Cardiac comorbidities in McArdle disease: case report and systematic review.

INTRODUCTION AND METHODS: Myophosphorylase deficiency, also known as McArdle disease or Glycogen Storage Disease type V (GSD-V), is an autosomal recessive metabolic myopathy that results in impaired glycogen breakdown in skeletal muscle. Despite being labelled as a "pure myopathy," cardiac involvement has been reported in some cases, including various cardiac abnormalities such as electrocardiographic changes, coronary artery disease, and cardiomyopathy. Here, we present a unique case of a 72-year-old man with GSD-V and both mitral valvulopathy and coronary artery disease, prompting a systematic review to explore the existing literature on cardiac comorbidities in McArdle disease. RESULTS: Our systematic literature revision identified 7 case reports and 1 retrospective cohort study. The case reports described 7 GSD-V patients, averaging 54.3 years in age, mostly male (85.7%). Coronary artery disease was noted in 57.1% of cases, hypertrophic cardiomyopathy in 28.5%, severe aortic stenosis in 14.3%, and genetic dilated cardiomyopathy in one. In the retrospective cohort study, five out of 14 subjects (36%) had coronary artery disease. DISCUSSION AND CONCLUSION: Despite McArdle disease primarily affecting skeletal muscle, cardiac involvement has been observed, especially coronary artery disease, the frequency of which was moreover found to be higher in McArdle patients than in the background population in a previous study from a European registry. Exaggerated cardiovascular responses during exercise and impaired glycolytic metabolism have been speculated as potential contributors. A comprehensive cardiological screening might be recommended for McArdle disease patients to detect and manage cardiac comorbidities. A multidisciplinary approach is crucial to effectively manage both neurological and cardiac aspects of the disease and improve patient outcomes. Further research is required to establish clearer pathophysiological links between McArdle disease and cardiac manifestations in order to clarify the existing findings.

Characterization of Phenotypic Variability in Becker Muscular Dystrophy for Clinical Practice and Towards Trial Readiness: A Two-Years Follow up Study.

Background: Becker muscular dystrophy (BMD) is a dystrophinopathy due to in-frame mutations in the dystrophin gene (DMD) which determines a reduction of dystrophin at muscle level. BMD has a wide spectrum of clinical variability with different degrees of disability. Studies of natural history are needed also in view of up-coming clinical trials. Objectives: From an initial cohort of 32 BMD adult subjects, we present a detailed phenotypic characterization of 28 patients, then providing a description of their clinical natural history over the course of 12 months for 18 and 24 months for 13 of them. Methods: Each patient has been genetically characterized. Baseline, and 1-year and 2 years assessments included North Star Ambulatory Assessment (NSAA), timed function tests (time to climb and descend four stairs), 6-minute walk test (6MWT), Walton and Gardner-Medwin Scale and Medical Research Council (MRC) scale. Muscle magnetic resonance imaging (MRI) was acquired at baseline and in a subgroup of 9 patients after 24 months. Data on cardiac function (electrocardiogram, echocardiogram, and cardiac MRI) were also collected. Results and conclusions: Among the clinical heterogeneity, a more severe involvement is often observed in patients with 45-X del, with a disease progression over two years. The 6MWT appears sensitive to detect modification from baseline during follow up while no variation was observed by MRC testing. Muscle MRI of the lower limbs correlates with clinical parameters.Our study further highlights how the phenotypic variability of BMD adult patients makes it difficult to describe an uniform course and substantiates the need to identify predictive parameters and biomarkers to stratify patients.

Proposal of a new clinical protocol for evaluating fatigability in adult SMA patients.

Objective: Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disease affecting the lower motor neuron, carrying a significant burden on patients' general motor skills and quality of life, characterized by a great variability in phenotypic expression. As new therapeutic options make their appearance on the scene, sensitive clinical tools and outcome measures are needed, especially in adult patients undergoing treatment, in which the expected clinical response is a mild improvement or stabilization of disease progression. Methods: Here, we describe a new functional motor scale specifically designed for evaluating the endurance dimension for the upper and lower limbs in adult SMA patients. Results: The scale was first tested in eight control healthy subjects and then validated in ten adult SMA patients, proving intra- and inter-observer reliability. We also set up an evaluation protocol by using wearable devices including surface EMG and accelerometer. Conclusions: The endurance evaluation should integrate the standard clinical monitoring in the management and follow-up of SMA adult patients.

Digital health and Clinical Patient Management System (CPMS) platform utility for data sharing of neuromuscular patients: the Italian EURO-NMD experience.

BACKGROUND: The development of e-health technologies for teleconsultation and exchange of knowledge is one of the core purposes of European Reference Networks (ERNs), including the ERN EURO-NMD for rare neuromuscular diseases. Within ERNs, the Clinical Patient Management System (CPMS) is a web-based platform that seeks to boost active collaboration within and across the network, implementing data sharing. Through CPMS, it is possible to both discuss patient cases and to make patients' data available for registries and databases in a secure way. In this view, CPMS may be considered a sort of a temporary storage for patients' data and an effective tool for data sharing; it facilitates specialists' consultation since rare diseases (RDs) require multidisciplinary skills, specific, and outstanding clinical experience. Following European Union (EU) recommendation, and to promote the use of CPMS platform among EURO-NMD members, a twelve-month pilot project was set up to train the 15 Italian Health Care Providers (HCPs). In this paper, we report the structure, methods, and results of the teaching course, showing that tailored, ERN-oriented, training can significantly enhance the profitable use of the CPMS. RESULTS: Throughout the training course, 45 professionals learned how to use the many features of the CPMS, eventually opening 98 panels of discussion-amounting to 82% of the total panels included in the EURO-NMD. Since clinical, genetic, diagnostic, and therapeutic data of patients can be securely stored within the platform, we also highlight the importance of this platform as an effective tool to discuss and share clinical cases, in order to ease both case solving and data storing. CONCLUSIONS: In this paper, we discuss how similar course could help implementing the use of the platform, highlighting strengths and weaknesses of e-health for ERNs. The expected result is the creation of a "map" of neuromuscular patients across Europe that might be improved by a wider use of CPMS.

Cardiac magnetic resonance findings and prognosis in type 1 myotonic dystrophy.

BACKGROUND: Cardiac involvement is a major determinant of prognosis in type 1 myotonic dystrophy (DM1), but limited information is available about myocardial remodeling and tissue changes. The aim of the study was to investigate cardiac magnetic resonance (CMR) findings and their prognostic significance in DM1. METHODS: We retrospectively identified all DM1 patients referred from a neurology unit to our CMR laboratory from 2009 to 2020. RESULTS: Thirty-four patients were included (aged 45 ±â€Š12, 62% male individuals) and compared with 68 age-matched and gender-matched healthy volunteers (43 male individuals, age 48 ±â€Š15 years). At CMR, biventricular and biatrial volumes were significantly smaller (all P < 0.05), as was left ventricular mass (P < 0.001); left ventricular ejection fraction (LVEF) and right ventricular ejection fraction (RVEF) were significantly lower (all P < 0.01). Five (15%) patients had a LVEF less than 50% and four (12%) a RVEF less than 50%. Nine patients (26%) showed mid-wall late gadolinium enhancement (LGE; 5 ±â€Š2% of LVM), and 14 (41%) fatty infiltration. Native T1 in the interventricular septum (1041 ±â€Š53 ms) was higher than for healthy controls (1017 ±â€Š28 ms) and approached the upper reference limit (1089 ms); the extracellular volume was slightly increased (33 ±â€Š2%, reference <30%). Over 3.7 years (2.0-5.0), 6 (18%) patients died of extracardiac causes, 5 (15%) underwent device implantation; 5 of 21 (24%) developed repetitive ventricular ectopic beats (VEBs) on Holter monitoring. LGE mass was associated with the occurrence of repetitive VEBs (P = 0.002). Lower LV stroke volume (P = 0.017), lower RVEF (P = 0.016), a higher LVMi/LVEDVI ratio (P = 0.016), fatty infiltration (P = 0.04), and LGE extent (P < 0.001) were associated with death. CONCLUSION: DM1 patients display structural and functional cardiac abnormalities, with variable degrees of cardiac muscle hypotrophy, fibrosis, and fatty infiltration. Such changes, as evaluated by CMR, seem to be associated with the development of ventricular arrhythmias and a worse outcome.

Pathophysiology and Management of Fatigue in Neuromuscular Diseases.

Fatigue is a major determinant of quality of life and motor function in patients affected by several neuromuscular diseases, each of them characterized by a peculiar physiopathology and the involvement of numerous interplaying factors. This narrative review aims to provide an overview on the pathophysiology of fatigue at a biochemical and molecular level with regard to muscular dystrophies, metabolic myopathies, and primary mitochondrial disorders with a focus on mitochondrial myopathies and spinal muscular atrophy, which, although fulfilling the definition of rare diseases, as a group represent a representative ensemble of neuromuscular disorders that the neurologist may encounter in clinical practice. The current use of clinical and instrumental tools for fatigue assessment, and their significance, is discussed. A summary of therapeutic approaches to address fatigue, encompassing pharmacological treatment and physical exercise, is also overviewed.

The role of magnetic resonance imaging in the diagnostic work-out of myopathies: differential diagnosis between inflammatory myopathies and muscular dystrophies.

OBJECTIVES: The differential diagnosis between idiopathic inflammatory myopathies (IIM) and muscular dystrophies (MD) may be challenging. We analysed the potential role of muscular magnetic resonance imaging (MRI) in the differential diagnosis between IIM and MD. METHODS: MRI of patients (91 IIM and 43 MD), studied with a standardised protocol, have been collected. The presence of oedema, muscular atrophy and intramuscular adipose changes were evaluated. Moreover, we computed a composite score for each MRI item to better discriminate between the two diseases. RESULTS: Oedema was significantly more prevalent in IIM compared with MD in pelvis muscles (p<0.001), anterior lodge and medial lodges (p=0.044) of the thighs. Adipose infiltration/substitution and muscular atrophy were more prevalent in MD, in particular adipose tissue was prevalent in all the compartments of the thighs (p<0.05), atrophy was prevalent at the thighs and pelvis muscles (p<0.001). The probability of IIM increased with higher oedema score and decreased with higher atrophy and intramuscular adipose infiltration/substitution scores. CONCLUSIONS: A different distribution of muscular involvement between IIM and MD has been identified. Muscular MRI may be useful in the differential diagnosis, potentially reducing the number of muscular biopsies that may be reserved only for doubtful cases.

Biomolecules of Muscle Fatigue in Metabolic Myopathies.

Metabolic myopathies are a group of genetic disorders that affect the normal functioning of muscles due to abnormalities in metabolic pathways. These conditions result in impaired energy production and utilization within muscle cells, leading to limitations in muscle function with concomitant occurrence of related signs and symptoms, among which fatigue is one of the most frequently reported. Understanding the underlying molecular mechanisms of muscle fatigue in these conditions is challenging for the development of an effective diagnostic and prognostic approach to test targeted therapeutic interventions. This paper outlines the key biomolecules involved in muscle fatigue in metabolic myopathies, including energy substrates, enzymes, ion channels, and signaling molecules. Potential future research directions in this field are also discussed.

Therapeutic opportunities and clinical outcome measures in Duchenne muscular dystrophy.

INTRODUCTION: Duchenne muscular dystrophy (DMD) is a devastatingly severe genetic muscle disease characterized by childhood-onset muscle weakness, leading to loss of motor function and premature death due to respiratory and cardiac insufficiency. DISCUSSION: In the following three and half decades, DMD kept its paradigmatic role in the field of muscle diseases, with first systematic description of disease progression with ad hoc outcome measures and the first attempts at correcting the disease-causing gene defect by several molecular targets. Clinical trials are critical for developing and evaluating new treatments for DMD. CONCLUSIONS: In the last 20 years, research efforts converged in characterization of the disease mechanism and development of therapeutic strategies. Same effort needs to be dedicated to the development of outcome measures able to capture clinical benefit in clinical trials.

Frailties and critical issues in neuromuscular diseases highlighted by SARS-CoV-2 pandemic: how many patients are still "invisible"?

Almost 90% of neuromuscular diseases (NMDs) are classified as rare diseases, defined as conditions affecting less than 5 individuals in 10.000 (0.05%). Their rarity and diversity pose specific challenges for healthcare and research. Epidemiological data on NMDs are often lacking and incomplete. The COVID-19 pandemic has further highlighted the management difficulties of NMDs patients and the necessity to continue the program of implementation of standard of care. This article summarizes the Italian experience during pandemic.

A Single mtDNA Deletion in Association with a LMNA Gene New Frameshift Variant: A Case Report.

BACKGROUND: Proximal muscle weakness may be the presenting clinical feature of different types of myopathies, including limb girdle muscular dystrophy and primary mitochondrial myopathy. LGMD1B is caused by LMNA mutation. It is characterized by progressive weakness and wasting leading to proximal weakness, cardiomyopathy, and hearth conduction block. OBJECTIVE: In this article, we describe the case of a patient who presented with limb-girdle weakness and a double trouble scenario -mitochondrial DNA single deletion and a new LMNA mutation. METHODS: Pathophysiological aspects were investigated with muscle biopsy, Western Blot analysis, NGS nuclear and mtDNA analysis and neuromuscular imaging (muscle and cardiac MRI). RESULTS: Although secondary mitochondrial involvement is possible, a "double trouble" syndrome can not be excluded. CONCLUSION: Implication deriving from hypothetical coexistence of two different pathological conditions or the possible secondary mitochondrial involvement are discussed.

Fatigue as a common signature of inflammatory myopathies: clinical aspects and care.

Fatigue is a common symptom in idiopathic inflammatory myopathies (IIMs), which greatly affects activities of daily life. Fatigue is a complex phenomenon that covers a range of dimensions from biological to behavioural, the pathophysiology of which is still poorly understood. The aim of this review is to describe the different determinants of fatigue in IIMs, discuss their clinical implications and how to evaluate and manage the condition, which are all relevant issues for the treating physicians in their everyday practice.

Anti-HMGCR antibodies and asymptomatic hyperCKemia. A case report.

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) related myositis is a form of immune-mediated necrotizing myopathy (IMNM). Anti-HMGCR autoantibodies target HMGCR, a glycoprotein linked to the endoplasmic reticulum implied in the cholesterol synthesis pathway, and exert a pathogenic effect on skeletal muscle cells. More than 60% of patients affected by HMGCR-related myositis shares statin-exposure in their medical history. Patients commonly experience CK levels elevation, myalgia, muscle weakness and soreness at variable extent, which manifest acutely or sub acutely with a progressively worsening course, in some cases mimicking limb-girdle muscular dystrophies (LGMD) phenotype and treatment is based on an immunosuppressive strategy. Here we present the peculiar case of a previously statins-exposed 72 y.o. asymptomatic man with persistent moderate hyperCKemia and high levels of anti-HMGCR, in which pharmacotherapy has not been initiated yet, while a wait-and-see approach has been adopted instead.

Next-generation sequencing application to investigate skeletal muscle channelopathies in a large cohort of Italian patients.

Non-dystrophic myotonias and periodic paralyses are a heterogeneous group of disabling diseases classified as skeletal muscle channelopathies. Their genetic characterization is essential for prognostic and therapeutic purposes; however, several genes are involved. Sanger-based sequencing of a single gene is time-consuming, often expensive; thus, we designed a next-generation sequencing panel of 56 putative candidate genes for skeletal muscle channelopathies, codifying for proteins involved in excitability, excitation-contraction coupling, and metabolism of muscle fibres. We analyzed a large cohort of 109 Italian patients with a suspect of NDM or PP by next-generation sequencing. We identified 24 patients mutated in CLCN1 gene, 15 in SCN4A, 3 in both CLCN1 and SCN4A, 1 in ATP2A1, 1 in KCNA1 and 1 in CASQ1. Eight were novel mutations: p.G395Cfs*32, p.L843P, p.V829M, p.E258E and c.1471+4delTCAAGAC in CLCN1, p.K1302R in SCN4A, p.L208P in ATP2A1 and c.280-1G>C in CASQ1 genes. This study demonstrated the utility of targeted next generation sequencing approach in molecular diagnosis of skeletal muscle channelopathies and the importance of the collaboration between clinicians and molecular geneticists and additional methods for unclear variants to make a conclusive diagnosis.

Estimating the impact of COVID-19 pandemic on services provided by Italian Neuromuscular Centers: an Italian Association of Myology survey of the acute phase.

INTRODUCTION: Since February 2020, the outbreak of COVID-19 in Italy has forced the health care system to undergo profound rearrangements in its services and facilities, especially in the worst-hit areas in Northern Italy. In this setting, inpatient and outpatient services had to rethink and reorganize their activities to meet the needs of patients during the "lockdown". The Italian Association of Myology developed a survey to estimate the impact of these changes on patients affected by neuromuscular disorders and on specialized neuromuscular centers during the acute phase of COVID-19 pandemic. METHODS: We developed an electronic survey that was sent to neuromuscular centers affiliated with the Italian Association of Myology, assessing changes in pharmacological therapies provision, outpatient clinical and instrumental services, support services (physiotherapy, nursing care, psychological support) and clinical trials. RESULTS: 40% of surveyed neuromuscular centers reported a reduction in outpatient visit and examinations (44.5% of centers in Northern regions; 25% of centers in Central regions; 50% of centers in Southern regions). Twenty-two% of centers postponed in-hospital administration of therapies for neuromuscular diseases (23.4% in Northern regions; 13.0% in Central regions; 20% in Southern regions). Diagnostic and support services (physiotherapy, nursing care, psychological support) were suspended in 57% of centers (66/43/44% in Northern, Central and Southern centers respectively) Overall, the most affected services were rehabilitative services and on-site outpatient visits, which were suspended in 93% of centers. Strategies adopted by neuromuscular centers to overcome these changes included maintaining urgent on-site visits, addressing patients to available services and promoting remote contact and telemedicine. CONCLUSIONS: Overall, COVID-19 pandemic resulted in a significant disruption of clinical and support services for patients with neuromuscular diseases. Despite the efforts to provide telemedicine consults to patients, this option could be promoted and improved further. A close collaboration between the different neuromuscular centers and service providers as well as further implementation of telehealth platforms are necessary to ensure quality care to NMD patients in the near future and in case of recurrent pandemic waves.