Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917801 (insomnia)
 10,606 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thalamic degenerations or dementias are poorly understood conditions. The familial forms are (1) selective thalamic degenerations and (2) thalamic degenerations associated with multiple system atrophy. Selective thalamic degenerations share clinical and pathologic features with fatal familial insomnia, an autosomal dominant disease linked to a mutation at codon 178 of the prion protein (PrP) gene that causes the substitution of asparagine for aspartic acid (178Asn mutation). We amplified the carboxyl terminal coding region of the PrP gene from subjects with selective thalamic dementia or thalamic dementia associated with multiple system atrophy. Three of the four kindreds with selective thalamic dementia and none of the three kindreds with thalamic dementia associated with multiple system atrophy had the PrP 178Asn mutation. Thus, analysis of the PrP gene may be useful in diagnosing the subtypes of thalamic dementia. Moreover, since selective thalamic dementia with the PrP 178Asn mutation and fatal familial insomnia share clinical and histopathologic features, we propose that they are the same disease.
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PMID:Analysis of the prion protein gene in thalamic dementia. 135 93

Fatal familial insomnia (FFI) is a subacute dementing illness originally described in 1986. The phenotypic characteristics of this disease include progressive untreatable insomnia, dysautonomia, endocrine and motor disorders, preferential hypometabolism in the thalamus as determined by PET scanning, and selective thalamic atrophy. These characteristics readily distinguish FFI from other previously described neurodegenerative conditions. Recently, FFI was shown to be linked to a mutation in the prion protein gene (PRNP) at codon 178, which results in the substitution of asparagine for aspartic acid. As such, FFI represents the most recent addition to the growing family of prion protein-related diseases. The mutation that results in FFI had previously been linked to a subtype of familial Creutzfeld-Jakob disease (178Asn CJD). The genotypic basis for the difference between FFI and 178AsnCJD lies in a polymorphism at codon 129 of the mutant prion protein gene: 129Met 178Asn results in FFI, 129Val 178Asn in CJD. The finding that the combination of a polymorphism and a single pathogenic mutation result in two distinct conditions represents a significant advance in our understanding of phenotypic variability.
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PMID:A novel mechanism of phenotypic heterogeneity demonstrated by the effect of a polymorphism on a pathogenic mutation in the PRNP (prion protein gene). 799 19

Fatal familial insomnia (FFI) is an inherited prion disease characterized by progressive insomnia and dysautonomia with only modest cognitive impairment early in the disease, associated with atrophy and gliosis in the medial thalamus, but without spongiform change. FFI is associated with an aspartic acid to asparagine mutation at codon 178 of the PrP gene (D178N) in conjunction with methionine at the codon 129 polymorphic site on the mutant allele (cis-129M). We report a pedigree with this genotype in which marked clinicopathologic phenotypic heterogeneity occurred including typical Creutzfeldt-Jakob disease, FFI, and what was thought to be an autosomal dominant cerebellar ataxia (ADCA)-like-illness, suggesting that the genotype-phenotype correlation is not as tight for this mutation as is frequently supposed.
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PMID:The D178N (cis-129M) "fatal familial insomnia" mutation associated with diverse clinicopathologic phenotypes in an Australian kindred. 927 May 95

Fatal familial insomnia (FFI) is an inherited prion disease linked to a mutation at codon 178 of the PRNP gene that results in aspartic acid to asparagine substitution, in coupling phase with methionine at position 129. The disease is characterized clinically by insomnia with disturbances of the autonomic, endocrine, and motor systems and neuropathologically by selective degeneration of the thalamus. Phenotypic variability is well known and has been linked to homozygosity or heterozygosity at PRNP codon 129. We report the clinical, neuropathologic, and biochemical findings and genomic analysis of a patient with FFI from a new Italian kindred. Although homozygous for methionine at codon 129, this patient showed some clinical and pathologic features most commonly found in heterozygotes.
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PMID:Fatal familial insomnia: genetic, neuropathologic, and biochemical study of a patient from a new Italian kindred. 952 Dec 57

Human prion diseases may be acquired as infectious diseases, they may be inherited in an autosomal dominant fashion or occur sporadically. Mutations and polymorphisms in the sequence of the coding region of the prion protein gene (PRNP) have been established as an important factor in all of these three types of prion diseases. Therefore, a total of 578 patients with suspect prion diseases referred to the German Creutzfeldt-Jakob disease (CJD) surveillance unit over a period of 4.5 years have been examined for mutations and polymorphisms in the coding region of PRNP. We found 40 cases with a missense mutation previously reported as pathogenic. Amongst these, the aspartate to asparagine change at codon 178 (D178N) was the most common mutation. All of these cases carried the D178N mutation in coupling with methionine at codon 129, resulting in the typical fatal familial insomnia (FFI) genotype. Most cases with pathogenic mutations were not found in the group of clinically "probable" cases according to established clinical criteria, supporting the notion that inherited prion diseases often exhibit atypical features. Two novel missense mutations (T188R and P238S) and several silent polymorphisms were found, demonstrating the quality of our screening procedure based on a modified version of the single-stranded conformational polymorphism technique. In "definite" CJD cases with no pathogenic mutation, the patients clinically classified as "probable" were mostly homozygous for methionine at the common polymorphism at codon 129, whereas there was a marked over-representation of patients homozygous for valine amongst those clinically classified as "possible". This large study on suspect cases of human prion diseases in Germany clearly shows that PRNP genetics is essential for a comprehensive analysis of prion diseases.
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PMID:Molecular genetics of human prion diseases in Germany. 1098 52

A 75-year-old man presented with a three-year history of progressively worsening insomnia and dementia. His mother and older sister had similar disorders. On initial examination, he was awake, apathetic, and disoriented but had no focal neurological deficits. Electroencephalography showed diffuse background slowing with neither periodic discharge nor sleeping activity. A single-photon emission CT scan showed significantly reduced cerebral perfusion in bilateral thalami, basal ganglia, and limbic cortices. In the late stage of his illness, he developed sphincter dysfunction. Laboratory studies showed increased T-lymphocytes and B-lymphocytes and reduced cortisol level. Cerebrospinal fluid 14-3-3 protein was absent. Genetic evaluations failed to show the aspartate to asparagine point mutation at codon 178 but disclosed an asparagine to serine substitution at codon 171 in one allele and a deletion of 24 base pairs in the other allele in the human prion protein gene. These findings led to a diagnosis of sporadic fatal insomnia, which is a recently described prion disease.
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PMID:Sporadic fatal insomnia with clinical, laboratory, and genetic findings. 2271 76

Fatal familial insomnia is a genetic prion disease, which is associated with the aspartic acid to asparagine substitution at codon 178 of the prion protein gene. Although the hallmark pathological feature is thalamic and olivary degeneration, there is a patient with an atypical fatal familial insomnia without the hallmark feature. The cause of the pathological variability is unclear. We analysed a Japanese fatal familial insomnia kindred and compared one atypical clinicopathological fatal familial insomnia phenotype case and typical fatal familial insomnia phenotype cases with transmission studies using multiple lines of knock-in mice and with protein misfolding cyclic amplification. We also analysed the transmissibility and the amplification properties of sporadic fatal insomnia. Transmission studies revealed that the typical fatal familial insomnia with thalamic and olivary degeneration showed successful transmission only using knock-in mice expressing human-mouse chimeric prion protein gene. The atypical fatal familial insomnia with spongiform changes showed successful transmission only using knock-in mice expressing bank vole prion protein gene. Two sporadic fatal insomnia cases with thalamic and olivary degeneration showed the same transmissibility as the typical fatal familial insomnia phenotype. Interestingly, one sporadic fatal insomnia case with thalamic/olivary degeneration and spongiform changes showed transmissibility of both the typical and atypical fatal familial insomnia phenotypes. Protein misfolding cyclic amplification could amplify both typical fatal familial insomnia cases and sporadic fatal insomnia cases but not the atypical fatal familial insomnia phenotype or other sporadic Creutzfeldt-Jakob disease subtypes. In addition to clinical findings and neuropathological features, the transmission properties and the amplification properties were different between the typical and atypical fatal familial insomnia phenotypes. It is suggested that two distinct prions were associated with the diversity in the fatal familial insomnia phenotype, and these two prions could also be detected in sporadic fatal insomnia.
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PMID:Two distinct prions in fatal familial insomnia and its sporadic form. 3295 12