p.(Arg50*), with 50% (n = 7) of the cohort being homozygous. Our cohort highlights the phenotypic variability seen in McArdle disease and underscores the potential for late-onset presentations. It emphasises the need for improved awareness and recognition of this condition amongst neurologists, rheumatologists and general physicians. A history of exercise intolerance and second wind phenomenon may not always be volunteered by the patient, underscoring the need to ask specific questions in clinic to extrapolate the relevant symptoms in this patient cohort., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

Faecal incontinence is recognised as a feature of myotonic dystrophy along with other symptoms of bowel dysfunction, but its prevalence is poorly defined. We have surveyed 152 unselected myotonic dystrophy patients. We identified issues with bowel control in 104 (68% of the study population). Forty-eight (32%) reported faecal incontinence in the 4 weeks prior to completion of the questionnaire. Fifty-six patients (37%) reported having to change their lifestyle because of incontinence issues at some point in the prior 4 weeks. This study shows a high frequency of life-changing symptoms in a large unselected, cohort of patients with myotonic dystrophy type 1, and highlights lower gastrointestinal symptoms as an important issue for further research., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

Autosomal recessive mutations in the ECEL1 gene have recently been associated with a wide phenotypic spectrum including severe congenital contractural syndromes and distal arthrogryposis type 5D (DA5D). Here, we describe four novel families with ECEL1 gene mutations, reporting 15 years of follow-up for four patients and detailed muscle pathological description for three individuals. In particular, we observed mild myopathic features, prominent core-like areas in one individual, and presence of nCAM positive fibres in three patients from 2 unrelated families suggesting a possible problem with innervation. Our findings expand current knowledge concerning the phenotypic and pathological spectrum associated with ECEL1 gene mutations and may suggest novel insights regarding the underlying pathomechanism of the disease., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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.)

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an inherited neuromuscular condition resulting from recessive mutations in the immunoglobulin mu-binding protein (IGHMBP2) gene. Affected individuals characteristically present in infancy with progressive distal weakness and respiratory distress secondary to diaphragmatic weakness. Considerable clinical heterogeneity has been described both in its presentation and phenotype in childhood; however little data pertaining to phenotype in adulthood have been reported to date. This report describes a 21 year old woman with genetically confirmed SMARD1 who has stable muscle weakness, normal cognitive abilities and is able to lead a socially integrated lifestyle, using mechanical ventilation only overnight. This report adds new evidence for clinical variability throughout the course of SMARD1., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Excessive daytime sleepiness (EDS), of very similar pattern to that seen in narcolepsy syndrome, is extremely common in myotonic dystrophy type 1 (DM1). In a significant minority it has a profound disabling effect on employment, social functioning and activities of daily living. Limited published studies have shown inconsistent results from use of the psychostimulant drug modafinil. A recent European Medicines Agency (EMA) review concluded that on current evidence regarding safety and efficacy, modafinil's use should be restricted to the treatment of narcolepsy. In other conditions (although DM1 was not specifically considered) it was concluded that there was insufficient evidence of benefit to outweigh potentially serious side-effects, including severe skin reactions and cardiac arrhythmia. Clinicians with extensive experience in the management of DM1 have found modafinil to be extremely effective in appropriately selected patients with a very low incidence of serious side-effects. Given the recent EMA review, patients have expressed concern about the potential restriction of the use of modafinil in DM1. This brief review is an audit of the experience of a large group of patients and their clinicians concerning EDS and DM1 and concludes that despite the limited literature there is strong evidence to support the use of modafinil in carefully selected patients., (Copyright © 2012 Elsevier B.V. All rights reserved.)

We describe clinical and muscle magnetic resonance imaging (MRI) findings in 11 cases (three familial and eight sporadic) with the form of spinal muscular atrophy characterised by predominant involvement of the lower limbs with weakness of the proximal and distal muscles and marked atrophy of the distal leg and foot muscles. All patients presented at birth with talipes, which were in extension in seven of the 11. Arm muscle and function were preserved and lower limbs appeared to be disproportionately shorter compared to trunk and upper limbs. Functional abilities were markedly affected and only one of the 11 is able to walk independently for long distances, while six require support of crutches and two use callipers for walking. One child lost ambulation following a fall. The course of the disease is relatively stable and the progression of disability appeared to be related mostly to increased contractures rather than to loss of muscle strength. Respiratory and cardiac function were well preserved. A neurogenic disorder was suggested by electromyography and/or muscle biopsy in all patients, while motor nerve conduction was consistently normal. Muscle MRI of the thighs revealed diffuse atrophic appearance with relative hypertrophy of the adductor longus and of the semitendinosus. Genetic studies excluded the involvement of the survival motor neuron gene but none of these families was sufficiently informative to study linkage to the locus on chromosome 12q23-q24 previously found to be involved in patients with similar phenotype. In our experience this form of spinal muscular atrophy affecting predominantly the lower limbs is a relatively common form and should be considered in the differential diagnosis of infants with talipes and weakness in the lower limbs. The identical clinical and imaging features of the sporadic and familial cases suggest that these cases are likely to be affected by the same condition.

The limb girdle muscular dystrophies are a heterogeneous group of conditions characterized by proximal muscle weakness and disease onset ranging from infancy to adulthood. We report here eight patients from seven unrelated families affected by a novel and relatively mild form of autosomal recessive limb girdle muscular dystrophy (LGMD2) with onset in the first decade of life and characterized by severe mental retardation but normal brain imaging. Immunocytochemical studies revealed a significant selective reduction of alpha-dystroglycan expression in the muscle biopsies. Linkage analysis excluded known loci for both limb girdle muscular dystrophy and congenital muscular dystrophies in the consanguineous families. We consider that this represents a novel form of muscular dystrophy with associated brain involvement. The biochemical studies suggest that it may belong to the growing number of muscular dystrophies with abnormal expression of alpha-dystroglycan.