Progressive Muscular Disease Research Articles

Development and Economic Evaluation of a Patient-Centered Care Model for Children With Duchenne Muscular Dystrophy: Protocol for a Quasi-Experimental Study.

Duchenne muscular dystrophy (DMD) is a rare progressive muscular disease that primarily affects boys. A lack of comprehensive care for patients living with DMD is directly associated with a compromised quality of life (QoL) for those affected and their caregivers. This disease also has a huge economic impact on families as its treatment requires substantial direct, indirect, and informal care costs. This study presents a protocol developed to evaluate the feasibility and efficacy of a patient-centered care (PCC) model for children with DMD. The care model was designed with the aim to empower families, improve QoL, and reduce economic burden on their families. This study is planned as a quasi-experimental study that will enroll 70 consecutive families with boys (aged 5-15 years) with DMD visiting a tertiary care center. The study is being conducted in 2 phases (preintervention and postintervention phases, referred to as phase 1 and phase 2, respectively). During phase 1, the patients received routine care. The study is now in phase 2, with the intervention currently being administered. The intervention is based on the PCC model individualized by the intervention team. The model has a comprehensive DMD telecare component that includes teleconsultation as one of its key components to reduce in-person physician visits at the health facility. Teleconsultation is especially beneficial for late-ambulatory and nonambulatory patients. Data on economic burden are being collected for out-of-pocket expenses for both phases during in-person visits via telephone or messaging apps on a monthly basis. QoL data for patients and their primary caregivers are being collected at 3 time points (ie, time of enrollment, end of phase 1, and end of phase 2). Outcome measures are being assessed as changes in economic burden on families and changes in QoL scores. Participant recruitment began in July 2021. The study is ongoing and expected to be completed by March 2023. The findings based on baseline data are expected to be submitted for publication in 2023. This paper outlines a research proposal developed to study the impact of a PCC model for patients with DMD in low- and middle-income countries (LMICs). This study is expected to provide evidence of whether a multicomponent, patient-centric intervention could reduce economic burdens on families and improve their QoL. The results of this study could guide policy makers and health professionals in India and other LMICs to facilitate a comprehensive care program for patients living with DMD. The economic impact of a rare disease is an important consideration to formulate or evaluate any health policy or intervention related to new treatments and financial support schemes. Clinical Trials Registry India (ICMR-NIMS) CTRI/2021/06/034274; https://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=56650. PRR1-10.2196/42491.

Limb girdle muscular disease caused by HMGCR mutation and statin myopathy treatable with mevalonolactone

Myopathy is the main adverse effect of the widely prescribed statin drug class. Statins exert their beneficial effect by inhibiting HMG CoA-reductase, the rate-controlling enzyme of the mevalonate pathway. The mechanism of statin myopathy is yet to be resolved, and its treatment is insufficient. Through homozygosity mapping and whole exome sequencing, followed by functional analysis using confocal microscopy and biochemical and biophysical methods, we demonstrate that a distinct form of human limb girdle muscular disease is caused by a pathogenic homozygous loss-of-function missense mutation in HMG CoA reductase (HMGCR), encoding HMG CoA-reductase. We biochemically synthesized and purified mevalonolactone, never administered to human patients before, and establish the safety of its oral administration in mice. We then show that its oral administration is effective in treating a human patient with no significant adverse effects. Furthermore, we demonstrate that oral mevalonolactone resolved statin-induced myopathy in mice. We conclude that HMGCR mutation causes a late-onset severe progressive muscular disease, which shows similar features to statin-induced myopathy. Our findings indicate that mevalonolactone is effective both in the treatment of hereditary HMGCR myopathy and in a murine model of statin myopathy. Further large clinical trials are in place to enable the clinical use of mevalonolactone both in the rare orphan disease and in the more common statin myopathy.

Dp71 and intellectual disability in Indonesian patients with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is an X-linked recessive progressive muscular disease marked by developmental delays due to mutations in the DMD gene, which encodes dystrophin. Brain comorbidity adds to the burden of limited mobility and significantly impacts patients' quality of life and their family. The changes of expression of dystrophin isoforms in the brain due to DMD gene mutations are thought to be related to the cognitive and neurobehavior profiles of DMD. This cross-sectional study aimed to characterize cognitive and neurodevelopmental profiles of patients with DMD and to explore underlying genotype-phenotype associations. Patients with DMD aged 5-18 years from Dr Sardjito Hospital and Universitas Gadjah Mada Academic Hospital from 2017-2022 were included. Multiplex ligation-dependent probe amplification and whole exome sequencing were used to determine mutations in the DMD genes. Cognitive function was measured by intelligence quotient testing using the Wechsler Intelligence Scale for Children and adaptive function tests with Vineland Adaptive Behavior Scales. The Autism Mental Status Exam and Abbreviated Conner's Rating Scale were used to screen for autism spectrum disorder (ASD) and attention deficit and hyperactivity disorder (ADHD), respectively. The mean total IQ score of DMD patients was lower than that of the general population (80.6 ± 22.0 vs 100 ± 15), with intellectual disability observed in 15 boys (29.4%). Of the 51 patients with DMD, the Dp71 group had the lowest cognitive performance with a total IQ score (46 ± 24.8; p = 0.003), while the Dp427 group and Dp140 group's total IQ scores were 83.0 ± 24.6 and 84.2 ± 17.5 respectively. There were no DMD patients with ASD, while 4 boys (7.8%) had comorbidity with ADHD. Boys with DMD are at higher risk of intellectual disability. The risk appears to increase with mutations at the 3' end of the gene (Dp71 disruption). Moreover, Dp71 disruption might not be associated with ADHD and ASD in patients with DMD.

Cardio-respiratory and phenotypic rescue of dystrophin/utrophin-deficient mice by combination therapy.

Duchenne muscular dystrophy (DMD) is a systemic progressive muscular disease caused by frame-disrupting mutations in the DMD gene. Although exon-skipping antisense oligonucleotides (AOs) are clinically approved and can correct DMD, insufficient muscle delivery limits efficacy. If AO activity can be enhanced by safe dietary supplements, clinical trials for efficacy can be undertaken rapidly to benefit patients. We showed previously that intravenous glycine enhanced phosphorodiamidate morpholino oligomer (PMO) delivery to peripheral muscles in mdx mice. Here, we demonstrate that the combination of oral glycine and metformin with intravenous PMO enhances PMO activity, dystrophin restoration, extends lifespan, and improves body-wide function and phenotypic rescue of dystrophin /utrophin double knock-out (DKO) mice without any overt adverse effects. The DKO mice treated with the combination without altering the approved administration protocol of PMO show improved cardio-respiratory and behavioral functions. Metformin and glycine individually are ineffective in DMD patients, but the combination of PMO with clinically-approved oral glycine and metformin might improve the efficacy of the treatment also in DMD patients. Our data suggest that this combination therapy might be an attractive therapy for DMD and potentially other muscle diseases requiring systemic treatment with AOs.

Quantifying Lower Limb Muscle Stiffness as Ambulation Function Declines in Duchenne Muscular Dystrophy with Acoustic Radiation Force Impulse Shear Wave Elastography

Duchenne muscular dystrophy (DMD) is a progressive muscular disease, but validated imaging tools to quantify muscle microstructure alteration as mobility declines are lacking. We aimed to determine the feasibility of using acoustic radiation force impulse shear-wave elastography (ARFI/SWE) in the quantitative assessment of lower limb muscle stiffness in DMD patients. Shear wave velocities (SWVs) of lower limbs were measured in 39 DMD patients and 36 healthy controls aged 3–20 y. Mean SWV values of the controls and of the DMD patients at different ambulatory stages were compared using analysis of variance with Bonferroni correction. The DMD group had increased lower limb muscle stiffness compared with controls. Stiffness of the tibialis anterior and medial gastrocnemius muscle decreased from ambulatory to early non-ambulatory stages, whereas stiffness of the rectus femoris muscle increased from ambulatory to late non-ambulatory stages. We describe how SWV changes in lower limb muscles have the potential to predict ambulatory decline in DMD.

A novel passive neck orthosis for patients with degenerative muscle diseases: Development & evaluation

The current study evaluated the effect of a passive neck orthosis, developed for patients suffering from progressive muscular diseases, on neck muscle activity in 10 adult healthy participants.The participants performed discrete head movements involving pure neck flexion (−10 to 30°), pure neck rotation (up to 30° left and right) and combined neck flexion-rotation (−10 to 30°) in steps of 10° by moving a cursor on a screen to reach predefined targets and staying on target for 10 s. Surface electromyography (EMG) was recorded from upper trapezius and sternocleidomastoid muscles and amplitudes were averaged over the static phases in trials with and without the orthosis. Moreover, the variability in head position and time required to perform the tasks were compared between conditions.Wearing the orthosis caused significant reductions (p = 0.027) in upper trapezius activity (a change of 0.2–1.5% EMGmax) while working against gravity. The activity level of the sternocleidomastoid muscle increased (p ≤ 0.025) by 0.3–1.0% EMGmax during pure and combined rotations without any pain reported.The orthosis showed potential to reduce the activity level of the upper trapezius muscle, the main load bearing muscle of the neck. Further study will be carried out to evaluate the effect in different patient groups.

DUCHENNE MUSCULAR DYSTROPHY - GENETICS: P.214Genetic profile of Chilean patients with Duchenne muscle dystrophy

Duchenne muscle dystrophy (DMD), is a progressive muscular disease, inherited as a X link. Is caused by the mutations of the dystrophin gene. Deletions of one or more exons account for approximately 50-65%, duplications 5-10% and point mutations 20-25%. Analyze the genetic profile of patients with DMD through regular checkups at the pediatric neurology department of the San Borja Arriarán Hospital. Retrospective descriptive study. Analysis of clinical records of 41 patients in evaluation by DMD, excluding patients diagnosed prior to the year 2010, with only biopsy and/ or PCR (polymerase chain reaction) without alterations. 41 patients with clinical manifestations and/or muscle biopsy with markedly reduced or no detectable dystrophin immunostaining, were studied by PCR, MLPA (multiplex ligation probe amplification) and/or Sanger sequencing techniques. 27/41 (66%) of patients had large deletions, 20/27 had compromised exons 44-55, and 3/26 had compromised exons 3-7. The most frequent deletion was exon 50, followed by exon 49. 3/41 (7,3%) presented duplications, which all affected exon 2. 10/41(24,4%) of patients had a negative MLPA, but a compatible muscle biopsy. In 1/41, sequencing was performed, showing nonsense mutation, in exon 41. Our study of the genetic profile of chileans patients is similar to previously reported, deletions are the most frequent alterations. It should be noted that biopsy continues to be an important tool for confirming diagnostics, due to our countries limited access to sequencing techniques. Because of this, we can extrapolate and conclude that the large percentage of patients with compatible muscle biopsy and negative MLPA, could correspond to point mutations, which would then coincide with the published. Therefore, it is important to make genetic diagnosis advances thus giving us the possibility of integrating new therapies and the ability to offer genetic counseling.

Full Body Transplantation, Is it Allowed?

Introduction In May 2016, an international medical team announced plans to perform the first full body transplantation (sometimes controversially designated as “head transplantation”) before the end of 2017. In their eagerness to cross what they call “the final frontier in transplant surgery”, team leaders Sergio Canavero and Xiaoping Ren brush aside all ethical and legal concerns, emphasising instead the (alleged) medical prospects for hitherto incurable diseases, such as progressive muscular disease and intractable cancer without brain metastases. In recent interviews they indicate that, although the estimated timeline will not be met, their project is going according to plan. Materials and Methods We conducted an extensive Internet search of the popular media and academic journals, collecting news items and articles that have been published on the topic, since Canavero first outlined his idea of spinal cord fusion in 2013. In addition, we consulted leading handbooks on the medical and criminal liability of medical professionals, examined relevant international guidelines, and analysed the few academic articles discussing medical experimentation in organ transplantation. Finally, we applied the relevant insights that emerged from this research to the topic of full body transplantation and investigated the legality of the procedure under the current state of medical knowledge. Results and Discussion We found that full body transplantation currently does not conform to the conditions that allow experimental and high-risk medical interventions to be legitimately performed under international and national law. Similarly, we discovered that full body transplantation, where this would be characterised as a research project instead of as a medical experiment, currently fails the conditions set out in international and national regulations. We concluded that it is very unlikely that prior ethics approval would be obtained, and that physicians who engage in full body transplantation are very likely to be found liable for medical malpractice. If this procedure would result in the death of the patient, the physicians involved would run a considerable risk of being held criminally liable for negligent homicide. The participating physicians will also risk severe disciplinary sanctions for professional misconduct, with a real possibility that they will be suspended or even banned from medical practice for life. Conclusion Under the current state of medical knowledge full body transplantation cannot legally be performed. Physicians attempting the procedure are very likely to be found civilly liable and to face severe disciplinary sanctions. In addition, they may under certain circumstances even be held criminally liable. Before an attempt to perform full body transplantation would be acceptable, the formidable surgical challenges first need to be resolved and the major ethical issues addressed.

Antioxidant Treatment and Induction of Autophagy Cooperate to Reduce Desmin Aggregation in a Cellular Model of Desminopathy.

Desminopathies, a subgroup of myofibrillar myopathies (MFMs), the progressive muscular diseases characterized by the accumulation of granulofilamentous desmin-positive aggregates, result from mutations in the desmin gene (DES), encoding a muscle-specific intermediate filament. Desminopathies often lead to severe disability and premature death from cardiac and/or respiratory failure; no specific treatment is currently available. To identify drug-targetable pathophysiological pathways, we performed pharmacological studies in C2C12 myoblastic cells expressing mutant DES. We found that inhibition of the Rac1 pathway (a G protein signaling pathway involved in diverse cellular processes), antioxidant treatment, and stimulation of macroautophagy reduced protein aggregation by up to 75% in this model. Further, a combination of two or three of these treatments was more effective than any of them alone. These results pave the way towards the development of the first treatments for desminopathies and are potentially applicable to other muscle or brain diseases associated with abnormal protein aggregation.

Congenital muscular dystrophy, cardiomyopathy, and peripheral neuropathy due to merosin deficiency: Peripheral nerve histology of cauda equina

Peripheral neuropathy, white matter abnormalities, and cardiomyopathy are associated findings with merosin-deficient congenital muscular dystrophy. Although characterization of the neuropathy with nerve conduction studies has been well documented, limited research has been able to correlate histopathology with nerve biopsy in humans. Our understanding of the mechanism, described as a demyelinating neuropathy, is mainly derived from mouse model studies. We report a 23-year-old male who succumbed to respiratory failure and ultimately cardiac arrhythmia in the setting of an uncharacterized end stage progressive muscular disease complicated by cardiomyopathy and severe scoliosis. Autopsy revealed extensive muscular atrophy and replacement by fibroadipose tissue throughout the skeletal muscle and myocardium. Immunohistochemical analysis of the muscle biopsy showed a complete loss of merosin. Thus, the cause for both his muscular disease and demyelinating neuropathy was established with the diagnosis of merosin-deficient muscular dystrophy. Nerve biopsy obtained from the cauda equina showed clear evidence of segmental demyelination and remyelination, providing a better understanding of the proximal peripheral nerve histopathological changes in this disease entity.

Exoskeletal meal assistance system (EMAS II) for patients with progressive muscular disease

Patients with muscle weakness such as muscular dystrophy usually need someone’s assistance in their daily activities. In order to reduce the caregiver burden and to improve quality of life (QOL) of the patients, various robotic technologies have been developed. This paper presents an exoskeletal assistance system EMAS II for the patients, which assists the upper extremity for the purpose of daily activities such as eating, writing, or other desk works. The EMAS II assists four DOF; shoulder flexion-extension, shoulder abduction-adduction, shoulder medial-lateral rotation, and elbow flexion-extension. The EMAS II has three kinds of user interfaces which are operated by residual functions of the patients, because it is important for patients’ health and initiative to use the residual functions. In order to control the four DOFs exoskeleton system using the interfaces with less DOF, the EMAS II simulates upper limb motion patterns of healthy people. The patterns are modeled by extracting correlations between the height of the wrist joint and that of the elbow joint. Therefore, users have only to control the position of their wrist joint to do tasks at a table. Through an experiment with a healthy subject, the feasibility of meal assistance by the EMAS II was confirmed. Furthermore, the system was applied to a spinal muscular atrophy patient in a clinical trial to check the usability. The experimental results indicated that the EMAS II could support the patient’s upper extremity to do tasks at a table.

Electrocardiographic changes in cases of duchenne muscular dystrophy

Duchene muscular dystrophy is an x-linked recessive progressive muscular disease. It presents in first year of life and is fatal by second decade mostly because of respiratory involvement and in 10% case because of cardiac failure. The cardiac involvement usually occurs after 10 years age. The incidence of cardiac involvement increases with increasing age affecting all patients by age of 18 years. Duchene muscular dystrophy(DMD) usually leads to dilated cardiomyopathy (DCM), congestive cardiac failure, arrhythmias, & sudden cardiac death. DMD may be associated with various ECG changes like sinus tachycardia, reduction of circadian index, decreased heart rate variability, short PR interval, right ventricular hypertrophy, S-T segment depression and prolonged QTc. Rarely it might be associated with Wolf Parkinson White syndrome(WPW syndrome). WPW syndrome is characterized by short PR interval, delta wave, and wide QRS complex and is a surface evidence of accessory pathway. It might be associated with supraventricular tachycardia and sudden cardiac death from ventricular tachycardia. To study ECG findings in cases of Duchenne muscular dystrophy. Materials and methods The study was conducted at Pediatric cardiology department, Prince Salman Heart Centre Riyadh. All patients diagnosed as Duchenne muscular dystrophy were included in the study. The diagnostic criteria were clinical, biochemical and confirmed by PCR. All patients underwent 12 lead ECG and long lead II in recumbent posture and 24 h holter monitoring and echocardiogram. The 24 h holter was applied to all patients. The were given a diary to record any symptoms like palpitation, syncope, chest pain or dyspnea during 24 holter monitoring. The holters were reviewed for heart rate and presence of any ectopics or arrhythmias. The electrocardiogram of all patients were reviewed and following parameters were noted ; characteristics heart rate, R waves, waves, R–S ratio, PR interval, delata wave, Q waves, QT interval, T wave, ST segment. The aforementioned ECG parameters were studied and measured manually and compared with published standard age matched normal values. The abnormal were findings were defined if were away from minimal or maximal limits for that age. A total of 20 patients were studied. All were male. The mean age of patients was 10 years. The mean weight of patients was 34.5 kg. Majority of patients (75%) were where wheelchair bound and 25% were ambulatory. The ECG abnormalities were noted in 80% of patients. Sinus tachycardia was present in 60% of patients. Tall R waves were present in 45% of patients with RS ratio more than 1 in lead V1 as well as deep S waves in leads V5 and V6.Short PR interval was noted in 3(15%) of patients. One patient had was diagnosed as WPW syndrome and had short PR interval, delta wave and wide QRS complex. 24 h holter monitoring was normal in all patients. The most frequent electrocardiographic findings described in cases of Duchenne muscular dystrophy are sinus tachycardia and tall R waves in right precordial leads as seen in our study. Similar findings are also observed in female carriers of Duchenne muscular dystrophy gene. The presence of sinus tachycardia may suggest cardiac dysfunction or autonomic dysregulation in these cases. Other interesting finding in our cases was short PR interval in 3 cases(15%) and presence of WPW syndrome features in one patient. We planned further study in these patients to correlate clinical, biochemical, echo and ECG findings.

Effects of non-contractile inclusions on mechanical performance of skeletal muscle

Glycogen storage disease II is an inherited progressive muscular disease in which the lack of functional acid 1–4 α-glucosidase results in the accumulation of lysosomal glycogen. In the present study, we examine the effect of these non-contractile inclusions on the mechanical performance of skeletal muscle. To this end, force developed in an isometrically contracting slice of a muscle was calculated with a finite element model. Force was calculated at several inclusion densities and distributions and compared to muscle lacking inclusions. Furthermore, ankle dorsal flexor torque was measured in situ of α-glucosidase null mice of 6 months of age and unaffected litter mates as was inclusion density in the dorsal flexor muscles.The calculated force loss was shown to be almost exclusively dependent on the inclusion density and less on the type of inclusion distribution. The force loss predicted by the model (6%) on the basis of measured inclusion density (3.3%) corresponded to the loss in mass-normalized strength in these mice measured in situ (7%).Therefore, we conclude that the mechanical interaction between the non-contractile inclusions and the nearby myofibrils is a key factor in the loss of force per unit muscle mass during early stages of GSD II in mice. As glycogen accumulation reaches higher levels in humans, it is highly probable that the impact of this mechanical interaction is even more severe in human skeletal muscle.

Bone mineral density and bone metabolism in Duchenne muscular dystrophy.

Very few studies on bone mineral density and bone metabolism in Duchenne muscular dystrophy (DMD) have been reported. DMD is a severe, progressive muscular disease resulting in death at a young age. No specific therapies are available, but corticosteroids induce improvement and slower progression of the disease. However, long-term steroid therapy is a serious risk factor for osteoporosis. This study was aimed at evaluating bone mineral density and calciotropic hormones in a group of children affected by DMD, with or without steroid therapy. Bone mineral density was measured by DXA scan on lumbar spine and total body. Evaluation of calcium, phosphorus, bone turnover markers and calciotropic hormones was performed. Thirty-two children affected by DMD were studied: twenty-two on long-term prednisone therapy, ten not taking corticosteroids. Bone mineral density was lower than normal for age in all patients, and even lower in the group of steroid-treated children. Trunk and lower limb bone mineral densities were more reduced than upper limb mineral density, especially in the steroid-treated subjects. A marked reduction in spine bone mineral density, hypocalciuria, low 25-hydroxyvitamin D levels, and increased bone turnover markers were observed, and even these especially in the steroid-treated group. In conclusion, decreased bone mineral density and derangement of calcium metabolism were present in DMD patients, and were worsening during corticosteroid therapy. It is thus recommended that bone and mineral metabolism be carefully evaluated in patients with DMD, so that appropriate measures could be taken, especially now that chronic corticosteroid therapy is frequently given.

Condylar cartilage in the muscular dystrophic mouse

The adaptability of condylar cartilage has been demonstrated previously after experimentally created functional alteration. This study was undertaken to examine the morphology of condylar cartilage in animals affected with a progressive muscular disease. Muscular dystrophic male mice (genotype: dy/dy, dy/ + x dy/ +, Jackson Laboratory, Maine) and corresponding unaffected control mice were decapitated at ages 3, 6, 9, and 12 weeks, and their heads processed for histology. The cellular morphology of the condylar cartilage in the youngest age group was similar in dystophic and control mice: the cartilage was a hypertrophic type. At ages 6 and 9 weeks, the maturational progression toward the nonhypertrophic form was observed in the dystrophic and control groups, the latter having flatter condylar heads. Differences were still evident at age 12 weeks. These observations were supported by measurements of the ratios of the mean cartilage thickness to condylar width (c/w), mean condylar height to width (h/w), and mean cartilage thickness to condylar height (c/h). This study supports the hypothesis that the adaptive nature of condylar cartilage may be regulated by the force levels to which the condyle is subjected.

Long-term turnover of selenite-Se in children with motor disorders.

The biological half-life (Tœ) of 75Se determined with whole body counting varied from 37 to 68 days in four children each suffering from one of the following diseases: Congenital muscular dystrophy (M.D), limb girdle type of M.D., nemaline myopathy, and Werdnig-Hoffmann disease (infantile spinal muscular atrophy) the T œ values of two boys with severe tetraplegy from 81 to 84 days. The Tœ values of the patients with progressive muscular diseases did not differ from those found in the patients with Duchenne type of M.D. in an earlier investigation, but they were significantly smaller than those of healthy controls.