Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy in humans and has been associated with a partial duplication of chromosome 17 (CMT type 1A). We have generated a transgenic rat model of this disease and provide experimental evidence that CMT1A is caused by increased expression of the gene for peripheral myelin protein-22 (PMP22, gas-3). PMP22-transgenic rats develop gait abnormalities caused by a peripheral hypomyelination, Schwann cell hypertrophy (onion bulb formation), and muscle weakness. Reduced nerve conduction velocities closely resemble recordings in human patients with CMT1A. When bred to homozygosity, transgenic animals completely fail to elaborate myelin. We anticipate that the CMT rat model will facilitate the identification of a cellular disease mechanism and serve in the evaluation of potential treatment strategies.

SummaryStiff-Man syndrome (SMS) is a rare disease of the central nervous system (CNS) characterized by progressive rigidity ofthe body musculature with superimposed painful spasms. An autoimmune origin of the disease has been proposed . In a caseload of more than 100 SMS patients, 60% were found positive for autoantibodies directed against the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD). Few patients, all women affected by breast cancer, were negative for GAD autoantibodies but positive for autoantibodies directed against a 128-kD synaptic protein.We report here that this antigen is amphiphysin . GAD and amphiphysin are nonintrinsic membrane proteins that are concentrated in nerve terminals, where a pool of both proteins is associated with the cytoplasmic surface of synaptic vesicles. GAD and amphiphysin are the only two known targets of CNS autoimmunity with this distribution. This finding suggests a possible link between autoimmunity directed against rytoplasmic proteins associated with synaptic vesicles and SMS.

These cases highlight the expanding spectrum of both PERM and anti-neuronal antibodies. Testing for DPPX antibodies should be considered in the diagnostic workup of patients with acquired hyperekplexia, cerebellar ataxia, and stiffness, because such patients might benefit from immunotherapy. Further studies are needed to elucidate both the entire clinical spectrum associated with DPPX antibodies and their role in pathogenesis.