Novel intronic mutation in MTM1 detected by RNA analysis in a case of X-linked myotubular myopathy
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Abstract:
X-linked myotubular myopathy (XLMTM) is a rare neuromuscular condition that presents with neonatal hypotonia and weakness and is associated with severe morbidities (including wheelchair, feeding tube, and ventilator dependence) and early death.1 It is defined by muscle biopsy features, including central nuclei, abnormal oxidative stain distribution, and type I fiber hypotrophy.2 Mutations in myotubularin ( MTM1 ) account for all genetically solved cases of XLMTM, but have not been discovered in all individuals with characteristic clinical and biopsy features.3 Of note, there are some forms of autosomal centronuclear myopathy that can resemble XLMTM, such as those associated with mutations in BIN1 , DNM2 , RYR1 , and SPEG , although rarely are such cases a complete phenocopy of XLMTM.4 In this study, we present a case that illustrates the importance of considering noncoding mutations as a cause of XLMTM and illustrate the utility of RNA analysis in individuals with a phenotype suggestive of a particular genetic diagnosis. Acknowledgment: The authors thank Etsuko Tsuchiya for assistance for REB and Valerion Therapeutics for support of longitudinal natural history study.Keywords:
Congenital myopathy
Phenocopy
Congenital muscle fiber type disproportion (CFTD) has been described as a form of congenital myopathy characterized by the smallness and marked predominance of type 1 fibers in a muscle biopsy. Clinical manifestations include hypotonia, nonprogressive muscle weakness, joint contractures, and skeletal deformities. However, it has also been noted that the same pathologic alterations appeared in clinically diverse conditions. Recently, we experienced a family, a mother and two children, in which a muscle biopsy showed the mother to have muscle fiber type disproportion. This case was unusual in that there was a significant progression of weakness, an absence of neonatal hypotonia, and other commonly associated musculo-skeletal deformities. In this report, we describe the clinicopathologic features of the family with a brief review about muscle fiber type disproportion.
Muscle contracture
Congenital myopathy
Proximal muscle weakness
Muscle Hypotonia
Muscle weakness
Nemaline myopathy
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Histopathological striated muscle examination is one of the most important and sensitive tests in diagnosis of muscle and/or nerve diseases. Although muscle biopsy is a relatively easy procedure, it is not frequently performed in small animal practice conditions. Different biopsy techniques have been described in veterinary literature. Punch biopsy of striated muscle appears to be a less invasive and quicker method in comparison with traditional surgical excision technique. Additionally, punch biopsy provide good quality and adequate amount of muscle tissue for diagnostic histopathological evaluation. The aim of this study is to describe striated muscle punch biopsy technique and to encourage use of it under the conditions of small animal practice. The described biopsy method can be specially advantageous in screening of inherited muscle diseases in affected litters or even wider animal population.
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Congenital myopathy
Compound heterozygosity
Central core disease
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ABSTRACT Introduction : The utility of repeat muscle biopsy has not been adequately evaluated. Methods : A retrospective review was undertaken of 144 repeat muscle biopsies performed from 1980 to 2017. Repeat biopsy was considered clinically relevant if it provided a new diagnosis, changed the existing diagnosis, or led to treatment changes or further investigations. Results : Repeat biopsy was abnormal in 118 cases, different from the initial biopsy in 67 cases, and specific in 40 cases. Factors with a significant effect on clinical relevance of the repeat biopsy ( P < 0.05) were an abnormal, specific, or inflammatory initial biopsy, proximal muscle weakness, absence of myalgia, and a repeat biopsy that is different, specific, or consistent with polymyositis or inclusion body myositis. Conclusions : Utility of repeat biopsy was limited to weak patients whose initial biopsy showed inflammatory myositis. Ongoing advances in the diagnosis of immune inflammatory myopathies have led to evolution of the role of repeat biopsy. Muscle Nerve , 2019
Nerve biopsy
myalgia
Inclusion body myositis
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Kyphoscoliosis
Congenital myopathy
Frontal Bossing
Abnormality
Muscle Hypotonia
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Muscular dystrophies are progressive, genetic disorders of muscle degeneration. The current gold standard for diagnosis is muscle biopsy or genetic studies. Muscle biopsy is an invasive procedure and genetic testing facilities are available only in a few centers. Thus, a diagnostic test that is easily available, simpler, and less invasive is desirable. Over the past 2 decades, skin biopsy has been evolving as a suitable option. Two cases of sarcoglycanopathy are described here, which have been correctly diagnosed by skin biopsy. Muscle biopsy has been used as the gold-standard diagnostic method. Skin biopsy can substitute for muscle biopsy as the preliminary diagnostic tool directing appropriate molecular testing. However, these results require validation in studies with an adequate sample size. This holds promise for the future when repeated biopsies will be required for evaluating protein rescue in trials of novel treatment options in these disorders.
Gold standard (test)
Skin biopsy
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The size and quality of muscle specimens obtained by use of a percutaneous biopsy technique were studied. All biopsies were performed under local anesthesia, using an 11-gauge biopsy needle. The mean +/- SEM size of specimens obtained from 128 biopsies of the semitendinosus muscles of 16 Alaskan Huskies was 23.8 +/- 4.4 mg. All biopsy specimens were of sufficient quality to permit histochemical differentiation of the fiber types by use of myosin ATPase staining. An additional 8 biopsy specimens were obtained from 1 dog and analyzed for muscle glycogen content. These specimens contained 50.6 +/- 7.2 mmol of glucose/kg of muscle wet weight. This modified biopsy procedure was free of notable complications, and repeatable use produced specimens of adequate size and quality for histologic and biochemical analysis. It is concluded that this procedure is a safe and reliable alternative to open biopsy for diagnosis and management of neuromuscular, metabolic, and nutritional myopathies.
Muscle fibre
Myosin ATPase
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Congenital muscular dystrophy
Muscle contracture
Muscle weakness
Presentation (obstetrics)
Muscle disorder
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Muscle biopsy is often incorrectly performed despite the fact that it is a relatively simple procedure. A consistently reproducible surgical technique in 93 open vastus lateralis muscle biopsies implemented in conjunction with neuromuscular and malignant hyperthermia research demonstrated 14 cases of malignant hyperthermia and a variety of forms of neuromuscular pathology. No wound complications or disabilities have resulted from this procedure. The procedure includes careful selection of biopsy site, regional anesthesia, atraumatic dissection, and immediate processing of the biopsy sample. A new muscle biopsy clamp is described. The authors recommend the vastus lateralis for the biopsy site unless another area of involvement is specifically indicated. Careful attention to technical details is required for optimal results.
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Abstract The ryanodine receptor RyR1 is the main sarcoplasmic reticulum Ca 2+ channel in skeletal muscle and acts as a connecting link between electrical stimulation and Ca 2+ -dependent muscle contraction. Abnormal RyR1 activity compromises normal muscle function and results in various human disorders including malignant hyperthermia, central core disease, and centronuclear myopathy. However, RYR1 is one of the largest genes of the human genome and accumulates numerous missense variants of uncertain significance (VUS), precluding an efficient molecular diagnosis for many patients and families. Here we describe a recurrent RYR1 mutation previously classified as VUS, and we provide clinical, histological, and genetic data supporting its pathogenicity. The heterozygous c.12083C>T (p.Ser4028Leu) mutation was found in thirteen patients from nine unrelated congenital myopathy families with consistent clinical presentation, and either segregated with the disease in the dominant families or occurred de novo. The affected individuals essentially manifested neonatal or infancy-onset hypotonia, delayed motor milestones, and a benign disease course differing from classical RYR1 -related muscle disorders. Muscle biopsies showed unspecific histological and ultrastructural findings, while RYR1 -typical cores and internal nuclei were seen only in single patients. In conclusion, our data evidence the causality of the RYR1 c.12083C>T (p.Ser4028Leu) mutation in the development of an atypical congenital myopathy with gradually improving motor function over the first decades of life, and may direct molecular diagnosis for patients with comparable clinical presentation and unspecific histopathological features on the muscle biopsy.
Central core disease
Congenital myopathy
Malignant hyperthermia
Muscle disorder
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