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Introduction/aims: In our experience, patients with late-onset facioscapulohumeral muscular dystrophy type 1 (FSHD1) are frequently misdiagnosed, some for many years. The aim of this report is to document this clinical experience including the presenting symptoms and misdiagnoses and to discuss the challenges in diagnosing patients with late-onset FSHD1., Methods: We performed a retrospective medical record review and recorded clinical data on patients with a genetically confirmed diagnosis of FSHD1, who began to have symptoms at 50 years of age or older, and either had no family history of FSHD1 or had a history of an undiagnosed weakness in a family member., Results: Thirteen patients, 7 men and 6 women, met the study inclusion criteria. Age of onset ranged from 52 to 74 (mean, 59.8) years, age of diagnosis ranged from 54 to 80 (mean, 66.5) years, and duration of symptoms from onset to diagnosis was 1 to 15 (mean, 6.7) years. Prior diagnoses included lumbosacral polyradiculopathy in five (38%); statin-related myopathy in two (15%); and one each of polymyositis, inclusion-body myositis, distal myopathy, limb-girdle muscular dystrophy, unspecific myopathy, and unspecified scapular winging. For eight patients (62%), family history was suspected in deceased members or if by confirmed DNA test postdiagnosis., Discussion: The diagnosis of late-onset FSHD1 is often delayed by many years with patients frequently receiving misdiagnoses. FSHD1 may not be considered in the differential diagnosis of late-onset weakness due to its rarity and because its clinical features are subtler, nonspecific, and mimic other neuromuscular disorders., (© 2023 Wiley Periodicals LLC.)

The diagnostic evaluation of a patient with suspected hereditary muscle disease can be challenging. Clinicians rely largely on clinical history and examination features, with additional serological, electrodiagnostic, radiologic, histopathologic, and genetic investigations assisting in definitive diagnosis. Hematological testing is inexpensive and widely available, but frequently overlooked in the hereditary myopathy evaluation. Hematological abnormalities are infrequently encountered in this setting; however, their presence provides a valuable clue, helps refine the differential diagnosis, tailors further investigation, and assists interpretation of variants of uncertain significance. A diverse spectrum of hematological abnormalities is associated with hereditary myopathies, including anemias, leukocyte abnormalities, and thrombocytopenia. Recurrent rhabdomyolysis in certain glycolytic enzymopathies co-occurs with hemolytic anemia, often chronic and mild in phosphofructokinase and phosphoglycerate kinase deficiencies, or acute and fever-associated in aldolase-A and triosephosphate isomerase deficiency. Sideroblastic anemia, commonly severe, accompanies congenital-to-childhood onset mitochondrial myopathies including Pearson marrow-pancreas syndrome and mitochondrial myopathy, lactic acidosis, and sideroblastic anemia phenotypes. Congenital megaloblastic macrocytic anemia and mitochondrial dysfunction characterize SFXN4-related myopathy. Neutropenia, chronic or cyclical, with recurrent infections, infantile-to-childhood onset skeletal myopathy and cardiomyopathy are typical of Barth syndrome, while chronic neutropenia without infection occurs rarely in DNM2-centronuclear myopathy. Peripheral eosinophilia may accompany eosinophilic inflammation in recessive calpainopathy. Lipid accumulation in leukocytes on peripheral blood smear (Jordans' anomaly) is pathognomonic for neutral lipid storage diseases. Mild thrombocytopenia occurs in autosomal dominant, childhood-onset STIM1 tubular aggregate myopathy, STIM1 and ORAI1 deficiency syndromes, and GNE myopathy. Herein, we review these hereditary myopathies in which hematological features play a prominent role., (© 2022 Wiley Periodicals LLC.)

Background: Hereditary myopathy with lactic acidosis (HML) is an autosomal recessive disease caused by an intron mutation in the iron-sulfur cluster assembly (ISCU) gene. The mutation results in aberrant splicing, where part of the intron is retained in the final mRNA transcript, giving rise to a truncated nonfunctional ISCU protein. Using an ISCU mini-gene system, we have previously shown that PTBP1 can act as a repressor of the mis-splicing of ISCU, where overexpression of PTBP1 resulted in a decrease of the incorrect splicing. In this study, we wanted to, in more detail, analyze the role of PTBP1 in the regulation of endogenous ISCU mis-splicing., Methods: Overexpression and knockdown of PTBP1 was performed in myoblasts from two HML patients and a healthy control. Quantification of ISCU mis-splicing was done by qRTPCR. Biotinylated ISCU RNA, representing wildtype and mutant intron sequence, was used in a pull-down assay with nuclear extracts from myoblasts. Levels of PTBP1 in human cell lines and mice tissues were analyzed by qRTPCR and western blot., Results: PTBP1 overexpression in HML patient myoblasts resulted in a substantial decrease of ISCU mis-splicing while knockdown of PTBP1 resulted in a drastic increase. The effect could be observed in both patient and control myoblasts. We could also show that PTBP1 interacts with both the mutant and wild-type ISCU intron sequence, but with a higher affinity to the mutant sequence. Furthermore, low levels of PTBP1 among examined mouse tissues correlated with high levels of incorrect splicing of ISCU., Conclusion: Our results show that PTBP1 acts as a dominant repressor of ISCU mis-splicing. We also show an inverse correlation between the levels of PTBP1 and ISCU mis-splicing, suggesting that the high level of mis-splicing in the skeletal muscle is primarily due to the low levels of PTBP1., (© 2018 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Introduction: Hereditary myopathies with early respiratory insufficiency as a predominant feature of the clinical phenotype are uncommon and underestimated in adults., Methods: We reviewed the clinical and laboratory data of patients with hereditary myopathies who demonstrated early respiratory insufficiency before the need for ambulatory assistance. Only patients with disease-causing mutations or a specific histopathological diagnosis were included. Patients with cardiomyopathy were excluded., Results: We identified 22 patients; half had isolated respiratory symptoms at onset. The diagnosis of the myopathy was often delayed, resulting in delayed ventilatory support. The most common myopathies were adult-onset Pompe disease, myofibrillar myopathy, multi-minicore disease, and myotonic dystrophy type 1. Single cases of laminopathy, MELAS (mitochondrial encephalomyopathy with lactic acidosis and strokelike events), centronuclear myopathy, and cytoplasmic body myopathy were identified., Conclusion: We highlighted the most common hereditary myopathies associated with early respiratory insufficiency as the predominant clinical feature, and underscored the importance of a timely diagnosis for patient care. Muscle Nerve 56: 881-886, 2017., (© 2017 Wiley Periodicals, Inc.)