Background: Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disorder due to an autosomal recessive mutation in the survival motor neuron 1 gene (SMN1), causing degeneration of the anterior horn cells of the spinal cord and resulting in muscle atrophy. This study aimed to report on the 36month follow-up of children with SMA treated with nusinersen before the age of 3 years. Changes in motor function, nutritional and ventilatory support, and orthopedic outcomes were evaluated at baseline and 36 months after intrathecal administration of nusinersen and correlated with SMA type and SMN2 copy number. Results: We found that 93% of the patients gained new motor skills during the 3 years-standing without help for 12 of 37 and walking with help for 11 of 37 patients harboring three SMN2 copies. No patients with two copies of SMN2 can stand alone or walk. Patients bearing three copies of SMN2 are more likely to be spared from respiratory, nutritional, and orthopedic complications than patients with two SMN2 copies. Conclusion: Children with SMA treated with nusinersen continue to make motor acquisitions at 3 years after initiation of treatment. Children with two SMN2 copies had worse motor, respiratory, and orthopedic outcomes after 3 years of treatment than children with three copies. (c) 2023 Published by Elsevier Masson SAS on behalf of French Society of Pediatrics.

Duchenne Muscular Dystrophy (DMD) is a neuromuscular disease that inevitably leads to total loss of autonomy. The new therapeutic strategies aim to both improve survival and optimise quality of life. Evaluating quality of life is nevertheless a major challenge. No DMD-specific quality of life scale to exists in French. We therefore produced a French translation of the English Duchenne Muscular Dystrophy module of the Pediatric Quality of Life Inventory (PedsQL TM DMD) following international recommendations. The study objective was to carry out a confirmatory validation of the French version of the PedsQL TM DMD for paediatric patients with DMD, using French multicentre descriptive cross-sectional data. The sample consisted of 107 patients. Internal consistency was acceptable for proxy-assessments, with Cronbach's alpha coefficients above 0.70, except for the Treatment dimension. For self-assessments, internal consistency was acceptable only for the Daily Activities dimension. Our results showed poor metric qualities for the French version of the PedsQL TM DMD based on a sample of about 100 children, but these results remained consistent with those of the original validation. This confirms the interest of its use in clinical practice.

Abstract Background Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disorder due to an autosomal recessive mutation in the survival motor neuron 1 gene (SMN1) causing degeneration of the anterior horn cells of the spinal cord and resulting in muscle atrophy. The aim of this paper is to report a 36-month follow-up of children with SMA treated with nusinersen before the age of 3 years. Change in motor function, nutritional and ventilatory support and orthopedics outcomes were evaluated at baseline and 36 months after intrathecal nusinersen and correlated with SMA type and SMN2 copy number. Results We report 88% of the patients who have gained new motor skills during the 3-years period, reaching standing without help and walking with help for 12/37 and 10/37 patients harboring 3 SMN2 copies respectively. No patients with 2 copies SMN2 can stand alone or walk. Patients bearing 3 copies of SMN2 are also more likely to be preserved from respiratory, nutritional and orthopedic complications than patients with 2 SMN2 copies. Conclusion Eventhough SMA patients improve with nusinersen, a lower number of SMN2 gene copies remains a predictor a of poorer evolution under treatment.

Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (median age at symptom onset 0.9 years, range: 0.0-2.0). Age of onset and age of death were significantly lower in patients who never acquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (median: 1.2 years, range: 0.8-4.0) and age of ambulation loss (median: 7 years, range: 1.2-38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype-phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA-related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopaedic, cardiac and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA-related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA-related respiratory and cardiac manifestations.

Duchenne muscular dystrophy (DMD) is an incurable disease caused by out-of-frame DMD gene deletions while in frame deletions lead to the milder Becker muscular dystrophy (BMD). In the last decade several antisense oligonucleotides drugs have been developed to induce a partially functional internally deleted dystrophin, similar to that produced in BMD, and expected to ameliorate the disease course. The pattern of dystrophin expression and functionality in dystrophinopathy patients is variable due to multiple factors, such as molecular functionality of the dystrophin and its distribution. To benchmark the success of therapeutic intervention, a clear understanding of dystrophin expression patterns in dystrophinopathy patients is vital. Recently, several groups have used innovative techniques to quantify dystrophin in muscle biopsies of children but not in patients with milder BMD. This study reports on dystrophin expression using both Western blotting and an automated, high-throughput, image analysis platform in DMD, BMD, and intermediate DMD/BMD skeletal muscle biopsies. Our results found a significant correlation between Western blot and immunofluorescent quantification indicating consistency between the different methodologies. However, we identified significant inter- and intradisease heterogeneity of patterns of dystrophin expression in patients irrespective of the amount detected on blot, due to variability in both fluorescence intensity and dystrophin sarcolemmal circumference coverage. Our data highlight the heterogeneity of the pattern of dystrophin expression in BMD, which will assist the assessment of dystrophin restoration therapies.

Duchenne muscular dystrophy (DMD) is characterized by progressive muscle wasting following repeated muscle damage and inadequate regeneration. Impaired myogenesis and differentiation play a major role in DMD as well as intracellular calcium (Ca2+) mishandling. Ca2+ release from the sarcoplasmic reticulum is mostly mediated by the type 1 ryanodine receptor (RYR1) that is required for skeletal muscle differentiation in animals. The study objective was to determine whether altered RYR1-mediated Ca2+ release contributes to myogenic differentiation impairment in DMD patients. The comparison of primary cultured myoblasts from six boys with DMD and five healthy controls highlighted delayed myoblast differentiation in DMD. Silencing RYR1 expression using specific si-RNA in a healthy control induced a similar delayed differentiation. In DMD myotubes, resting intracellular Ca2+ concentration was increased, but RYR1-mediated Ca2+ release was not changed compared with control myotubes. Incubation with the RYR-calstabin interaction stabilizer S107 decreased resting Ca2+ concentration in DMD myotubes to control values and improved calstabin1 binding to the RYR1 complex. S107 also improved myogenic differentiation in DMD. Furthermore, intracellular Ca2+ concentration was correlated with endomysial fibrosis, which is the only myopathologic parameter associated with poor motor outcome in patients with DMD. This suggested a potential relationship between RYR1 dysfunction and motor impairment. Our study highlights RYR1-mediated Ca2+ leakage in human DMD myotubes and its key role in myogenic differentiation impairment. RYR1 stabilization may be an interesting adjunctive therapeutic strategy in DMD.

Spinal muscular atrophy type 1 (SMA-1) is a severe neurodegenerative disorder, which in the absence of curative treatment, leads to death before 1 year of age in most cases. Caring for these short-lived and severely impaired infants requires palliative management. New drugs (nusinersen) have recently been developed that may modify SMA-1 natural history and thus raise ethical concerns about the appropriate level of care for patients. The national Hospital Clinical Research Program (PHRC) called “Assessment of clinical practices of palliative care in children with Spinal Muscular Atrophy Type 1 (SMA-1)” was a multicenter prospective study conducted in France between 2012 and 2016 to report palliative practices in SMA-1 in real life through prospective caregivers' reports about their infants' management. Thirty-nine patients were included in the prospective PHRC (17 centers). We also studied retrospective data regarding management of 43 other SMA-1 patients (18 centers) over the same period, including seven treated with nusinersen, in comparison with historical data from 222 patients previously published over two periods of 10 years (1989–2009). In the latest period studied, median age at diagnosis was 3 months [0.6–10.4]. Seventy-seven patients died at a median 6 months of age[1–27]: 32% at home and 8% in an intensive care unit. Eighty-five percent of patients received enteral nutrition, some through a gastrostomy (6%). Sixteen percent had a non-invasive ventilation (NIV). Seventy-seven percent received sedative treatment at the time of death. Over time, palliative management occurred more frequently at home with increased levels of technical supportive care (enteral nutrition, oxygenotherapy, and analgesic and sedative treatments). No statistical difference was found between the prospective and retrospective patients for the last period. However, significant differences were found between patients treated with nusinersen vs. those untreated. Our data confirm that palliative care is essential in management of SMA-1 patients and that parents are extensively involved in everyday patient care. Our data suggest that nusinersen treatment was accompanied by significantly more invasive supportive care, indicating that a re-examination of standard clinical practices should explicitly consider what treatment pathways are in infants' and caregivers' best interest. This study was registered on clinicaltrials.gov under the reference NCT01862042 (https://clinicaltrials.gov/ct2/show/study/NCT01862042?cond=SMA1&rank=8).

Background Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of the anterior horn cells of the spinal cord. Nusinersen has been covered by public healthcare in France since May 2017. The aim of this article is to report results after 1 year of treatment with intrathecal nusinersen in children with SMA types 1 and 2 in France. Comparisons between treatment onset (T0) and after 1 year of treatment (Y1) were made in terms of motor function and need for nutritional and ventilatory support. Motor development milestone achievements were evaluated using the modified Hammersmith Infant Neurologic Examination–Part 2 (HINE-2) for patients under 2 years of age and Motor Function Measure (MFM) scores for patients over 2 years of age. Results Data on 204 SMA patients (type 1 or 2) were retrospectively collected from the 23 French centers for neuromuscular diseases. One hundred and twenty three patients had been treated for at least 1 year and were included, 34 of whom were classified as type 1 (10 as type 1a/b and 24 as type 1c) and 89 as type 2. Survival motor Neuron 2 ( SMN2) copy numbers were available for all but 6 patients. Patients under 2 years of age ( n = 30), had significantly higher HINE-2 scores at year 1 than at treatment onset but used more nutritional and ventilatory support. The 68 patients over 2 years of age evaluated with the Motor Function Measure test had significantly higher overall scores after 1 year, indicating that their motor function had improved. The scores were higher in the axial and proximal motor function (D2) and distal motor function (D3) parts of the MFM scale, but there was no significant difference for standing and transfer scores (D1). No child in either of the two groups achieved walking. Conclusion Nusinersen offers life-changing benefits for children with SMA, particularly those with more severe forms of the disorder. Caregiver assessments are positive. Nevertheless, patients remain severely disabled and still require intensive support care. This new treatment raises new ethical challenges.

Mutations in ATP1A3 lead to different phenotypes having in common acute neurological decompensation episodes triggered by a specific circumstance and followed by sequelae. Alongside Alternating Hemiplegia of Childhood (AHC), Rapid-onset Dystonia Parkinsonism (RDP) and Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, Sensorineural hearing loss syndrome (CAPOS), a new Relapsing Encephalopathy with Cerebellar Ataxia (RECA) phenotype was published in 2015. We describe herein eight new pediatric cases. Most of them had no specific history when the first neurological decompensation episode occurred, before the age of 5 years, triggered by fever with severe paralytic hypotonia followed by ataxia with or without abnormal movements. Neurological sequelae with ataxia as the predominant symptom were present after the first episode in three cases and after at least one subsequent relapse in five cases. Five of the eight cases had a familial involvement with one of the two parents affected. The phenotype-genotype correlation is unequivocal with the causal substitution always located at position 756. The pathophysiology of the dysfunctions of the mutated ATPase pump, triggered by fever is unknown. Severe recurrent neurological decompensation episodes triggered by fever, without any metabolic cause, should lead to the sequencing of ATP1A3.

Background: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. Methods: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator–treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. Results: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0–7.2] and 5.1 [2.0–9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711–0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642–0.959), and the calibration slope was 1.082 (95% CI, 0.643–1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. Conclusions: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03058185.

Congenital myopathies are clinically and genetically heterogeneous, and are classified based on typical structural abnormalities on muscle sections. Recessive mutations in the striated muscle preferentially expressed protein kinase (SPEG) were recently reported in patients with centronuclear myopathy (CNM) associated in most cases with dilated cardiomyopathy. Here we report the identification of novel biallelic truncating SPEG mutations in a patient with moderate congenital myopathy without clinical and histological hallmarks of CNM and without cardiomyopathy. This study expands the phenotypic spectrum of SPEG-related myopathy and prompts to consider SPEG for congenital myopathies without specific histological features.

Objective: Alternating hemiplegia of childhood (AHC) is a rare neurological disorder character characterized by transient episodes of alternating hemiplegia/hemiparesis, dystonic attacks, paroxysmal abnormal ocular movements, epileptic seizuresand episodes of autonomic dysfunction, usually starting within the first year of life. In life. In 2012, mutations in ATP1A3, encoding the α3-subunit of the Na(+)/K(+)-ATPase pump, were shown to be the main cause of AHC. Mutations in ATP1A3 also cause other clinically-related neurological disorders: rapid-onset dystonia parkinsonism (RDP); CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss) syndrome; RECA (relapsing encephalopathy with cerebellar ataxia), and early infantile epileptic encephalopathy. We report the results of 4 years genetic screening of French patients with AHC or related disorders. Methods: Between 2012 and 2016, we have screened DNA sample from 162 patients for ATP1A3 mutations by Sanger sequencing or, more recently, by next-generation sequencing. Clinical records of all patients have been reviewed after genetic analysis. Results: We have found pathogenic or likely pathogenic ATP1A3 mutations in 59 index cases. A de novo mutation was found in all but 6 patients with clinical features fulfilling the criteria of AHC. The p.Glu818Lys mutation was found in two families with a clinical diagnosis of CAPOS. The p.Arg756Cys was found in 4 patients with a clinical diagnosis of RECA. The p.Arg756His mutations were found in a patient with RDP, but no mutations were identified in patients with isolated dystonia. Conclusion: This study confirms that ATP1A3 mutations are responsible for most cases of AHC, CAPOS or RECA. Analysis of clinical records led to identify only 6 patients with AHC without mutations on ATP1A3. These patients, together with patients from other countries have been included in an international genetic study, aiming at identifying other AHC-causing genes.

ABSTRACT:Selenoprotein-related myopathy (SEPN1-RM) is a rare disease with a variable clinical presentation. The selenoprotein N1 gene (SEPN1) mutation causing this congenital muscular dystrophy was identified in 2001. Sleep-disordered breathing (SDB) may occur in young patients with SEPN1-RM who are still able to walk. We report the cases of two children with SEPN1-RM who presented with SDB at the ages of 7 and 12 years and for whom long-term nocturnal noninvasive ventilation yielded significant improvement. Based on literature review and our current cases, it seems that there is no obvious relationship between the time since SDB onset and outcome of pulmonary function tests or limb muscle weakness. We therefore suggest that SDB should be systematically screened for in patients with SEPN1-RM, at regular intervals using nocturnal polysomnography.

La sélénopathie est une myopathie rare dont la présentation clinique est atypique, marquée notamment par l’apparition précoce des troubles respiratoires du sommeil, à la différence de la dystrophie musculaire de Duchenne et l’amyotrophie spinale infantile. Nous cherchons ici à évaluer l’apparition de troubles respiratoires du sommeil chez 2 enfants atteints de sélénopathie. Nous rapportons l’évolution de la fonction respiratoire diurne et nocturne de 2 enfants porteurs d’une sélénopathie, à l’aide d’EFR, d’oxymétrie nocturne, de capnographie nocturne et de polysmonographie. Ces deux enfants ont présenté des troubles respiratoires du sommeil à 7 et 12 ans alors qu’ils étaient encore ambulants et que leur fonction respiratoire diurne était encore relativement préservée. Depuis, ils sont traités par ventilation non invasive nocturne, celle-ci ayant permis la résolution des troubles respiratoires du sommeil et une nette amélioration de leur qualité de sommeil. La description de ces deux cas et la revue de la littérature permettent de montrer qu’il n’existe pas de corrélation entre le la date de la survenue de ces troubles respiratoires du sommeil et la fonction respiratoire diurne, d’une part, et le degré de faiblesse musculaire des membres, d’autre part. Nous proposons ainsi un dépistage des troubles respiratoires du sommeil systématique dès le diagnostic de sélénopathie, répété régulièrement, idéalement par une polysomnographie, ou à défaut, par une oxymétrie et une capnographie nocturnes.

BACKGROUND:Deficient nucleotide excision repair (NER) activity causes a variety of autosomal recessive diseases including xeroderma pigmentosum (XP) a disorder which pre-disposes to skin cancer, and the severe multisystem condition known as Cockayne syndrome (CS). In view of the clinical overlap between NER-related disorders, as well as the existence of multiple phenotypes and the numerous genes involved, we developed a new diagnostic approach based on the enrichment of 16 NER-related genes by multiplex amplification coupled with next-generation sequencing (NGS).METHODS:Our test cohort consisted of 11 DNA samples, all with known mutations and/or non pathogenic SNPs in two of the tested genes. We then used the same technique to analyse samples from a prospective cohort of 40 patients. Multiplex amplification and sequencing were performed using AmpliSeq protocol on the Ion Torrent PGM (Life Technologies).RESULTS:We identified causative mutations in 17 out of the 40 patients (43%). Four patients showed biallelic mutations in the ERCC6(CSB) gene, five in the ERCC8(CSA) gene: most of them had classical CS features but some had very mild and incomplete phenotypes. A small cohort of 4 unrelated classic XP patients from the Basque country (Northern Spain) revealed a common splicing mutation in POLH (XP-variant), demonstrating a new founder effect in this population. Interestingly, our results also found ERCC2(XPD), ERCC3(XPB) or ERCC5(XPG) mutations in two cases of UV-sensitive syndrome and in two cases with mixed XP/CS phenotypes.CONCLUSIONS:Our study confirms that NGS is an efficient technique for the analysis of NER-related disorders on a molecular level. It is particularly useful for phenotypes with combined features or unusually mild symptoms. Targeted NGS used in conjunction with DNA repair functional tests and precise clinical evaluation permits rapid and cost-effective diagnosis in patients with NER-defects.

Objective Cockayne syndrome is an autosomal recessive leukodystrophy and multisystem disorder characterized by mental retardation, microcephaly, severe growth failure, sensorial impairment, peripheral neuropathy and cutaneous photosensitivity. It belongs to the family of DNA repair and transcription disorders together with xeroderma pigmentosum and trichothiodystrophy. Clinical and genetic diagnosis still remains challenging. Our goal was to develop a unique and efficient mutation-screening strategy for Cockayne syndrome and related disorders and to improve our understanding of the clinical spectrum of these conditions. Methods We have designed a novel targeted high-throughput sequencing approach for the diagnosis of Cockayne syndrome and related DNA repair disorders. We have studied 30 patients presenting with the cardinal clinical features of Cockayne syndrome or related DNA repair disorders. Results We have identified the causative mutations in 14 of the 30 patients. Three patients showed biallelic mutations in the ERCC6/CSB gene, 2 patients in the ERCC8/CSA gene, 1 patient in the ERCC2/XPD gene, 1 patient in the ERCC3/XPB, 1 patient in the ERCC5/XPG, 6 in the POLH gene. We present the clinical, neurological and radiological phenotypes of these patients with regard to our experience of a well-characterized cohort of more than 100 Cockayne patients previously studied in our center and we discuss the implications for diagnosis and prognosis purposes. Conclusion This novel approach enables us to rapidly confirm the genetic diagnosis of Cockayne syndrome and related disoders and to unravel the molecular defect in atypical and overlapping clinical presentations. Cockayne syndrome is an autosomal recessive leukodystrophy and multisystem disorder characterized by mental retardation, microcephaly, severe growth failure, sensorial impairment, peripheral neuropathy and cutaneous photosensitivity. It belongs to the family of DNA repair and transcription disorders together with xeroderma pigmentosum and trichothiodystrophy. Clinical and genetic diagnosis still remains challenging. Our goal was to develop a unique and efficient mutation-screening strategy for Cockayne syndrome and related disorders and to improve our understanding of the clinical spectrum of these conditions. We have designed a novel targeted high-throughput sequencing approach for the diagnosis of Cockayne syndrome and related DNA repair disorders. We have studied 30 patients presenting with the cardinal clinical features of Cockayne syndrome or related DNA repair disorders. We have identified the causative mutations in 14 of the 30 patients. Three patients showed biallelic mutations in the ERCC6/CSB gene, 2 patients in the ERCC8/CSA gene, 1 patient in the ERCC2/XPD gene, 1 patient in the ERCC3/XPB, 1 patient in the ERCC5/XPG, 6 in the POLH gene. We present the clinical, neurological and radiological phenotypes of these patients with regard to our experience of a well-characterized cohort of more than 100 Cockayne patients previously studied in our center and we discuss the implications for diagnosis and prognosis purposes. This novel approach enables us to rapidly confirm the genetic diagnosis of Cockayne syndrome and related disoders and to unravel the molecular defect in atypical and overlapping clinical presentations.

BACKGROUND:Exon skipping therapy is an emerging approach in Duchenne Muscular Dystrophy (DMD). Antisense oligonucleotides that induce skipping of exon 51, 44, 45, or 53 are currently being evaluated in clinical trials. These trials were designed on the basis of data available in general DMD population.OBJECTIVES:Our objective was to compare the clinical and functional statuses of non-ambulant DMD patients theoretically treatable by exon 53 skipping and of DMD patients with other mutations.METHODS:We first compared fifteen non-ambulant DMD patients carrying deletions theoretically treatable by exon 53 skipping (DMD-53) with fifteen closely age-matched DMD patients with mutations not treatable by exon 53 skipping (DMD-all-non-53) then with fifteen DMD patients carrying deletions not treatable by exon 53 skipping (DMD-del-non-53).RESULTS:We found that DMD-53 patients had a lower left ventricular ejection fraction, more contractures and they tend to have weaker grips and pinch strengths than other DMD patients. DMD-53 patients lost ambulation significantly younger than other DMD patients. This result was confirmed by comparing ages at loss of ambulation in all non-ambulant DMD patients of the DMD cohort identified in a molecular diagnostic lab.CONCLUSIONS:These prospective and retrospective data demonstrate that DMD-53 patients have clinically more severe phenotypes than other DMD patients.