Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration. Brain 131

Recessive Charcot-Marie-Tooth disease type-4J (CMT4J) and its animalmodel, the pale tremormouse (plt), are caused bymutations of the FIG4 gene encoding a PI(3,5)P2 5-phosphatase.We describe the 9-year clinical course of CMT4J, including asymmetric, rapidly progressive paralysis, in two siblings. Sensory symptoms were absent despite reduced numbers of sensory axons. Thus, the phenotypic presentation of CMT4J clinically resembles motor neuron disease.Time-lapse imaging of fibroblasts from CMT4J patients demonstrates impaired traffick-ing of intracellular organelles because of obstruction by vacuoles. Further characterization of pltmice identified axonal degeneration in motor and sensory neurons, limited segmental demyelination, lack of TUNEL staining and lack of accumulation of ubiquitinated protein in vacuoles of motor and sensory neurons.This study repre-sents the first documentation of the natural history of CMT4J. Physical obstruction of organelle trafficking by vacuoles is a potential novel cellular mechanism of neurodegeneration