Loss Of Ambulation Research Articles

Genotype characterization and delayed loss of ambulation by glucocorticoids in a large cohort of patients with Duchenne muscular dystrophy

BackgroundDuchenne muscular dystrophy (DMD) is the most common genetic muscle disease in human. We aimed to describe the genotype distribution in a large cohort of Chinese DMD patients and their delayed loss of ambulation by glucocorticoid (GC) treatments. This is to facilitate protocol designs and outcome measures for the emerging DMD clinical trials.ResultsA total of 1163 patients with DMD were recruited and genotyped. Genotype variations were categorized as large deletions, large duplications, and small mutations. Large deletions were further analyzed for those amenable to exon-skipping therapies. Participants aged 5 years or older were grouped into GC-treated and GC-naïve groups. Clinical progression among different genotypes and their responses to GC treatments were measured by age at loss of ambulation (LOA). Among the mutation genotypes, large deletions, large duplications, and small mutations accounted for 68.79%, 7.14%, and 24.07%, respectively. The mean age at diagnosis was 4.59 years; the median ages at LOA for the GC-naïve, prednisone/prednisolone-treated, and deflazacort-treated groups were 10.23, 12.02, and 13.95 years, respectively. The “deletion amenable to skipping exon 44” subgroup and the nonsense-mutation subgroup had older ages at LOA than the “other deletions” subgroup. Subgroups were further analyzed by both genotypes and GC status. All genotypes showed significant beneficial responses to GC treatment. Deletions amenable to skipping exon 44 showed a lower hazard ratio (0.155). The mean age at death was 18.57 years in this DMD group.ConclusionGenotype variation influences clinical progression in certain DMD groups. Beneficial responses to GC treatment were observed among all DMD genotypes. Compared with other genotypes, deletions amenable to skipping exon 44 had a lower hazard ratio, which may indicate a stronger protective effect of GC treatments on this subgroup. These data are valuable for designing future clinical trials, as clinical outcomes may be influenced by the genotypes.

Ataluren Delays Loss of Ambulation and Decline in Pulmonary Function in Patients with Nonsense Mutation Duchenne Muscular Dystrophy (2553)

Ataluren Delays Loss of Ambulation and Decline in Pulmonary Function in Patients with Nonsense Mutation Duchenne Muscular Dystrophy (2553)

International retrospective natural history study of LMNA-related congenital muscular dystrophy.

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.

Micro-dystrophin gene therapy prevents heart failure in an improved Duchenne muscular dystrophy cardiomyopathy mouse model.

Gene replacement for Duchenne muscular dystrophy (DMD) with micro-dystrophins has entered clinical trials, but efficacy in preventing heart failure is unknown. Although most patients with DMD die from heart failure, cardiomyopathy is undetectable until the teens, so efficacy from trials in young boys will be unknown for a decade. Available DMD animal models were sufficient to demonstrate micro-dystrophin efficacy on earlier onset skeletal muscle pathology underlying loss of ambulation and respiratory insufficiency in patients. However, no mouse models progressed into heart failure, and dog models showed highly variable progression insufficient to evaluate efficacy of micro-dystrophin or other therapies on DMD heart failure. To overcome this barrier, we have generated the first DMD mouse model to our knowledge that reproducibly progresses into heart failure. This model shows cardiac inflammation and fibrosis occur prior to reduced function. Fibrosis does not continue to accumulate, but inflammation persists after function declines. We used this model to test micro-dystrophin gene therapy efficacy on heart failure prevention for the first time. Micro-dystrophin prevented declines in cardiac function and prohibited onset of inflammation and fibrosis. This model will allow identification of committed pathogenic steps to heart failure and testing of genetic and nongenetic therapies to optimize cardiac care for patients with DMD.

Deep phenotyping of an international series of patients with late-onset dysferlinopathy.

To describe the clinical, pathological, and molecular characteristics of late-onset (LO) dysferlinopathy patients. Retrospective series of patients with LO dysferlinopathy, defined by an age at onset of symptoms ≥30years, from neuromuscular centers in France and the International Clinical Outcome Study for dysferlinopathy (COS). Patients with early-onset (EO) dysferlinopathy (<30years) were randomly selected from the COS study as a control group, and the North Star Assessment for Dysferlinopathy (NSAD) and Activity Limitation (ACTIVLIM) scores were used to assess functionality. Muscle biopsies obtained from 11 LO and 11 EO patients were revisited. Forty-eight patients with LO dysferlinopathy were included (28 females). Median age at onset of symptoms was 37 (range30-57) years and most patients showed a limb-girdle (n=26) or distal (n=10) phenotype. However, compared with EO dysferlinopathy patients (n=48), LO patients more frequently showed atypical phenotypes (7 vs. 1; p=0.014), including camptocormia, lower creatine kinase levels (2855 vs. 4394 U/L; p=0.01), and higher NSAD (p=0.008) and ACTIVLIM scores (p=0.016). Loss of ambulation in LO patients tended to occur later (23±4.4years after disease onset vs. 16.3±6.8years; p=0.064). Muscle biopsy of LO patients more frequently showed an atypical pattern (unspecific myopathic changes) as well as significantly less necrosis regeneration and inflammation. Although LO patients more frequently showed missense variants (39.8% vs. 23.9%; p=0.021), no differences in dysferlin protein expression were found on Western blot. Late-onset dysferlinopathy patients show a higher frequency of atypical presentations, are less severely affected, and show milder dystrophic changes in muscle biopsy.

“Pulmonary dysfunction in children with Duchenne muscular dystrophy may appear earlier than we thought – analysis using novel methodology based on z-scores."

IntroductionRespiratory status is one of the main factors affecting the length of survival in patients with Duchenne muscular dystrophy (DMD) – the most common, severe, progressive muscular dystrophy.The aim: (1) to assess pulmonary function in DMD patients using the z-score method and (2) to identify factors affecting it, irrespective of the disease progress.Material and methodsWe evaluated 55 boys (aged 5 – 18 years) with DMD. The spirometry was performed with: forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), peak expiratory flow (PEF) analysis as absolute values (in litres or litres/min), % predicted value (%pv) and z-scores [z]. The need of ventilation support, ambulatory status, steroid therapy were collected.Results25(45%) subjects were non-ambulatory, 38(69%) used steroid therapy. Mean FVC[z] -2.4±2.2, FEV1[z] -2.0±1.9, PEF[z] -1.5±1.3 value significantly decrease with age (r=-0.62/-0.65/-0.55; p&lt;0.001 respectively), after reaching the peak values between 9-12 or 6-9 years of age depending on analysis method (absolute, %pv or z-score). The results fell below normal range (z-score&lt;-1.64) at the age of 9.8/10.4/11.6 years and below 80%pv at 10.7/13.2/13.2 for FVC/FEV1/PEF, respectively. The pulmonary function test results were significantly lower in non-ambulant (p&lt;0.001) and non-steroid patients (p&lt;0.02).ConclusionsAnalysis of pulmonary function test based on z-score shows that deterioration of pulmonary function in DMD males may appear earlier than we thought measured by %pv and absolute values. Early loss of ambulation, lack of or delayed steroid therapy are risk factors for worse pulmonary outcomes. To confirm these findings cohort longitudinal studies are necessary.

Early mobility after fragility hip fracture: a mixed methods embedded case study

BackgroundFollowing a hip fracture up to 60% of patients are unable to regain their pre-fracture level of mobility. For hospitalized older adults, the deconditioning effect of bedrest and functional decline has been identified as the most preventable cause of ambulation loss. Recent studies demonstrate that this older adult population spends greater than 80% of their time in bed during hospitalization, despite being ambulatory before their fracture. We do not fully understand why there continues to be such high rates of sedentary times, given that evidence demonstrates functional decline is preventable and early mobility recommendations have been available for over a decade.MethodsA descriptive mixed method embedded case study was selected to understand the phenomenon of early mobility after fragility hip fracture surgery. In this study, the main case was one post-operative unit with a history of recommendation implementation, and the embedded units were patients recovering from hip fracture repair. Data from multiple sources provided an understanding of mobility activity initiation and patient participation.ResultsActivity monitor data from eighteen participants demonstrated a mean sedentary time of 23.18 h. Median upright time was 24 min, and median number of steps taken was 30. Qualitative interviews from healthcare providers and patients identified two main categories of themes; themes external to the person and themes unique to the person. We identified four factors that can influence mobility; a patient’s pre-fracture functional status, cognitive status, medical unpredictability, and preconceived notions held by healthcare providers and patients.ConclusionsThere are multi-level factors that require consideration with implementation of best practice interventions, namely, systemic, healthcare provider related, and patient related. An increased risk of poor outcomes occurs with compounding multiple factors, such as a patient with low pre-fracture functional mobility, cognitive impairment, and a mismatch of expectations. The study reports several variables to be important considerations for facilitating early mobility. Communicating mobility expectations and addressing physical and psychological readiness are essential. Our findings can be used to develop meaningful healthcare provider and patient-centred interventions to address the risks of poor outcomes.

The role of imaging in characterizing the cardiac natural history of Duchenne muscular dystrophy.

Duchene muscular dystrophy (DMD) is a rare but devastating disease resulting in progressive loss of ambulation, respiratory failure, DMD-associated cardiomyopathy (DMD-CM), and premature death. The use of corticosteroids and supportive respiratory care has improved outcomes, such that DMD-CM is now the leading cause of death. Historically, most programs have focused on skeletal myopathy with less attention to the cardiac phenotype. This omission is rather astonishing since patients with DMD possess an absolute genetic risk of developing cardiomyopathy. Unfortunately, heart failure signs and symptoms are vague due to skeletal muscle myopathy leading to limited ambulation. Traditional assessment of cardiac symptoms by the New York Heart Association American College of Cardiology/American Heart Association Staging (ACC/AHA) classification is of limited utility, even in advanced stages. Echocardiographic assessment can detect cardiac dysfunction late in the disease course, but this has proven to be a poor surrogate marker of early cardiovascular disease and an inadequate predictor of DMD-CM. Indeed, one explanation for the paucity of cardiac therapeutic trials for DMD-CM has been the lack of a suitable end-point. Improved outcomes require a better proactive treatment strategy; however, the barrier to treatment is the lack of a sensitive and specific tool to assess the efficacy of treatment. The use of cardiac imaging has evolved from echocardiography to cardiac magnetic resonance imaging to assess cardiac performance. The purpose of this article is to review the role of cardiac imaging in characterizing the cardiac natural history of DMD-CM, highlighting the prognostic implications and an outlook on how this field might evolve in the future.

Comparison of Long-term Ambulatory Function in Patients with Duchenne Muscular Dystrophy Treated with Eteplirsen and Matched Natural History Controls.

Background:Duchenne muscular dystrophy (DMD) is a rare, X-linked, fatal, degenerative neuromuscular disease caused by DMD gene mutations. A relationship between exon skipping and dystrophin production in exon 51-amenable patients treated with eteplirsen (EXONDYS 51®) is established. Once-weekly eteplirsen significantly increased dystrophin, with slower decline in ambulatory function compared to baseline. Long-term treatment with eteplirsen leads to accumulation of dystrophin over time and observed functional benefits in patients with DMD.Objective:Compare long-term ambulatory function in eteplirsen-treated patients versus controls.Methods:Study 201/202 included 12 eteplirsen-treated patients assessed twice/year for ambulatory function over 4 years. Ambulatory evaluations (6-minute walk test [6MWT], loss of ambulation, and North Star Ambulatory Assessment [NSAA]) were compared with matched controls from Italian Telethon and Leuven registries.Results:At Years 3 and 4, eteplirsen-treated patients demonstrated markedly greater mean 6MWT than controls (difference in change from baseline of 132 m [95%CI (29, 235), p = 0.015] at Year 3 and 159 m [95%CI (66, 253), p = 0.002] at Year 4). At Year 4, a significantly greater proportion of eteplirsen-treated patients were still ambulant versus controls (10/12 vs 3/11; p = 0.020). At Year 3, eteplirsen-treated patients demonstrated milder NSAA decline versus controls (difference in change from baseline of 2.6, 95%CI [-6, 11]), however, the difference was not statistically significant; Year 4 control NSAA data were not available.Conclusion:In this retrospective matched control study, eteplirsen treatment resulted in attenuation of ambulatory decline over a 4-year observation period, supporting long-term benefit in patients with DMD.

Stakeholder perspectives of pediatric powered wheelchair standing devices: a qualitative study.

To explore and describe the experiences and perspectives of various stakeholders regarding the use of powered wheelchair standing devices (PWSDs). The purposive sample included: children aged 6 to 18 years who used a PWSD (n=8; diagnoses: cerebral palsy, spinal muscular atrophy, spina bifida, spinal cord injury), parents of children 18 years of age or younger who used a PWSD (n=12), rehabilitation professionals working with children who used a PWSD (n=12), and professionals working at companies manufacturing PWSDs (n=3). Data were gathered via face-to-face interviews conducted either in person or via Zoom® and analyzed using the constant comparative method. Three main themes emerged in the data: (1) 'Stand-on-demand' revealed how participants perceived PWSDs as allowing children to stand whenever and wherever they wanted, thereby increasing participation; (2) 'It's more than weight-bearing' uncovered participants' perceptions of psychological and physical benefits from PWSD use; and (3) 'Ecosystems influencing PWSD acquisition and use' revealed child- and non-child-related factors perceived as influencing children's procurement and use of a PWSD. Use of a PWSD was perceived as providing a unique opportunity for children to stand whenever and wherever they desired. Findings suggest the possible transdiagnostic application of PWSDs. What this paper adds The ability to stand when desired was unique to powered wheelchair standing device (PWSD) use. Participants perceived numerous psychological and physical benefits from PWSD use. Child- and non-child-related factors influenced procurement and use of a PWSD.

Prevalence of Scoliosis in Cerebral Palsy

Background: Significant structural deformity of the spine often accompanies cerebral palsy. Progression of curve will eventually lead to pain, loss of ambulation, sitting balance. The aetiology of scoliosis in CP has yet to be well defined. Objective: The objective of this study was to find incidence of scoliosis in different sub-types of cerebral palsy. Method: A total population of 30 children with cerebral palsy aged 5 to 20 years followed with examination and assessment for scoliosis in a health care setting was analysed. GMFCS level, CP subtype, age at diagnosis, gender dominance of the condition were correlates registered. Effect of 5 factors on progression of the curve and type of scoliosis dominant in cerebral palsy was studied. Results: Of the 30 subjects initially enrolled in the study, 19 of them with scoliosis in which incidence of 28% was found among spastic quadriplegia followed by 24% in diplegia. The risk of scoliosis increased with GMFCS level and age. 22% of children showed moderate scoliosis with respect to scoliosis appearance questionnaire. Conclusions: Scoliosis was most common in the spastic group with the highest incidence in the spastic quadriplegics. There was a definite inverse relationship between the level of ambulation and scoliosis: the higher the level of ambulation the lower the incidence of scoliosis. Moderate scoliosis was found because progression of curve is expected to continue until skeletal maturity.

An Unusual Case of Thiamine Deficiency in a Total Parenteral Nutrition-Dependent Child Secondary to Munchausen by Proxy

An Unusual Case of Thiamine Deficiency in a Total Parenteral Nutrition-Dependent Child Secondary to Munchausen by Proxy

Feasibility of salvage decompressive surgery for pending paralysis due to metastatic spinal cord compression

ObjectiveMetastatic spinal cord compression (MSCC) is a frequent phenomenon in cancer disease, often leading to severe neurological deficits. Especially in patients with complete motor paralysis, regaining the ability to walk is an important treatment goal. Our study, therefore, aimed to assess the neurological outcome of patients with MSCC and complete motor paralysis after decompressive surgery. MethodsPatients with MSCC and complete motor paralysis, surgically treated by decompressive surgery between 2004–2014 at a single institution were retrospectively analyzed. Clinical patient data were collected from medical records. To assess the neurological outcome, Frankel grade (FG) at admission and discharge were compared. Statistical analysis was performed to identify factors associated with an ambulatory status after surgery. ResultsTwenty-eight patients were included in this study. The majority of metastases (57 %) were located in the thoracic spine and 75 % showed extraspinal tumor spread. The median interval between loss of ambulation and surgery was 35 h (IQR: 29–70). Posterior circumferential decompression without stabilization was performed in all cases within 24 h of admission. Neurological function improved in 17 patients (63 %) and seven (26 %) even regained the ability to walk following surgery. The rate of complications was low (7%). In statistical analysis, only the Karnofsky Performance Index (KPI) displayed a significant predictive value for an ambulatory status at discharge. ConclusionsOur findings indicate that severely affected MSCC patients with complete motor paralysis might benefit from decompressive surgery even when the loss of ambulation occurred more than 24 h ago.

Cervical Injury Outcomes among Older Adults Admitted to an Inpatient Trauma Service.

Older adults are an increasing proportion of patients admitted to trauma services. Trauma in older adults' results from many mechanisms of injury with the distribution of mechanisms of injury among older adults different than those of younger adults. The acute management of these injuries may determine the patients' ability to return to independent living. It is known that prolonged immobilization of older patients results in deterioration of their functional status and increases the likelihood of hospital acquired complications, notably pneumonia, delirium, and loss of ambulation. We reviewed 213 patients aged 65 and older admitted to our trauma services who sustained cervical spine injuries that were either placed in c spine immobilization or were not to understand the outcomes associated with their mechanism of injury. The youngest patients (65-74 years) were proportionately more likely to have sustained high energy injuries associated with motor vehicle crashes (36%) with a mortality rate of 11.5%. The oldest age group (> 85 years) had a higher mortality rate from falls from standing injuries (31%). Patients discharged with a collar were more likely to return to independent living. In addition, 96% of the patients that died in the acute care setting were not in cervical collar immobilization. Patients under 85 years with a cervical spine injury should be placed in c-spine immobilization and aggressively managed with a multidisciplinary team approach. The older adult trauma population requires specialty care including rapid cervical spine evaluation and prescreening of functional status on admission. The NEXUS guideline should be enhanced for the older adult trauma population.

Association of Initial Maximal Motor Ability With Long-term Functional Outcome in Patients With COL6-Related Dystrophies.

To accurately categorize the phenotypes of individuals with collagen VI-related dystrophies (COL6-RDs) during the first years of life to predict long-term motor function and pulmonary function, to provide phenotype-specific anticipatory care, and to improve clinical trial readiness. This retrospective, multicenter, international study analyzed the relationship of long-term motor and pulmonary function with the initial maximal motor ability achieved in individuals with COL6-RD. We studied 119 patients with COL6-RD from Spain (n = 54) and the United States (n = 65). The early maximal motor milestones of ability to rise from the floor unassisted and ability to climb 4 steps without holding onto a railing demonstrated reliability in distinguishing between 3 COL6-RD phenotypic subgroups: (1) Ullrich congenital muscular dystrophy, (2) intermediate COL6-RD, and (3) Bethlem myopathy. Long-term motor function and pulmonary function are strongly correlated with the maximal motor ability achieved during the first years of life. Maximal motor capacity can predict other disease-relevant events such as the age at loss of ambulation and the need for the initiation of nocturnal noninvasive ventilation. This work proposes a prospective phenotypic classification for COL6-RDs that will enable an accurate prediction of a patient's COL6-RD phenotype during the first years of life. The ability to establish a patient's COL6-RD phenotypic classification early will enable a more accurate prognosis of future motor and pulmonary function, thus improving anticipatory clinical care, and it will be instrumental in aiding the design of future clinical trials by allowing early stratification of trial cohorts.

Case Report: Duchenne Muscular Dystrophy in a 6-Year-Old Boy

Duchenne Muscular Dystrophy (DMD) is an X-link reccessive disorder, caused by mutation in dystrophin gene. Therefore body is incapable to synthesize dystrophin, the protein needed for muscle contraction. The incidence of DMD 1: 4000 male with age 3 to 5 years. Furthermore the patient will experience functional decline, loss of ambulation and early death due to cardiac or respiratory failure. Patient will be unable to walk at the beginning of second decade and usually decease at the age of 20s. Hereby we reported a male, 6-years-old presented with weakness on both of his legs. Patient had history of recurrent falls while walking and difficulty to climb stairs since 3-years-old. Patient also had difficulty to stand up immediately from sitting position. He had to grab his feet in order to make climb movement before stand up. Physical examination showed pseudo hypertrophy of calf muscle and positive Gower Maneuver. Laboratory examination showed creatinin kinase 16.891 (about 113 times higher than normal value). EMG revealed lesion of the muscle. Biopsy was taken from left muscle gastrocnemius and showed variability of muscle size without regeneration and fibrosis. The result of genetic test showed deletion of Dp427c and exon 1-2 of dystrophin gen. After been treated with corticosteroid for a year, the patient showed improvement in his gait moreover the weakness on both of his legs has became lessen. We emphasized the importance of early and accurate diagnosis of DMD for better quality of life.

Gene editing and modulation for Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by loss of dystrophin protein, encoded by the DMD gene. DMD manifests early in childhood as difficulty walking, progresses to loss of ambulation by the teens, and leads to death in early adulthood. Adeno-associated virus-vectorized gene therapies to restore dystrophin protein expression using gene replacement or antisense oligonucleotide-mediated pre-mRNA splicing modulation have emerged, making great strides in uncovering barriers to gene therapies for DMD and other genetic diseases. While this first-generation of DMD therapies are being evaluated in ongoing clinical trials, uncertainties regarding durability and therapeutic efficacy prompted the development of new experimental therapies for DMD that take advantage of somatic cell gene editing. These experimental therapies continue to advance toward clinic trials, but questions remain unanswered regarding safety and translatable efficacy. Here we review the advancements toward treatment of DMD using gene editing and modulation therapies, with an emphasis on those nearest to clinical applications.

Respiratory decline in adult patients with Becker muscular dystrophy: A longitudinal study

Becker muscular dystrophy (BMD) is a rare hereditary neuromuscular disease, caused by a genetic defect in the Duchenne Muscular Dystrophy (DMD) gene. We studied the natural history of respiratory function and its affecting factors in 23 adult BMD patients. These important data are needed for (future) clinical trials in BMD but are largely lacking. Patients had a median age of 51 years (28–78y) and median follow-up duration of 14 years (2–25y). We analysed 190 pulmonary function measurements with a median interval of one year (1–17y) and measured a 1.00% decline of Forced Vital Capacity percent predicted (FVC%pred) per year (p = 0.004). Loss of ambulation significantly increased the annual rate of FVC decline and was dependent of patient's body mass index (BMI; p = 0.015), with increases in BMI correlating with an even more rapid deterioration of FVC. A decline in Medical Research Council (MRC) sum score was significantly correlated with a decline in FVC (p = 0.003). We conclude that adult BMD patients experience a significant but mild respiratory decline. However, this decline is significantly more rapid and clinically relevant after loss of ambulation, which warrants a more vigilant follow-up of respiratory function in this subgroup.

Gene modification strategies using AO-mediated exon skipping and CRISPR/Cas9 as potential therapies for Duchenne muscular dystrophy patients.

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease affecting 1 in 5000 young males worldwide annually. Patients experience muscle weakness and loss of ambulation at an early age, with ∼75% reduced life expectancy. Recently developed genetic editing strategies aim to convert severe DMD phenotypes to a milder disease course. Among these, the antisense oligonucleotide (AO)-mediated exon skipping and the adeno-associated viral-delivered clustered regularly interspaced short palindromic repeat (CRISPR) associated protein 9 (adeno-associated viral (AAV)-delivered CRISPR/Cas9) gene editing have shown promising results in restoring dystrophin protein expression and functionality in skeletal and heart muscle in both animals and human cells in vivo and in vitro. However, therapeutic benefits currently remain unclear. The aim of this review is to compare the potential therapeutic benefits, efficacy, safety, and clinical progress of AO-mediated exon skipping and CRISPR/Cas9 gene-editing strategies. Both techniques have demonstrated therapeutic benefit and long-term efficacy in clinical trials. AAV-delivery of CRISPR/Cas9 may potentially correct disease-causing mutations following a single treatment compared to the required continuous AO/PMO-delivery of exon skipping drugs. The latter has the potential to increase the dystrophin expression in skeletal/heart muscle with sustained effects. However, therapeutic challenges including the need for optimised delivery must be overcome in to advance current clinical data.

Quadriceps muscle strength in Duchenne muscular dystrophy and effect of corticosteroid treatment.

ObjectivesIn Duchenne muscular dystrophy, quadriceps weakness is recognized as a key factor in gait deterioration. The objective of this work was three-fold: first, to document the strength of the quadriceps in corticosteroid-naïve DMD boys; second, to measure the effect of corticosteroids on quadriceps strength; and third, to evaluate the correlation between baseline quadriceps strength and the age when starting corticosteroids with the loss of ambulation.MethodsQuadriceps muscle strength using hand-held dynamometry was measured in 12 ambulant DMD boys who had never taken corticosteroids and during corticosteroid treatment until the loss of ambulation.ResultsBaseline quadriceps muscle strength at 6 years of age was 28% that of normal children of the same age; it decreased to 15% at 8 years and to 6% at 10 years. The increase in quadriceps muscle strength obtained after 1 year of corticosteroid treatment had a strong direct correlation with the baseline strength (R = 0.96). With corticosteroid treatment, the age of ambulation loss showed a very strong direct relationship (R = 0.92) with baseline quadriceps muscle strength but only a very weak inverse relationship (R = -0.73) with the age of starting treatment. Age of loss of ambulation was 10.3 ± 0.5 vs 19.1 ± 4.7 (P < 0.05) in children with baseline quadriceps muscle strength less than or greater than 40 N, respectively.ConclusionsCorticosteroid-naïve DMD boys have a quantifiable severe progressive quadriceps weakness. This long-term study, for the first time, shows that both of the positive effects obtained with CS treatment, i.e. increasing quadriceps strength and delaying the loss of ambulation, have a strong and direct correlation with baseline quadriceps muscle strength. As such, hand-held dynamometry may be a useful tool in the routine physical examination and during clinical trial assessment.