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Inherited prion encephalopathy associated with the novel PRNP H187R mutation

A clinical study

From the National Institute of Neurological Disorders and Stroke (Drs. Bütefisch, Park, Hallett, and Goldfarb), National Institutes of Health, Bethesda, and the American Red Cross J.H. Holland Laboratory (Dr. Cervenakova), Rockville, Maryland; and Department of Pathology (Dr. Gambetti), Case Western Reserve University School of Medicine, Cleveland, Ohio.

Address correspondence and reprint requests to Dr. L.G. Goldfarb, National Institutes of Health, 10 Center Dr., MSC 1361, Bldg. 10, Rm. 4B37, Bethesda, MD 20892-1361; e-mail: goldfarb{at}codon.nih.gov

OBJECTIVE: To describe a variant of prion encephalopathy associated with the recently identified H187R mutation in the prion protein (PRNP) gene.

METHODS: The authors studied a multigenerational American family with nine affected individuals. Clinical examination included imaging, EEG, and CSF analysis with 14-3-3 protein testing. Histopathology was characterized by examination of a brain biopsy from an H187R mutation-positive patient.

RESULTS: The disease in this family is caused by the PRNP H187R mutation and characterized by autosomal dominant inheritance, median age at disease onset of 42 years (range 33 to 50 years), and median duration of illness of 12 years (range 8 to 19 years). Clinical signs include progressive dementia, ataxia, myoclonus, and seizures. Histopathologic features consist of distinctive "curly" prion protein deposits with a strictly laminar distribution in the cerebral cortex and minimal astrogliosis in the absence of amyloid plaques or spongiosis.

CONCLUSION: A variant of prion encephalopathy associated with the novel H187R mutation in the PRNP gene displays distinctive clinical and immunostaining characteristics that further expand the boundaries of human prion disease.

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