Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology最新文献

Background: Pompe disease is a lysosomal storage disorder that primarily affects muscles, and its natural history has been transformed over the past 20 years by therapies designed to restore the deficient enzyme function, from the first enzyme replacement therapies (ERTs) to the gene therapy currently in development. However, despite these ground-breaking innovations, the importance of a multi-system and rehabilitative approach remains critical, as it addresses the complex systems involved in the disease and optimizes the success of pharmacological treatments.

Methods: We conducted a narrative review of the current pharmacological treatments approved for Pompe disease, as well as those undergoing clinical trials. We also reviewed international recommendations for managing respiratory, musculoskeletal, and cardiac function specially focusing on the late-onset form.

Results: There are no universally agreed guidelines for the multidisciplinary management and many recommendations are based on expert consensus and small interventional studies. Nevertheless, combined approaches involving ERT therapy along with specific rehabilitation and nutritional programs appear to yield beneficial effects.

Conclusions: Pompe disease, one of the first neuromuscular diseases to benefit from the approval of disease-modifying therapies, is a paradigm for the importance of an integrated therapeutic-rehabilitative approach.

Objectives: Non-dystrophic myotonias (NDM) are rare diseases due to mutations in the voltage-gated sodium (Nav1.4) and chloride (ClC-1) channels expressed in skeletal muscle fibers. We provide an up-to-date review of pharmacological treatments available for NDM patients and experimental studies aimed at identifying alternative treatments and at better understanding the mechanisms of actions.

Methods: Literature research was performed using PubMed and ClinicalTrial.gov.

Results: Today, the sodium channel blocker mexiletine is the drug of choice for treatment of NDM. Alternative drugs include other sodium channel blockers and the carbonic anhydrase inhibitor acetazolamide. Preclinical studies suggest that activators of ClC-1 channels or voltage-gated potassium channels may have antimyotonic potential.

Conclusions: An increasing number of antimyotonic drugs would help to design a precision therapy to address personalized treatment of myotonic individuals.

Carriers of genetic diseases including female carriers of X-linked disorders are traditionally believed to be asymptomatic due to the compensatory presence of the unmutated gene on the other allele. However, in recent decades numerous contributions have appeared in the literature showing how females carrying X-linked diseases can also present signs and symptoms linked to the specific gene defect. To explain the clinical manifestations observed in female carriers, several mechanisms leading to a reduced protein expression have been hypothesized, in particular the role of the X-chromosome inactivation (XCI). In this review, the focus will be on the relationship between skewed XCI and the development of muscle or cardiac symptoms in female carriers of the most frequent types of muscle disorders such as Duchenne and Becker muscular dystrophies, Emery-Dreifuss muscular dystrophy and Myotubular Myopathy. In all cases, there is a tendency for females with a more severe phenotype to have a skewed pattern of XCI, while females with an intermediate phenotype have a random pattern. Given the increasing recognition of important clinical presentations in females with X-linked muscle disorders and the recent availability of causal therapies for these diseases, specific guidelines are desirable and recommended that allow women to be properly recognized and have access to appropriate therapies.

Objectives: Facioscapulohumeral muscular dystrophy (FSHD) is a common genetic disorder characterized by progressive muscle weakness, especially in the face, shoulders, and upper limbs. Despite extensive research, the underlying pathogenesis and clinical variability remain incompletely understood. This review aims to summarize recent advances in FSHD research, focusing on genetic and epigenetic factors and the potential for precision medicine.

Methods: A comprehensive review of recent literature was conducted, examining molecular mechanisms such as mutations in the D4Z4 region, DUX4 expression, RNA interference (RNAi) and antisense oligonucleotides (AOs). Clinical variability was analyzed to assess different disease phenotypes. Clinical trials investigating potential treatments, especially those targeting DUX4, were also reviewed.

Results: FSHD shows significant clinical variability, with different progression rates across phenotypes. The 4qA allele is linked to more typical forms of the disease, but epigenetic factors, including DNA methylation and miRNA expression, also influence disease severity. Despite progress, the exact molecular mechanisms driving disease expression remain unclear. Clinical trials, such as Losmapimod, show promise in slowing muscle degeneration, though results remain inconsistent.

Conclusions: FSHD presents significant challenges for therapy development due to its genetic complexity and clinical variability. Ongoing research is needed to clarify pathogenesis and identify reliable biomarkers. Future therapeutic strategies should focus on precision medicine, integrating genetic, clinical, and imaging data to optimize patient stratification and treatment efficacy.

Spinal Muscular Atrophy (SMA) is a progressive neuromuscular disorder caused by SMN1 gene mutations, leading to inevitable motoneuronal degeneration. The introduction of disease modifying therapies has dramatically altered its natural history, shifting management from palliative to proactive approach. The new phenotypes and differences in treatment response and efficacy, are all contributing to reshape our understanding of the disease itself. This paper aims to analyze the lessons derived from the recent therapeutic advances, focusing on key aspects such as therapeutic windows, impact of early treatment and both disease progression and treatment efficacy modifiers. Ultimately, we also aim to give insights on new models of data analysis being explored to optimize patient trajectories and individualize treatment strategies.

Our experience and the overall review of clinical trials and real-world data confirm that early treatment maximizes motor outcomes, especially when started in the pre-clinical phase of the disease. The significant clinical improvements in symptomatic type I infants treated at different ages has provided evidence of an expanded 'therapeutic window', previously reported as limited to the first few months after birth on the basis of neurophysiological findings. The available data also provide evidence that function at baseline, SMN2 copy number, and age at treatment all appear to represent critical determinants of response. The availability of long-term data is increasingly used to pilot new predictive models to support clinical decision-making and to adapt therapeutic goals based on patient-specific variables.

Objectives: Mutations in the FHL1 gene have been associated with a diverse spectrum of X-linked diseases affecting skeletal and cardiac muscle. Six clinically distinct human myopathies can be recognized, including reducing body myopathy (RBM), X-linked dominant scapuloperoneal myopathy (SPM), X-linked myopathy with postural muscle atrophy (XMPMA), rigid spine syndrome (RSS), hypertrophic cardiomyopathy (HCM) and type 6 Emery- Dreifuss muscular dystrophy (EDMD). The core features of all described FHL1opathies are mostly scapuloperoneal muscle weakness, rigid spine, cardiac involvement, and cytoplasmic bodies in the muscle biopsy.

Methods: We systematically reviewed the medical literature between the years 2000 and 2024 regarding the phenotype and genotype description of FHL1-associated myopathies.

Results: Here, we report two novel patients presenting with an X-linked myopathy with postural muscle atrophy (XMPMA) caused by the c.672 C > G FHL1 gene mutation.

Conclusion: When encountering these features in a patient, one may consider screening for an FHL1 mutation. The course ranges from a severe fatal course with early onset to very mild features with late onset. Once a dystrophinopathy has been excluded, increased CK values in male subjects with possible X-linked inheritance should always trigger FHL1 gene screening.

Bethlem myopathy (BM) was first described in 1976 by Bethlem and van Wijngaarden in patients who presented a myopathy characterized by slowly progressive muscle weakness and typical flexion contractures of the long finger flexors, wrists, elbows, pectoralis muscles and ankles. Patients with Bethlem myopathy usually become symptomatic during the first or second decade of life. The condition is in most cases slowly progressive and more than two thirds of patients over 50 years of age may require aids for ambulation. Inheritance is usually autosomal dominant. However, patients with autosomal recessive (AR) BM have been recently reported in Literature. Cardiac involvement is usually absent. Respiratory muscle involvement necessitating nocturnal respiratory support is rarely reported in association with severe weakness later in life.

We describe a further case of ARBM in a 52-year-old man who presented a slowly progressive myopathy but developed a severe progressive respiratory involvement requiring ventilatory support.

Tubular aggregate myopathy is a rare neuromuscular condition associated with the presence of myofibers protein accumulations, in the form of dense tubular aggregates. Clinically it is characterized by proximal muscular weakness, exercise-induced cramps, myalgias, and ocular features such as ophthalmoplegia and pupillary abnormalities. The involvement of the central nervous system is rare and not completely elucidated. Variants in STIM1, ORAI1, CASQ1 genes are frequently associated with tubular aggregate myopathy. Here we describe a 35-year-old man who presented neonatal hypotonia, motor delay, seizures, and sensorineural hearing loss. During a SARS-CoV-2 infection at the age of 35, he developed myoclonus, encephalopathy, and marked muscular weakness. A deltoid muscle biopsy revealed the presence of tubular aggregates. Genetic analyses including a Whole Genome sequencing failed to reveal a genetic cause. In conclusion, we enlarge the clinical spectrum of tubular aggregate myopathy associated with central nervous system involvement.