Neuropathy target esterase gene mutations cause motor neuron disease. S. Rainier1, M. Bui1, L. Ming1, E. Plein1, D. Thomas1, D. Tokarz1, C. Delaney1, J.W. Albers1, R.J. Richardson1,2, J.K. Fink1,3. 1) Dept. of Neurology, University of Michigan, Ann Arbor, MI 48109; 2) Toxicology Program, University of Michigan, Ann Arbor, MI 48109; 3) Geriatric Research, Education and Clinical Center, Ann Arbor Veteran's Affairs Medical Center,Ann Arbor, MI 48109.

   We evaluated two unrelated kindreds in which affected subjects exhibited autosomal recessive, slowly progressive lower extremity spastic weakness associated with wasting of distal upper and lower extremity muscles. Subjects met clinical criteria for amyotrophic lateral sclerosis (ALS) and conformed to Troyer syndrome. Magnetic resonance imaging demonstrated spinal cord atrophy and electromyography identified motor axonopathy. Genetic analysis of one consanguineous kindred suggested linkage between the disorder and a 22 cM locus on chromosome 19p13, a region containing neuropathy target esterase (NTE). Analysis of NTEs coding sequence in this family showed an M1012V mutation disrupting an inter-species conserved residue in NTEs catalytic domain in both affected individuals but not unaffected individuals or 98 control subjects. Analysis of NTEs coding sequence in the second non-consanguinous kindred showed that affected subjects were compound heterozygotes for two NTE mutations: one allele had 2826A>G mutation which causes substitution of an inter-species conserved residue R890H in NTEs catalytic domain; the other allele had a 4 bp insertion (NTE mRNA position 3104) which causes protein truncation after residue 1020. These mutations were present separately in each carrier parent and absent in 98 control subjects.
   Discovering that NTE mutations cause corticospinal and peripheral motor axon degeneration in these families indicates the importance of the NTE pathway in maintaining axonal integrity; raises the possibility that NTE pathway disturbance contributes to other motor neuron disorders including ALS and primary lateral sclerosis; and supports the role of NTE in the pathogenesis of organophosphorous compound-induced delayed neurotoxicity. Understanding the pathogenesis of NTE-mutation motor neuron disease will provide insight into the treatment of this and other motor neuron diseases.