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(American Journal of Pathology. 1999;155:1901-1913.)
© 1999 American Society for Investigative Pathology

Regular Articles

Familial Encephalopathy with Neuroserpin Inclusion Bodies

Richard L. Davis^*, Peter D. Holohan, Antony E. Shrimpton^*, Arthur H. Tatum^*, John Daucher^*, George H. Collins^*, Robert Todd, Charles Bradshaw, Paul Kent, David Feiglin^§, Arthur Rosenbaum^¶, Mark S. Yerby^||, Cheng-Mei Shaw^**, Felicitas Lacbawan and Daniel A. Lawrence

From the Departments of Pathology,^*
Pharmacology,
Neurology,
Nuclear Medicine,^§
and Radiology,^¶
State University of New York Health Science Center, Syracuse, New York; the Departments of Neurology, Public Health, and Obstetrics and Gynecology,^||
Oregon Health Sciences University, Portland, Oregon; the Department of Pathology,^**
University of Washington School of Medicine, Seattle, Washington; the National Human Genome Research Institute,
National Institutes of Health, Bethesda, Maryland; and the American Red Cross Holland Laboratories,
Rockville, Maryland

We report on a new familial neurodegenerative disease with associated dementia that has presented clinically in the fifth decade, in both genders, and in each of several generations of a large family from New York State—a pattern of inheritance consistent with an autosomal dominant mode of transmission. A key pathological finding is the presence of neuronal inclusion bodies distributed throughout the gray matter of the cerebral cortex and in certain subcortical nuclei. These inclusions are distinct from any described previously and henceforth are identified as Collins bodies. The Collins bodies can be isolated by simple biochemical procedures and have a surprisingly simple composition; neuroserpin (a serine protease inhibitor) is their predominant component. An affinity-purified antibody against neuroserpin specifically labels the Collins bodies, confirming their chemical composition. Therefore, we propose a new disease entity—familial encephalopathy with neuroserpin inclusion bodies (FENIB). The conclusion that FENIB is a previously unrecognized neurodegenerative disease is supported by finding Collins bodies in a small kindred from Oregon with familial dementia who are unrelated to the New York family. The autosomal dominant inheritance strongly suggests that FENIB is caused by mutations in the neuroserpin gene, resulting in intracellular accumulation of the mutant protein.

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