The Na+ leak-current channel (NALCN) regulates locomotion, respiration, and intellectual development. Previous work highlighted striking similarities between characteristic movement phenotypes of NALCN-deficient animals (Drosophila and Caenorhabditis elegans) and the major symptoms of Parkinson's disease and primary progressive freezing gait. We have discovered novel physiological connections between the NALCN, K+ channels, and gap junctions that mediate regulation of locomotion in C. elegans. Drugs that block K+ channels and gap junctions or that activate Ca++ channels significantly improve movement of NALCN-deficient animals. Loss-of-function of the NALCN creates an imbalance in ions, including K+ and Ca++ , that interferes with normal cycles of depolarization-repolarization. This work suggests new therapeutic strategies for certain human movement disorders. J. Comp. Neurol. 525:1109-1121, 2017. © 2016 Wiley Periodicals, Inc.

To report a patient with primary progressive freezing gait (PPFG) whose degeneration of corticofugal tract (CFT) from the supplementary motor area (SMA) was demonstrated using diffusion tensor tractography (DTT). A 66-year-old woman presented with a solitary symptom of a sudden transient break on walking (i.e., freezing gait), which slowly progressed for 4 years. Imaging evidence using magnetic resonance imaging and F-florinated-N-3-fluoropropyl-2-β-carboxymethoxy-3-β-(4-lodophenyl) nortropane positron emission tomography scanning was unremarkable, and our patient's symptom was not affected by dopamine agonist medication. Based on the clinical symptoms and imaging findings, we diagnosed our patient as having PPFG. From the patient and 20 age- and sex- matched normal controls, diffusion tensor imaging data were acquired using a 1.5 T magnetic resonance scanner. In DTT findings, the CFT from the left SMA was partially torn and thinned. Moreover, the fractional anisotropy value and tract volume of CFT from the left SMA were more than two standard deviations lower than those of normal controls. In our opinion, the lesion in the CFT from the left SMA in our patient was attributed to the occurrence of PPFG. We believe that the results of this study suggest one of the pathological mechanisms for the occurrence of gait difficulty in PPFG.