Novel cofilin-2 (CFL2) four base pair deletion causing nemaline myopathy

Nemaline myopathy is one of the major subtypes of congenital myopathy and is known to be caused by mutations in nine genes including cofilin-2 ( CFL2 ).1 Typical nemaline myopathy presentations include proximal weakness, hypotonia, respiratory difficulties and facial weakness.1 This study was approved by The University of Western Australia Human Research Ethics Committee with written consent from patients. After an uneventful birth the proband was admitted to the intensive care unit (ICU) with respiratory distress, although he did not require mechanical ventilation and was discharged after 5 days. A few weeks later he was readmitted following recurrent episodes of apnoea lasting seconds, associated with cyanosis. Most episodes presented after feeding and were aborted by stimulation. Upon admission to ICU, hypotension and respiratory acidosis were detected and orotracheal intubation and mechanical ventilation initiated. After correcting metabolic disturbances, the patient remained hypotonic, though fully awake and alert when taken off sedation. Extraocular movements were estimated to be normal and deep tendon reflexes were present. Head circumference was on the third centile. Extubation failed and the patient required 24-h continuous ventilation support before passing away at 12 months. Nerve conduction studies, MRI, EEG and echocardiography were normal. An electromyograph (EMG) showed apparent myotonic discharges and serum creatine kinase (CK) was mildly elevated. The proband was Saudi Arabian and his parents were first cousins (figure 1A). Two cousins of the proband (figure 1A III:3 and III.4) had a similar disease, both requiring 24-h mechanical ventilation. One cousin (III:3) passed away at 14 months, while the 10-month-old brother (III:4) is still on 24-h ventilation. Due to the severity of the disease in the proband, diagnostic mutation analysis of SMN1 and ACTA1 was performed, but both were excluded. Figure 1 Genetic, histological and immunohistochemical analysis of the CFL2 variant identified through whole exome sequencing. (A) Partial pedigree …