DISCORDANT CLINICOPATHOLOGIC PHENOTYPES IN A JAPANESE KINDRED OF FATAL FAMILIAL INSOMNIA

The GAC→AAC mutation at codon 178 (D178N) of prion protein (PrP) gene ( PRNP ) results in 2 distinct clinicopathologic phenotypes dependent on codon 129 polymorphism of the mutant allele: fatal familial insomnia (FFI) with methionine encoded in codon 129 and familial Creutzfeldt-Jakob disease (CJD) with valine.1,2 However, some D178N patients who had homozygosity for methionine at codon 129 (D178N-129MM) were reported recently to have the CJD phenotype.3–5 The cause for these clinicopathologic diversities is unclear. We report a Japanese son–mother pair who presented with FFI and CJD phenotypes. ### Case reports. #### Patient 1 (proband). A 54-year-old man, born to nonconsanguineous parents, developed dysphagia and loss of appetite. Later, he showed peculiar movement in sleep, followed by insomnia and hypersomnolence. Diplopia, intention tremor, ataxic gait, sleep apnea, fluctuant low-grade fever, tachycardia, hyperhidrosis, constipation, and impotence also followed. He was admitted to hospital 7 months after the onset of symptoms. Neurologic examination showed mild memory disturbance, cerebellar ataxia, myoclonus, brisk deep tendon reflexes, sleep apnea, and dysautonomia. He did not show akinetic mutism. He moved continuously during sleep. EEG showed no periodic synchronous discharge (PSD), and polysomnography showed loss of deep sleep and marked reduction of REM sleep. Brain MRI showed only mild atrophy. In the cerebral cortex and thalamus, hypoperfusion and hypometabolism were detected by SPECT with 99mTc-ECD and PET with 18F-2-fluorodeoxy-d-glucose. He died 13 months after the onset of symptoms. PRNP analysis, with informed consent, on leukocyte DNA showed D178N-129MM. Histologic examination showed spongiform changes limited to the cingulate gyrus and subiculum, and severe neuronal loss and fibrillary gliosis in the centromedian and dorsomedial nucleus of the thalamus and in the inferior olivary nucleus (figure, A, D, and G). Immunohistochemical analysis showed no pathologic PrP (PrPSc) deposition in the cerebral cortex, thalamus, or inferior olivary nucleus. Western blot analysis (WB) showed very …