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BK Helsinger, KC Golnik, H Dimashkieh, GM de Courten-Myers; Divergence Weakness in Fatal Familial Insomnia . Invest. Ophthalmol. Vis. Sci. 2002;43(13):1468.
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Purpose: To report an association between divergence weakness and fatal familial insomnia Methods: A father and son complained of double vision and underwent ophthalmologic examination. Brain histopathology was obtained at autopsy. Western blot analysis using the monoclonal antibody (3F4) to the prion protein was performed, looking for protease resistant prion protein (PrPres). Polymerase chain reaction amplification of the coding region of the prion protein gene, followed by sequence analysis, was done, looking for the point mutation at codon 178 which is present in fatal familial insomnia. This mutation results in an asparagine-for-aspartic acid substitution (D178N). Codon 129 was also analyzed for the presence of a methionine (Met) coding triplet in the mutant allele. The D178N mutation, coupled with Met at codon 129, confirms the diagnosis of fatal familial insomnia. Results: Ophthalmologic examination was normal except for divergence weakness in both patients. Microscopic evaluation of stained sections of the son's brain at autopsy revealed PAS+ granules in neurons and glia in the periacqueductal gray and raphe nucleus of the mesencephalon, multifocal cortical regions in layers III, V, and VI, basal ganglia, superior and inferior olives, and posterior horns of the spinal cord. These areas also stained positive for glial fibrillary acidic protein. Electron microscopy showed neurons with large aggregates of stored granules consisting of large, cytoplasmic, membrane-bound, globoid, osmophilic aggregates. The granules tended to form fingerprint bodies, and they autoflouresced under UV light. An initial diagnosis of adult neuronal ceroid lipofuscinosis was made; however, subsequent findings in the patient's father led to further evaluation. The father's autopsy showed mild hydrocephalus and leptomeningeal fibrosis. Microscopic examination revealed bilaterally symmetrical loss of neurons and gliosis in the dorsomedial thalamic nuclei. There was also severe atrophy and gliosis of the inferior olives bilaterally and of the dentate nucleus. The cerebral cortex appeared unremarkable except for a small focus of spongiform change in the visual cortex. The histopathology suggested fatal familial insomnia. DNA analysis detected PrPres in focal areas of the occipital cortex. The D178N mutation was present, and the patient was homozygous Met/Met at codon 129. The son's DNA analysis, done in retrospect, showed PrPres with the D178N mutation and Met/Val heterozygosity at codon 129. Conclusion: Both father and son had fatal familial insomnia and divergence weakness.
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