SEPN1-related Rigid Spine Muscular Dystrophy

Excerpt

To the Editor: A 7-y-old boy, born to non-consanguineous parents, presented with low-grade fever and cough for the past 3 d followed by shallow breathing efforts and decline in sensorium. He had delay in the attainment of motor milestones since early infancy. On examination, he had reduced muscle bulk, neck stiffness with restriction of neck flexion movements, rigid spine, proximal limb-girdle and intercostal weakness, hyperlaxity at metacarpophalangeal joints, bilateral shoulder and ankle contractures, with diminished muscle stretch reflexes. A clinical diagnosis of collagen VI associated muscular dystrophy was initially considered. However, in view of the rigid spine, cervico-axial weakness and progressive respiratory insufficiency, rigid spine muscular dystrophy was also considered. Investigations showed mildly elevated muscle specific creatine phosphokinase (215 U/L), normal 24 h-Holter electrocardiogram, and echocardiography and compensated respiratory acidosis (PaCO₂ between 45 to 106 mmHg) with metabolic alkalosis. Muscle biopsy was normal. Limited electromyography (biceps brachii), and nerve conduction study were normal. Targeted next-generation sequence analysis for muscular dystrophy genes revealed a previously unreported homozygous three base pair insertion c.826_827insCCT in exon 6 of the selenoprotein N1 (SEPN1) gene on chromosome 1 which resulted in an in-frame insertion of serine between codon 276 and 277 (p. Ala276_Cys277insSer) which was confirmed by Sanger sequencing and found damaging by polyphen analysis. Both parents were detected to be asymptomatic carriers of this variation using Sanger sequencing. Another unreported heterozygous missense variation in exon 1 of the KBTBD13 gene (chr15:65369293; A > A/G) was also detected that resulted in the amino acid substitution of Glycine for Glutamic acid at codon 47 (p.E47G; ENST00000432196). However, this variation in heterozygous condition was also detected in his unaffected father. Hence this variation was unlikely not to be associated with the clinical condition of the index patient. No mutations were identified in COL6A1, COL6A2 and COL6A3 genes. He required prolonged mechanical ventilation through tracheostomy tube and supportive care. Currently, at 3 y follow-up, he is well and needs intermittent positive pressure home ventilation. …