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To correlate the North Star Ambulatory Assessment (NSAA) and timed rise from floor (TRF) recorded at age of expected peak with age at loss of ambulation (LOA) in Duchenne muscular dystrophy (DMD).Male children with DMD enrolled in the UK North Start Network database were included according to the following criteria: follow-up longer than 3 years, one NSAA record between 6 years and 7 years 6 months (baseline), at least one visit when older than 8 years. Data about corticosteroid treatment, LOA, genotype, NSAA, and TRF were analysed. Age at LOA among the different groups based on NSAA and TRF was determined by log-rank tests. Cox proportional hazard models were used for multivariable analysis.A total of 293 patients from 13 different centres were included. Mean (SD) age at first and last visit was 5 years 6 months (1 year 2 months) and 12 years 8 months (2 years 11 months) (median follow-up 7 years 4 months). Higher NSAA and lower TRF at baseline were associated with older age at LOA (p0.001). Patients scoring NSAA 32 to 34 had a probability of 0.61 of being ambulant when older than 13 years compared with 0.34 for those scoring 26 to 31. In multivariable analysis, NSAA, TRF, and corticosteroid daily regimen (vs intermittent) were all independently associated with outcome (p=0.01).Higher functional abilities at peak are associated with older age at LOA in DMD. This information is important for counselling families. These baseline measures should also be considered when designing clinical trials.

Predicting the trajectory of rare degenerative diseases can be extremely beneficial, especially when these predictions are personalised to be relevant for a specific patient. These predictions can help inform and advise patients, families, and clinicians about the next stages of treatment and care. Obtaining such predictions, however, can be challenging, especially when data is limited. In particular, it is important that these predictions do not rely too heavily on general trends from the wider afflicted population while not relying exclusively on the, potentially sparse, data from the patient in question. We present a case study, wherein a modelling framework is developed for predicting a patient’s long term trajectory, using a mix of data from the patient of concern and a database of previously observed patients. This framework directly accounts for the temporal structure of a patient’s trajectory, effortlessly handles a large amount of missing data, allows for a wide range of patient progression, and offers a robust quantification of the various uncertainties. We showcase this framework to an example involving Duchenne Muscular Dystrophy, where it provides promising results.

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.

SLC5A7 encodes the presynaptic sodium-dependant high-affinity choline transporter 1 (CHT), which uptakes choline to the presynaptic nerve terminal following the breakdown of acetylcholine by the acetylcholinesterase within the synaptic cleft. We report 5 patients from three consanguineous families with congenital myasthenic syndrome type 20 caused by novel mutations in SLC5A7. The individuals from family 1 and 2 were homozygous for c.320G>A; (p.Arg107His) and c.886G>A (p.Ala296Thr), respectively, and their phenotype was characterised by recurrent apnoeic attacks early after birth and learning and speech difficulties in childhood. Individuals from family 3 were homozygous for c.1240T>A (p.Tyr414Asn) and suffered from more severe central and peripheral manifestations with lack of spontaneous movements and respiratory drive and overall minimal response to external stimuli. All individuals tested showed neurophysiological defects compatible with impaired neuromuscular transmission. Combined treatment with cholinesterase inhibitors and β2-adrenergic agonists was beneficial in patients from family 1 and 2. Affected individuals from family 3 died from complications directly related to their underlying genetic condition. This report provides three novel pathogenic variants in SLC5A7 and highlights the variability in the clinical phenotype, severity and prognosis of this syndrome.

Objective To describe clinical features and disease progression of Selenoprotein N‐related myopathy in a large multicenter cohort of patients. Methods Cross‐sectional multicenter data analysis of 60 patients (53 families) with Selenoprotein N‐related myopathy and single‐center retrospective longitudinal analysis of 25 patients (21 families) over a median period of 5.3 years. Results The majority of patients (46/60, 77%) presented before age 2 years with hypotonia, poor head/neck control, and developmental delay. At last assessment (median age 14 years; range 2.5 to 36 years), 10/60 patients had minimal or no ambulation. Ventilatory support was initiated in 50/60 patients at a mean Forced Vital Capacity (FVC) of 38% and at a median age of 13 years. Forty‐five/60 patients developed scoliosis (at median age 12.1 years) and 18 had scoliosis surgery at a median age of 13.6 years. Five children needed nasogastric feeds and/or gastrostomy. Longitudinal data analysis on 25 patients showed progressive decline of Hammersmith functional motor scores (estimated annual change −0.55 point), time to walk 10 meter, time standing from sitting, and from lying. Sixteen patients had weights

Aminoacyl-tRNA synthetases (ARSs) are ubiquitous, ancient enzymes that charge amino acids to cognate tRNA molecules, the essential first step of protein translation. Here, we describe 32 individuals from 21 families, presenting with microcephaly, neurodevelopmental delay, seizures, peripheral neuropathy, and ataxia, with de novo heterozygous and bi-allelic mutations in asparaginyl-tRNA synthetase (NARS1). We demonstrate a reduction in NARS1 mRNA expression as well as in NARS1 enzyme levels and activity in both individual fibroblasts and induced neural progenitor cells (iNPCs). Molecular modeling of the recessive c.1633C>T (p.Arg545Cys) variant shows weaker spatial positioning and tRNA selectivity. We conclude that de novo and bi-allelic mutations in NARS1 are a significant cause of neurodevelopmental disease, where the mechanism for de novo variants could be toxic gain-of-function and for recessive variants, partial loss-of-function.

Centronuclear myopathies are early-onset muscle diseases caused by mutations in several genes including MTM1, DNM2, BIN1, RYR1 and TTN The most severe and often fatal X-linked form of myotubular myopathy (XLMTM) is caused by mutations in the gene encoding the ubiquitous lipid phosphatase myotubularin, an enzyme specifically dephosphorylating phosphatidylinositol-3-phosphate and phosphatidylinositol-3,5-bisphosphate. Because XLMTM patients have a predominantly muscle-specific phenotype a number of pathogenic mechanisms have been proposed, including a direct effect of the accumulated lipid on the skeletal muscle calcium channel ryanodine receptor 1, a negative effect on the structure of intracellular organelles and defective autophagy. Animal models knocked out for MTM1 show severe reduction of ryanodine receptor 1 mediated calcium release but, since knocking out genes in animal models does not necessarily replicate the human phenotype, we considered it important to study directly the effect of MTM1 mutations on patient muscle cells. The results of the present study show that at the level of myotubes MTM1 mutations do not dramatically affect calcium homeostasis and calcium release mediated through the ryanodine receptor 1, though they do affect myotube size and nuclear content. On the other hand, mature muscles such as those obtained from patient muscle biopsies exhibit a significant decrease in expression of the ryanodine receptor 1, a decrease in muscle-specific microRNAs and a considerable up-regulation of histone deacetylase-4. We hypothesize that the latter events consequent to the primary genetic mutation, are the cause of the severe decrease in muscle strength that characterizes these patients.

Background and ObjectivesThe decline of respiratory function in Duchenne muscular dystrophy (DMD) is associated with sleep disordered breathing (SDB) and alteration of nocturnal gas exchange, first manifesting as nocturnal hypoventilation (NH). However, the correlation between the pulmonary function measured by spirometry (PFT) and the onset of SDB with or without NH is unclear. The aims of this study are to identify the prevalence and features of SDB and to investigate the relationship between lung function determined by forced vital capacity (FVC) and sleep abnormalities in a large pediatric DMD population.MethodsThis was a retrospective, single-center cohort study. FVC% predicted (FVC%) was calculated using predicted equations from the Global Lung Function Initiative. NH was defined by transcutaneous (tc) CO2 >50 mm Hg for >25% of total sleep time (TST), borderline NH by a mean tcCO2 between 45 and 50 mm Hg or tcCO2>50 mm Hg for ≤25% of TST, and clinically meaningful obstructive sleep apnea (OSA) by obstructive apnea-hypopnea index >5. The sensitivity, specificity, and positive and negative predictive values of FVC < 50% to indicate the presence of nocturnal hypoventilation were calculated.ResultsOne hundred thirty-four patients underwent 284 sleep studies and 1222 PFT. The mean (SD) age at the first and the last sleep study was 12.9 (2.7) and 14.3 (2.6) years, respectively. Borderline NH (n = 31) was detected in both ambulant and early-nonambulant participants, while 100% of NH cases (n = 14) were nonambulant. NH was detected in 4 of the 14 patients despite an FVC >50%. Seventeen of the 26 patients with OSA presented with concomitant NH or borderline NH. FVC DiscussionFVC% 50%. These results are relevant for the clinical management of SDB.

Mutations in COL13A1 cause synaptic basal lamina-associated congenital myasthenic syndrome type 19. Rodriguez Cruz et al. describe the clinical and genetic spectrum associated with COL13A1 mutations, and the key clinical features to look out for., Next generation sequencing techniques were recently used to show mutations in COL13A1 cause synaptic basal lamina-associated congenital myasthenic syndrome type 19. Animal studies showed COL13A1, a synaptic extracellular-matrix protein, is involved in the formation and maintenance of the neuromuscular synapse that appears independent of the Agrin-LRP4-MuSK-DOK7 acetylcholine receptor clustering pathway. Here, we report the phenotypic spectrum of 16 patients from 11 kinships harbouring homozygous or heteroallelic mutations in COL13A1. Clinical presentation was mostly at birth with hypotonia and breathing and feeding difficulties often requiring ventilation and artificial feeding. Respiratory crisis related to recurrent apnoeas, sometimes triggered by chest infections, were common early in life but resolved over time. The predominant pattern of muscle weakness included bilateral ptosis (non-fatigable in adulthood), myopathic facies and marked axial weakness, especially of neck flexion, while limb muscles were less involved. Other features included facial dysmorphism, skeletal abnormalities and mild learning difficulties. All patients tested had results consistent with abnormal neuromuscular transmission. Muscle biopsies were within normal limits or showed non-specific changes. Muscle MRI and serum creatine kinase levels were normal. In keeping with COL13A1 mutations affecting both synaptic structure and presynaptic function, treatment with 3,4-diaminopyridine and salbutamol resulted in motor and respiratory function improvement. In non-treated cases, disease severity and muscle strength improved gradually over time and several adults recovered normal muscle strength in the limbs. In summary, patients with COL13A1 mutations present mostly with severe early-onset myasthenic syndrome with feeding and breathing difficulties. Axial weakness is greater than limb weakness. Disease course improves gradually over time, which could be consistent with the less prominent role of COL13A1 once the neuromuscular junction is mature. This report emphasizes the role of collagens at the human muscle endplate and should facilitate the recognition of this disorder, which can benefit from pharmacological treatment.

BackgroundDuchenne muscular dystrophy (DMD) is caused by DMD mutations leading to dystrophin loss. Full length Dp427 is the primary dystrophin isoform expressed in skeletal muscle and is also expressed in the central nervous system (CNS). Two shorter isoforms, Dp140 and Dp71, are highly expressed in the CNS. While a role for Dp140 and Dp71 on DMD CNS co-morbidities is well known, relationships between lack of Dp140 and Dp71 and DMD motor outcomes are not. We have conducted a series of investigations addressing this.MethodsFunctional outcome data from 387 DMD boys aged 4.0-15.4 years was subdivided by DMD mutation expected effect on isoform expression; Group 1 (Dp427 absent, Dp140/Dp71 present, n=201); group 2 (Dp427/Dp140 absent, Dp71 present, n=152); and group 3 (Dp427/Dp140/Dp71 absent, n=34). Relationships between isoform group and North Star ambulatory assessment (NSAA) scores, 10m walk/run and rise times were explored using regression analysis. We used Capillary Western immunoassay (Wes) analysis to study Dp427, Dp140 and Dp71 production in wild-type and DMD skeletal muscle and myogenic cultures. Grip strength was studied in wild-type, mdx (Dp427 absent, Dp140/Dp71 present), mdx52 (Dp427/Dp140 absent, Dp71 present) and DMD-null (lacking all isoforms) mice.ResultsIn DMD boys, we found a strong association between isoform group and motor function. In DMD boys, mean NSAA scores at 5 years of age were 6.1 points lower in group 3 than group 1 (ppp=0.09) and 1.6 points lower in group 2 than group 1 (p=0.04).Average grip strength in peak force at 3 months of age was higher in mdx than mdx52 mice (p=0.01).Dp427, but not Dp71, was produced in normal skeletal muscle; low levels of Dp71 were detected in DMD skeletal muscle. High Dp71 levels were present in wild-type and DMD myogenic cultures.ConclusionsDMD boys lacking Dp140 and Dp140/Dp71 displayed worse motor function with a cumulative effect of isoform loss. DMD mouse models lacking Dp427 and Dp140 had lower grip strength than those lacking Dp427 but not Dp140. Our results highlight the importance of considering the effects of dystrophin isoform loss on DMD motor impairment, with important implications for understanding the complex relationship between brain and muscle function in DMD and patient stratification for clinical trials.

SummaryRNA-binding proteins (RBPs) are essential for post-transcriptional regulation and processing of RNAs. Pathogenic missense variants in RBPs underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, inclusion body myopathy, distal myopathy, and Paget’s disease of the bone. Here, we present ten independent families with a severe, progressive, early-onset muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD), caused by heterozygous frameshift variants in the prion-like domain of hnRNPA2B1. We found that in contrast with the previously reported missense variants, the frameshift hnRNPA2B1 variants do not promote, but rather decelerate the fibrillization of the protein. Importantly, the frameshift variants harbor altered nuclear-localization sequences and exhibit reduced affinity for the nuclear-import receptor, Karyopherin-β2, which promotes their cytoplasmic accumulation in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with hnRNPA2B1 to include a severe, early-onset disease reminiscent of OPMD, caused by a distinct class of frameshift variants that alter its nucleocytoplasmic transport dynamics.

Knowledge of health related quality of life (HRQOL) in the immediate phase following DMD diagnosis has not been well-characterized. It is important to understand HRQOL early in disease for both clinical care and studies of treatment. The relationship between parent-proxy and child self-report HRQOL and their associations with medical, psycho-social and behavioral symptoms deserve study. In this study HRQOL was measured using the PedsQL inventory in parent/caregiver and corticosteroid-naïve boys (ages 4 to 7 years) participating in the FOR-DMD study. Agreement between the parent-proxy report and the boys' self-report HRQOL was measured using intraclass correlation coefficients (ICCs). Factors associated with HRQOL, including standardized psychosocial and behavioral measures in this cross-sectional sample, were explored using correlations. The results showed that the level of agreement between 70 dyads of child self-report and parent-proxy ratings of HRQOL was poor for the generic PedsQL total score (ICC=0.48, 95% CI (0.23, 0.66)) and its subscale scores, and was similarly low for the neuromuscular disease module (ICC=0.24, 95% CI (0.00, 0.45)). Parents rated their child's HRQOL as poorer than the children rated themselves in all scales. Psychosocial outcome measures were more highly associated with HRQOL measures than disease severity or patient demographic variables. In the early phases of DMD, child and parent-proxy HRQOL ratings were discordant. In early DMD, psychosocial and behavioral aspects appear to be more relevant to HRQOL than disease severity factors.

Background Walker Warburg dystroglycanopathy is the most severe subtype of congenital muscular dystrophies. It is characterised by four consistent features -cobble stone lissencephaly, cerebellar malformation ,retinal abnormalities and muscular dystrophy. The incidence is estimated at 1.2 per 100,000 live births and the life-span in these children is around 3 years. There are more than fifteen causative genes and transmission is autosomal recessive. Case We describe a boy, born in Kuwait to parents of a consanguineous marriage ,premature at 34 weeks gestation with hypotonia, antenatal hydrocephalus and severe eye abnormalities. An MRI brain done at the referring hospital showed cobblestone lissencephaly and severe ventricular dilatation. He was transferred to our centre at corrected age 38 weeks for neurosurgical and medical management. Clinical examination showed central hypotonia with a lack of purposeful movements, macrocephaly from hydrocephalus, left eye buphthalmos and congenital glaucoma, a blind microphthalmic right eye, hearing impairment and bilateral medullary nephrocalcinosis. The creatinine kinase was elevated at 3996U/l. A genetic panel for muscular dystrophy done here detected a homozygous ISPD c.1186G>T p. (Gly396Ter) pathogenic sequence variant, confirming ISPD-related congenital muscular dystrophy. Complications included cerebrospinal fluid leak post ventriculoperitoneal (VP) shunt insertion, recurrent aspiration pneumonia and urinary tract infections.Of note, he developed hypothermia as a side effect from Timolol eye drops as part of his treatment for glaucoma. He underwent a fundoplication gastrostomy ;slowly tolerating feeds with anti-reflux medications, breathing comfortably in air and cooing in response to parents’ handling. Within a comprehensive multidisciplinary team effort , lung protective strategies, regular occupational and physiotherapy, he made a good recovery. He was successfully repatriated home with good parental care at corrected age 7 months Conclusion Prognosis may be poor in WWS, however it is most ethical to provide holistic care, optimise the quality of life and direct genetic counselling.

On average children with hypermobility achieve motor milestones later than peers without. This study looked at the prevalence of hypermobility in a sample of Duchenne Muscular Dystrophy (DMD) and aimed to determine if hypermobility has an impact on walking age and delays attainment of functional skills assessed by the North Star Ambulatory Assessment (NSAA). This is a retrospective study of 158 boys with DMD aged 3 to 8 years (±3 months). During clinical appointments each boy was assessed using the NSAA, joint ranges measured and age of walking noted. Hypermobility was determined using the revised Beighton scale where a score above 4 is considered hypermobile. The young DMD population had a higher percentage, 18%, of hypermobility compared to healthy controls, 7%. The pattern of hypermobility in DMD differed as well; knees and elbows were more commonly hypermobile compared to the expected ankles and thumbs. In DMD only 5% had hypermobile ankles compared to 22%. Hypermobility in DMD ankles often quickly tightened. Non hypermobile DMD boys walked on average at 17.8 mths (range 10–36 mths). This was similar to hypermobile boys; average 19 mths (range 13–36 mths). Hypermobile DMD boys were found to have a lower average NSAA at each age point than those who weren’t hypermobile, approximately 6 months behind. Both DMD groups gained functional skills with increased age until 6.5 (non hypermobile) and 7 years (hypermobile). Both groups subsequently declined. Hypermobility is more common in DMD and impacts development of later functional skills, however doesn’t dramatically influence age of walking started. Hypermobility should be therefore be considered when predicting the development of later skills. There are however other factors which can alter progression of NSAA including behaviour. More research is needed to further understand the impact of hypermobility in the DMD population especially for later years and loss of ambulation.

Matriglycan [-GlcA-β1,3-Xyl-α1,3-]n serves as a scaffold in many tissues for extracellular matrix proteins containing laminin-G domains including laminin, agrin, and perlecan. Like-acetyl-glucosaminyltransferase 1 (LARGE1) synthesizes and extends matriglycan on α-dystroglycan (α-DG) during skeletal muscle differentiation and regeneration; however, the mechanisms which regulate matriglycan elongation are unknown. Here, we show that Protein O-Mannose Kinase (POMK), which phosphorylates mannose of core M3 (GalNAc-β1,3-GlcNAc-β1,4-Man) preceding matriglycan synthesis, is required for LARGE1-mediated generation of full-length matriglycan on α-DG (~150 kDa). In the absence of Pomk gene expression in mouse skeletal muscle, LARGE1 synthesizes a very short matriglycan resulting in a ~ 90 kDa α-DG which binds laminin but cannot prevent eccentric contraction-induced force loss or muscle pathology. Solution NMR spectroscopy studies demonstrate that LARGE1 directly interacts with core M3 and binds preferentially to the phosphorylated form. Collectively, our study demonstrates that phosphorylation of core M3 by POMK enables LARGE1 to elongate matriglycan on α-DG, thereby preventing muscular dystrophy.

Background: TRAPPC11, a subunit of the transport protein particle (TRAPP) complex is important for complex integrity and anterograde membrane transport from the endoplasmic reticulum (ER) to the ER-Golgi intermediate compartment. Several individuals with TRAPPC11 mutations have been reported with muscle weakness and other features including brain, liver, skeletal and eye involvement. A detailed analysis of brain and muscle biopsies will further our understanding of the presentation and etiology of TRAPPC11-disease. Methods: We describe five cases of early-onset TRAPPC11–related muscular dystrophy with a systematic review of muscle pathology in all five individuals, post-mortem brain pathology findings in one individual, and membrane trafficking assays in another. Results: All affected individuals presented in infancy with muscle weakness, motor delay and elevated serum creatine kinase (CK). Additional features included cataracts, liver disease, intellectual disability, cardiomyopathy, movement disorder, and structural brain abnormalities. Muscle pathology in all five revealed dystrophic changes, universal hypoglycosylation of alpha-dystroglycan and variably reduced dystrophin-associated complex proteins. Membrane trafficking assays showed defective Golgi trafficking in one individual. Neuropathological examination of one individual revealed cerebellar atrophy, granule cell hypoplasia, Purkinje cell (PC) loss and dendritic neurodegeneration, reduced alpha-dystroglycan (IIH6) expression in PC and dentate neurons, and absence of neuronal migration defects. Conclusions: This report suggests that recessive mutations in TRAPPC11 are linked to muscular dystrophies with hypoglycosylation of alpha-dystroglycan. The structural brain involvement that we document for the first time resembles the pathology previously reported in N-linked congenital disorders of glycosylation (CDG) such as PMM2-CDG, suggesting defects in multiple glycosylation pathways in this condition.

Nusinersen (NUS), the first treatment approved for Spinal Muscular Atrophy type 1 (SMA1), was made available in the UK for SMA1 through the Expanded Access Program (EAP) in 2017. The Great Ormond Street Respiratory (GSR) score was developed as an objective respiratory assessment for children with SMA1 during their treatment. Aims: Track respiratory status of SMA1 children over the course of Nusinersen treatment and compare GSR scores amongst SMA1 sub-types. Single centre study on SMA1 patients using the GSR score at set time points: prior to first NUS dose; 2 weeks post end of loading doses; 2 weeks post-subsequent doses. GSR score ranges 1–28, being 1–9 = Stable minimal support, thorough to 23–28 = Poor reserve with maximum support. 20 SMA1 children underwent NUS treatment between January 2017 - November 2018. Median age of diagnosis was 5.0 months. NUS started at median of 9.57 months. From 5th dose onwards, GSR scores were significantly lower for Type 1C patients compared to Type 1B By month 18, irrespective of subtypes, the whole cohort appears to stabilise GSR Scores. As treatment duration increases, an overall stabilisation of respiratory status across the cohort was observed. Further longitudinal studies are needed to validate the GSR.

To explore the clinical course of patients presenting with facioscapulohumeral dystrophy type 1 (FSHD1) in childhood, with a view to identifying areas where they differed from older patients and where extra support or monitoring might be required.A retrospective case-notes review of children with FSHD1 seen at a tertiary paediatric neuromuscular centre between 2002 and 2016 was performed. Data collected included age at and nature of presentation, path to diagnosis, genetic testing results, motor function, and occurrence of extramuscular features and complications.Eighteen children (11 females, seven males; mean [SD] age at latest review 13y 10mo [3y 9mo], range 8-19y) from 16 families were identified. Age at onset of FSHD1 correlated with the size of deletion (r=0.81) and most presentations were in children either younger than 5 years or older than 10 years. Children with onset before 5 years were more likely to present with non-muscular symptoms and to develop extramuscular pathology, including developmental and psychiatric issues, hearing or visual impairments, and problems involving respiratory function and nutrition. No cases of epilepsy or cardiac arrhythmia were identified but two children died.The complexity and severity of FSHD1 presenting in early childhood underlines the importance of a multidisciplinary approach to the disorder.Young children often present with non-muscular pathology in facioscapulohumeral dystrophy type 1 (FSHD1), especially hearing loss. Age at onset in paediatric FSHD1 appears bimodal: under 5 years or in adolescence. Prolonged delays to diagnosis are common. Children with very early-onset FSHD1 may require nutritional and/or respiratory support. Developmental and psychiatric comorbidities are common.CARACTERÍSTICAS CLÍNICAS DE LA DISTROFIA FASCIOESCAPULOHUMERAL 1 EN LA NIÑEZ: OBJETIVO: Explorar el curso clínico de los pacientes que presentan distrofina fascioescapulohumeral tipo 1 (FSHD1) en la niñez; con un enfoque que identifique las áreas que difieren de otros pacientes mayores; y, que tipo de soporte extra o monitorización podrían requerir. MÉTODO: Estudio retrospectivo de revisión de casos de niños con FSHD1, que fueron seguidos en un centro neuromuscular pediátrico terciario entre los años 2002 y 2016. La información recogida incluye edad y forma de presentación, algoritmo diagnóstico, resultados de los estudios genéticos, función motriz y aparición de síntomas extra-musculares y complicaciones. RESULTADOS: Dieciocho niños (11 niñas y siete varones; media [desviación standard] edad de la última revisión 13 años 10 meses [3 años 9 meses] rango 8-19 años) de 16 familias fueron identificados. La edad de aparición de del FSHD1 se correlacionó con el tamaño de la deleción (r = 0.81) y la mayor parte de los debuts fueron en niños menores de 5 años o mayores de 10. Aquellos niños cuyo inicio fue antes de los 5 años, mayormente se presentaban con síntomas no-musculares y desarrollaron patología extra-muscular que incluían afectación del desarrollo y psiquiátrica, pérdida auditiva o visual, y, problemas que concernían a la función respiratoria o la nutrición. No se detectaron casos de arritmia o epilepsia, sin embargo, dos niños fallecieron. INTERPRETACIÓN: La complejidad y severidad de la presentación de la FSHD1 en la infancia temprana, resalta la importancia de un abordaje multidisciplinar de esta condición de salud.ASPECTOS CLÍNICOS DA DISTROFIA MUSCULAR FACIO-ESCAPULO-UMERAL 1 NA INFÂNCIA.: OBJETIVO: Explorar o curso clínico de pacientes apresentando distrofia muscular facio-escapulo-tipo 1 (DFEU1) na infância, com vistas a identificar áreas em que eles diferem de pacientes mais velhos, e onde suporte ou monitoramento adicionais podem ser necessários. MÉTODO: Uma revisão retrospectiva de casos de crianças com DFEU1 atendidas em um centro pediátrico neuromuscular terciário entre 2002 e 2016 foi realizada. Os dados coletados incluíram idade e natureza da apresentação, caminho até o diagnóstico, resultados de testes genéticos, função motora, e ocorrência de aspectos extramusculares e complicações. RESULTADOS: Dezoito crianças (11 do sexo feminino, sete do sexo masculino; média [desvio padrão] da idade na última visita 13a10m [3a 9m], variação 8-19a) de 16 famílias foram identificadas. A idade no início da DFEU1 correlacionou com o tamanho da deleção (r = 0,81) e a maior parte das apresentações foram em crianças ou com menos de 5 anos ou com mais de 10 anos. Crianças com início antes de 5 anos tinham maior probabilidade de apresentar sintomas não-musculares e de desenvolver patologia extra-muscular, incluindo questões desenvolvimentais e psiquiátricas, deficiência auditiva ou visual, e problemas envolvendo função respiratória e nutrição. Nenhum caso de epilepsia ou arritmia cardiac foi identificado, mas duas crianças foram a óbito. INTERPRETAÇÃO: A complexidade e severidade da DFEU1 com apresentação precoce na infância realça a importância de abordagem multidisciplinar para esta desordem.

The conduct and interpretation of electromyography in children is considered difficult and therefore often avoided. We assessed the diagnostic accuracy of the paediatric electromyography protocol used in our tertiary reference centre and compared it to muscle biopsy results and clinical diagnosis. Electromyography was performed in unsedated children with suspected neuromuscular diseases between January 2010 and September 2017 and was analysed quantitatively. Muscle pathology was classified into seven groups based on existing histopathology reports. The clinical diagnosis, including myopathic, neurogenic and non-neuromuscular categories was used as the gold standard. 171 children between the age of 12 days to 17.4 years were included in the analysis. 41 children (24%) were under the age of 2 years at the time of electromyography. 98 (57%) children were diagnosed with a myopathic disorder, 18 (11%) with a neurogenic disease and 55 (32%) as not having a primary neuromuscular disorder. In detecting myopathic disease, electromyography performed as well as muscle biopsy (sensitivity 87.8% for electromyography vs. 84.5% for muscle biopsy; specificity 75.7% vs. 86.4%). This also applied to children under the age of 2 years (sensitivity 81.8% vs. 86.4%). Quantitative analysis of a limited electromyography protocol performed in unsedated children is a very valuable diagnostic tool.

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.

BackgroundDefects in glycosylation of alpha-dystroglycan (α-DG) cause autosomal-recessive disorders with wide clinical and genetic heterogeneity, with phenotypes ranging from congenital muscular dystrophies to milder limb girdle muscular dystrophies. Patients show variable reduction of immunoreactivity to antibodies specific for glycoepitopes of α-DG on a muscle biopsy. Recessive mutations in 18 genes, including guanosine diphosphate mannose pyrophosphorylase B (GMPPB), have been reported to date. With no specific clinical and pathological handles, diagnosis requires parallel or sequential analysis of all known genes.MethodsWe describe clinical, genetic and biochemical findings of 21 patients withGMPPB-associated dystroglycanopathy.ResultsWe report eight novel mutations and further expand current knowledge on clinical and muscle MRI features of this condition. In addition, we report a consistent shift in the mobility of beta-dystroglycan (β-DG) on Western blot analysis of all patients analysed by this mean. This was only observed in patients with GMPPB in our large dystroglycanopathy cohort. We further demonstrate that this mobility shift in patients with GMPPB was due to abnormalN-linked glycosylation of β-DG.ConclusionsOur data demonstrate that a change in β-DG electrophoretic mobility in patients with dystroglycanopathy is a distinctive marker of the molecular defect inGMPPB.

We report 2 families with undiagnosed recessive presynaptic congenital myasthenic syndrome (CMS). Whole exome or genome sequencing identified segregating homozygous variants in VAMP1: c.51_64delAGGTGGGGGTCCCC in a Kuwaiti family and c.146G>C in an Israeli family. VAMP1 is crucial for vesicle fusion at presynaptic neuromuscular junction (NMJ). Electrodiagnostic examination showed severely low compound muscle action potentials and presynaptic impairment. We assessed the effect of the nonsense mutation on mRNA levels and evaluated the NMJ transmission in VAMP1lew/lew mice, observing neurophysiological features of presynaptic impairment, similar to the patients. Taken together, our findings highlight VAMP1 homozygous mutations as a cause of presynaptic CMS. Ann Neurol 2017;81:597–603

Pathogenic variants in the Glycyl-tRNA synthetase gene cause the allelic disorders Charcot-Marie-Tooth disease type 2D and distal hereditary motor neuropathy type V. We describe clinical features in 8 unrelated patients found to have Glycyl-tRNA synthetase variants by Next Generation Sequencing. In addition to upper limb predominant symptoms, other presentations included failure to thrive, feeding difficulties and lower limb dominant symptoms. Variability in the age at testing ranged from 14 months to 59 years. The youngest being symptomatic from 3 months and ventilator-dependent. Sequence variants were reported as pathogenic, p.(Glu125Lys), p.(His472Arg); likely pathogenic, p.(His216Arg), p.(Gly327Arg), p.(Lys510Gln), p.(Met555Val); and of uncertain significance, p.(Arg27Pro). Our case series describes novel Glycyl-tRNA synthetase variants and demonstrates the clinical utility of Next Generation Sequencing testing for patients with hereditary neuropathy. Identification of novel variants by Next Generation Sequencing illustrates that there exists a wide spectrum of clinical features and supports the newer simplified classification of neuropathies.

Corticosteroids (CSs) have prolonged survival and respiratory function in boys with Duchenne muscular dystrophy (DMD) when compared with CSs-naïve boys.The differential impact of frequently used CSs and their regimens on long-term (5 years) cardiorespiratory progression in children with DMD is unknown.This was a retrospective longitudinal study including children with DMD followed at Dubowitz Neuromuscular Centre, Great Ormond Street Hospital London, England, from May 2000 to June 2017. Patients enrolled in any interventional clinical trials were excluded. We collected patients' anthropometrics and respiratory (FVC, FVC % predicted and absolute FVC, and noninvasive ventilation requirement [NIV]) and cardiac (left ventricular shortening function [LVFS%]) function. CSs-naïve patients had never received CSs. Patients who were treated with CSs took either deflazacort or prednisolone, daily or intermittently (10 days on/10 days off) for1 month. Average longitudinal models were fitted for yearly respiratory (FVC % predicted) and cardiac (LVFS%) progression. A time-to-event analysis to FVC % predicted 50%, NIV start, and cardiomyopathy (LVFS% 28%) was performed in CS-treated (daily and intermittent) vs CS-naïve patients.There were 270 patients, with a mean age at baseline of 6.2 ± 2.3 years. The median follow-up time was 5.6 ± 3.5 years. At baseline, 263 patients were ambulant. Sixty-six patients were treated with CSs daily, 182 patients underwent CSs intermittent60% treatment, and 22 were CS-naïve patients. Yearly FVC % predicted declined similarly from 9 years (5.9% and 6.9% per year, respectively; P = .27) in the CSs-daily and CSs-intermittent groups. The CSs-daily group declined from a higher FVC % predicted than the CSs-intermittent group (P .05), and both reached FVC % predicted 50% and NIV requirement at a similar age,2 years later than the CS-naïve group. LVFS% declined by 0.53% per year in the CSs-treated group irrespective of the CSs regimen, significantly slower (P .01) than the CSs-naïve group progressing by 1.17% per year. The age at cardiomyopathy was 16.6 years in the CSs-treated group (P .05) irrespective of regimen and 13.9 years in the CSs-naïve group.CSs irrespective of the regimen significantly improved respiratory function and delayed NIV requirement and cardiomyopathy.

Background SMA is a severe neuromuscular disorder characterised by progressive muscle atrophy, weakness, paralysis. Scoliosis is a highly prevalent feature and surgery is almost invariably required in ‘sitters’. However, data are limited on post-surgical secondary outcomes (respiratory, motor function, weight gain, skeletal pain, satisfaction). Methods 1. We retrospectively reviewed the notes of 33 patients who never walked/lost the ability to walk (SMA type II/III) and underwent spinal fusion (25), magnetic (4) or traditional (4) growth rods at Great Ormond Street Hospital; 2. We developed a phone interview and run a focus group for families on post-surgical satisfaction. Results The curve was successfully corrected in all patients. Median follow-up before and after surgery was 3.9 (0.9–12.3) and 3.7 (0.4–10.5) years respectively. Mean annual rate of Forced Vital Capacity% decline improved after surgery in SMA II: -2.8 versus -7.4 (p 5% of total weight) needed gastrostomy. Skeletal pain was frequently documented, especially hip pain (13/33) requiring painkillers (8), intra-articular steroids (1), surgical intervention (1). Nine/10 families participating in the phone interview reported major improvements in posture, physical appearance, self-image; all rated the procedure as very successful. However, 7/10 did not report significant improvements in quality of life due to reduced mobility and increased unmet care needs. Five families attended the focus group highlighting positive and negative aspects of their experiences. Conclusion This study provided relevant data and suggestions to improve the current post-operative multidisciplinary approach of scoliosis surgery in children with SMA.

Objective: To describe the genetic and clinical features of a simplex patient with distal hereditary motor neuropathy (dHMN) and lower limb spasticity (Silver-like syndrome) due to a mutation in the sigma nonopioid intracellular receptor–1 gene ( SIGMAR1 ) and review the phenotypic spectrum of mutations in this gene. Methods: We used whole-exome sequencing to investigate the proband. The variants of interest were investigated for segregation in the family using Sanger sequencing. Subsequently, a larger cohort of 16 unrelated dHMN patients was specifically screened for SIGMAR1 mutations. Results: In the proband, we identified a homozygous missense variant (c.194T>A, p.Leu65Gln) in exon 2 of SIGMAR1 as the probable causative mutation. Pathogenicity is supported by evolutionary conservation, in silico analyses, and the strong phenotypic similarities with previously reported cases carrying coding sequence mutations in SIGMAR1 . No other mutations were identified in 16 additional patients with dHMN. Conclusions: We suggest that coding sequence mutations in SIGMAR1 present clinically with a combination of dHMN and pyramidal tract signs, with or without spasticity, in the lower limbs. Preferential involvement of extensor muscles of the upper limbs may be a distinctive feature of the disease. These observations should be confirmed in future studies.

AimAssessment of the efficacy of vitamin D replenishment and maintenance doses required to attain optimal levels in boys with Duchenne muscular dystrophy (DMD).Method25(OH)-vitamin D levels and concurrent vitamin D dosage were collected from retrospective case-note review of boys with DMD at the Dubowitz Neuromuscular Centre. Vitamin D levels were stratified as deficient at 75 nmol/L.Result617 vitamin D samples were available from 197 boys (range 2–18 years)—69% from individuals on corticosteroids. Vitamin D-naïve boys (154 samples) showed deficiency in 28%, insufficiency in 42%, adequate levels in 24% and optimal levels in 6%. The vitamin D-supplemented group (463 samples) was tested while on different maintenance/replenishment doses. Three-month replenishment of daily 3000 IU (23 samples) or 6000 IU (37 samples) achieved optimal levels in 52% and 84%, respectively. 182 samples taken on 400 IU revealed deficiency in 19 (10%), insufficiency in 84 (47%), adequate levels in 67 (37%) and optimal levels in 11 (6%). 97 samples taken on 800 IU showed deficiency in 2 (2%), insufficiency in 17 (17%), adequate levels in 56 (58%) and optimal levels in 22 (23%). 81 samples were on 1000 IU and 14 samples on 1500 IU, with optimal levels in 35 (43%) and 9 (64%), respectively. No toxic level was seen (highest level 230 nmol/L).ConclusionsThe prevalence of vitamin D deficiency and insufficiency in DMD is high. A 2-month replenishment regimen of 6000 IU and maintenance regimen of 1000–1500 IU/day was associated with optimal vitamin D levels. These data have important implications for optimising vitamin D dosing in DMD.

The aim of this prospective multicentric study was to document disease progression in young boys affected by Duchenne muscular dystrophy (DMD) between age 3 and 6 years (±3 months) using the North Star Ambulatory Assessment scale. One hundred fifty-three DMD boys (573 assessments) younger than 6 years (mean: 4.68, SD: 0.84) with a genetically proven DMD diagnoses were included. Our results showed North Star Ambulatory Assessment scores progressively increased with age. The largest increase was observed between age 3 and 4 years but further increase was steadily observed until age of 6 years. Using a multiple linear regression analysis, we found that both the use of corticosteroids and the site of mutation significantly contributed to the North Star Ambulatory Assessment changes (p 0.001). At each age point, boys on corticosteroid treatment had higher scores than corticosteroid naïve ones (p 0.001). Similarly, patients with mutations downstream exon 44, had lower baseline scores and lower magnitude of changes compared to those with mutations located at the 5' end of the gene (p 0,001). Very few boys achieved the age appropriate maximum score. These results provide useful information for the assessment and counselling of young DMD boys and for the design of clinical trials in this age group.

Background Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. Method The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. Results Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. Conclusion Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate.

Aim to report the experience in patients with SMA type 1 treated in the Nusinersen expanded access program (EAP) in a single centre that have the largest UK cohort of patients with SMA type 1 (24 patients). Infantile SMA type 1 is the most common form of classic proximal 5q-SMA and also the most severe with inability to achieve independent sitting and limited life expectancy. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene resulting in insufficient SMN protein levels. Nusinersen (commercial name SPINRAZA) is a modified antisense oligonucleotide that, administered via consecutive intrathecal injections, modulates the splicing of the SMN2 mRNA transcript to include exon 7, thereby increasing the production of full-length SMN protein. Following the promising results of a large international phase II clinical trial (ENDEAR) nusinersen has received FDA and EMA approval and is currently offered under EAP in several European countries. Methods The motor abilities of all patients recruited in the EAP were systematically assessed using a validated score of motor function developed specifically for patients with SMA type 1 (CHOP-intend scale) and the Hammersmith Infant Neurological Examination-part 2 (HINE-2 motor milestone assessment). Information on SMN2 copies was collected from the patients’’ medical records while data on nutrition and respiratory function was collected at each visit prior drug administration. Results Twenty-one/24 patients with SMA type 1 (age range 3 months-9 years) were recruited into the EAP from March 2017. One patient is under evaluation while two patients are already recruited into an open label trial using the same drug. To date, patients in the EAP tolerated well the lumbar puncture procedure performed using local anaesthetic and no side effects or adverse events related to the drug were noted. In 75% of the patients an improvement of the CHOP-Intend total score was observed after the 4th or 5th injection. Conclusion Our data confirm the safety of intrathecal Spinraza treatment in SMA type 1 as well as a degree of motor function improvement. More longitudinal data is necessary to evaluate the long-term benefits, the respiratory muscle response and the best responders.

Background and Objectives: Nemaline myopathy may be caused by pathogenic variants in the TPM3 gene and is then called NEM1. All previously identified disease-causing variants are point mutations including missense, nonsense and splice-site variants. The aim of the study was to identify the disease-causing gene in this patient and verify the NM diagnosis. Methods: Mutation analysis methods include our self-designed nemaline myopathy array, The Nemaline Myopathy Comparative Genomic Hybridisation Array (NM-CGH array), whole-genome array-CGH, dHPLC, Sanger sequencing and whole-exome sequencing. The diagnostic muscle biopsy was investigated further by routine histopathological methods. Results: We present here the first large (17–21 kb) aberration in the α-tropomyosinslow gene (TPM3), identified using the NM-CGH array. This homozygous deletion removes the exons 1a and 2b as well as the promoter of the TPM3 isoform encoding Tpm3.12st. The severe phenotype included paucity of movement, proximal and axial weakness and feeding difficulties requiring nasogastric tube feeding. The infant died at the age of 17.5 months. Muscle biopsy showed variation in fibre size and rods in a population of hypotrophic muscle fibres expressing slow myosin, often with internal nuclei, and abnormal immunolabelling revealing many hybrid fibres. Conclusions: This is the only copy number variation we have identified in any NM gene other than nebulin (NEB), suggesting that large deletions or duplications in these genes are very rare, yet possible, causes of NM.

Duchenne Mmuscular Ddystrophy (DMD) related cardiomyopathy is associated with significant perioperative mortality. Cardiac MRI (CMR) has not previously been systematically evaluated as pre-operative assessment tool for heart function in DMD. Our aim was to establish whether CMR versus echocardiography contributes to pre-operative DMD assessment.Case records were retrospectively reviewed of 35 consecutive DMD boys who underwent evaluation for surgical procedures between 2010 and 2013.Echocardiography revealed a median left ventricular (LV) shortening fraction (SF) of 29/% (range: 7-44). 37% of boys (13/35) had abnormal SF25%, 66% (23/35) showed hypokinesia and 26% (9/35) had LV dilatation. CMR revealed a median left ventricular ejection fraction (LVEF) of 52% (range: 27-67%). 57% of boys (20/35) had abnormal LVEF55%, 71% (25/35) had hypokinesia, and 82% late gadolinium enhancement. Extensive versus minimal late gadolinium enhancement was associated with reduced left ventricular ejection fraction (48% vs 58%; p = 0.003) suggesting more severe cardiomyopathy. Although echocardiography shortening fraction correlated with CMR ejection fraction (rs = 0.67; p0.001), three-quarter of echocardiography studies had suboptimal scanning windows and in 26% measurements significantly over- or underestimated left-ventricular function compared to CMR.Our findings clearly demonstrate the added value of CMR versus echocardiography in assessing DMD-cardiomyopathy. Particularly when echocardiographic scanning windows are suboptimal, CMR should be considered to allow accurate pre-operative cardiac assessment.

BackgroundThymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy.ObjectiveTo perform a retrospective natural history study of a large cohort of patients with TK2 deficiency.MethodsThe study was conducted by 42 investigators across 31 academic medical centres.ResultsWe identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion.ConclusionsIn TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late-onset form. Our observations provide essential information for planning future clinical trials in this disorder.

Purpose\ud In 2012 we reported in six individuals a clinical condition almost indistinguishable from PLOD1-kyphoscoliotic Ehlers-Danlos syndrome (PLOD1-kEDS), caused by biallelic mutations in FKBP14, and characterized by progressive kyphoscoliosis, myopathy, and hearing loss in addition to connective tissue abnormalities such as joint hypermobility and hyperelastic skin. FKBP14 is an ER-resident protein belonging to the family of FK506-binding peptidyl-prolyl cis-trans isomerases (PPIases); it catalyzes the folding of type III collagen and interacts with type III, type VI, and type X collagens. Only nine affected individuals have been reported to date.\ud \ud Methods\ud We report on a cohort of 17 individuals with FKBP14-kEDS and the follow-up of three previously reported patients, and provide an extensive overview of the disorder and its natural history based on clinical, biochemical, and molecular genetics data.\ud \ud Results\ud Based on the frequency of the clinical features of 23 patients from the present and previous cohorts, we define major and minor features of FKBP14-kEDS. We show that myopathy is confirmed by histology and muscle imaging only in some patients, and that hearing impairment is predominantly sensorineural and may not be present in all individuals.\ud \ud Conclusion\ud Our data further support the extensive clinical overlap with PLOD1-kEDS and show that vascular complications are rare manifestations of FKBP14-kEDS.

SH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A malignant hyperthermia (MH)-like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca2+ release. Co-immunoprecipitation of STAC3 with CaV 1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and CaV 1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH-like episodes is reported. While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of CaV 1.1 sarcolemma mislocalization or impaired STAC3-CaV 1.1 interaction.

Background Classic proximal 5q-SMA is a progressive motor neuron disorder leading to muscle weakness and atrophy and is the most common genetic cause of infantile mortality, with an incidence of 1/10,000 livebirths. Based on onset and severity of disease, SMA is classified in 4 subtypes, with the infantile SMA type 1, the most common variant, being also the most severe. In particular SMA type 1 babies never achieve the ability to sit independently, and without intervention their life expectancy is less than one year. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene resulting in insufficient SMN protein levels. SMN2, a nearly identical copy of SMN1, cannot compensate for the loss of SMN1 because of predominant skipping of exon 7 during pre-mRNA splicing. Nusinersen (commercial name SPINRAZA) is a modified antisense oligonucleotide that, administered via consecutive intrathecal injections, modulates the splicing of the SMN2 mRNA transcript to include exon 7, thereby increasing the production of full-length SMN protein. Project Following the promising results of a large international phase II clinical trial (ENDEAR) where 40% of nusinersen-treated patients reached a motor milestone response versus none on the placebo arm, nusinersen has received FDA and EMA approval and is currently marketed for all types of SMA in US. In several European countries the drug was offered to the trial sites as part of an expanded access program (EAP). GOSH recruited the greatest number of UK trial participants and have the largest UK cohort of patients with SMA type 1. We present the experience and challenges delivering nusinersen under the EAP in a cohort of 20 patients with SMA type 1 treated from March-August 2017. Preliminary data on motor function as systematically assessed using the CHOP-intend scale and the Hammersmith Infant Neurological Examination (HINE scale) will also be presented.

Marie Wright (Specialist Registrar): A 4-month-old female infant was referred with a 4-week history of tachypnoea and faltering growth. She was the first child of healthy unrelated parents, and was conceived following two early miscarriages. Noteworthy family history included the unexplained sudden deaths of her mother’s sibling aged 8 months and a 12-year-old first cousin. The pregnancy was complicated by intrauterine growth restriction, and birth weight at 37 weeks’ gestation was 2.5 kg (second centile). She had no respiratory compromise in the neonatal period, and initially established good weight gain and met developmental milestones age appropriately. At 12 weeks old, she was observed by her parents to be tachypnoeic. Her work of breathing gradually increased over the next month, but was not associated with cough, stridor or systemic symptoms. Simultaneously, her weight drifted to below the 0.4th centile. At first presentation, the infant appeared malnourished but was alert and interactive. She had marked respiratory distress and a paradoxical breathing pattern with indrawing of the abdomen on inspiration, but respiratory examination was otherwise unremarkable. Muscle strength and tone were normal, but she had positional talipes and correctable flexion deformities of her fingers. Oxygen saturation was 95% in air, and gas exchange was normal on capillary blood gas analysis (pH 7.44, pCO2 4.66 kPa, HCO3 24 mmol/L, BE −0.2 mmol/L). ECG and echocardiogram were normal. Chest X-ray showed an elevated right hemidiaphragm (figure 1), and unilateral diaphragmatic paralysis was confirmed on fluoroscopic ultrasound. Rhinovirus and Adenovirus were detected on nasopharyngeal aspirate viral PCR. Figure 1 Chest X-ray at 4 months of age. Andy Bush (Professor of Respiratory Paediatrics): These clinical features are suggestive of a progressive neuromuscular disorder with relative preservation of limb muscle function and early respiratory muscle involvement. There are several possible causes; the likeliest diagnosis is spinal muscular atrophy with respiratory distress type 1 …

Despite corticosteroids being the only treatment documented to improve strength and function in boys with Duchenne muscular dystrophy (DMD) corticosteroid prescription is inconsistent and in some countries, corticosteroids are not prescribed. We are conducting a clinical trial that (1) compares the 3 most frequently prescribed corticosteroid regimes; (2) standardizes treatment of DMD complications; and (3) standardizes prevention of corticosteroid side effects. Investigators at 38 sites in 5 countries plan to recruit 300 boys aged 4-7 who are randomly assigned to one of three regimens: daily prednisone; daily deflazacort; or intermittent prednisone (10days on/10days off). Boys are followed for a minimum of 3years to assess the relative effectiveness and adverse event profiles of the different regimens. The primary outcome is a 3-dimensional variable consisting of log-transformed time to rise from the floor, forced vital capacity, and subject/parent satisfaction with treatment, each averaged over all post-baseline visits. The study protocol includes evidence- and consensus-based treatment of DMD complications and of corticosteroid side effects. This study seeks to establish a standard corticosteroid regimen for DMD. Since all new interventions for DMD are being developed as add-on therapies to corticosteroids, defining the optimum regimen is of importance for all new treatments.

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.