Glucocorticoid (GC) therapy improves strength in Duchenne muscular dystrophy (DMD) and delays onset and progression of scoliosis. This study aims to review rate of occurrence of scoliosis in non-ambulant paediatric DMD patients and assess rate of its progression in patients on different GC regimes vs those not on GC. We reviewed clinical and radiological records of 109 non-ambulant DMD patients who attended the Dubowitz Neuromuscular Centre in London, UK, between October 2019 to date. Age at most recent spinal assessment was 9.8-18.5 years (median 15, mean 14.9 years). 83/109 patients were on GC treatment, 49% on intermittent or alternate days regime, 28% on daily regime, and remaining were not on GC therapy. Mean age at time of loss of ambulation (LoA) was 10.5 years. Anteroposterior X-ray films were performed in 83 patients after visual inspection in clinic suggested possible spinal curve (total 209 films). Scoliosis was defined as Cobb angle >10°. At last X-ray, 75/83 patients had scoliosis, with Cobb angle range being 10-108° (median 30°, average 34.7°). Forty-one patients had Cobb angle >30°. Eight patients from this cohort (6 on intermittent GC and 2 not on GC) had spinal surgery. Scoliosis was more frequent in patients not on GC (84%) and those on intermittent GC treatment (71%) vs those on daily GC (50%). Patients on daily GC demonstrated older age at onset of scoliosis (median 16.7 years) vs those on intermittent regime or not on GC (median 13.3 and 13.1 years, respectively). Patients on daily GC also showed slower progression over time, with an + 1.5°/year annual change in Cobb angle, vs + 6.5°/year in the cohort on intermittent GC and those not on GC. These results confirm previous data on protective effect of daily GC regarding scoliosis development, compared to intermittent regime. However, further analysis is needed to better assess effect of variables, in particular age at LoA and time since LoA, into development and progression of scoliosis in DMD. Glucocorticoid (GC) therapy improves strength in Duchenne muscular dystrophy (DMD) and delays onset and progression of scoliosis. This study aims to review rate of occurrence of scoliosis in non-ambulant paediatric DMD patients and assess rate of its progression in patients on different GC regimes vs those not on GC. We reviewed clinical and radiological records of 109 non-ambulant DMD patients who attended the Dubowitz Neuromuscular Centre in London, UK, between October 2019 to date. Age at most recent spinal assessment was 9.8-18.5 years (median 15, mean 14.9 years). 83/109 patients were on GC treatment, 49% on intermittent or alternate days regime, 28% on daily regime, and remaining were not on GC therapy. Mean age at time of loss of ambulation (LoA) was 10.5 years. Anteroposterior X-ray films were performed in 83 patients after visual inspection in clinic suggested possible spinal curve (total 209 films). Scoliosis was defined as Cobb angle >10°. At last X-ray, 75/83 patients had scoliosis, with Cobb angle range being 10-108° (median 30°, average 34.7°). Forty-one patients had Cobb angle >30°. Eight patients from this cohort (6 on intermittent GC and 2 not on GC) had spinal surgery. Scoliosis was more frequent in patients not on GC (84%) and those on intermittent GC treatment (71%) vs those on daily GC (50%). Patients on daily GC demonstrated older age at onset of scoliosis (median 16.7 years) vs those on intermittent regime or not on GC (median 13.3 and 13.1 years, respectively). Patients on daily GC also showed slower progression over time, with an + 1.5°/year annual change in Cobb angle, vs + 6.5°/year in the cohort on intermittent GC and those not on GC. These results confirm previous data on protective effect of daily GC regarding scoliosis development, compared to intermittent regime. However, further analysis is needed to better assess effect of variables, in particular age at LoA and time since LoA, into development and progression of scoliosis in DMD.

Congenital myasthenic syndromes (CMS) are a group of rare inherited disorders of neuromuscular transmission. Rapsyn (receptor-associated protein of the synapse) is a post-synaptic protein that binds to the acetylcholine receptor (AChR) subunits and has a crucial role in AChR clustering at the post synaptic membrane. We describe the clinical characteristics, molecular genetic findings, and long-term clinical outcomes in 43 patients with CMS due to RAPSYN mutations seen at three UK specialist neuromuscular centres. 43 patients (20 females) with confirmed RAPSYN mutations and at least one follow-up visit were included. Median age at last follow up was 18 years (range 4-73 years). Symptoms at onset, included arthrogryposis 41%, ptosis 44%, respiratory involvement 48%, limb weakness/motor delay 67% and feeding difficulties 62%. Recurrent apnoea was the commonest respiratory symptom, 46% required short term and 7% required long-term respiratory support for apnoea management. 32% patients required nasogastric or gastrostomy feeding. Typical pattern of weakness was ptosis, facial weakness, axial, generalised or proximal weakness in limbs. 95% patients had ptosis, 62% patients had a divergent/ convergent squint and ophthalmoplegia was absent in all but one. All patients achieved independent ambulation, median age in 27 patients was 16 months (range 12- 48 months). At last follow up, all but one patient was independently ambulant. At last follow up 25% patients had no CMS features, 37% only ptosis and remainder had mild limb weakness. All patients were on normal oral diet except one who remained on mixture of oral and gastrostomy feeds since childhood. Patients who required long-term respiratory support in childhood were weaned off it successfully and no patient had respiratory crisis after 7 years of age. Except for 2, all patients had N88K mutation (homozygous in 14 patients). All but one patient was on treatment. Pyridostigmine was first line with good response in all treated patients, 28% required additional 3,4 diaminopyridine and 2% salbutamol. Two patients were able to reduce treatment in 2nd/3rd decade. In summary, this is the largest cohort of RAPSYN patients with clinical and genetic characteristics and also long-term outcome which was of consistent clinical improvements after 1st decade and stability in adult life in majority of patients, a crucial information for treating clinicians, patients and families. Congenital myasthenic syndromes (CMS) are a group of rare inherited disorders of neuromuscular transmission. Rapsyn (receptor-associated protein of the synapse) is a post-synaptic protein that binds to the acetylcholine receptor (AChR) subunits and has a crucial role in AChR clustering at the post synaptic membrane. We describe the clinical characteristics, molecular genetic findings, and long-term clinical outcomes in 43 patients with CMS due to RAPSYN mutations seen at three UK specialist neuromuscular centres. 43 patients (20 females) with confirmed RAPSYN mutations and at least one follow-up visit were included. Median age at last follow up was 18 years (range 4-73 years). Symptoms at onset, included arthrogryposis 41%, ptosis 44%, respiratory involvement 48%, limb weakness/motor delay 67% and feeding difficulties 62%. Recurrent apnoea was the commonest respiratory symptom, 46% required short term and 7% required long-term respiratory support for apnoea management. 32% patients required nasogastric or gastrostomy feeding. Typical pattern of weakness was ptosis, facial weakness, axial, generalised or proximal weakness in limbs. 95% patients had ptosis, 62% patients had a divergent/ convergent squint and ophthalmoplegia was absent in all but one. All patients achieved independent ambulation, median age in 27 patients was 16 months (range 12- 48 months). At last follow up, all but one patient was independently ambulant. At last follow up 25% patients had no CMS features, 37% only ptosis and remainder had mild limb weakness. All patients were on normal oral diet except one who remained on mixture of oral and gastrostomy feeds since childhood. Patients who required long-term respiratory support in childhood were weaned off it successfully and no patient had respiratory crisis after 7 years of age. Except for 2, all patients had N88K mutation (homozygous in 14 patients). All but one patient was on treatment. Pyridostigmine was first line with good response in all treated patients, 28% required additional 3,4 diaminopyridine and 2% salbutamol. Two patients were able to reduce treatment in 2nd/3rd decade. In summary, this is the largest cohort of RAPSYN patients with clinical and genetic characteristics and also long-term outcome which was of consistent clinical improvements after 1st decade and stability in adult life in majority of patients, a crucial information for treating clinicians, patients and families.

INTRODUCTION/AIMS:Mutations amenable to skipping of specific exons have been associated with different motor progression in Duchenne muscular dystrophy (DMD). Less is known about their association with long-term respiratory function. In this study we investigated the features of respiratory progression in four DMD genotypes relevant in ongoing exon-skipping therapeutic strategies. METHODS:This was a retrospective longitudinal study including DMD children followed by the UK NorthStar Network and international AFM Network centers (May 2003 to October 2020). We included boys amenable to skip exons 44, 45, 51, or 53, who were older than 5 years of age and ambulant at first recorded visit. Subjects who were corticosteroid-naive or enrolled in interventional clinical trials were excluded. The progression of respiratory function (absolute forced vital capacity [FVC] and calculated as percent predicted [FVC%]) was compared across the four subgroups (skip44, skip45, skip51, skip53). RESULTS:We included 142 boys in the study. Mean (standard deviation) age at first visit was 8.6 (2.5) years. Median follow-up was 3 (range, 0.3-8.3) years. In skip45 and skip51, FVC% declined linearly from the first recorded visit. From the age of 9 years, FVC% declined linearly in all genotypes. Skip44 had the slowest (2.7%/year) and skip51 the fastest (5.9%/year) annual FVC% decline. The absolute FVC increased progressively in skip44, skip45, and skip51. In skip53, FVC started declining from 14 years of age. DISCUSSION:The progression of respiratory dysfunction follows different patterns for specific genotype categories. This information is valuable for prognosis and for the evaluation of exon-skipping therapies.

Objective: Autoimmune myasthenia gravis (AMG) is a rare condition in childhood with variable clinical phenotypes and outcomes. Few studies suggested MG remission could relate to age of disease onset and to ethnic background. Disease-specific autoantibodies (Abs) status, including low affinity cell-based assays (CBA), has never been studied. Methods: We retrospectively investigated prognostic features for MG remission in 70 AMG patients presenting before 16 years old. Results: Our cohort had a heterogeneous ethnicity (51% Caucasian), and clinical presentation (50% ocular MG). We collected 62 seropositive patients, of whom 83% with Abs against the acetylcholine receptor (AchR) detecting both with standard or CBA. After median follow up of 4.5 years, 20% had MG remission, and 25% did not improve. There was a significant difference among ethnic groups, since the Caucasian and Asian patients appeared to have more favorable MG outcome. The detection of low Affinity Abs to AChR was another significant predictor of remission, whereas age at disease onset and gender were not. Conclusion: Different racial background and Abs status appeared the most relevant prognostic features for AMG in children. These factors could be easily evaluated in the diagnostic phase, and thus they need to be considered if helping to determine whose patients need more extensive treatment and follow-ups.

Pathogenic variants in the MYH7 gene, encoding for the slow beta cardiac myosin heavy chain, cause heterogeneous, mostly dominant, cardiac and skeletal myopathies. We describe a large cohort of UK patients with MYH7 associated myopathy, including 26 patients from 11 families (age range 2-68 yrs) recruited from 3 tertiary neuromuscular centres. Review of muscle examination, respiratory and cardiac function, serum CK level and muscle biopsy was performed retrospectively from case notes. Age at diagnosis ranged from 0-62 years. All patients presented skeletal muscle weakness. Symptoms at onset included hypotonia, proximal, axial and distal weakness, scapuloperoneal weakness, foot drop and scoliosis. Distal to proximal progression of weakness in lower limbs and to the upper limbs was seen in 6 patients. Finger extensor weakness with postural tremor was seen in two patients. Four patients lost ambulation (range 10-50 yrs). Muscle hypertrophy, mostly of the calves, was seen in 6 patients. Eight patients had scoliosis and one patient had spinal rigidity. Eight patients had cardiomyopathy, mostly hypertrophic, in one with onset at 2 years. Six patients had respiratory insufficiency, 4 required non-invasive ventilation from a mean age of 28.5 years (range 8-54 yrs). CK values ranged from normal to 1000 U/l. Muscle biopsies from 12 patients showed myopathic changes with variable combination of fibre type disproportion, cores and minicores. All patients were heterozygous for dominant pathogenic, mostly missense MYH7 variants. This work further expands current genotypic and phenotypic knowledge on MYH7 associated myopathies and highlights the major intra- and interfamilial variability in this rare myopathy. The data also emphasizes the wide spectrum of clinical severity and importance of early management and anticipatory care of MYH7 associated myopathy patients, in particular of cardiac and respiratory complications.

Recessive mutations in the NEB gene encoding nebulin are the most common known cause of nemaline myopathy (NEB-NM). Natural history studies on NEB-NM are limited and mostly focused on cross sectional data. We present a retrospective longitudinal study of 24 NEB-NM patients seen at the Dubowitz Neuromuscular Centre and the Evelina Children's Hospital, London. Age range was 2.93-27 years (median 17.34 yrs), follow up range 1.75-12.25 years (median 4.75 yrs), with a median of 5 yearly follow-up/patients (2-13 yrs). All patients were homozygous or compound heterozygous for 2 NEB variants. Altogether, 26 variants were identified, 4 missense, 17 frameshift, 5 splice site. Longitudinal motor function scores on the Hammersmith Functional Motor Scale were available for 13 patients, with a median of 4 assessments/child. Two patients with severe NEB-NM never sat independently, 2 with the typical form lost ambulation at 6 and 12 years, respectively. All other patients were ambulant at last follow-up. 17 patients (70%) developed scoliosis and/or kyphosis, 7 had spinal surgery at a median age of 15 years (11-16.42 yrs). Forced vital capacity % trends were available for 12 patients, with a median of 4 yearly measurements/child. 9/24 (37.5%) patients required nocturnal non-invasive ventilation at a median age of 8 years (2-18.5 yrs). Two patients with severe NEB-NM required tracheostomy before age 6 months and one, with typical form, after spinal surgery at 11 years. One patient died aged 19 years due to respiratory complications. Weight trends were available for 16 patients, with a median of 4.5 measurements/child. Gastrostomy was needed in 11/24 (46%) at a median age of 4 years (0-15.75 yrs). Statistical analysis is now in progress to describe trajectories and calculate estimated change/year of motor abilities, FVC and weight. This study expands knowledge on clinical course of NEB-NM and further emphasizes the importance of long-term multidisciplinary assessment and management.

Recessive TTN gene variants cause congenital myopathy (CM) with variable presentation, progression and pathological features. Massive parallel sequencing allows TTN gene analysis and is highlighting the considerable prevalence of this myopathy. The UK highly specialised service for CM started TTN analysis in 2016. We present results of TTN gene analysis in 57 patients with clinical and/or pathological features suggestive of congenital titinopathy. We divided patients into 4 groups based on genetic findings. Cohort 1 include 37 patients with recessive TTN variants in trans. Patients had early onset muscle weakness, predominantly proximal and axial, often with frequent scoliosis and Achilles tendons contractures. Cardiomyopathy and/or congenital heart defect were present in 6 patients. Muscle MRI showed variable pattern of involvement in 14 patients. Cohort 1A: 13 patients carried 2 predicted pathogenic TTN variants (nonsense, frameshift or splice site). Cohort 1B: 7 patients were compound heterozygous for a pathogenic and a missense change and had typical congenital titinopathy phenotype, indistinguishable from Cohort 1A. Cohort 1C: 17 patients had one pathogenic and one missense change in trans, with more variable clinical and/or pathological features of congenital titinopathy. Cohort 2: 20 patients had a single monoallelic TTN change. Among these, 5 patients (cohort 2A) had one predicted pathogenic TTN variant and a typical congenital titinopathy phenotype as cohort 1A-B. Functional characterisation of missense variants is necessary to clarify the diagnosis of cohorts 1B-C, while further investigations such as whole genome and/or transcriptome analysis can aid identification of additional pathogenic variants in cohort 2A. These findings highlight the complexity of TTN gene analysis in CM and underlines the importance of a detailed clinical, MRI and pathological investigation to complement genetic testing and aid variant interpretation in genes as complex and large as TTN.

Laminin a2-deficient congenital muscular dystrophy (MDC1A) is the most common form of congenital muscular dystrophy, due to recessive LAMA2 gene mutations. As novel therapeutic approaches are getting closer to potential clinical applications, more detailed natural history data and disease specific outcome measures are needed. Here we present a retrospective cross-sectional and longitudinal study on a cohort of genetically and/or pathologically diagnosed paediatric MDC1A patients from the Dubowitz Neuromuscular centre in London, seen between 1985 and 2019 and with complete or trace laminin-alpha 2 in muscle biopsies. Data on disease onset, survival, motor function, scoliosis, respiratory and cardiac function, feeding, and instrumental and genetic investigations were collected by case note reviews. The cohort includes 47 patients (39 families), with a median age at first and last assessment of 2 and 11.7 years, respectively. Median follow-up length was 7.7 years (range 0-18 years), from one to 22 visits/patient (median 6 visits). Seven patients died at median age of 12 years. Four patients achieved independent ambulation (median age 3.5 years) and 6 were able to do few steps with KAFOs and external support. Thirty-three patients developed scoliosis (median age 6.3 years) and 9 underwent spinal surgery. Thirty-one patients had respiratory impairment. Twenty patients required nocturnal non-invasive ventilation (median age 9.5 years), but none daytime or invasive ventilation. Twenty patients had gastrostomy (median age 5 years), mainly because of failure to thrive, 12 still receiving oral feeds at last follow-up. Four patients had partial seizures and 1 learning difficulties. Clinically significant cardiac involvement was not observed in this cohort. In conclusion, this is one of the largest studies on MDC1A providing detailed information on comorbidities and disease progression.

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.

Assessment of the efficacy of vitamin D repletion and maintenance doses to attain sufficiency levels in DMD boys. 25-OH vitamin D levels and concurrent vitamin D dose were collected from retrospective case-note review of DMD boys seen at Dubowitz Neuromuscular Centre. Vitamin D levels were stratified as deficient 75 nmol/l. 617 levels were available from 197 boys (tested 1–7 times). The median age at level estimation was 9.7 years (2–18). 90% levels were performed whilst on corticosteroid. The vitamin D supplement-naïve group, comprising 154 samples from 125 boys, showed deficiency in 70%, insufficiency in 24%, and sufficiency in 6%. The vitamin D supplemented group, comprising 463 samples from 164 boys, was tested whilst on different oral maintenance or replenishment doses. A three month replenishment regime of daily 3000 IU (no = 23 samples from 20 patients) or 6000 IU (no = 37 samples from 32 patients) achieved sufficiency in 52% and 84%, respectively. 22 samples (form 17 boys) collected on maintenance dose of 200 IU/day showed deficiency in 13 (59%) and insufficiency in 7 (32%). 182 samples (from 121 boys) taken on 400 IU/day revealed deficiency in 104 (57%) and insufficiency in 67 (37%). 97 samples (from 66 boys) were taken on 800 IU/day, with deficiency in 19 (20%) and insufficiency in 56 (58%). 81 samples (from 55 boys) were on 1000 IU and 14 samples (from 11 patients) were on 1500 IU, with sufficiency in 40 (50%) and 9 (64%), respectively. No toxic level was seen in this cohort (highest level −230 nmol/l). The prevalence of Vitamin D deficiency and insufficiency in DMD is high. A three month replenishment regime of 6000 IU was more effective than 3000 IU in achieving Vitamin D sufficiency. Maintenance daily doses of 200 or 400 IU demonstrated sufficiency in 14% and 1000 IU daily achieved sufficiency in 50% of samples obtained from boys treated with this regime. These data have important implications for optimising vitamin D dosing in DMD.

Standards of care including corticosteroid and non-invasive ventilation (NIV) have significantly changed the course of DMD and improved survival so that now transition into adult care is common. To describe the morbidity and mortality in a large pediatric DMD population with contemporary care and identify the milestones of disease progression, the Dubowitz Neuromuscular Centre offers diagnosis and management of DMD through the childhood years, with transition to adult teams at age 17 years. Retrospective analysis of this DMD cohort was undertaken. Patients were identified from existing databases and disease course, medical interventions, and outcomes were collated. Over the past 20 years, 310 DMD boys, born between 1989 and 2013 were seen, with 18 ± 6 sequential assessments for the individual patient. Overall, 63% lost ambulation at a mean age of 11 ± 2.0 years in the corticosteroid treated group, compared to 9 ± 1.0 in the steroid naïve group. 231/310 were older than 10 years, and in this subgroup, 50% developed scoliosis, 20% use NIV (age at initiation 14.3 ± 2 years) and 51% have echocardiographic cardiomyopathy (age at onset 12.3 ± 2.9 years). All patients with cardiomyopathy were treated with ACE inhibitor ± beta-blocker. 93 patients were transitioned to adult service. At the time of transition, 57% had FVC <60%, 32% were on NIV, 85% had cardiomyopathy, and 26% were on corticosteroid treatment. 10/93 were on tube feeding. 20 patients died at 14.9 ± 2.5 years. Death was cardiac-related in 6, sudden in 2, pneumonia in 5 (3 on NIV), gastrointestinal complications in 2, and perioperative in 2. Despite the improved survival, there still is significant mortality in DMD in the childhood years. Cardiomyopathy was the most frequent cause of death, and gastrointestinal related mortality also plays an important role. These data will help direct care to reduce mortality and has implications in development of adult services.

Autophagy is a fundamental cellular degradative pathway and involves several tightly regulated steps conserved throughout evolution. We have recently identified recessive null mutations in EPG5, encoding a protein with a crucial role in autolysosome formation, as the cause of Vici syndrome (VS), a severe multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. The consistently associated myopathy shares prominent vacuoles as the most striking histopathological feature with the primary autophagic vacuolar myopathies (AVMs), Danon disease and X-linked myopathy with excessive autophagy (MEAX). Here we report 2 sisters presenting from childhood with generalized weakness, elevated CK levels (5–10× normal) and a characteristic pattern of selective involvement on muscle MRI. Progression was relentless in the index case, resulting in almost complete paralysis requiring a gastrostomy and continuous invasive ventilation within a decade. Muscle biopsies showed increased variability in fibre size, multiple internal nuclei, fat and endomysial connective tissue increase, and abnormal glycogen content. Autophagic vacuoles with sarcolemmal features were prominent and confirmed on EM. Whole exome sequencing revealed a paternally inherited heterozygous EPG5 frame shift mutation (g.43534647G > A, c.721C > T, p.R241∗). Investigation of the EPG5 transcript by RT-PCR of mRNA from fibroblasts revealed a rearrangement in the other transcribed allele, with non-coding X-chromosomal material inserted into EPG5 exon 23. Further functional studies in patient-derived fibroblasts suggested a moderate disturbance of autophagic flux. We speculate that the inserted sequence partially disrupts epg5 function, resulting in a “milder” phenotype compared to typical VS. Our findings define a novel EPG5-related vacuolar myopathy and indicate that EPG5 mutations ought to be considered in unresolved patients with suggestive features. Autophagy is a fundamental cellular degradative pathway and involves several tightly regulated steps conserved throughout evolution. We have recently identified recessive null mutations in EPG5, encoding a protein with a crucial role in autolysosome formation, as the cause of Vici syndrome (VS), a severe multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. The consistently associated myopathy shares prominent vacuoles as the most striking histopathological feature with the primary autophagic vacuolar myopathies (AVMs), Danon disease and X-linked myopathy with excessive autophagy (MEAX). Here we report 2 sisters presenting from childhood with generalized weakness, elevated CK levels (5–10× normal) and a characteristic pattern of selective involvement on muscle MRI. Progression was relentless in the index case, resulting in almost complete paralysis requiring a gastrostomy and continuous invasive ventilation within a decade. Muscle biopsies showed increased variability in fibre size, multiple internal nuclei, fat and endomysial connective tissue increase, and abnormal glycogen content. Autophagic vacuoles with sarcolemmal features were prominent and confirmed on EM. Whole exome sequencing revealed a paternally inherited heterozygous EPG5 frame shift mutation (g.43534647G > A, c.721C > T, p.R241∗). Investigation of the EPG5 transcript by RT-PCR of mRNA from fibroblasts revealed a rearrangement in the other transcribed allele, with non-coding X-chromosomal material inserted into EPG5 exon 23. Further functional studies in patient-derived fibroblasts suggested a moderate disturbance of autophagic flux. We speculate that the inserted sequence partially disrupts epg5 function, resulting in a “milder” phenotype compared to typical VS. Our findings define a novel EPG5-related vacuolar myopathy and indicate that EPG5 mutations ought to be considered in unresolved patients with suggestive features.