Clinical, Histopathologic, and Genetic Features of Patients With Myofibrillary and Distal Myopathies: Experience From the Italian Network.

BACKGROUND AND OBJECTIVES: The diagnostic process for myofibrillar myopathies (MFM) and distal myopathies (DM) is particularly complex because of the large number of causative genes, the existence of still molecularly undefined disease entities, and the overlapping features between the 2 categories. This study aimed to characterize a large cohort of patients affected by MFM and DM and identify the most important diagnostic and prognostic aspects of these diseases. METHODS: Patients with either a myopathological diagnosis of MFM or a clinical diagnosis of DM were included in this retrospective multicentric national study. Demographic, genetic, clinical, and histopathologic data of anonymized patients were collected from the neuromuscular centers of the Italian Association of Myology network. RESULTS: Data regarding 132 patients with MFM (mean age 57.0 ± 15.8 years, 49% female) and 298 patients with DM (mean age 50.7 ± 15.9 years, 40% female) were gathered from 20 neuromuscular centers. 69 patients fulfilled the criteria for both groups (distal myopathies with myofibrillar pathology, DM-MP). Molecular confirmation was achieved in 63% of the patients. Fifty-two percent of the patients with MFM carried pathogenic variants in either DES (n = 30), MYOT (n = 20), or DNAJB6 (n = 18), which were also the most frequent disease-causing genes in DM-MP, while GNE (n = 44) and MYH7 (n = 23) were the genes most commonly carrying pathogenic variants in DM. The mean age at onset varied from <25 years in patients with causative variants in MYH7 and DYSF to 59 years in patients with myotilinopathies. Cardiac involvement was reported in 29% of patients with MFM and 16% of patients with DM, with DES and MYH7 variants significantly associated with the development of cardiomyopathy. Respiratory impairment was more prevalent in patients with TTN and DES variants and rare in other disorders such as GNE myopathy and dysferlinopathies, which were instead associated, together with DNAJB6-related and PLIN4-related myopathies, with the risk of losing ambulation during the disease course. DISCUSSION: The Italian cohort of patients with MFM and DM recapitulates the phenotypic heterogeneity and the partial overlap between the 2 groups. However, in relative contrast to the encountered phenotypic variability, only 5 genes accounted for most of the molecular diagnoses. Specific genetic entities are associated with significantly increased risk of developing cardiorespiratory complications or loss of ambulation, which has relevant prognostic implications.

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.

LGMD phenotype due to a new gene and dysferlinopathy investigated by next-generation sequencing.

In this issue of Neurology® Genetics, Endo et al.(1) report 3 cases of limb-girdle muscular dystrophy (LGMD) phenotype with mental retardation or hyperCKemia found by next-generation sequencing (NGS) to have a variant in the POMGNT2 gene, which has so far been recognized only as causing congenital muscular dystrophy (CMD).