NEONATAL HYPOTONIA CAN BE A SODIUM CHANNELOPATHY: RECOGNITION OF A NEW PHENOTYPE

摘要

A 23-year-old French woman had an uncomplicated labor producing a male infant by vaginal delivery (case 4-2 in the table). The initial Apgar score was 10 but very rapidly he developed generalized hypotonia with impaired suckling. Respiration was initially uncompromised.Full blood count, electrolyte profile, C-reactive protein, and blood glucose were all within normal limits. Nasogastric feeding was initiated and the infant was transferred to the pediatric neurology service.Examination on the first day found the child to be difficult to wake. Major generalized hypotonia was confirmed with only slight movement of the limbs to stimulation. Reflexes were reduced. Systemic examination was unremarkable. From the second day frequent oxygen desaturations were recorded during sleep and he required nasal oxygen therapy for 5 days. A chest x-ray was normal. Over the following week gradual spontaneous improvement occurred. On day 8 examination was normal and no further respiratory or nutritional support was required.The infant's older brother born 3 years earlier also had transient generalized hypotonia with suckling difficulties but with full recovery. At the age of 3 he began to suffer episodes of muscle paralysis triggeredby cold. The mother of the two children had also had cold exacerbated episodes of muscle stiffness (confirmed to be myotonia on EMG) and paralysis from the age of 4. Her father, grandmother, and great-grandmother experienced similar episodes.Direct DNA sequencing confirmed the presence of the missense I693T mutation in the domain II S4-5 cytoplasmic loop of the alpha subunit of the voltage-gated skeletal muscle sodium channel (Nav1.4) in affected members of this family including both cases with neonatal hypotonia. This mutation has been reported and validated as a paramyotonia congenita mutation.We have also identified the I693T sodium channel mutation in four additional cases of neonatal hypotonia with or without feeding and respiratory symptoms. These four cases are from two unrelated English families and siblings from one French family (family 3). The table oudines the clinical findings in each case. Earlier generations in families 1, 3, and 4 reported a history of paramyotonia congenita but not of neonatal hypotonia.