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From the Division of Neuropathology (Drs. Manetto, Medori, and Gambetti), Institute of Pathology, Case Western Reserve University, Cleveland, OH; Clinica Neurologica dell' Università di Bologna (Drs. Cortelli, Montagna, Tinuper, Baruzzi, and Lugaresi), Bologna; Clinica Neurologica dell' Università di Verona (Dr. Rizzuto), Verona; Istituto Neurologico C. Besta (Drs. Bugiani and Tagliavini), Milano, Italy; Institutions Universitaires de Psychiatrie (Dr. Bouras), Chene-Bourg/Genève, Switzerland; Clinique Neurologique and Laboratoire de Neuropathologie R. Escourolle (Drs. Rancurel and Hauw). Hôpital de La Salpêtrière, Paris, France; and Laboratoire de Neuropathologie et de Recherche sur les Peptides du Système Nerveux, (Drs. Vanderhaeghen and Mailleux), Laboratoire d'Anatomie Pathologique et de Microscopie Electronique Universitè Libre de Bruxelles, Anderlecht, Belgium.
In 1986, we reported two anatomoclinical observations of a familial condition that we called "fatal familial insomnia" (FFI). We now present the pedigree as well as the clinical and neuropathologic findings in five new subjects. The pedigree includes 288 members from six generations. Men and women are affected in a pattern consistent with an autosomal dominant inheritance. The age of onset of the disease varies between 37 and 61 years; the course averages 13 months with a range of 7 to 25 months. Progressive insomnia (polygraphically proven in two cases); autonomic disturbances including hyperhidrosis, hyperthermia, tachycardia, and hypertension; and motor abnormalities including ataxia, myoclonus, and pyramidal dysfunction, were present in every case, but with variable severity and time of presentation. Sleep and autonomic disorders were the earliest signs in two subjects, motor abnormalities were dominant in one, and others had intermediate clinical patterns. Pathologically, all the cases had severe atrophy of the anterior ventral and mediodorsal thalamic nuclei. Other thalamic nuclei were less severely and inconsistently affected. In addition, most of the cases had gliosis of the cerebral cortex, a moderate degree of cerebellar atrophy with "torpedoes," and severe atrophy of the inferior olivary nuclei. One case also showed spongy degeneration of the cerebral cortex. We conclude that all the lesions were primary, and that FFI is a multisystem disease in which the different structures are primarily affected with different severity. The insomnia appears to correlate best with the major thalamic pathology. The possibility that FFI belongs to the group identified as prion diseases or diseases transmitted by unconventional agents is examined.
Address correspondence and reprint requests to Dr. Pierluigi Gambetti, Division of Neuropathology, Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106.
Supported by NIH Merit Award AG00795.
Received June 20, 1991. Accepted for publication in final form July 31, 1991.
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