CMT 4J: Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degen

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Brain. 2008 Jun 12.

Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal

degeneration.

Zhang X, Chow CY, Sahenk Z, Shy ME, Meisler MH, Li J.

Department of Neurology, Wayne State University, School of Medicine,

Detroit, MI, Department of Human Genetics, University of Michigan,

Ann Arbor, MI, Columbus Children's Research Institute, Department of

Neurology, Ohio State University, Columbus, OH and D. Dingell VA

Medical Center, Detroit, MI, USA.

Recessive Charcot-Marie-Tooth disease type-4J (CMT4J) and its animal

model, the pale tremor mouse (plt), are caused by mutations of the

FIG4 gene encoding a PI(3,5)P(2) 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 trafficking of intracellular organelles because

of obstruction by vacuoles.

Further characterization of plt mice 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 represents the first documentation of the natural history

of CMT4J. Physical obstruction of organelle trafficking by vacuoles

is a potential novel cellular mechanism of neurodegeneration.