A Study On Clinics, Pathology And Gene Mutation Of Fatal Familial Insomnia In A Family Of Hubei Province

【Background】 Fatal familial insomnia (FFI) is an inherited (autosomaldominant) prion disease in which asparagine is substituted for aspartic acid at the178codon of the PrNP gene. The chief clinical features of FFI include a progressive andferocious insomnia, waking―sleep,‖hallucinations, autonomic disturbancessuggestive of sympathetic overdrive (tachycardia, hypertension, hyperhidrosis,hyperthermia), a rise in circulating catecholamine levels, cognitive changes (such asattentional disturbance and short-term memory deficits without a loss in generalintelligence), motor system deficits (ataxia), and endocrine manifestations. Latercognitive changes involve a confusional state resembling dementia and, ultimately,death. The average age of the disease is approximately50years, with most casesoccurring between age20and61.The typical duration of FFI is between7and36months, and18months on average. The neuropathologic manifestations of FFIinclude thalamic degeneration, with selective involvement of the anterior ventral andmediodorsal thalamic nuclei, inferior olivary and cerebellar changes, and somespongiform changes of the cerebral cortex. The diagnosis of this disease currentlyrelies mainly on the clinical,pathological changes, and other comprehensiveconsideration. At present, although understanding of the disease has been furthered,its exact pathogenesis still remains unclear. Recently, in order to seek new diagnosis,treatment, and prevention methods，many scholars discuss its pathogenesis from protein level, genetic and gene mutations.However, there is few reports about FFI both at home and abroad, especially inforensic medicine profession. Focusing on the first FFI home of Hubei province inforensic work, this paper trys to provide theoretical guidance for the forensicidentification workbased on analysis clinical application, HE dyed,immunohistochemical techniques, prion gene sequencing, pedigree survey technologyfor further study of the FFI etiology, clinical manifestation, pathological changes,gene characteristics, pathogenesis, and diagnosis【Objective】 To provide reference material for forensic pathologyidentification and understanding of the FFI, this paper applies clinical analysis, HEdyed, immunohistochemical techniques, prion gene sequencing, pedigree surveytechnology with a FFI pedigree which is the first FFI home of Hubei province inforensic work.【Materials and Methods】 This paper chooses FFI family case material, firstlicense brain specimens, the normal temperature preservation of the wax and slice aswell as the blood of the first license and her relatives from the Department of ForensicScience, Tongji Medical College, Huazhong University of Science and Technology asanalysis objects. The brain specimens of10%formalin fixed liquid, paraffin,conventional slice, HE dyeing and immunohistochemical: Congo red stain, Schiffreaction technique of-(PAS), medullary phospholipids alkaline protein (MBP), CD68,CD43, CD20, CD3, CD79a, NF dyeing, dyeing the analysis. Gene sequencingtechnology on the proband and family members of blood to the prion protein genesequence analysis, and sequencing results were analyzed.【Results】1. Family survey: mother of the proband died have similarsymptoms, a high index of suspicion for the FFI, but it can not be verified; the proband’s aunt also had similar symptoms, insomnia symptoms, but during the dayshe can work and live a normal life.2. Carcasses and pathological changes of theproband: the brain, especially the hypothalamic neuronal degeneration, nerve cell lossand gliosis; cerebellar Purkinje cells decreased or was condensed, denatured;Immunohistochemistry: the right frontal pole, thalamus Congo red (-); thalamus andputamen some neurons lipofuscin granules show the PAS (+); no PrP amyloidplaques.4. Genetic characteristics: PRNP of the proband and her aunt532G mutationinto A, in which178amino acids-aspartic acid (Asp, where the sequence of basesGAC) was mutated to asparagine (Asn, where the sequence of bases AAC), that isD178N mutation, the mutation and129methionine (Met, where the sequence of basesATG) chain, in line with the characteristics of the human FFI gene mutation.【Conclusion】1. In Hubei province, we found the first FFI pedigree, which isthe second case in mainland of China.2. The neuropathological changes of theproband in the family are hypothalamic neurons, demyelination and gliosis, and theyare the same with what described in foreign reports.3The diagnosis of prion proteingene sequence is more reliable, so it could be considered when suspicious cases areappeared.