NALCN Dysfunction as a Cause of Disordered Respiratory Rhythm With Central Apnea.

Abstract

The sodium leak channel nonselective protein (NALCN) is a regulator of the pacemaker neurons that are responsible for rhythmic behavior (including respiration), maintaining the resting membrane potential, and are required for action potential production. <i>NALCN</i>-null mice show early death associated with disrupted respiratory rhythms, characterized by frequent and profound apneas. We report 3 children (2 siblings) with compound heterozygous mutations in <i>NALCN</i> associated with developmental impairment, hypotonia, and central sleep-disordered breathing causing apneas. Supplemental oxygen normalized the respiratory rhythm. <i>NALCN</i> mutations have been previously reported to cause severe hypotonia, speech impairment, and cognitive delay as well as infantile neuroaxonal dystrophy and facial dysmorphism. Nonsynonymous changes in the 2 affected extracellular loops may be responsible for the deleterious effect on the stability of the respiratory rhythm. Although oxygen is known to be a stabilizer of respiratory rhythm in central apnea in children, its role in NALCN dysfunction requires further investigation.