RESUMEN
INTRODUCTION: Congenital myasthenic syndromes are rare. Mutations in MUSK were first described in 2004. Thirteen patients have been reported to date, mostly with a relatively mild course. The molecular diagnosis has implications for choice of treatment and genetic counseling. METHODS: Clinical course and electrophysiological, pathological, and genetic findings were assessed. RESULTS: We describe the case of a boy with prenatal onset and severe respiratory symptoms with a persisting need for ventilation. The patient had severe bulbar symptoms, marked axial weakness causing a "dropped head," and some facial and proximal weakness. Ophthalmoparesis developed during the first year of life. Salbutamol led to improvement, 3,4-diaminopyridine had a modest effect, but pyridostigmine produced deterioration. Two novel mutations in MUSK were found by whole exome sequencing. CONCLUSIONS: We expand the phenotype of congenital myasthenic syndromes with MUSK mutations, describing a more severe clinical course with prenatal onset. Predominant bulbar and respiratory weakness with facial and axial weakness and ophthalmoparesis are diagnostic clues.
Asunto(s)
Debilidad Muscular/genética , Mutación/genética , Síndromes Miasténicos Congénitos/genética , Proteínas Tirosina Quinasas Receptoras/genética , Receptores Colinérgicos/genética , Preescolar , Humanos , Masculino , Debilidad Muscular/etiología , Síndromes Miasténicos Congénitos/complicaciones , Músculos del Cuello/patologíaRESUMEN
SNURPORTIN-1, encoded by SNUPN, plays a central role in the nuclear import of spliceosomal small nuclear ribonucleoproteins. However, its physiological function remains unexplored. In this study, we investigate 18 children from 15 unrelated families who present with atypical muscular dystrophy and neurological defects. Nine hypomorphic SNUPN biallelic variants, predominantly clustered in the last coding exon, are ascertained to segregate with the disease. We demonstrate that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients' primary fibroblasts and CRISPR/Cas9-mediated mutant cell lines. Additionally, mutant nuclei exhibit defective spliceosomal maturation and breakdown of Cajal bodies. Transcriptome analyses reveal splicing and mRNA expression dysregulation, particularly in sarcolemmal components, causing disruption of cytoskeletal organization in mutant cells and patient muscle tissues. Our findings establish SNUPN deficiency as the genetic etiology of a previously unrecognized subtype of muscular dystrophy and provide robust evidence of the role of SPN1 for muscle homeostasis.