Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are the most common inherited neuromuscular diseases. Following the identification of a pathogenic causative variant in the DMD gene of a proband, potential carriers can be informed of their risk of having offspring with the disease. Germline mosaicism is a variant that is confined to the gonads that can be transmitted to offspring and is usually reported when a non-carrier of a DMD pathogenic variant has two or more offspring carrying the variant in question. On average, one third of cases are the result of a de novo variant, and as DMD and BMD are prone to germline mosaicism, its inclusion in genetic counseling is mandatory. In this retrospective cohort study, we presented clinical data from an unpublished DMD/BMD cohort of 332 families with incidence of germline mosaicism in families with de novo transmission of 8.1%. This is also the first systematic literature review searching PubMed to provide an accurate assessment of the current literature on germline mosaicism in DMD and BMD, including 17 case reports and 20 original studies. The incidence of documented germline mosaicism in de novo event families ranged from 6.0 to 40%, with a mean of 8.3%. The estimated recurrence risk for mothers of a patient with a proven de novo causal variant ranged from 4.3 to 11%, with a mean of 5.8% for a male fetus. By providing an up-to-date and comprehensive overview of the literature, this review aims to improve our understanding of germline mosaicism in DMD and to promote the development of effective strategies and reliable data for occurrence risk assessment in genetic counseling of de novo event families.

OBJECTIVE: Only few studies investigated social cognition in Becker muscular dystrophy (BMD). However, brain dystrophin deficiency could be a neural substrate for cognitive, emotional, and neuropsychological features in BMD.
METHODS: We compared interoceptive accuracy and interpersonal comfort distance in two brothers with BMD presenting with the same genetic deletion and a healthy control. When possible, we collected neuropsychological and psychopathological assessments.
RESULTS: Our BMD patients were significantly different in interoceptive accuracy, with patient 1 being extremely accurate and patient 2 being significantly less accurate than his brother but more accurate than the control. Interestingly, they presented opposite patterns of interpersonal distance. Patient 1 was comfortable with very short interpersonal distance (≤50 cm from the confederate/object) vs the control and patient 2. By contrast, patient 2 preferred larger distance vs the control and patient 1. Patient 1 also presented difficulties in social and emotional skills on the psychopathological assessment.
CONCLUSIONS: We are aware this is a small sample; nonetheless, this is also the first description of such aspects in BMD and the first report ever of such divergent behavioral pattern. As impaired social cognition affects the quality of life and social relationship, further studies are needed for a closer understanding of involved mechanisms.

UNASSIGNED: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are neuromuscular diseases. DMD is the most prevalent in children. It affects dystrophin production, reducing the patient\'s mobility and quality of life. New technologies have become a part of physical therapy in DMD and BMD. During the COVID-19 pandemic, conducting telerehabilitation through virtual reality-based games could help these children maintain their physical abilities.
UNASSIGNED: This study examined if the use of a virtual platform in a multimodal intervention program changes the results of the 6-minute walk test (6MWT) in children with DMD and BMD. The main objective was to test whether children with DMD and BMD obtain different results on the 6MWT after completing 10 telerehabilitation treatment sessions. The secondary objective was to measure whether other specific motor scales also produce different results after the 10 defined sessions.
UNASSIGNED: This was a descriptive, open, and quasi-experimental study with a prospective A-B (control-intervention) design. A sample of 12 participants who fulfilled the inclusion criteria followed the program for 5 weeks with 10 telerehabilitation sessions. During the sessions, the participants used virtual reality glasses to train for the treatment goals. All participants were assessed in person before and after the intervention. Analysis was performed using R software according to the different functional assessments performed for each test.
UNASSIGNED: The participants showed a 19.55-meter increase in the 6MWT. Motor function also remained stable according to other scales used to assess it. The North Start Ambulatory Assessment scores were stable in both treatment conditions (P=.20). Furthermore, the timed up and go test results were 0.1 seconds faster in the telerehabilitation condition, and the Motor Function Measure in all of the 3 dimensions showed no significant differences (P=.08). Finally, the Effort Perception Infant scale showed that during the training, fatigue increased in the middle and decreased by the end of the sessions, but the perception throughout the sessions was lower even as the exercise intensity increased.
UNASSIGNED: There were no differences between conventional and telerehabilitation treatments, so the telerehabilitation tool could be used without harming children with DMD and BMD, facilitating their access to therapies and stimulating learning to maintain their functional capacity. Therefore, telerehabilitation in general may be helpful in maintaining motor function in children with DMD and BMD. The learning effect helped reduce the feeling of fatigue in the children during the program.

UNASSIGNED: Elevated transaminases and/or creatine phosphokinase can indicate underlying muscle disease. Therefore, this study aims to determine the frequency of Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD) in male children and Pompe disease (PD) in male and female children with isolated hypertransaminasemia.
UNASSIGNED: This multi-center, prospective study enrolled patients aged 3-216 months with serum alanine transaminase (ALT) and/or aspartate transaminase (AST) levels >2× the upper limit of normal (ULN) for ≥3 months. Patients with a known history of liver or muscle disease or physical examination findings suggestive of liver disease were excluded. Patients were screened for creatinine phosphokinase (CPK) levels, and molecular genetic tests for DMD/BMD in male patients and enzyme analysis for PD in male and female patients with elevated CPK levels were performed. Genetic analyses confirmed PD. Demographic, clinical, and laboratory characteristics of the patients were analyzed.
UNASSIGNED: Overall, 589 patients [66.8% male, mean age of 63.4 months (standard deviation: 60.5)] were included. In total, 251 patients (188 male and 63 female) had CPK levels above the ULN. Of the patients assessed, 47% (85/182) of male patients were diagnosed with DMD/BMD and 1% (3/228) of male and female patients were diagnosed with PD. The median ALT, AST, and CPK levels were statistically significantly higher, and the questioned neurological symptoms and previously unnoticed examination findings were more common in DMD/BMD patients than those without DMD/BMD or PD (p < 0.001).
UNASSIGNED: Questioning neurological symptoms, conducting a complete physical examination, and testing for CPK levels in patients with isolated hypertransaminasemia will prevent costly and time-consuming investigations for liver diseases and will lead to the diagnosis of occult neuromuscular diseases.
UNASSIGNED: Clinicaltrials.gov NCT04120168.

UNASSIGNED: No treatments are approved for Becker muscular dystrophy (BMD). This study investigated the efficacy and safety of givinostat, a histone deacetylase pan-inhibitor, in adults with BMD.
UNASSIGNED: Males aged 18-65 years with a diagnosis of BMD confirmed by genetic testing were randomized 2:1 to 12 months treatment with givinostat or placebo. The primary objective was to demonstrate statistical superiority of givinostat over placebo for mean change from baseline in total fibrosis after 12 months. Secondary efficacy endpoints included other histological parameters, magnetic resonance imaging and spectroscopy (MRI and MRS) measures, and functional evaluations.
UNASSIGNED: Of 51 patients enrolled, 44 completed treatment. At baseline, there was greater disease involvement in the placebo group than givinostat, based on total fibrosis (mean 30.8 vs. 22.8%) and functional endpoints. Mean total fibrosis did not change from baseline in either group, and the two groups did not differ at Month 12 (least squares mean [LSM] difference 1.04%; p = 0.8282). Secondary histology parameters, MRS, and functional evaluations were consistent with the primary. MRI fat fraction in whole thigh and quadriceps did not change from baseline in the givinostat group, but values increased with placebo, with LSM givinostat-placebo differences at Month 12 of -1.35% (p = 0.0149) and -1.96% (p = 0.0022), respectively. Adverse events, most mild or moderate, were reported by 88.2% and 52.9% patients receiving givinostat and placebo.
UNASSIGNED: The study failed to achieve the primary endpoint. However, there was a potential signal from the MRI assessments suggesting givinostat could prevent (or slow down) BMD disease progression.

BACKGROUND: Glucocorticoid steroids are standard of care in Duchenne Muscular Dystrophy (DMD) to slow disease course. Use of glucocorticoids in other muscular dystrophies, including Becker (BMD) and Limb Girdle (LGMD), has been less explored. Recently, preclinical studies conducted in DMD and LGMD mouse models showed once-weekly prednisone was associated with improved muscle performance without activation of muscle atrophy genes.
OBJECTIVE: To determine safety and tolerability of once-weekly prednisone in patients with LGMD and BMD.
METHODS: We conducted an open label, exploratory single center study of of once-weekly prednisone at 0.75-1 mg/Kg in LGMD (n = 19) and BMD (n = 1) (mean age 35, range 18-60). The LGMD participants represented multiple different LGMD subtypes, and the study included ambulatory and non-ambulatory participants. Participants were assessed at baseline and 24 weeks for vital signs, blood biomarkers, and for patient-reported side effects. As secondary endpoints, functional muscle testing and body composition were measured.
RESULTS: Over the 24-week study, there were no significant changes in blood pressure, HgbA1C, or lipid profiles. We observed a reduction in serum creatine kinase over the study interval. Whole body DEXA scanning suggested a possible increase in lean mass and a reduction in adiposity. Functional measures suggested trends in improved muscle performance.
CONCLUSIONS: In this single center, open label pilot study, once-weekly prednisone was safe and well tolerated. Additional investigation of once-weekly prednisone in a larger cohort and for a longer period of time is warranted.

Introduction: With the advent of emerging molecular therapies for muscular dystrophies, the need for knowledge about natural history course of such diseases is of utmost importance in the preparation for future trials. However, for Becker muscular dystrophy such knowledge is scarce. Objective: In this 1-year follow-up study, we examined disease progression in Becker muscular dystrophy by monitoring changes in MRI-assessed muscle fat fraction (FF) in axial and lower limb muscles and quantitative muscle strength of axial muscles. Methods and Materials: Sixteen patients with Becker muscular dystrophy were investigated by (1) muscle strength of the trunk using a Biodex dynamometer and (2) Dixon muscle MRI of paraspinal and lower limb muscles. Quantitative MRI data was analyzed in two parts: The first part consisted of all participants (N = 16). The second analysis assessed two separate groups comprising lesser affected participants (N = 5) and more severely affected patients (n = 11). Results: Trunk extension and flexion strength remained stable from baseline to follow-up. MRI did not show any significant increase in muscle FF % from baseline to follow-up in all patients, except for multifidus at the spinal level T12 (p = 0.01). However, when we analyzed the two subgroups, according to disease severity, FF% increased in the lesser severely affected group at L4/L5 erector spinae (p = 0.047), sartorius (p = 0.028), gracilis (p = 0.009), tibialis anterior (p = 0.047), peroneals (p = 0.028), and gastrocnemius medialis (p = 0.009), while the severely affected group only increased significantly at T12 multifidus (p = 0.028) and T12 erector spinae (p = 0.011). No difference in muscle strength was observed in the two subgroups. Conclusion: Our results add to the existing knowledge about the natural rate of disease progression in BMD. As quantitative MRI was able to identify changes where strength assessment was not, MRI could be a strong biomarker for change in BMD. However, our findings show that it is important to stratify patients with BMD according to phenotype for future clinical trials.

We performed an observational, natural history study of males with in-frame dystrophin gene deletions causing Becker muscular dystrophy (BMD). A prospective natural history study collected longitudinal medical, strength, and timed function assessments. Eighty-three participants with genetically confirmed BMD were enrolled (age range 5.6-75.4 years). Lower extremity function and the percentage of participants who retained ambulation declined across the age span. The largest single group of participants had in-frame deletions that corresponded to an out-of-frame deletion treated with an exon 45 skip to restore the reading frame. This group of 54 participants showed similarities in baseline motor functional assessments when compared to the group of all others in the study. A prospective natural history cohort with in-frame dystrophin gene deletions offers the potential to contribute to clinical trial readiness for BMD and to analyze therapeutic benefit of exon skipping for Duchenne muscular dystrophy.

Dysphagia is reported in patients with Duchenne or Becker muscular dystrophy. Our clinical experience suggests that, compared with Duchenne patients, impaired mastication and swallowing occur early in Becker patients relative to their skeletal muscle involvement. The aim of this study was to assess dysphagia in Duchenne and Becker patients in relation to ambulatory capacity.
In patients in the early ambulatory stage, clinical symptoms, quantitative muscle ultrasound of the orofacial muscles, and maximum bite force were assessed. The 6-Minute Walk Test (6MWT) was used to measure ambulatory capacity.
Eleven Duchenne and 11 Becker patients were included. Although Becker patients had a greater 6MWT distance than Duchenne patients, the occurrence of mastication and swallowing difficulties was similar. The temporalis muscle was significantly thicker in Becker patients.
Clinicians should be aware of dysphagia in both groups, even when ambulation is still well preserved.

Duchenne and Becker muscular dystrophies are the most common muscle diseases and are both currently incurable. They are caused by mutations in the dystrophin gene, which lead to the absence or reduction/truncation of the encoded protein, with progressive muscle degeneration that clinically manifests in muscle weakness, cardiac and respiratory involvement and early death. The limits of animal models to exactly reproduce human muscle disease and to predict clinically relevant treatment effects has prompted the development of more accurate in vitro skeletal muscle models. However, the challenge of effectively obtaining mature skeletal muscle cells or satellite stem cells as primary cultures has hampered the development of in vitro models. Here, we discuss the recently developed technologies that enable the differentiation of skeletal muscle from human induced pluripotent stem cells (iPSCs) of Duchenne and Becker patients. These systems recapitulate key disease features including inflammation and scarce regenerative myogenic capacity that are partially rescued by genetic and pharmacological therapies and can provide a useful platform to study and realize future therapeutic treatments. Implementation of this model also takes advantage of the developing genome editing field, which is a promising approach not only for correcting dystrophin, but also for modulating the underlying mechanisms of skeletal muscle development, regeneration and disease. These data prove the possibility of creating an accurate Duchenne and Becker in vitro model starting from iPSCs, to be used for pathogenetic studies and for drug screening to identify strategies capable of stopping or reversing muscular dystrophinopathies and other muscle diseases.