Fatal familial insomnia and sporadic fatal insomnia.

Fatal familial insomnia (FFI) and sporadic fatal insomnia (sFI), or thalamic form of sporadic Creutzfeldt-Jakob disease MM2 (sCJDMM2T), are prion diseases originally named and characterized in 1992 and 1999, respectively. FFI is genetically determined and linked to a D178N mutation coupled with the M129 genotype in the prion protein gene (PRNP) at chromosome 20. sFI is a phenocopy of FFI and likely its sporadic form. Both diseases are primarily characterized by progressive sleep impairment, disturbances of autonomic nervous system, and motor signs associated with severe loss of nerve cells in medial thalamic nuclei. Both diseases harbor an abnormal disease-associated prion protein isoform, resistant to proteases with relative mass of 19 kDa identified as resPrPTSE type 2. To date at least 70 kindreds affected by FFI with 198 members and 18 unrelated carriers along with 25 typical cases of sFI have been published. The D178N-129M mutation is thought to cause FFI by destabilizing the mutated prion protein and facilitating its conversion to PrPTSE. The thalamus is the brain region first affected. A similar mechanism triggered spontaneously may underlie sFI.

An overview of human prion diseases.

Prion diseases are transmissible, progressive and invariably fatal neurodegenerative conditions associated with misfolding and aggregation of a host-encoded cellular prion protein, PrP(C). They have occurred in a wide range of mammalian species including human. Human prion diseases can arise sporadically, be hereditary or be acquired. Sporadic human prion diseases include Cruetzfeldt-Jacob disease (CJD), fatal insomnia and variably protease-sensitive prionopathy. Genetic or familial prion diseases are caused by autosomal dominantly inherited mutations in the gene encoding for PrP(C) and include familial or genetic CJD, fatal familial insomnia and Gerstmann-Sträussler-Scheinker syndrome. Acquired human prion diseases account for only 5% of cases of human prion disease. They include kuru, iatrogenic CJD and a new variant form of CJD that was transmitted to humans from affected cattle via meat consumption especially brain. This review presents information on the epidemiology, etiology, clinical assessment, neuropathology and public health concerns of human prion diseases. The role of the PrP encoding gene (PRNP) in conferring susceptibility to human prion diseases is also discussed.

A review of smoking behavior and smokers evidence (chemical modification, inducing nicotine metabolism, and individual variations by genotype: dopaminergic function and personality traits).

The nicotine metabolism of CYP2A6 (CYP2A6*1A,*1B, and *1C), and the cholecystokinin (CCK; which modulates the release of dopamine) and CCK-A receptor gene and personality traits for NEO-FFI, was investigated for the mechanism for elucidation of the smoking behavior in Japanese populations. The frequency of the CYP2A6*4C allele, which is a whole deleted allele of the human CYP2A6 gene, was higher, whereas that of CYP2A6*1A/*1B heterozygotes with higher nicotine metabolism activity was lower in nonsmokers than in smokers. There was also a significant difference between the current smoking and nonsmoking groups in the allele frequency of the CCK -45C/T polymorphism. It was also shown that the Openness (O) factor for smokers was significantly higher than that of nonsmokers; however, there were no significant differences in the Neuroticism (N), Extraversion (E), Agreeable (A), and Conscientiousness (C) scores among smokers than nonsmokers. It was suggested that the CYP2A6*4C allele may prevent the carrier from smoking, and being a CYP2A6*1A/*1B heterozygote and the CCK T allele may be risk factors for developing smoking behavior. Also, it is possible that persons with a low score in Openness may be refraining from smoking because they have a general negative impression toward smoking.

[Studies on heredity rule of the first genealogy regarding fatal familial insomnia in Henan province].

OBJECTIVE: To investigate the epidemiological, genealogic characteristic, familial history of the families with fatal familial insomnia, its clinical and pathological features as well as the heredity rule of related genes. METHODS: 135 familial members of 7 eras were studied. Vein blood samples from patients as well as from some familial members were collected. PRNP gene was studied with PCR, its serial was determined and then authenticated with Nsp I . Brain tissue was obtained for neuropathological test and PrP(Sc) test with Western blot method. RESULTS: Clinical symptoms of the 2 diagnosed cases were typical. 11 familial members died of similar neural disease. 32 samples of their familial members, codon at D178N of PRNP of 11 members was mutated, with mutation rate as 34.38% while D129N showed as methionine. Brain tissue of both probands denaturalized into spongiform and the nerve fiber was absent but PrP(Sc) protein was identified. CONCLUSION: Genealogy was described in the family with fatal familial insomnia since the patients had typical clinical symptoms and pathological characteristics. It seemed necessary to confirm cases of fatal familial insomnia and their genealogy with epidemiological data and to investigate its gene characteristics as well as with neuropathological and Western blot tests.

Estudio videopolisomnográfico en un paciente con sospecha de insomnio familiar fatal / Video-polisomnografic monitoring in a fatal familial insomnia clinical suspect case

Objetivo. Demostrar las alteraciones neurofisiológicas y del comportamiento del ciclo vigilia-sueño características del insomnio familiar fatal (IFF), en un paciente con sospecha clínica y posterior diagnóstico genético. Paciente y método. Varón de 39 años. Presenta historia familiar compatible con IFF. En el curso de 5 meses manifiesta impotencia, insomnio progresivo y episodios diurnos de sueño con apneas, mioclonías, automatismos y gesticulaciones. Al ingreso, presenta diplopía, hipertensión arterial e hiperhidrosis. Se realizó una monitorización videopolisomnográfica durante 24 h. Cada segundo de registro fue clasificado según los criterios de Sforza (1995). Resultados. Vigilia: ojos cerrados, actividad motora en miembros inferiores. Ritmo alfa posterior reactivo a 8-9 Hz. Sueño: breves episodios de sueño no REM y REM, de características atípicas, con ausencia de sueño profundo y disminución de actividad spindle, en asociación con mioclonías, gesticulaciones y apneas. Insomnio de conciliación. Tras indicar alprazolam (1 mg por vía oral y 0,5 mg sublingual), presentó patrón no REM durante 3,5 h, sin actividad motora y sin apneas. Discusión y conclusiones. Los hallazgos polisomnográficos se caracterizaron por grave alteración de la organización cíclica del sueño, disminución del tiempo total de sueño y patrones no REM y REM atípicos. La administración de alprazolam permitió aumentar el sueño nocturno, con desaparición de las sacudidas motoras y las apneas (AU)

Objective. To demonstrate the neurophysiologic and behavior disorders in the wake-sleep cycle typical of fatal familial insomnia (IFF), in a case with clinical suspect and latter genetic diagnostic. Patient and method. Male 39 year old. Family history of an IFF syndrome. Within 5 months he developed impotence, progressive insomnia and episodes of daytime somnolence associated with apneas, myoclonus and anormal motor behavior. He was hospitalized with diplopia, high blood pressure and hyperhidrosis. We carried out a video-polisomnografic long-term monitoring during 24 hours. Each second of the record was classified according to the de Sforza criterium (1995). Results. Waking: closed eyes, restless movements of legs. Responsive posterior alpha rhythm at 8-9 Hz. Sleep: brief episodes of "NREM" and "REM" sleep of atipical features, such as absence of slow wave sleep and marked reduction of spindle frequency activity, with myoclonus, gesturing and apneas. At night, impossibility in falling asleep. After alprazolam, "NREM" sleep during 3,5 hours, without motor activity nor apneas. Discussion and conclusions. The polisomnografic findings characterized by severe alteration of the cyclic sleep organization, reduction in total sleep time and atipical patterns of "NREM" and "REM" sleep. Administration of alprazolam (1 mg orally and 0.5 mg sublingually) allowed increasing night-time sleep, dissapearing jerks and apneas (AU)

Prion susceptibility and protective alleles exhibit marked geographic differences.

A total of 616 chromosomes from control individuals of all major continental groups, and six individuals affected by either Creutzfeldt-Jakob disease (CJD) or fatal familial insomnia (FFI), were typed with a new single-reaction protocol method and were also sequenced, with total reproducibility to screen variation at important positions (385A>G: M129V and 655G>A: E219K) in the human prion protein gene (PRNP). We have found, for the first time, that 129V allele is highly represented in some populations from the Americas, and that 129M and 129V are in similar frequencies in Africa. The 129M susceptibility allele was found at high frequencies in Old World populations, very high in the Pacific ( approximately 81%) and up to 93% in Central and East Asia, but at a low frequency (approximately 30%) in Native Americans. The protective 219L allele was restricted to Asian and Pacific populations. Susceptibility alleles exhibit marked geographic differences in frequency, and thus, differences in probability to develop prion diseases.

Hereditary Creutzfeldt-Jakob disease and fatal familial insomnia.

Studies on hereditary CJD and FFI have contributed greatly to the understanding of all forms of prion disease. Most importantly, they have provided strong support for the prion hypothesis [2]. The linkage of pathogenic PRNP mutations to human prion disease strengthens the notion that a change in PrP conformation is a key event that triggers the development of the disease. Although hereditary CJD and FFI account for only 10% of all cases of human prion disease, they provide a unique opportunity for studying disease pathogenesis initiated by perturbation in the PrP structure. An understanding of the events that accompany a change in PrP conformation has far-reaching implications for sCJD (the most common form of the disease) and for sporadic fatal insomnia. A wealth of available evidence indicates that a common pathway in disease pathogenesis may be shared by both the sporadic and the hereditary forms of prion disease, except that the initiating events are stochastic in the former, rather than predetermined by the presence of a germ-line mutation. In addition, investigations of hereditary CJD and FFI have provided plausible mechanisms of phenotypic heterogeneity in prion disease, a phenomenon analogous to the "prion strain" diversity in animal prion disease. Although many other neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, and Huntington's chorea are fairly homogeneous in disease phenotype, prion disease includes many clinically and pathologically distinct disease entities. In hereditary prion disease, the disease phenotype is likely to be determined by the combined effect of pathogenic mutations, codon 129 polymorphism, and the type of PrPSc. The pathogenic mutations include point mutations that are located mostly in the central and C-terminal region of PrP, and deletion and insertion mutations that are located in the N-terminal region. It is conceivable that these distinct types of mutations may result in differential changes in conformation or stability of PrP. The codon 129 polymorphism plays a twofold role in modulating the disease outcome. On the mutant allele, it determines the basic features of the disease phenotype--as in the case of FFI and CJD178--that result respectively from the coupling of M or V at codon 129 with the D178N mutation. On the normal allele, it may modulate the severity of the phenotype. A PrPSc subtype is encoded by the PRNP haplotype, and subsequently is generated by a conformational conversion process that transforms the cellular isoform to the pathogenic protein. The site for the formation of a specific PrPSc conformer and its accumulation in different brain regions are likely to contribute to the clinical features and pathologic lesions. The phenotypic homogeneity in other neurologic diseases, including Alzheimer's disease, may be due, in part, to the lack of a powerful genetic modifier such as the codon 129 polymorphism in the PrP gene, and the lack of the ability of affected gene products such as PrP to assume multiple protein conformations. Clearly, the remaining issue in the understanding of pathogenesis of prion disease is a detailed and accurate knowledge of the in vivo processes and conditions for the formation of PrPSc that inevitably lead to the development and expression of the disease. This knowledge will enable the development of a rational and effective strategy for therapeutic intervention.