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Role of muscle biopsy in genetic era

Resumo

Introduction: Innovations in genetic testing have revolutionized the diagnosis of hereditary myopathies. However, the detection of variants of uncertain significance makes the interpretation of some cases difficult. In addition, hereditary myopathies can mimic acquired diseases that have specific treatment, such as inflammatory myopathies. Thus, muscle biopsy may have a defining role in the diagnosis of myopathies. Here we present three cases in which the muscle biopsy allowed a diagnostic conclusion by complementing or guiding the genetic evaluation. Case 1: female infant with neonatal hypotonia and delayed motor development. NGS panel revealed heterozygous VUS in the RYR1 gene. The biopsy showed signs of neurogenic disease. New genetic testing revealed homozygous pathogenic variant in the SMN1 gene, concluding the diagnosis of spinal muscular atrophy. Case 2: 4 year old boy with neonatal hypotonia, muscle weakness, dysphagia and respiratory distress. Exome sequencing found no pathogenic variants that would justify the clinical picture. Muscle biopsy showed myotubular myopathy. A microarray detected a deletion in MTM1gene, which causes X-linked myotubular myopathy. Case 3: 12 year old male, with frequent falls, gait alteration and progressive muscle weakness. Genetic investigation of symptomatic relatives did not clarify the diagnosis. In muscle biopsy, several reducing bodies were identified. Genetic testing detected a deletion in the FHL1 gene, which causes, in addition to reducing body myopathy, Emery-Dreifuss muscular dystrophy type 6, X-linked myopathy with postural muscle atrophy and X-linked scapuloperoneal myopathy.
Discussion: The case 1 shows limitations of the exome as a tool for genetic diagnosis, as the reading depth can be variable and sometimes insufficient. In case 2, the exome did not detect the pathogenic variant because it is a copy number variation; the biopsy directed the microarray to the region of the X chromosome where the suspected gene is located, confirming the diagnosis. In case 3, the final diagnosis was guided by the histopathological finding, which suggested the causative gene; this gene, however, can cause different myopathies, and it is only possible to define the type through muscle biopsy.
Conclusion: In genetic era, muscle biopsy may play a role in diagnosing hereditary myopathies when genetic testing is inconclusive.

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Doenças Neuromusculares