Assessment of the quality of life in patients with LGMD. The case of transportinopathy.

The Quality of Life (QOL) is influenced by several disease-related factors, support, resources, expectations, and aspirations, within the disease-related concepts. The Individualized Neuromuscular Quality of Life (INQoL) is a validated muscle disease-specific measure of the QoL developed from the experiences of patients with muscle disease and can be used for people or large cohorts. This review of QoL in transportinopathy cases reports adjustments in an autosomal dominant (AD) LGMD, and a comparison is made with autosomal recessive (AR) LGMD evaluated by INQoL. The locus for this form of LGMD with AD inheritance was found on chromosome 7, and then identification of the gene and its encoded protein (transportin-3) was obtained in 2013. A large three-generation family with several branches in Spain and Italy was previously reported and described in detail. Some patients had an early onset weakness, but others had an adult onset of the disease, as late as 58 years. The severity of the appearance of the phenotype is correlated with QoL and progresses with age. Assessing the impact on their QoL is particularly relevant to know whether the treatment is reducing their suffering.

Evaluating avalglucosidase alfa for the management of late-onset Pompe disease.

INTRODUCTION: Glycogenosis type II (GSDII) is a rare autosomal disorder that is caused by the deficiency of alpha-glucosidase, a lysosomal enzyme that hydrolyzes glycogen to glucose. Autophagy dysregulation plays a critical role. Importantly, since 2006, both patients with infantile (classic Pompe disease) and adult GSDII (late-onset Pompe disease or LOPD) have been treated with enzyme replacement therapy (ERT). To support this use, several double-blind and observational studies including large cohorts of GSDII patients have been undertaken and have shown ERT to be effective in modifying the natural course of disease. Indeed, most LOPD cases improve in the first 20 months of treatment in a six-minute walk test (6MWT), while those who are untreated do not; instead, their response declines over time. AREAS COVERED: The author reviews avalglucosidase alpha, a therapy approved by both the FDA and European regulatory agencies. Herein, the author considers the pathophysiological approaches such as the role of enzyme entry, autophagy, and the response to ERT treatment of motor and respiratory components. EXPERT OPINION: There has been a notable drive toward the research of various aspects of this disease regarding the role of new enzyme penetration and immune adverse events. Consequently, avalglucosidase alpha might be a further step forward.

Physical activity practiced at a young age is associated with a less severe subsequent clinical presentation in facioscapulohumeral muscular dystrophy.

BACKGROUND: In facioscapulohumeral muscular dystrophy (FSHD), it is not known whether physical activity (PA) practiced at young age is associated with the clinical presentation of disease. To assess this issue, we performed a retrospective cohort study concerning the previous practice of sports and, among them, those with medium-high cardiovascular commitment in clinically categorized carriers of a D4Z4 reduced allele (DRA). METHODS: People aged between 18 and 60 were recruited as being DRA carriers. Subcategory (classical phenotype, A; incomplete phenotype, B; asymptomatic carriers, C; complex phenotype, D) and FSHD score, which measures muscle functional impairment, were assessed for all participants. Information on PAs was retrieved by using an online survey dealing with the practice of sports at a young age. RESULTS: 368 participants were included in the study, average age 36.6 years (SD = 9.4), 47.6% male. The FSHD subcategory A was observed in 157 (42.7%) participants with average (± SD) FSHD score of 5.8 ± 3.0; the incomplete phenotype (category B) in 46 (12.5%) participants (average score 2.2 ± 1.7) and the D phenotype in 61 (16.6%, average score 6.5 ± 3.8). Asymptomatic carriers were 104 (subcategory C, 28.3%, score 0.0 ± 0.2). Time from symptoms onset was higher for patients with A (15.8 ± 11.1 years) and D phenotype (13.3 ± 11.9) than for patients with B phenotype (7.3 ± 9.0). The practice of sports was associated with lower FSHD score (-17%) in participants with A phenotype (MR = 0.83, 95% CI = 0.73-0.95, p = 0.007) and by 33% in participants with D phenotype (MR = 0.67, 95% CI = 0.51-0.89, p = 0.006). Conversely, no improvement was observed in participants with incomplete phenotype with mild severity (B). CONCLUSIONS: PAs at a young age are associated with a lower clinical score in the adult A and D FSHD subcategories. These results corroborate the need to consider PAs at the young age as a fundamental indicator for the correct clinical stratification of the disease and its possible evolution.

Advances in Dystrophinopathy Diagnosis and Therapy.

Dystrophinopathies are x-linked muscular disorders which emerge from mutations in the Dystrophin gene, including Duchenne and Becker muscular dystrophy, and dilated cardiomyopathy. However, Duchenne muscular dystrophy interconnects with bone loss and osteoporosis, which are exacerbated by glucocorticoids therapy. Procedures for diagnosing dystrophinopathies include creatine kinase assay, haplotype analysis, Southern blot analysis, immunological analysis, multiplex PCR, multiplex ligation-dependent probe amplification, Sanger DNA sequencing, and next generation DNA sequencing. Pharmacological therapy for dystrophinopathies comprises glucocorticoids (prednisone, prednisolone, and deflazacort), vamorolone, and ataluren. However, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and ß-blockers are the first-line to prevent dilated cardiomyopathy in dystrophinopathy patients. Duchenne muscular dystrophy gene therapy strategies involve gene transfer, exon skipping, exon reframing, and CRISPR gene editing. Eteplirsen, an antisense-oligonucleotide drug for skipping exon 51 from the Dystrophin gene, is available on the market, which may help up to 14% of Duchenne muscular dystrophy patients. There are various FDA-approved exon skipping drugs including ExonDys-51 for exon 51, VyonDys-53 and Viltolarsen for exon 53 and AmonDys-45 for exon 45 skipping. Other antisense oligonucleotide drugs in the pipeline include casimersen for exon 45, suvodirsen for exon 51, and golodirsen for exon 53 skipping. Advances in the diagnosis and therapy of dystrophinopathies offer new perspectives for their early discovery and care.

The role of sleep in neuromuscular disorders.

Sleep represents a major frontier both in clinical myology and as a new possibility for delivering treatment to neuromuscular patients since various neuromuscular cases present a variable degree of disordered sleep and such conditions should be diagnosed and prevented, i.e., sleep apnea and hypoxemia. These sleep disorders are present in dystrophinopathies and in various types of limb-girdle muscular dystrophies (LGMD). Excessive daytime sleepiness (EDS) is found in patients affected by spastic paraparesis or cerebellar ataxia but is rather common in both myotonic dystrophy type 1 and 2, and the correction of sleep disorders is therefore important to improve their daily quality of life (QoL) and consequent daily functioning. Other types of sleep dysfunction such as insomnia, a reduction in rapid eye movement (REM) sleep, loss of normal REM, or sleep-disordered breathing are found in other disorders including myasthenia, ataxias, spastic paraparesis, Charcot-Marie-Tooth disease, and neurogenic disorders, including polyneuropathies, and need appropriate treatment. Research done on this topic aims to incorporate a variety of nuances in metabolic disorders such as those in late-onset Pompe disease and are such as those in late-onset Pompe disease who are susceptible to enzyme replacement therapy (ERT). The overarching goal is to explore both the diagnosis and methodology of sleep-related problems in both genetic and acquired neuromuscular disorders. We also review the type of available treatment opportunities utilized to improve neuromuscular patients' QoL.

History of international connections of myology in Europe.

Over the past centuries, myology as a basic and clinical science has passed through three major stages of development: the classical period, the modern nosographic stage, and the molecular era. The classical period spans the sixteenth century up to the earlier parts of the twentieth century. During this time, several major muscle diseases were clinically and pathologically characterized, including Duchenne muscular dystrophy (DMD), myotonic dystrophy, and facio-scapulo-humeral dystrophy, by master clinicians such as Duchenne, Erb, Becker, Steinert, Landouzy, Dejerine, Meryon, and others. These accomplishments laid solid foundations for the following modern era with nosographic classification and the following molecular era. European clinicians and scientists were major contributors to the modern era in the second half of the twentieth century, which is characterized by three major discoveries. First, it was observed that substantial elevation of the serum activity of creatine kinase indicates muscle damage or destruction. Then, the adaptation of modern histo-and cytochemical techniques to the study of muscle biopsies markedly improved the diagnostic accuracy and made possible the identification of new changes and structures. Thirdly, the advent of modern biochemical techniques permitted the identification of various enzyme defects/storage diseases such as Pompe disease, McArdle's disease, and carnitine deficiency states. The molecular era was made possible by the strikingly fast development of molecular biology and its application to muscle diseases. This permitted the identification of gene defects in many inherited diseases, leading to an accurate and specific diagnosis. The growth of international collaboration in Europe was achieved through the exchange of international scientists and collaborative networks.

Progress in muscle research through the international congress of neuromuscular diseases (ICNMD): a narrative review.

Progress in muscle research has been through different phases over the past decades. Here are reviewed the advances presented at the International Congresses of Neuromuscular Diseases (ICNMD). In the '60 to '80 muscle physiology and interpretations of muscle biopsy were the major focuses, diagnosis of muscle disorders was advanced utilizing histochemical, and ultrastructural techniques, and the focus of first to IVth ICNMD was prevention and Muscle Disorders classification as major issues. After that from '80 to 2000 muscle neuromuscular junction (NMJ) immunology, biochemistry, molecular biology , therapeutic trials, and genetics were the major developments and represented the focus of research in following ICNMD from the Vth to the Xth. From 2000 to 2020 personalized medicine,genotype-phenotype correlation, and the use of DNA/RNA profiling , Imaging was developed and represented substantial signs of progress that were presented in ICNMD XIth to XVIIth. The future is evolving toward a major involvement of the pharmaceutical industry with new drugs and gene-delivered therapy, the use of biomarkers and robotics as well as of artificial intelligence, both for interpreting morphology, DNA, and imaging diagnostic, and such developments will be reflected in research presented in future Congresses.

Effects of Triheptanoin on Mitochondrial Respiration and Glycolysis in Cultured Fibroblasts from Neutral Lipid Storage Disease Type M (NLSD-M) Patients.

Neutral lipid storage disease type M (NLSD-M) is an ultra-rare, autosomal recessive disorder that causes severe skeletal and cardiac muscle damage and lipid accumulation in all body tissues. In this hereditary pathology, the defective action of the adipose triglyceride lipase (ATGL) enzyme induces the enlargement of cytoplasmic lipid droplets and reduction in the detachment of mono- (MG) and diglycerides (DG). Although the pathogenesis of muscle fiber necrosis is unknown, some studies have shown alterations in cellular energy production, probably because MG and DG, the substrates of Krebs cycle, are less available. No tests have been tried with medium-chain fatty acid molecules to evaluate the anaplerotic effect in NLSD cells. In this study, we evaluated the in vitro effect of triheptanoin (Dojolvi®), a highly purified chemical triglyceride with seven carbon atoms, in fibroblasts obtained from five NLSD-M patients. Glycolytic and mitochondrial functions were determined by Seahorse XF Agylent Technology, and cellular viability and triglyceride content were measured through colorimetric assays. After the addition of triheptanoin, we observed an increase in glycolysis and mitochondrial respiration in all patients compared with healthy controls. These preliminary results show that triheptanoin is able to induce an anaplerotic effect in NLSD-M fibroblasts, paving the way towards new therapeutic strategies.

Duchenne Muscular Dystrophy Gene therapy.

Duchenne and Becker muscular dystrophies are allelic X-linked recessive neuromuscular diseases affecting both skeletal and cardiac muscles. Therefore, owing to their single X chromosome, the affected boys receive pathogenic gene mutations from their unknowing carrier mothers. Current pharmacological drugs are palliative that address the symptoms of the disease rather than the genetic cause imbedded in the Dystrophin gene DNA sequence. Therefore, alternative therapies like gene drugs that could address the genetic cause of the disease at its root are crucial, which include gene transfer/implantation, exon skipping, and gene editing. Presently, it is possible through genetic reprogramming to engineer AAV vectors to deliver certain therapeutic cargos specifically to muscle or other organs regardless of their serotype. Similarly, it is possible to direct the biogenesis of exosomes to carry gene editing constituents or certain therapeutic cargos to specific tissue or cell type like brain and muscle. While autologous exosomes are immunologically inert, it is possible to camouflage AAV capsids, and lipid nanoparticles to evade the immune system recognition. In this review, we highlight current opportunities for Duchenne muscular dystrophy gene therapy, which has been known thus far as an incurable genetic disease. This article is a part of Gene Therapy of Rare Genetic Diseases thematic issue.

Clinical and biochemical footprints of inherited metabolic disorders: X. Metabolic myopathies.

Metabolic myopathies are characterized by the deficiency or dysfunction of essential metabolites or fuels to generate energy for muscle contraction; they most commonly manifest with neuromuscular symptoms due to impaired muscle development or functioning. We have summarized associations of signs and symptoms in 358 inherited metabolic diseases presenting with myopathies. This represents the tenth of a series of articles attempting to create and maintain a comprehensive list of clinical and metabolic differential diagnoses according to system involvement.

Neutral lipid storage disease with myopathy: A 10-year follow-up case report.

Mutations in PNPLA2 gene encoding for adipose triglyceride lipase (ATGL), involved in triglyceride degradation, lead to an inborn error of neutral lipid metabolism. The disorder that results in abnormal storage of neutral lipid is known as neutral lipid storage disease with myopathy (NLSDM). We report the follow-up of a 30-year-old woman with NLSDM, asymptomatic until age 23. At the age of 18, a high level of CPK and neutral lipid abnormal accumulation in muscle and skin cells suggested NLSDM diagnosis, afterwards confirmed by PNPLA2 analysis. After 5 years, she developed weakness in the upper and lower extremities. She was put on a low-fat diet with medium-chain triglycerides (MCT) oil supplementation but, although her CPK level decreased, myopathy continued to progress. At present, she presents severe skeletal myopathy without cardiac involvement. In this patient, no beneficial effects on progressive skeletal muscle weakness were detected after the MCT diet, probably due to complete loss of PNPLA2 expression.

LGMD D2 TNPO3-Related: From Clinical Spectrum to Pathogenetic Mechanism.

Limb-girdle muscular dystrophies (LGMDs) are clinically and genetically heterogeneous diseases presenting with a wide clinical spectrum. Autosomal dominant LGMDs represent about 10-15% of LGMDs and include disorders due to defects of DNAJB6, transportin-3 (TNPO3), HNRNPDL, Calpain-3 (CAPN3), and Bethlem myopathy. This review article aims to describe the clinical spectrum of LGMD D2 TNPO3-related, a rare disease due to heterozygous mutation in the TNPO3 gene. TNPO3 encodes for transportin-3, which belongs to the importin beta family and transports into the nucleus serine/arginine-rich (SR) proteins, such as splicing factors, and HIV-1 proteins, thus contributing to viral infection. The purpose of this review is to present and compare the clinical features and the genetic and histopathological findings described in LGMD D2, performing a comparative analytical description of all the families and sporadic cases identified. Even if the causative gene and mutations of this disease have been identified, the pathogenic mechanisms are still an open issue; therefore, we will present an overview of the hypotheses that explain the pathology of LGMD D2 TNPO3-related.

Recommendations for traveling to altitude with neurological disorders.

BACKGROUND: Several neurological conditions might worsen with the exposure to high altitude (HA). The aim of this review was to summarize the available knowledge on the neurological HA illnesses and the risk for people with neurological disorders to attend HA locations. METHODS: A search of literature was conducted for several neurological disorders in PubMed and other databases since 1970. The neurological conditions searched were migraine, different cerebrovascular disease, intracranial space occupying mass, multiple sclerosis, peripheral neuropathies, neuromuscular disorders, epileptic seizures, delirium, dementia, and Parkinson's disease (PD). RESULTS: Attempts were made to classify the risk posed by each condition and to provide recommendations regarding medical evaluation and advice for or against traveling to altitude. Individual cases should be advised after careful examination and risk evaluation performed either in an outpatient mountain medicine service or by a physician with knowledge of HA risks. Preliminary diagnostic methods and anticipation of neurological complications are needed. CONCLUSIONS: Our recommendations suggest absolute contraindications to HA exposure for the following neurological conditions: (1) Unstable conditions-such as recent strokes, (2) Diabetic neuropathy, (3) Transient ischemic attack in the last month, (4) Brain tumors, and 5. Neuromuscular disorders with a decrease of forced vital capacity >60%. We consider the following relative contraindications where decision has to be made case by case: (1) Epilepsy based on recurrence of seizure and stabilization with the therapy, (2) PD (± obstructive sleep apnea syndrome-OSAS), (3) Mild Cognitive Impairment (± OSAS), and (4) Patent foramen ovale and migraine have to be considered risk factors for acute mountain sickness.

An updated review on the role of prescribed exercise in the management of Amyotrophic lateral sclerosis.

Introduction: Amyotrophic Lateral Sclerosis is a group of sporadic or familial disorders, characterized by upper and lower motor neuron involvement, with variable progression.Areas covered: The authors present the role of exercise in counteracting muscle disuse, particularly on limb weakness, that might antagonize denervation. The persistence of inactivity can affect many systems and the patient can develop deconditioning, muscle joint tightness, which causes contractures and pain. The main area of the review is the evaluation of the studies done on ALS exercise rehabilitation protocols, this was done by the evaluation of outcome function and patient independence exerting a positive psychological impact on both patients and caregivers. A second target is underlying differences between endurance and resistance exercise protocols, which may throw light on the biological mechanism of skeletal muscle repair, functional performance, and metabolism. The authors present not only exercise trials but also molecular biomarkers that might help define changes induced by physical rehabilitation. Our findings might help to achieve the best rehabilitation program. A standardized rehabilitation protocol is important: the instructed patients may continue therapy at home or be followed by telemedicine.Expert opinion: This review evaluates exercise rehabilitation, a controversial issue, evidence is weak and non-conclusive but represents the art status.

Recurrent N209* ABHD5 mutation in two unreported families with Chanarin Dorfman Syndrome.

ABHD5 protein is widely involved in lipid and energy homeostasis. Mutations in the ABHD5 gene are associated with the onset of Neutral Lipid Storage Disease with Ichthyosis (NLSDI), historically known as Chanarin Dorfman Syndrome (CDS). CDS is a rare autosomal recessive lipid storage disease, characterized by non-bullous congenital ichthyosiform eritrhoderma (NCIE), hepatomegaly and liver steatosis. Myopathy, neurosensory hearing loss, cataracts, nystagmus, strabismus, and mental impairment are considered additional findings. To date, 151 CDS patients have been reported all over the world. Here we described two additional families with patients affected by CDS from Turkey. Our patients were a 42 and 22-years old men, admitted to the Hospital for congenital ichthyosis. Hepatic steatosis and myopathy were also detected in both patients. ABHD5 molecular analysis revealed the presence of N209* mutation. Our data enlarge the cohort of CDS patients and provide a revision of muscle clinical findings for this rare inborn error of neutral lipid metabolism.

Exercise, nutrition and enzyme replacement therapy are efficacious in adult Pompe patients: report from EPOC Consortium.

Pompe Disease, also known as glycogenosis type 2, is due to deficiency in lysosomal alpha- glucosidase, a lysosomal hydrolase, which presents infantile and late onset subtypes (LOPD). The myopathy in LOPD can be reversed by Enzyme Replacement Therapy (ERT), but might benefit from a concomitant low carbohydrate - high protein diet and aerobic exercise treatment. From 65 Late onset Pompe cases, we were able to obtain in 58 a self-reported evaluation, most of them gave a positive efficacy evaluation of Enzyme Replacement Therapy and they were classified by a self-administered scale as Responders or non-Responders. A cooperative study of a clinical group on LOPD monitored age, sex, BMI, Gardner-Medwin-Walton scale and six minute walking test (6MWT). The only clinical parameters that were significantly associated with a Responder category were the pre-ERT walking distance (p<0.035) and the use of regular diet, exercise or both (p<0.029). The present study shows that in LOPD this condition can be treated by ERT, but also benefits from concomitant diet and aerobic exercise therapy.

ETF dehydrogenase advances in molecular genetics and impact on treatment.

Electron transfer flavoprotein dehydrogenase, also called ETF-ubiquinone oxidoreductase (ETF-QO), is a protein localized in the inner membrane of mitochondria, playing a central role in the electron-transfer system. Indeed, ETF-QO mediates electron transport from flavoprotein dehydrogenases to the ubiquinone pool. ETF-QO mutations are often associated with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD, OMIM#231680), a multisystem genetic disease characterized by various clinical manifestations with different degrees of severity. In this review, we outline the clinical features correlated with ETF-QO deficiency and the benefits obtained from different treatments, such as riboflavin, L-carnitine and/or coenzyme Q10 supplementation, and a diet poor in fat and protein. Moreover, we provide a detailed summary of molecular and bioinformatic investigations, describing the mutations identified in ETFDH gene and highlighting their predicted impact on enzymatic structure and activity. In addition, we report biochemical and functional analysis, performed in HEK293 cells and patient fibroblasts and muscle cells, to show the relationship between the nature of ETFDH mutations, the variable impairment of enzyme function, and the different degrees of RR-MADD severity. Finally, we describe in detail 5 RR-MADD patients carrying different ETFDH mutations and presenting variable degrees of clinical symptom severity.