title: SEPN1-related myopathy in three patients: novel mutations and diagnostic clues.
abstract: Mutations in SEPN1 cause selenoprotein N (SEPN)-related myopathy (SEPN-RM) characterized by early-onset axial and neck weakness, spinal rigidity, respiratory failure and histopathological features, ranging from mild dystrophic signs to a congenital myopathy pattern with myofibrillar disorganization. We report on clinical and instrumental features in three patients affected with a congenital myopathy characterized by prevalent neck weakness starting at different ages and mild myopathy, in whom we performed diagnosis of SEPN-RM. The patients presented myopathic signs since their first years of life, but the disease remained unrecognized because of a relatively benign myopathic course. In two cases, myopathic features were stable after 2 years of follow-up, but respiratory involvement worsened. The muscle MRI and muscle biopsy showed a typical pattern of SEPN-RM. Molecular diagnosis revealed two novel homozygous mutations in SEPN1, c.1176delA and c.726_727InsTCC.
  
  
  CONCLUSIONS
  This report underlines the clinical diagnostic clues of early neck and axial weakness to suspect a SEPN-RM and the usefulness of muscle MRI in conjunction with clinical features to achieve the diagnosis. Our data confirm the slow progression of respiratory involvement in spite of the relatively stable course of myopathy. We report two previously undescribed mutations in SEPN1.
  
  
  BACKGROUND
  • Mutations in SEPN1 cause myopathy characterized by early-onset axial and neck weakness spinal rigidity and respiratory failure. • SEPN-related myopathies have been initially associated with four distinct histopathological entities that however appear more mixed in recently described cases. What is New: • SEPN-related myopathies can remain unrecognized because of the normal early motor development and relatively benign myopathic course of the disease. • Our study adds two novel homozygous mutations to the number of reported pathogenic SEPN1 variants.
authors.affiliation: Unit of Child Neurology, Foundation IRCCS C.Besta Neurological Institute, Milan, Italy. anna.ardissone@istituto-besta.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Ardissone
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS C.Besta Neurological Institute, Milan, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Bragato
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS C.Besta Neurological Institute, Milan, Italy.
authors.forename: Flavia
authors.initials: F
authors.lastname: Blasevich
authors.affiliation: Neuroradiology Unit, Foundation IRCCS C.Besta Neurological Institute, Milan, Italy.
authors.forename: Elio
authors.initials: E
authors.lastname: Maccagnano
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS C.Besta Neurological Institute, Milan, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Salerno
authors.affiliation: Unit of Child Neurology, Foundation IRCCS C.Besta Neurological Institute, Milan, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Gandioli
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS C.Besta Neurological Institute, Milan, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Morandi
authors.affiliation: Neuromuscular Diseases and Neuroimmunology Unit, Foundation IRCCS C.Besta Neurological Institute, Milan, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Mora
authors.affiliation: Unit of Child Neurology, Foundation IRCCS C.Besta Neurological Institute, Milan, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Moroni
mesh_terms: D000293:Adolescent; D001921:Brain / Q000000981:diagnostic imaging; D002648:Child; D002675:Child, Preschool; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000175:diagnosis*; D009334:Neck Muscles / Q000002:abnormalities*; D012131:Respiratory Insufficiency / Q000209:etiology; D051140:Selenoproteins / Q000235:genetics*
chemical_list: D009124:Muscle Proteins; C435489:SELENON protein, human; D051140:Selenoproteins
keywords: Congenital myopathy; Dropped head syndrome; Muscle MRI; SEPN-RM; SEPN1