Hereditary myopathies and myositis share similar clinical features, making diagnosis challenging. The 2017 EULAR/ACR classification criteria for idiopathic inflammatory myopathies (myositis) provide a probability score for myositis and its subtypes. This study aims to test the accuracy of these criteria in distinguishing myositis from hereditary myopathies and to identify diagnostic pitfalls. This retrospective study examined data from 105 patients diagnosed with genetically confirmed myotonic dystrophy type 1 and 2 (DM1 and DM2), facioscapulohumeral muscular dystrophy (FSHD), limb girdle muscular dystrophy (LGMD) and Duchenne and Becker muscular dystrophy (DMD and BMD). The performance of the 2017 EULAR/ACR criteria for myositis was tested on patient data to identify variables leading to misdiagnosis. Of the 105 patients with hereditary myopathy, 50% of DM1, 47.8% of DM2, 25% of FSHD, 35.3% of LGMD, 0% of BMD, and 36.4% of DMD patients were misclassified according to the 2017 EULAR/ACR criteria as having "possible", "probable" or "definite" myositis, resulting in an overall specificity of 63.8%. The most frequently proposed myositis subtype in misclassified cases was inclusion body myositis. Analysis of the individual criteria items revealed that proximal muscle weakness, increased CK, perifascicular atrophy and endomysial infiltration in the muscle biopsy were particularly misleading factors. The diagnostic challenge of differentiating between inflammatory and hereditary myopathies is reflected by the relatively low specificity of the classification criteria in this study. Relevant factors leading to misdiagnosis include similarities in clinical presentation and diagnostic findings, as well as late-onset disease manifestations, e.g., in LGMD, DM1, DM2.

Fuchs endothelial corneal dystrophy (FECD) is a heritable disorder distinguished by a progressive degeneration of the corneal endothelium. In its late-onset form, FECD has been associated with a trinucleotide repeat (TNR) expansion (CTG18.1) located in an intronic region of the TCF4 gene, whose frequency is variable among different ancestry groups. Since its discovery, studies investigating CTG18.1-mediated pathogenesis have steadily increased, yet much concerning the unique and tissue-specific clinical features of the disease, as well as its heritable mode of transmission, remain poorly understood. The field of repeat expansion disorders has greatly informed mechanistic understanding of CTG18.1-mediated FECD. In particular, molecular mechanisms underlying myotonic dystrophy type 1, attributed to a CTG expansion in the 3' UTR of the DMPK gene, have considerably informed the FECD field, despite its stark contrast in terms of multisystemic manifestations and variable age at onset. In this work, we critically discuss the non-mutually shared pathogenic parallelisms existing between the pathologies, as well as the unique molecular signatures exhibited by FECD and DM1, speculating on potential research directions for future investigations. Moreover, we discuss the few studies published over the past decade describing the occurrence of FECD in DM1 patients. Here, we debate possible shared molecular signatures that could explain FECD development as a consequence of a non-coding CTG expansion, irrespective of loci (e.g. DMPK or TCF4), and discuss experimental approaches to explain whether these pathologies share toxic mechanisms that arise from these distinct repeat elements.

This article reviews the genetic basis, pathogenic mechanisms, epidemiology, clinical presentation, multiorgan involvement, and multidisciplinary management of myotonic dystrophy type 1 (DM1) and type 2 (DM2), as well as the differential diagnosis of myotonic disorders (DM versus nondystrophic myotonic disorders) and electrical myotonia. Due to underdiagnosis, the prevalence of DM is likely higher than currently recognized. Patients with late-onset or mild phenotypes with little or no skeletal muscle involvement may never be evaluated by a neurologist and thus never diagnosed. Still, DM1 is the most common muscular dystrophy in adults. Scientific progress in understanding the pathogenic mechanism of DM and its broad and variable phenotype has facilitated the design of gene therapy clinical trials in DM1. Nucleic acid-based therapies that target expanded DNA or RNA are in early-stage clinical development. Although caused by a different genetic variation, DM2 shares a common pathogenic mechanism with DM1, which is hopeful for a cure for both subtypes. Neurologists and other clinicians need to recognize DM to ensure prompt diagnosis, effective symptom management, and prevention of life-threatening events. Life-threatening events (eg, sudden death) may occur at any time in the disease course and not necessarily in patients with more severe phenotypes. Investigational drugs may have the potential to have a greater disease-modifying effect when initiated in the early or mild stages of disease, rather than in advanced stages where the therapeutic window may have been missed.

Late-onset myopathies are defined as muscle diseases that begin after the age of 50 years. Some myopathies present classically in the elderly, whereas others may have a variable age of onset, including late-onset presentation. The purpose of this review is to summarize and comment on the most recent evidence regarding the main diagnosis of late-onset myopathies focusing on genetic causes. Although late-onset myopathies (LOM) are expected to be predominantly acquired myopathies, some common genetic myopathies, such as facioscapulohumeral muscular dystrophy (FSHD), can present late in life, usually with an atypical presentation. In addition, metabolic myopathies, which are classically early-onset diseases, are also diagnoses to be considered, particularly as they may be treatable. Late-onset multiple acyl-CoA dehydrogenase deficiency (MADD) has recently been identified as a cause of subacute LOM with a dramatic response to riboflavin supplementation. Inclusion body myositis is the most frequent of all LOM. Myotonic dystrophy type 2, FSHD and oculopharyngeal muscular dystrophy are the most frequent causes of genetic LOM. We summarize the major differential diagnoses and the clinical features on clinical examination that are suggestive of a genetic diagnosis to provide a diagnostic approach.

Cognitive deficits and abnormal cognitive aging have been associated with Myotonic dystrophy type 1 (DM1), but the knowledge of the extent and progression of decline is limited. The aim of this study was to examine the prevalence of signs of neurocognitive disorder (mild cognitive impairment and dementia) in adult patients with DM1. A total of 128 patients with childhood, juvenile, adult, and late onset DM1 underwent a screening using the Montreal Cognitive Assessment (MoCA). Demographic and clinical information was collected. The results revealed that signs of neurocognitive disorder were relatively rare among the participants. However, 23.8 % of patients with late onset DM1 (aged over 60 years) scored below MoCA cut-off (=23), and this group also scored significantly worse compared to patients with adult onset. Age at examination were negatively correlated with MoCA scores, although it only explained a small portion of the variation in test results. Other demographic and clinical factors showed no association with MoCA scores. In conclusion, our findings indicate a low prevalence of signs of neurocognitive disorder in adult patients with DM1, suggesting that cognitive deficits rarely progress to severe disorders over time. However, the performance of patients with late onset DM1 suggests that this phenotype warrants further exploration in future studies, including longitudinal and larger sample analyses.