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.
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.
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.
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.
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.
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.
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.
Abstract Rare neurological diseases as a whole share peculiar features as motor and/or cognitive impairment, an elevated disability burden, a frequently chronic course and, in present times, scarcity ...of therapeutic options. The rarity of those conditions hampers both the identification of significant prognostic outcome measures, and the development of novel therapeutic approaches and clinical trials. Collection of objective clinical data through digital devices can support diagnosis, care, and therapeutic research. We provide an overview on recent developments in the field of digital tools applied to rare neurological diseases, both in the care setting and as providers of outcome measures in clinical trials in a representative subgroup of conditions, including ataxias, hereditary spastic paraplegias, motoneuron diseases and myopathies.
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.
Abstract Introduction/Aims Fatigue (subjective perception) and fatigability (objective motor performance worsening) are relevant aspects of disability in individuals with spinal muscular atrophy ...(SMA). The effect of nusinersen on fatigability in SMA patients has been investigated with conflicting results. We aimed to evaluate this in adult with SMA3. Methods We conducted a multicenter retrospective cohort study, including adult ambulant patients with SMA3, data available on 6‐minute walk test (6MWT) and Hammersmith Functional Motor Scale—Expanded (HFMSE) at baseline and at least at 6 months of treatment with nusinersen. We investigated fatigability, estimated as 10% or higher decrease in walked distance between the first and sixth minute of the 6MWT, at baseline and over the 14‐month follow‐up. Results Forty‐eight patients (56% females) were included. The 6MWT improved after 6, 10, and 14 months of treatment ( p < 0.05). Of the 27 patients who completed the entire follow‐up, 37% improved (6MWT distance increase ≥30 m), 48.2% remained stable, and 14.8% worsened (6MWT distance decline ≥30 m). Fatigability was found at baseline in 26/38 (68%) patients and confirmed at subsequent time points ( p < 0.05) without any significant change over the treatment period. There was no correlation between fatigability and SMN2 copy number, sex, age at disease onset, age at baseline, nor with 6MWT total distance and baseline HFMSE score. Discussion Fatigability was detected at baseline in approximately 2/3 of SMA3 walker patients, without any correlation with clinical features, included motor performance. No effect on fatigability was observed during the 14‐month treatment period with nusinersen.
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.
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.
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.
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.
Objective
The aim of this study was to provide an overview of the clinical phenotypes associated with 4 SMN2 copies.
Methods
Clinical phenotypes were analyzed in all the patients with 4 SMN2 copies ...as part of a nationwide effort including all the Italian pediatric and adult reference centers for spinal muscular atrophy (SMA).
Results
The cohort includes 169 patients (102 men and 67 women) with confirmed 4 SMN2 copies (mean age at last follow‐up = 36.9 ± 19 years). Six of the 169 patients were presymptomatic, 8 were classified as type II, 145 as type III (38 type IIIA and 107 type IIIB), and 8 as type IV. The remaining 2 patients were asymptomatic adults identified because of a familial case. The cross‐sectional functional data showed a reduction of scores with increasing age. Over 35% of the type III and 25% of the type IV lost ambulation (mean age = 26.8 years ± 16.3 SD). The risk of loss of ambulation was significantly associated with SMA type (p < 0.0001), with patients with IIIB and IV less likely to lose ambulation compared to type IIIA. There was an overall gender effect with a smaller number of women and a lower risk for women to lose ambulation. This was significant in the adult (p = 0.009) but not in the pediatric cohort (p = 0.43).
Interpretation
Our results expand the existing literature on natural history of 4 SMN2 copies confirming the variability of phenotypes in untreated patients, ranging from type II to type IV and an overall reduction of functional scores with increasing age. ANN NEUROL 2023;94:1126–1135
