Effect of Chinese herbal medicines on the overall survival of patients with muscular dystrophies in Taiwan.

ETHNOPHARMACOLOGICAL RELEVANCE: Muscular dystrophies are a rare, severe, and genetically inherited group of disorders characterized by progressive loss of muscle fibers, leading to muscle weakness. The current treatment plan for muscular dystrophies includes the use of steroids to slow muscle deterioration by dampening the inflammatory response. AIM OF THE STUDY: Chinese herbal medicine (CHM) has been offered as an adjunctive therapy in Taiwan's medical healthcare plan, making it possible to track CHM usage in patients with muscular dystrophic disease. Therefore, we explored the long-term effects of CHM use on the overall mortality of patients with muscular dystrophies. MATERIALS AND METHODS: A total of 581 patients with muscular dystrophies were identified from the database of Registry for Catastrophic Illness Patients in Taiwan. Among them, 80 and 201 patients were CHM users and non-CHM users, respectively. Student's t-test, chi-squared test, Cox proportional hazard model, and Kaplan-Meier curve (log-rank test) were used for evaluation. Association rules and network analyses were performed to explore the combination of CHMs used in muscular dystrophies. RESULTS: Compared to non-CHM users, there were more female patients, more comorbidities, including chronic pulmonary disease and peptic ulcer disease in the CHM user group. Patients with prednisolone usage exhibited a lower risk of overall mortality than those who did not, after adjusting for age, sex, use of CHM, and comorbidities. CHM users showed a lower risk of overall mortality after adjusting for age, sex, prednisolone use, and comorbidities. The cumulative incidence of the overall survival was significantly higher in CHM users. Association rule and network analysis showed that one main CHM cluster was commonly used to treat patients with muscular dystrophies in Taiwan. The cluster includes Yin-Qiao-San, Ban-Xia-Bai-Zhu-Tian-Ma-Tang, Zhi-Ke (Citrus aurantium L.), Yu-Xing-Cao (Houttuynia cordata Thunb.), Che-Qian-Zi (Plantago asiatica L.), and Da-Huang (Rheum palmatum L.). CONCLUSIONS: Our data suggest that adjunctive therapy with CHM may help to reduce the overall mortality among patients with muscular dystrophies. The identification of the CHM cluster allows us to narrow down the key active compounds and may enable future therapeutic developments and clinical trial designs to improve overall survival in these patients.

Adolescent Hyperuricemia with Lipid Storage Myopathy: A Clinical Study.

BACKGROUND In this study, we investigated the clinical and pathological features of patients with lipid storage myopathy (LSM) complicated with hyperuricemia, to improve clinicians' understanding of metabolic multi-muscular disorder with metabolic disorders, and to reduce the risk of missed diagnosis of LSM. MATERIAL AND METHODS From January 2005 to December 2017, 8 patients underwent muscle biopsy and diagnosed by muscle pathology and genetic testing in our hospital. All 8 patients were in compliance with LSM diagnosis. We collected data on the patient's clinical performance, adjuvant examination, treatment, and outcomes to provide a comprehensive report and description of LSM patients with hyperuricemia. RESULTS All patients were diagnosed as having ETFDH gene mutations. The main clinical manifestations of patients were chronic limb and trunk weakness, limb numbness, and muscle pain. The serum creatine kinase (CK) values in all patients were higher than normal values. Electromyography showed 3 cases of simple myogenic damage and 3 cases of neurogenic injury. Hematuria metabolic screening showed that 2 patients had elevated glutaric aciduria, and 1 patient had elevated fatty acyl carnitine in the blood. All patients were given riboflavin treatment, and the clinical symptoms were significantly improved, and 3 patients returned to normal uric acid levels after treatment. Pathological staining showed an abnormal deposition of lipid droplets in muscle fibers. CONCLUSIONS If an adolescent hyperuricemia patient has abnormal limb weakness, exercise intolerance, and elevated serum CK values, clinicians need to be highly alert to the possibility of LSM. Early diagnosis and treatment of LSM should improve the clinical symptoms and quality of life and reduce complications.

A limb-girdle muscular dystrophy 2I model of muscular dystrophy identifies corrective drug compounds for dystroglycanopathies.

Zebrafish are a powerful tool for studying muscle function owing to their high numbers of offspring, low maintenance costs, evolutionarily conserved muscle functions, and the ability to rapidly take up small molecular compounds during early larval stages. Fukutin-related protein (FKRP) is a putative protein glycosyltransferase that functions in the Golgi apparatus to modify sugar chain molecules of newly translated proteins. Patients with mutations in the FKRP gene can have a wide spectrum of clinical symptoms with varying muscle, eye, and brain pathologies depending on the location of the mutation in the FKRP protein. Patients with a common L276I FKRP mutation have mild adult-onset muscle degeneration known as limb-girdle muscular dystrophy 2I (LGMD2I), whereas patients with more C-terminal pathogenic mutations develop the severe Walker-Warburg syndrome (WWS)/muscle-eye-brain (MEB) disease. We generated fkrp-mutant zebrafish that phenocopy WWS/MEB pathologies including severe muscle breakdowns, head malformations, and early lethality. We have also generated a milder LGMD2I-model zebrafish via overexpression of a heat shock-inducible human FKRP (L276I) transgene that shows milder muscle pathology. Screening of an FDA-approved drug compound library in the LGMD2I zebrafish revealed a strong propensity towards steroids, antibacterials, and calcium regulators in ameliorating FKRP-dependent pathologies. Together, these studies demonstrate the utility of the zebrafish to both study human-specific FKRP mutations and perform compound library screenings for corrective drug compounds to treat muscular dystrophies.

Fisioterapia aquática no tratamento de criança com distrofia muscular congênita merosina negativa: relato de caso / Aquatic physical therapy in the treatment of a child with merosin-deficient congenital muscular dystrophy: case report

Este relato de caso descreve um programa de fisioterapia aquática para uma criança com distrofia muscular congênita (DMC) merosina negativa. Objetivo: Verificar a interferência da fisioterapia aquática na velocidade e no índice de gasto energético durante o deslocamento sentado em superfície plana, e no alcance funcional com os membros superiores devido a fraqueza proximal que acomete estes pacientes visando maior independência. Métodos: Como instrumentos de avaliação foram utilizados a Medida da Função Motora (MFM); o Functional Reach Test (FRT); foi verificado o Índice de Gasto Energético (IGE) no deslocamento sentado; assim como o tempo gasto neste deslocamento e a ativação muscular com a eletromiografia (EMG). O programa durou 12 semanas e a intervenção incluiu atividades para melhorar a mobilidade e a agilidade no deslocamento sentado e o alcance na postura sentada. Resultados: Na MFM a variação no escore das duas dimensões (D2 e D3) focadas na terapia foi de 6,8%. O alcance funcional melhorou 16 centímetros (cm) e o tempo do deslocamento sentado diminuiu 19 segundos (s). O gasto energético diminuiu 252,31 batimentos por minuto (bpm). Conclusão: A fisioterapia aquática foi eficaz para melhora da agilidade no deslocamento sentado e na funcionalidade de membros superiores (MMSS) de uma criança com DMC merosina negativa

This case report describes an aquatic therapy program for a child with Merosin-Deficient Congenital Muscular Dystrophy. Objective: This study sought to investigate the effect of aquatic physical therapy on the speed and the rate of energy expenditure while moving around on a flat surface, in addition to the functional reach of the upper limbs suffering from the proximal weakness that affects these patients seeking greater independence. Methods: The Motor Function Measurement (MFM) and the Functional Reach Test (FRT) were used as assessment tools; the Energy Expenditure Index (EEI) was measured in seated locomotion, as well as the time spent, and muscle activation was measured via electromyography (EMG). The program lasted 12 weeks and included activities to improve mobility and agility as well as reaching from the seated position. Results: In the MFM the change in the score of the two dimensions (D2 and D3) that the treatment focused on was 6.8%. The functional reach improved by 16 centimeters (cm) and the amount of time moving while sitting decreased by 19 seconds (s). Energy expenditure decreased by 252.31 beats per minute (bpm). Conclusion: The aquatic physical therapy was effective for agility improvement in seated locomotion and upper limb functionality of a 6-year-old child with Merosin-Deficient Congenital Muscular Dystrophy

Laminin-111 protein therapy reduces muscle pathology and improves viability of a mouse model of merosin-deficient congenital muscular dystrophy.

Merosin-deficient congenital muscular dystrophy type 1A (MDC1A) is a lethal muscle-wasting disease that is caused by mutations in the LAMA2 gene, resulting in the loss of laminin-α2 protein. MDC1A patients exhibit severe muscle weakness from birth, are confined to a wheelchair, require ventilator assistance, and have reduced life expectancy. There are currently no effective treatments or cures for MDC1A. Laminin-α2 is required for the formation of heterotrimeric laminin-211 (ie, α2, ß1, and γ1) and laminin-221 (ie, α2, ß2, and γ1), which are major constituents of skeletal muscle basal lamina. Laminin-111 (ie, α1, ß1, and γ1) is the predominant laminin isoform in embryonic skeletal muscle and supports normal skeletal muscle development in laminin-α2-deficient muscle but is absent from adult skeletal muscle. In this study, we determined whether treatment with Engelbreth-Holm-Swarm-derived mouse laminin-111 protein could rescue MDC1A in the dy(W-/-) mouse model. We demonstrate that laminin-111 protein systemically delivered to the muscles of laminin-α2-deficient mice prevents muscle pathology, improves muscle strength, and dramatically increases life expectancy. Laminin-111 also prevented apoptosis in laminin-α2-deficient mouse muscle and primary human MDC1A myogenic cells, which indicates a conserved mechanism of action and cross-reactivity between species. Our results demonstrate that laminin-111 can serve as an effective protein substitution therapy for the treatment of muscular dystrophy in the dy(W-/-) mouse model and establish the potential for its use in the treatment of MDC1A.

Combined effects of muscular dystrophy, ecological stress, and selenium on blood antioxidant status in broiler chickens.

The results obtained in this study demonstrated that experimentally induced alimentary muscular dystrophy (MD) in Cobb 500 broiler chickens resulted in increased plasma concentrations of malondialdehyde (MDA), deviations in activities of erythrocyte antioxidant enzymes Cu,Zn-SOD (decrease), and CAT (increase) as well as reduction in plasma concentrations of trace elements Cu, Zn, and Se in affected birds. These data evidenced the presence of oxidative stress in birds with MD, reared both under conditions of ecological comfort and ecological stress. The increased MDA and САТ levels and the reduced Cu,Zn-SOD, Cu, Zn, and Se concentrations in healthy chickens reared under unfavorable microclimatic conditions such as higher air temperature and humidity, higher ammonia concentrations, and lower light intensity were indicative about an induced ecological stress. After the 10-day oral treatment with a selenium-containing preparation, the levels of MDA, Cu,Zn-SOD, CAT, Cu, Zn, and Se attained their normal values in chickens with MD, reared under ecologically comfortable conditions. According to our results, ecological stress was shown to exert independently a significant adverse effect upon the levels of the studied parameters and possibly to be a cause for their slower and not complete normalization despite the selenium therapy in experimental broiler chickens.

Effect of creatine supplementation on skeletal muscle of mdx mice.

Dystrophic mice (mdx) and their controls (C57/Bl10) were fed for 1 month with a diet with or without creatine (Cr) enrichment. Cr supplementation reduced mass (by 19%, P < 0.01) and mean fiber surface (by 25%, P < 0.05) of fast-twitch mdx muscles. In both strains, tetanic tension increased slightly (9.2%) without reaching statistical significance (P = 0.08), and relaxation time increased by 16% (P < 0.001). However, Cr had no protective effect on the other hallmarks of dystrophy such as susceptibility to eccentric contractions; large numbers of centrally nucleated fibers in tibialis anterior; and elevated total calcium content, which increased by 85% (P = 0.008) in gastrocnemius mdx muscles. In conclusion, Cr may be a positive intervention for improving function of dystrophic muscle.

Tardanza en el diagnóstico de la distrofia muscular de Duchenne en Chile / Delayed diagnosis of Duchenne muscular dystrophy in Chile

Background: Duchenne muscular dystrophy is the most frequent neuromuscular disease in children. Aim: To determine the causes of delayed diagnosis of the disease. Patients and methods: The clinical records of 61 children diagnosed as Duchenne progressive muscular dystrophy were analyzed. Results: the first symptoms of the disease were noticed at a mean age of 1.5 years. Parents consulted at the mean age of 3 years, but the accurate diagnosis was made at a mean age of 5.7 years. In only 15 percent of children, the disease was diagnosed in the first four years of age. Less than 20 percent of children were referred for an adequate study and the rest were managed mainly as flat feet. Conclusions: Duchenne dystrophy is the most common neuromuscular disorder in children, with an incidence of 1 in 3679 male newborns. The lack of recognition of non specific symptoms such as retardation in independent walking and frequent falls as forms of presentation, is probably the most important cause of diagnostic delay. Strong recommendation is made to measure creatinphosphokinase and to study every male child that is not walking independently by the age of 18 months

[Duchenne muscular dystrophy. Effects of vitamin E administration on urinary luminescence]. / Distrofia muscular de Duchenne. Efecto de la administración de vitamina E sobre la luminiscencia urinaria.

BACKGROUND: Urinary luminescence is increased in patients with Duchenne muscular dystrophy, probably due to the higher oxidative stress present in this disease. AIM: To assess the effects of vitamin E supplementation on urinary luminescence in children with Duchenne muscular dystrophy. PATIENTS AND METHODS: Eighteen children with muscular dystrophy aged 12.2 years old and nine control children aged 10 years old, received 400 IU/day of vitamin E during one month. Prior to supplementation and twice a week thereafter, spot urine samples were obtained to measure urinary luminescence in a scintillation counter. RESULTS: There was a wide variability in urinary luminescence within and between children. Mean values decreased after vitamin E supplementation in six of nine controls and in 12 of 18 children with muscular dystrophy. CONCLUSIONS: Vitamin E supplementation significantly decreases urinary luminescence in healthy children and in patients with Duchenne muscular dystrophy. Therefore, it could be useful for the treatment of this disease.

Inspiratory muscle training in the patient with neuromuscular disease.

Pulmonary complications due to respiratory muscle dysfunction are commonly a source of morbidity and mortality in patients with neuromuscular diseases. This review discusses the adverse effects of respiratory muscle weakness on pulmonary mechanics and examines the role that inspiratory muscle training may play in reversing pulmonary dysfunction in these individuals. In asymptomatic persons, it is well established that the inspiratory muscles can be trained to increase both force and endurance. In patients with neuromuscular diseases, the effects of training protocols on force and endurance are more controversial. This article reviews seven studies that have evaluated respiratory muscle training in a total of 75 patients with varied neuromuscular disorders. Training regimens included breathing through inspiratory resistive loads and isocapnic hyperpnea. Despite methodologic differences among studies, investigators have generally shown that the inspiratory muscles are similar to other skeletal muscle groups in that they can be trained for both force and endurance in these patients. The training-related improvements in inspiratory muscle performance are more pronounced in patients who are less severely affected by their disease. In those patients who have disease to the extent that they are already retaining carbon dioxide, there is little change in force or endurance with training. In these individuals, the inspiratory muscles may already be working at a level sufficiently severe to provide a training stimulus with each breath. No adverse effects of inspiratory muscle training were reported. Inspiratory muscle training can improve force and endurance in patients with neuromuscular weakness.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of electrical stimulation on muscles of children with Duchenne and Becker muscular dystrophy.

Twelve children with progressive muscular dystrophy (10 Duchenne and 2 Becker type) were included in a low-frequency electrical stimulation (LFES) program of the right tibialis anterior (TA) muscle for three months. Muscle strength was estimated by measuring torques in the ankle during short attempts of maximal voluntary isometric contraction (MVIC) in the direction of dorsal flexion of the foot. Muscle fatigue was assessed by the decrease of force during sustained (1-minute) voluntary contraction. The measurements were carried out before the beginning of the stimulation program and immediately after its conclusion. At the end of the stimulation program there were higher torques in 10 out of 12 children in the stimulated leg. The increase in torques in the stimulated leg was statistically significant (p < 0.01). Regarding the fatigue of the stimulated muscle there was no change after the conclusion of stimulation.

Long-term electrical stimulation of muscles in children with Duchenne and Becker muscular dystrophy.

Nine children suffering from progressive muscular dystrophy (7 Duchenne and 2 Becker) were included in a program of low-frequency electrical stimulation (LFES) of the right tibialis anterior (TA) muscle. Muscle strength and muscle fatigue were estimated by measuring torques in the ankle during attempts of maximal voluntary contraction (MVC) in the direction of dorsal flexion of the foot and during electrically evoked contractions (EEC). No important increase in the strength of the stimulated muscles was noticed in 4 boys whose muscles were stimulated for 3 months. The muscles of 5 boys who were subjected to electrical stimulation for 9 months showed an improvement; 6 measurements made during the stimulation program revealed that changes of torques in the ankle of the right stimulated extremity were significantly different (P less than 0.001) from the changes of torques in the ankle of the left nonstimulated extremity.

Excessive muscular fatigue in patients with spastic paraparesis.

We used intermittent tetanic contractions and 31P magnetic resonance spectroscopy to investigate human tibialis anterior muscle metabolism and fatigability in a group of patients with spastic paraparesis and in normal controls. During intermittent tetanic stimulation, the decline in tension was significantly greater in patients than in controls, and the half-relaxation time of the tetanus was more prolonged. Moreover, the decline in phosphocreatine and intracellular pH was significantly greater in patients than in controls. These observations suggest that biochemical changes in the muscles of patients with upper motor neuron lesions may contribute to their excessive fatigability.

[Selenium and vitamin E in patients with progressive muscular dystrophy]. / Sélénium et vitamine E chez les malades atteints de dystrophie musculaire progressive.

Serum levels of selenium and vitamin E were prospectively studied in children with Duchenne de Boulogne muscular dystrophy of variable age and muscular status. In contrast with previous studies, we found no differences with controls. However, we believe that selenium and vitamin E, two natural antioxydants, may contribute to the pathophysiology of pseudohypertrophic muscular dystrophy. A study of the effects of supplementation is on-going.

Therapeutic possibilities of chronic low frequency electrical stimulation in children with Duchenne muscular dystrophy.

To evaluate the therapeutic possibilities of chronic electrical stimulation, muscle function studies and quantitative tests of physical assessment were used to monitor the response of quadriceps femoris to prolonged low frequency stimulation. Comparative studies of the maximum voluntary and electrically elicited responses of muscles of young ambulant children with Duchenne muscular dystrophy, when compared to those of normal children's muscles, revealed lower values of maximum voluntary contraction, significant slowing (P less than 0.001) of mean relaxation times and a higher resistance to fatigue testing. Intermittent chronic low frequency stimulation resulted in a significant (P less than 0.01) increase in mean maximum voluntary contraction of the stimulated muscles compared with the mean force exerted by the unstimulated control muscles. There are clear therapeutic possibilities for the use of chronic low frequency stimulation in these children.

Respiratory muscle training in Duchenne muscular dystrophy.

Twenty two boys with Duchenne muscular dystrophy were entered into a randomised double blind crossover trial to compare respiratory muscle training with a Triflow II inspirometer and 'placebo' training with a mini peak flow meter. Supine posture was associated with significantly impaired lung function, but respiratory muscle training showed no benefit.

Carnitine deficiency, mitochondrial dysfunction and the heart. Identical defect of oxidative phosphorylation in muscle mitochondria in cardiomyopathy due to carnitine loss and in Duchenne muscular dystrophy.

Cardiomyopathies are often caused by a metabolic defect. Carnitine deficiency and mitochondrial defects in the metabolism of acyl-CoA, including defects in oxidative phosphorylation, start the same circular mechanism of mitochondrial doom. Patients with cardiomyopathy due to carnitine loss are cured by carnitine supplementation. In such a patient we found defective oxidative phosphorylation in isolated muscle mitochondria. The stimulation of the respiratory rate with all substrates by ADP was decreased, probably the cause of inhibition of the adenine nucleotide translocator by accumulating long-chain acyl-CoA. The same condition was encountered in patients with Duchenne muscular dystrophy, who often get cardiomyopathy in the course of the disease process.