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Brain Advance Access originally published online on June 12, 2008
Brain 2008 131(8):1990-2001; doi:10.1093/brain/awn114
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© The Author (2008). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration

Xuebao Zhang1, Clement Y. Chow2, Zarife Sahenk3,4, Michael E. Shy1, Miriam H. Meisler2 and Jun Li1,5

1Department of Neurology, Wayne State University, School of Medicine, Detroit, MI, 2Department of Human Genetics, University of Michigan, Ann Arbor, MI, 3Columbus Children's Research Institute, 4Department of Neurology, Ohio State University, Columbus, OH and 5John D. Dingell VA Medical Center, Detroit, MI, USA

Correspondence to: Jun Li, MD, PhD, Department of Neurology, Wayne State University School of Medicine, Detroit, MI 48201 E-mail: junli{at}med.wayne.edu

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)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 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.

Key Words: FIG4 or SAC3 gene; PI(3,5)P2-5-phosphatase; neuronopathy; axonal degeneration; vacuoles; amyotrophic lateral sclerosis; motor neuron disease; segmental demyelination; Schwann cells

Abbreviations: CMT4B1, Charcot-Marie-Tooth type 4B1; CMT4J, Charcot-Marie-Tooth disease type-4J; DRG, dorsal root ganglion; EMG, electromyogram; IHC, immunohistochemistry; MAG, myelin-associated glycoprotein; MND, motor neuron disease; NCS, nerve conduction studies; NF, neurofilament; NFp, phosphorylated neurofilaments; VAPB, vesicle-associated membrane protein-associated protein-B; VCP, valosin-containing protein

Received March 21, 2008. Revised May 2, 2008. Accepted May 12, 2008.


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