Loss Of Ambulation Research Articles

One in five patients with Duchenne muscular dystrophy dies from other causes than cardiac or respiratory failure

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder with increasing life expectancy from late teens to over 30 years of age. The aim of this nationwide study was to explore the prevalence, life expectancy and leading causes of death in patients with DMD in Sweden. Patients with DMD were identified through the National Quality Registry for Neuromuscular Diseases in Sweden, the Swedish Registry of Respiratory Failure, pathology laboratories, neurology and respiratory clinics, and the national network for neuromuscular diseases. Age and cause of death were retrieved from the Cause of Death Registry and cross-checked with medical records. 373 DMD patients born 1970–2019 were identified, of whom 129 patients deceased during the study period. Point prevalence of adult patients with DMD on December 31st 2019 was 3.2 per 100,000 adult males. Birth prevalence was 19.2 per 100,000 male births. Median survival was 29.9 years, the leading cause of death being cardiopulmonary in 79.9% of patients. Non-cardiopulmonary causes of death (20.1% of patients) mainly pertained to injury-related pulmonary embolism (1.3 per 1000 person-years), gastrointestinal complications (1.0 per 1000 person-years), stroke (0.6 per 1000 person-years) and unnatural deaths (1.6 per 1000 person-years). Death from non-cardiopulmonary causes occurred at younger ages (mean 21.0 years, SD 8.2; p = 0.004). Age at loss of independent ambulation did not have significant impact on overall survival (p = 0.26). We found that non-cardiopulmonary causes contribute to higher mortality among younger patients with DMD. We present novel epidemiological data on the increasing population of adult patients with DMD.

Pharmacology and toxicology of eteplirsen and SRP-5051 for DMD exon 51 skipping: an update.

Duchenne muscular dystrophy (DMD) afflicts 1 in 5000 newborn males, leading to progressive muscle weakening and the loss of ambulation between the ages of 8 and 12. Typically, DMD patients pass away from heart failure or respiratory failure. Currently, there is no cure, though exon-skipping therapy including eteplirsen (brand name Exondys 51), a synthetic antisense oligonucleotide designed to skip exon 51 of the dystrophin gene, is considered especially promising. Applicable to approximately 14% of DMD patients, a phosphorodiamidate morpholino oligomer (PMO) antisense oligonucleotide eteplirsen received accelerated approval by the US Food and Drug Administration (FDA) in 2016. Throughout clinical trials, eteplirsen has been well tolerated by patients with no serious drug-related adverse events. The most common events observed are balance disorder, vomiting, and skin rash. Despite its safety and promise of functional benefits, eteplirsen remains controversial due to its low production of dystrophin. In addition, unmodified PMOs have limited efficacy in the heart. To address these concerns of efficacy, eteplirsen has been conjugated to a proprietary cell-penetrating peptide; the conjugate is called SRP-5051. Compared to eteplirsen, SRP-5051 aims to better prompt exon-skipping and dystrophin production but may have greater toxicity concerns. This paper reviews and discusses the available information on the efficacy, safety, and tolerability data of eteplirsen and SRP-5051 from preclinical and clinical trials. Issues faced by eteplirsen and SRP-5051, including efficacy and safety, are identified. Lastly, the current state of eteplirsen and exon-skipping therapy in general as a strategy for the treatment of DMD are discussed.

Nerve Root Sparing En Bloc Resection of Sacral Chondrosarcoma: Technical Note and Review of the Literature.

Total en bloc sacrectomy provides the best long-term local control for large primary bony sacral tumors, but often requires lumbosacral nerve root sacrifice leading to loss of ambulation and/or bowel, bladder, and/or sexual dysfunction. Nerve-sparing techniques may be an option for some patients that avoid these outcomes and accordingly improve postoperative quality of life. To describe the technique for a posterior-only en bloc hemisacrectomy with maximal nerve root preservation and to summarize the available literature. A 38-yr-old woman with a 7.7×5.4×4.5 cm biopsy-proven grade 2 chondrosarcoma involving the left L5-S2 posterior elements underwent a posterior-only left hemisacrectomy tri-rod L3-pelvis fusion. A systematic review of the English literature was also conducted to identify other descriptions of high sacrectomy with distal sacral nerve root preservation. Computer-aided navigation facilitated an extracapsular resection that allowed preservation of the left-sided L5 and S3-Co roots. Negative margins were achieved and postoperatively the patient retained ambulation and good bowel/bladder function. Imaging at 9-mo follow-up showed no evidence of recurrence. The systematic review identified 4 prior publications describing 6 total patients who underwent nerve-sparing sacral resection. Enneking-appropriate resection was only obtained in 1 case though. Here we describe a technique for distal sacral nerve root preservation during en bloc hemisacrectomy for a primary sacral tumor. Few prior descriptions exist, and the present technique may help to reduce the neurological morbidity of sacral tumor surgery.

P.172 Diffusion MRI characteristics change in select cerebral white matter tracts after decompressive surgery for degenerative cervical myelopathy

Background: Degenerative cervical myelopathy is characterized by progressive compression of the spinal cord resulting in debilitating loss of dexterity, independent ambulation, and sphincter control. Diffusion tensor imaging (DTI) has shown that, compared to healthy controls, myelopathy patients have decreased integrity of the corticospinal tracts and corpus callosum (Bernabeu-Sanz et al, 2020). Methods: Twenty-six myelopathy patients consented to cerebral diffusion tensor imaging (3 Tesla, 32 directions, b=1000) preoperatively, as well as 6-weeks, 12-weeks, and 6-months postoperatively. Average mean diffusivity (MD), fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity (AD) were measured in the corticospinal tracts, forceps major, and forceps minor. Results: Both MD and RD decreased from 6-12 weeks postoperatively in the right corticospinal tract. The forceps major of the corpus callosum showed an initial postoperative increase in MD followed by a subsequent increase in FA and decrease in RD 3-6 months postoperatively. The AD of the forceps major increased both immediately and 3-6 months postoperatively. Conclusions: Changes in microstructural integrity of the corticospinal tract and forceps major over the postoperative recovery period suggest a pattern of recovery in myelopathy patients. This study is the first to report postoperative DTI changes in myelopathy-relevant white matter tracts in the brain.

Osteomalacic Myopathy in Children and Adolescents with Vitamin-D Deficiency.

Osteomalacic myopathy secondary to vitamin-D deficiency is an under-recognized cause of muscle weakness in children and adolescents. To describe a cohort of children and adolescents with osteomalacic myopathy. Pediatric neurology unit of a tertiary care hospital. Charts of children and adolescents with osteomalacic myopathy were retrospectively reviewed for demographics, clinical presentation, laboratory investigations, and treatment response. Diagnosis of vitamin-D deficiency was made on the basis of a combination of clinical, biochemical, and radiographic findings. Response to treatment with vitamin-D confirmed vitamin-D deficiency as the cause of myopathic symptoms. Twenty-six children-15 girls and 11 boys aged between 20 months and 19 years-with osteomalacic myopathy were identified. Fifteen (58%) children were between 10 years and 19 years of age. Twenty-one (81%) children presented with myopathic symptoms of progressive walking difficulty, with eventual loss of ambulation in six. Four children came to attention through hypocalcemic seizures. One nonambulatory child with cerebral palsy presented with loss of previously attained ability to roll over and sit. All children had proximal muscle weakness on examination. Fifteen (58%) children had clinical signs of rickets. All the children who underwent biochemical (n = 24) and radiographic (n = 16) investigations had results consistent with vitamin-D deficiency. Only in one child, the diagnosis of osteomalacic myopathy was made on the basis of clinical findings. Response to vitamin D was uniformly good. Vitamin-D deficiency should be considered in the differential diagnosis of proximal myopathy in children and adolescents.

Labor market participation and productivity costs for female caregivers of minor male children with Duchenne and Becker muscular dystrophies

Duchenne and Becker muscular dystrophies (DBMD) are X-linked neuromuscular disorders characterized by progressive muscle weakness, leading to decreased mobility and multisystem complications. We estimate productivity costs attributable to time spent by a parent caring for a male child under the age of 18 y with DBMD, with particular focus on female caregivers of boys with Duchenne muscular dystrophy (DMD) who have already lost ambulation. Primary caregivers of males with DBMD in the Muscular Dystrophy Surveillance and Research Tracking Network (MD STARnet) were surveyed during 2011-2012 on family quality of life measures, including labor market outcomes. Of 211 respondents, 96 female caregivers of boys with DBMD were matched on state, year of survey, respondent's age, child's age, and number of minor children with controls constructed from Current Population Survey extracts. Regression analysis was used to estimate labor market outcomes and productivity costs. Caregivers of boys with DBMD worked 296 h less per year on average than caregivers of unaffected children, translating to a $8816 earnings loss in 2020 U.S. dollars. Caregivers of boys with DMD with ≥4 y of ambulation loss had a predicted loss in annualized earnings of $23,995, whereas caregivers of boys with DBMD of the same ages who remained ambulatory had no loss of earnings. Female caregivers of non-ambulatory boys with DMD face additional household budget constraints through income loss. Failure to include informal care costs in economic studies could understate the societal cost-effectiveness of strategies for managing DMD that might prolong ambulation.

Sertoli Cells Improve Myogenic Differentiation, Reduce Fibrogenic Markers, and Induce Utrophin Expression in Human DMD Myoblasts.

Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in DMD gene translating in lack of functional dystrophin and resulting in susceptibility of myofibers to rupture during contraction. Inflammation and fibrosis are critical hallmarks of DMD muscles, which undergo progressive degeneration leading to loss of independent ambulation in childhood and death by early adulthood. We reported that intraperitoneal injection of microencapsulated Sertoli cells (SeC) in dystrophic mice translates into recovery of muscle morphology and performance thanks to anti-inflammatory effects and induction of the dystrophin paralogue, utrophin at the muscle level, opening new avenues in the treatment of DMD. The aim of this study is to obtain information about the direct effects of SeC on myoblasts/myotubes, as a necessary step in view of a translational application of SeC-based approaches to DMD. We show that (i) SeC-derived factors stimulate cell proliferation in the early phase of differentiation in C2C12, and human healthy and DMD myoblasts; (ii) SeC delay the expression of differentiation markers in the early phase nevertheless stimulating terminal differentiation in DMD myoblasts; (iii) SeC restrain the fibrogenic potential of fibroblasts, and inhibit myoblast-myofibroblast transdifferentiation; and, (iv) SeC provide functional replacement of dystrophin in preformed DMD myotubes regardless of the mutation by inducing heregulin β1/ErbB2/ERK1/2-dependent utrophin expression. Altogether, these results show that SeC are endowed with promyogenic and antifibrotic effects on dystrophic myoblasts, further supporting their potential use in the treatment of DMD patients. Our data also suggest that SeC-based approaches might be useful in improving the early phase of muscle regeneration, during which myoblasts have to adequately proliferate to replace the damaged muscle mass.

Cost of Illness in Patients with Duchenne Muscular Dystrophy in Portugal: The COIDUCH Study.

ObjectiveThe aim of this study was to estimate the cost of illness (COI) of Duchenne muscular dystrophy (DMD) and its relation to disease progression, using age as a proxy, and according to the ambulatory status of patients.MethodsWe conducted a cross-sectional study of patients diagnosed with DMD identified through the Portuguese Neuromuscular Patients Association (APN). Data regarding patient and caregiver demographics, patient health status, resource utilization and cost, and informal care were collected using a custom semistructured questionnaire. Labor productivity and absenteeism losses were captured using the Work Productivity and Activity Impairment questionnaire. Costs were valued using a societal perspective.ResultsA total of 46 patient–caregiver pairs were included, of which eight of the patients were ambulant and 38 were nonambulant. Age had a decreasing effect on COI, independent of the patient’s disease stage. Annualized lifetime costs were at their highest in nonambulant patients around the mean age of loss of ambulation (10 years of age). The mean per patient stage-specific costs (year 2019 values) of DMD were estimated at €48,991 in the nonambulant stage and €19,993 in the ambulant stage. Direct nonmedical costs were the main cost drivers, followed by indirect costs.ConclusionsOur results indicate a close relation between overall disease costs and disease progression. DMD is associated with a substantial economic burden, which appears to be larger around the time ambulation is lost (10 years of age). The availability of new therapeutic options that delay disease progression, especially loss of ambulation, may prove to be highly beneficial for not only patients with DMD but also their families and society.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41669-021-00303-5.

Characterizing demographics, comorbidities, and costs of care among populations with Duchenne muscular dystrophy with Medicaid and commercial coverage.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe X-linked progressive neurodegenerative disease characterized by loss of ambulation, cardiomyopathy, respiratory insufficiency, and early mortality. Few data are available that describe the direct medical costs among patients with DMD in the United States. OBJECTIVE: To characterize the demographics, comorbidity burden, and direct monthly costs of care among patients with DMD with Medicaid and with commercial insurance coverage. METHODS: IBM MarketScan Commercial and Multi-State Medicaid claims (2013-2018) were used to identify males aged 30 years or under with diagnostic codes for muscular dystrophy or DMD; additional exclusion criteria were applied to identify those with probable DMD. Baseline characteristics and comorbidities were tabulated. The frequency of health care resource use and median (interquartile range [IQR]) monthly costs (in 2018 USD) were estimated from those with at least 12 months of continuous follow-up. RESULTS: Median (IQR) baseline ages were similar between the Medicaid (14 [9-20] years; n = 2,007) and commercial (15 [9-21] years; n = 1,964) DMD cohorts. The frequency of comorbidities over the period was slightly higher with those on Medicaid. The median duration of follow-up was 3.1 years among members of the Medicaid DMD cohort and 1.7 years among the commercial DMD cohort. Median monthly resource use was generally higher among the Medicaid DMD cohort; nonetheless, median (IQR) monthly costs were similar at $1,735 ($367-$5,281) for the Medicaid DMD cohort vs $1,883 ($657-$6,796) for the commercial DMD cohort. CONCLUSIONS: The demographic characteristics and median direct medical costs were similar between patients with commercial vs Medicaid coverage, even though patients with Medicaid coverage had higher resource use. Despite challenges in definitively identifying DMD patients using claims data, these findings help characterize contemporary DMD populations in the United States and the related direct economic burden to the payer. DISCLOSURES: This study was funded by Sarepta Therapeutics, Inc. Klimchak and Gooch are employees of Sarepta Therapeutics Inc. Szabo, Qian, and Popoff are employees of Broadstreet HEOR, which received funds from Sarepta Therapeutics, Inc., for work on this study. Iannaccone has received research funding or consulting fees from Avexis, Biogen, Fibrogen, Mallinkrodt, Regeneron, Sarepta Therapeutics, Inc., Scholar Rock, PTC Therapeutics, Pfizer, MDA, CureSMA, NIH, Genentech-Roche, and BCBS. Publication of the study results was not contingent on the sponsor's approval or censorship of the manuscript. Information from this study was presented, in part, at the AMCP Virtual Annual Meeting, April 21-24, 2020.

Long term treatment with ataluren\u2014the Swedish experience

IntroductionAtaluren is a relatively new treatment for male patients with Duchenne muscular dystrophy (DMD) due to a premature stop codon. Long-term longitudinal data as well as efficacy data on non-ambulant patients are still lacking. Here we present the results from a long-term follow-up study of all DMD patients treated with ataluren and followed at the Queen Silvia Children’s Hospital in Gothenburg, Sweden, with focus on the evolution of patients’ upper motor and respiratory function over time.MethodsThis is a retrospective longitudinal case-series study of all male DMD patients treated with ataluren and followed at the Queen Silvia Children’s Hospital in Gothenburg, Sweden, since 2008.ResultsOur eleven patients had a median exposure to ataluren of 2312 days which is almost a fourfold higher than previous studies. Loss of ambulation occurred at a median age of 13.2 years. Patients who lost ambulation prior to 13.2 years of age had received ataluren for 5 years, whereas patients who continued to be ambulatory after 13.2 years of age had received ataluren for 6.5 years until loss of ambulation or last follow-up if still ambulatory. Four of six non ambulatory patients had Performance of the Upper Limb scores above the expected mean values over time. All but one patient maintained a pulmonary decline above the expected over time. All ambulatory patients increased in their predicted forced vital capacity (FVC) with 2.8 to 8.2% annually. Following loss of ambulation, 5 of 6 patients declined in predicted FVC (%), with annual rate of decline varying from 1.8 to 21.1%. The treatment was safe and well tolerated throughout the follow-up period.ConclusionsThis is the first study to present long-term cumulative treatment outcomes over a median period of 6.3 years on ataluren treatment. Our results indicate a delay in loss of ambulation, as well as a slower decline in FVC and upper limb motor function even after loss of ambulation. We suggest that treatment with ataluren should be initiated as soon as the diagnosis is confirmed, closely monitored and, in case of sustainable benefit, continued even after loss of ambulation.

Characterization of sleep-disordered breathing in children with Duchenne muscular dystrophy by the American Academy of Sleep Medicine criteria vs disease-specific criteria: what are the differences?

Individuals with Duchenne muscular dystrophy (DMD) frequently develop sleep-disordered breathing. Noninvasive ventilation is often prescribed for sleep-disordered breathing treatment based on the American Academy of Sleep Medicine (AASM) criteria. In 2018, DMD disease-specific criteria for sleep-disordered breathing were established. Our study aimed to examine the clinical interpretation differences using these different criteria. We performed a multicenter, retrospective chart review of children with DMD followed at The Hospital for Sick Children, Toronto, Canada, and Rady Children's Hospital, San Diego, California, who underwent polysomnography from August 1, 2012, to February 29, 2020. Baseline characteristics and polysomnography data were summarized using descriptive statistics. Agreement for the diagnosis of sleep-disordered breathing evaluated by kappa statistics and sensitivity/specificity analysis was assessed. One hundred five male children with DMD (mean ± SD age: 12.1 ± 3.8 years; body mass index z score: 0.2 ± 2.3) were included. The proportions of children with DMD that met at least 1 AASM criterion and at least 1 DMD criterion were 45.7% and 67.6%, respectively. We found that 32.4% of children met neither AASM nor DMD criteria. Overall agreement between AASM and DMD criteria was moderate (k = 0.57). There was almost perfect agreement in sleep apnea diagnosis (k = 0.90); however, there was only slight agreement in hypoventilation diagnosis (k = 0.12) between AASM and DMD criteria. There were more children with DMD diagnosed with nocturnal hypoventilation and prescribed noninvasive ventilation using DMD criteria compared with AASM criteria. Future studies should address whether the prescription of noninvasive ventilation for children with DMD based on both criteria is associated with different clinical outcomes. Hurvitz MS, Sunkonkit K, Massicotte C, Li R, Bhattacharjee R, Amin R. Characterization of sleep-disordered breathing in children with Duchenne muscular dystrophy by the American Academy of Sleep Medicine criteria vs disease-specific criteria: what are the differences? J Clin Sleep Med. 2022;18(2):609-615.

Renadirsen, a Novel 2'OMeRNA/ENA® Chimera Antisense Oligonucleotide, Induces Robust Exon 45 Skipping for Dystrophin In Vivo.

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease caused by out-of-frame or nonsense mutation in the dystrophin gene. It begins with a loss of ambulation between 9 and 14 years of age, followed by various other symptoms including cardiac dysfunction. Exon skipping of patients’ DMD pre-mRNA induced by antisense oligonucleotides (AOs) is expected to produce shorter but partly functional dystrophin proteins, such as those possessed by patients with the less severe Becker muscular dystrophy. We are working on developing modified nucleotides, such as 2′-O,4′-C-ethylene-bridged nucleic acids (ENAs), possessing high nuclease resistance and high affinity for complementary RNA strands. Here, we demonstrate the preclinical characteristics (exon-skipping activity in vivo, stability in blood, pharmacokinetics, and tissue distribution) of renadirsen, a novel AO modified with 2′-O-methyl RNA/ENA chimera phosphorothioate designed for dystrophin exon 45 skipping and currently under clinical trials. Notably, systemic delivery of renadirsen sodium promoted dystrophin exon skipping in cardiac muscle, skeletal muscle, and diaphragm, compared with AOs with the same sequence as renadirsen but conventionally modified by PMO and 2′OMePS. These findings suggest the promise of renadirsen sodium as a therapeutic agent that improves not only skeletal muscle symptoms but also other symptoms in DMD patients, such as cardiac dysfunction.

DMD/BMD – OUTCOME MEASURES: EP.123 Functional trajectories of upper limb and pulmonary function before and after loss of ambulation in Duchenne muscular dystrophy

Characterization of disease progression in DMD patients around loss of ambulation (LoA) is needed to inform selection criteria and choice of endpoints in clinical trials including these patients. We analyzed upper limb and pulmonary function in the years immediately before and after LoA (defined as inability to walk 10 meters) using data from 51 boys with DMD from the PRO-DMD-01 natural history study (data provided by CureDuchenne). Included boys were ambulatory at their first study assessment and non-ambulatory at a follow-up assessment.

DMD – CLINICAL CARE: EP.101 Appendicular lean mass index (ALMI) changes in patients with dystrophinopathies

The musculo-skeletal phenotype of patients with dystrophinopathies range from Severe DMD with loss of ambulation (LOA) before age 13 years, to Intermediate DMD with LOA between 13 to 16 years and asymptomatic patients with Becker muscular dystrophy (BMD). Compared to healthy controls, we found that males with DMD have progressive decline in Appendicular Lean Mass Index (ALMI) with age and with worsening functional mobility. The age-related trajectories of ALM/ALMI in pediatric patients with BMD and Intermediate DMD have not yet been characterized. We aimed to: (1) compare ALM/ALMI of pediatric male patients with DMD in different stages of disease with that of patients with BMD; (2) compare ALM trajectories of patients with Intermediate DMD and BMD with those of typical DMD; and (3) compare ALM trajectories by the 4 DMD genotypes – mutations in exons 1-30, 31-44, 45 – 62 and 63-79. We conducted a retrospective longitudinal study of 499 patients (ages 2 – 20 y) with DMD (466 typical DMD; 33 DMD Intermediate) and 46 patients with BMD and normal motor function. ALM and ALMI (kg/m2) were measured by dual energy X-ray absorptiometry (DXA). ALM and ALMI from 693 healthy male controls were used as a reference to calculate age-specific Z-scores. Results: Mean ALMI Z-scores of DMD patients fell below -2 around age 12y while that of BMD patients remained within ± 2 without decline. ALMI of DMD patients declined after age 10 y while BMD patients accrued ALM but at a slower rate than healthy controls. ALMI started to decline in the milder Intermediate DMD patients around age 14 y. DMD patients with mutations in exons 63-79 appear to have greater declines in ALMI after age 10 y than DMD patients with the other 3 genotypes. Our data on ALMI trajectories in pediatric patients with dystrophinopathies can provide insight for clinical care management needs as well as inform clinical trial design for therapeutic trials in DMD and BMD.

DMD - TREATMENT: EP.142 Age at loss of ambulation in patients with DMD from the STRIDE Registry and the CINRG Natural history study: a matched cohort analysis

DMD - TREATMENT: EP.142 Age at loss of ambulation in patients with DMD from the STRIDE Registry and the CINRG Natural history study: a matched cohort analysis

DMD/BMD - GENETICS: EP.113 Lack of correlation between DMD exon 2 duplication splicing choices and phenotype severity

Duchenne muscular dystrophy (DMD) is an X-linked disorder caused by mutations in the DMD gene. About 75% of DMD mutations are deletions or duplications while the remaining are small mutations. Exon 2 duplication is the most frequent duplication and is associated with variable phenotypes, ranging from mild to severe. We profiled the muscle biopsy splicing pattern of DMD exon 2 duplication in seven DMD patients (identified by MLPA) using the Agilent High Sensitivity assay. Four patients showed classical DMD phenotype, with loss of ambulation within 13-year-old while in the other three patients ambulation was lost >age 15. We found four different transcripts due to different splicing choices: the exon2-exon2 duplicated transcript (79%), the intron1-exon2-exon2 transcript, which incorporates an upstream region of intron 1, generating a premature stop codon (13%), a transcript with both exon 2 skipped (3%) and a transcript skipping one exon 2, which generates a normal messenger (6%), this last represented in all seven DMD muscles. We did not identify a phenotype-specific DMD splicing pattern in the seven exon 2 duplicated DMD patients. All DMD patients show a similar percentage of wild type transcript (6%), and the very low amount of the transcript skipping both exon 2 suggests that dystrophin rescue due to the alternative ATG translation start site in exon 5 may not play a major role in disease severity. Our results therefore indicate lack of correlation between DMD exon 2 duplication splicing choices and DMD phenotype.

NEW GENES AND DISEASES: EP.301 The alpha2-subunit of the AP2 clathrin adaptor as the causal gene in an atypical myopathy with granulofilamentous inclusions

Clathrin-mediated endocytosis is the best characterized process for the entry of proteins and lipids at the plasma membrane of eukaryotic cells. We have previously shown that at costameres, muscle adhesion and force transmission sites, clathrin recruited by the AP2 adaptor forms flat plaques required for actin and desmin intermediate filament organization. Here, we describe a patient presenting a progressive muscular atrophy with loss of ambulation, complete tetraplegia, ophthalmoplegia, severe scoliosis and lower limb contractures and no cardiac involvement. Electron microscopy of muscle biopsy revealed inclusions composed of filamentous material, vacuoles, honeycomb structures and thin granular material surcharge. This case was classified as a myofibrillar myopathy with granulofilamentous inclusion bodies despite no mutation in DES, FHL1, CRYAB and other usual suspect genes. Whole exome sequencing identified two compound heterozygote single-nucleotide variants in the AP2A2 gene encoding the AP2 a2-subunit. Immunofluorescent labeling on muscle sections displayed intracellular aggregates positive for AP2, clathrin and desmin. Depletion of total AP2 in mouse muscle induced a dystrophic phenotype with severe force loss, subsarcolemmal disorganization, vacuoles and neuromuscular junction defects while specifically depleting AP2 a2-subunit induced small subsarcolemmal disorganization and light neuromuscular junction defects. Lastly, transferrin uptake assays of endocytosis function in the patient fibroblasts showed a decrease in endocytosis rates compared to fibroblasts from his healthy parents. Altogether, our results suggest that AP2A2 could be the causal gene in this family and AP2A2 mutations leading to a severe but atypical myopathy. Mutations in AP2A2 could represent the first case in a wider family of atypical myopathies with desmin inclusions caused by mutations in genes encoding proteins of the endocytosis machinery.

DMD - TREATMENT: EP.149 Delay in Duchenne muscular dystrophy progression with eteplirsen: longer time to loss of ambulation versus standard of care

Eteplirsen is indicated to treat Duchenne muscular dystrophy (DMD) with genetic mutations amenable to exon 51 skipping. Previous analyses have shown that eteplirsen is associated with significant and clinically meaningful delays in time to loss of ambulation (LOA). Additional data now allow for more comprehensive analysis of a larger number of eteplirsen-treated patients. The objective of this abstract is to estimate the treatment benefit of eteplirsen versus standard-of-care (SOC) for time to LOA from birth using a post-hoc analysis of individual patient level data.

DMD – CLINICAL CARE: EP.111 Evolution of scoliosis management in Duchenne muscular dystrophy

The long-term effects of scoliosis surgery on respiratory function and longevity in Duchenne muscular dystrophy (DMD) have been debated. Corticosteroids, respiratory care and cardioprotection have altered the natural history of DMD, making decisions regarding scoliosis management even more challenging. The aim of this study was to present the evolution of scoliosis management over time and its impact on disease-related outcomes, with focus on life expectancy and causes of death. All male patients born since 1st January 1970 who died by 31st December 2019 and were followed at a medical clinic in Sweden with a confirmed diagnosis of DMD were included in the study. Patients were identified via the National Quality Registry for Neuromuscular Diseases (NMiS), the Swedish National Registry for Respiratory Failure (Swedevox) and the pathology laboratories performing skeletal muscle biopsies in Sweden. Data was collected from the patients’ medical records in a systematic manner. We identified 129 patients, of whom approximately 80% had confirmed scoliosis by last follow-up or death at a median age of 30 years. 28 patients were treated solely with thoracolumbosacral orthosis (TLSO). Scoliosis surgery was performed in almost half of scoliosis patients, at a median age of 15.4 years. Median time from loss of ambulation to scoliosis surgery was 5.4 years. The evolution of scoliosis management over time, disease-related outcomes before and after scoliosis surgery, as well as correlation to other therapies, such as corticosteroids and non-invasive ventilation, will be presented. Scoliosis management in DMD is complex, necessitating multidisciplinary evaluation of comorbidities and close monitoring. Its evolution and impact on life expectancy and causes of death will be discussed.

LGMD: EP.192 Predicting loss of ambulation in LGMDR9

LGMD: EP.192 Predicting loss of ambulation in LGMDR9