Fatal familial insomnia

Introduction to fatal familial insomnia The disease is a subacute familial TSE. It is characterized by ineffective insomnia, autonomic dysfunction and motor signs. The histopathology is characterized by selective atrophy of the ventral ventral and dorsal medial nucleus. Earlier, the disease was mixed with familial CJD. In 1986, Lugaresi et al. of the Bologna University School of Medicine in Italy first reported and described in detail the first case of the disease, named lethal familial insomnia. Since then, human prion has added a new member. basic knowledge The proportion of illness: 0.001% (rare, with genetic history.) Susceptible people: no specific population Mode of infection: non-infectious Complications: brain atrophy

Causes of fatal familial insomnia

(1) Causes of the disease

Fatal familial insomnia (FFI) is a recently confirmed familial human prion disease.

PrP gene mutation

FFI is an autosomal dominant hereditary disease associated with the 129Met 178Asn haplotype. 17 FFI patients of 5 families that have been unrelated have PRNP 178 codon mutations, and the single allele of this codon is Asp Asn substitution (178Asn), in addition, FFP patient PRNP gene 129 codon Met / Val polymorphism is also significantly uneven distribution, the distribution of this polymorphism in the normal Caucasian population is Met / Met 0.37, Met / Va10 .51, Va1/Va10.12; in FFI patients, Me/Met 0.82, Met/Val 0.18, Val/Va10, further analysis found that the 129 codons of the PRNP mutant alleles of FFI patients were all Met.

Can be passed to mice

The disease can be transmitted to mice, but the success rate is lower than other prion diseases. After the disease was discovered in 1986, it was tried to pass it to experimental animals. Several experimental animals were used to inoculate a variety of experimental animals, including 18 Non-human primates ended in failure. In August 1995, Japanese scholar Li Shirun and other British scholar Collinge reported that infected mice were almost simultaneously successful.

Li Shirun et al. Inoculated 19 NZW strain mice with a thalamic homogenate brain of 1 patient with FFI. The patient had a 24 bp deletion between PrP gene codons 51 and 91, belonging to the FFI family reported by Bosque et al in 1992, and having the same 24 bp. 24 NZW mice were inoculated into the frontal cortex of patients with deficient but no PrPsc dementia as control. In the experimental group, 19 mice, 1 died shortly after inoculation, 1 died in 218 days after inoculation, and 14 died in 397506 after inoculation. On the daytime, there were typical symptoms of spongiform encephalopathy. The remaining 3 were observed to be 620 days old. Histopathological examination showed that there was no neuropathological change in one mouse died at 218 days after inoculation, but there was a very small amount of PrPsc precipitation in the thalamus. 14 clinically-infected mice had characteristic lesions such as spongiform degeneration, astrocytosis, neuron loss and PrPsc precipitation. The clinical manifestations and neuropathological changes of FFI-inoculated mice were indistinguishable from CJD-inoculated mice, except for the precipitation of PrPsc in the thalamus. Others had significant sputum vaccination in the primary vaccinated mice. The control group died or culled at different times during the observation period. No lesions such as spongiform degeneration or PrPsc were observed. The other 19 were still 620 days old. Collinge et al. used two brains of FFI patients to inoculate two transgenic mice expressing human PrP, Tg110 and Tg152, Tg110 and Tg152 human PrP, respectively, which are 50% of normal human brain expression levels. And 200%, the vaccinated patients with brain homogenate of each group of transgenic mice have one or more cases, the incidence of Tg152 infection is higher (Table 1); the incubation period is 438 ~ 641 days, from the occurrence of neurological symptoms The duration of the stagnation (culling) was 19 days, with an average of 3.8±1.1 days. The control transgenic mice were still alive for 700 days. Histopathological examination showed that the cortex, deep gray matter and white matter of the mice showed neuron spongy vacuoles. Dilated, astrocyte diffuse hyperplasia, enhanced immunocytochemical staining of glial fibrillary acidic protein, amyloid precipitation Congo red staining and PrP immunohistochemical staining were all negative; age-matched control brain of transgenic mice Only the senile changes were shown, and the mouse brain homogenate was inoculated by FFI for immunoblotting, whether it was monoclonal antibody 3F4 specific for human PrP or polyclonal antibody R073 which responded to human and mouse, all tested mice. All Sex; direct neurotoxicity inoculated CJD examination under the same conditions transgenic mice were positive, suggesting the incidence of negative mouse PrP detection of PrP not possible, but more likely due to loss of function of normal PrP.

Low levels of PrPsc in the brain of patients with FFI

The brain homogenate of FFI patients contained PrPsc, but the level was lower than that of CJD and other prion diseases. Medori et al examined 5 cases and 4 cases were positive. After treatment with proteinase K, Westen blotting produced 2 major fragments of 29 and 27 kDa, while sporadic CJD always produces 3 major segments of 29, 25 and 21 kDa. Monar et al. reported that FFI produced 2 major segments of 28 and 26 kDa. After long exposure, the film also showed a minor segment of 19 kDa. Does the FFI PrPsc mode and other modes? The familial prion disease is different, which is unique to FFI, and remains to be determined. The amount of anti-protease PrP seems to be related to the course of the disease, but not to the severity of lesions in each brain region; because it is in the thalamus of FFI patients. The amount is not significantly higher than other brain regions, but is abundant in the basal ganglia of a patient with hypothalamic histological lesions.

(two) pathogenesis

The histopathology of this disease is mainly thalamic atrophy (Table 2). The anterior and dorsal medial nucleus of the thalamus are severely invaded. The medial nucleus and occipital nucleus of the thalamus are often damaged. The other thalamic nuclei are affected. The cortex usually shows very mild to moderate astroglial hyperplasia, and affects the deep layer and extends to the shallow white matter. In the case of the test, only two cases of widespread spongy edema, the two cases are more Long (2532 months), also has periodic EEG; a patient with a 13-week course of focal spongy edema is limited to the hippocampus, the lower olives often severely atrophy, and the cerebellar cortex is only slightly mild to moderate. Atrophy, other brain areas are generally normal, of the 14 cases examined, 4 cases of basal ganglia have very mild gliosis, and 1 case of moderate glial hyperplasia.

Lethal familial insomnia prevention

In view of the fact that there is no effective treatment for scorpion venom disease, it is extremely important to prevent it. There is no vaccine-susceptible population.

1. Control the source of infection to slaughter scorpion venomous diseases and suspected sick animals, and properly handle the carcasses of animals, effectively killing scorpion venom methods including incineration, autoclaving at 132 ° C for 1 h, 5% calcium hypochlorite or 1 mol /L sodium hydroxide for 60min soaking, etc.; restricting or prohibiting the production of medical products derived from blood products and animal materials in infected areas; patients with scorpion venom and any neurodegenerative diseases, who have received organ extracting hormone therapy, Those with a family history of scorpion venom and those who have lived in the affected area for a certain period of time are not allowed to serve as donors of organs, tissues and body fluids; they are monitored for hereditary prion family, and genetic counseling and eugenics screening.

2. Cut off the transmission route to eliminate the abuse of human tissue, do not eat animal meat and products of scorpion venom disease, do not feed animals with animal tissue feed, medical procedures strictly follow the disinfection procedures, and advocate the use of disposable neurosurgical instruments.

Fatal familial insomnia complications Complications brain atrophy

Concurrent brain atrophy.

Fatal familial insomnia symptoms common symptoms hallucinations, dreams, sleep disorders, lethargy, dysarthria, myoclonus, wood, stiffness, ataxia, unclear

Generally speaking, there are three different manifestations at the beginning of the disease: 1 sleep disorder, usually patients complained of insomnia, excitement during sleep, multiple dreams; 2 sports signs such as dysarthria and ataxia; 3 memory disorders, with the development of the disease The patient presents all the symptoms of FFI, involving systems such as exercise, endocrine and autonomic nerves, as follows:

1. Sleep and insomnia Progressive insomnia, insomnia is increasing, which has been proven in 8 patients in 4 families undergoing polysomnography or overnight EEG recording, with diazepam and barbiturate When the sleeping pills are not effective, the patient also presents a progressive dreamlike state and hallucinations, and the stage is stupid and lethargic.

2. Identify functional labor memory, attention and visual motor (visumotor) function is impaired, but still maintain global intelligence.

3. Patients with autonomic nervous system exhibit hyperhidrosis, tachycardia, fever, high blood pressure and irregular breathing.

4. The dysarthria of the motor system is progressively weighted until the teeth are unclear, and the difficulty of swallowing, ataxia, spontaneous and stimulating myoclonus, hyperreflexia and Babinski sign.

5. Endocrine system adrenocorticotropic hormone (ACTH) levels decreased, cortisol and catecholamine levels increased, growth hormone, prolactin and melatonin 24h rhythm abnormalities.

Fatal familial insomnia

Peripheral blood routine examination is normal

1. EEG activity associated with deep sleep is reduced or disappeared.

2. [18F] PET examination, the metabolism of the thalamus area is preferentially reduced.

3. During EEG sleep: -activity, sleep fusiform wave, K complex reduced or even completely disappeared; rapid eye movement (REM) phase abnormality; during awakening: progressive flat background activity, slow activity, unable to produce drugs Induced sleep activity [only 2 of the 7 patients examined showed periodic peak activity, and the two patients had a long course of disease, 25 and 32 months, respectively, and sporadic splegiosis of the cerebral cortex.

4. 4 cases of positron emission tomography (PET) scan, 2 cases of metabolic loss (-36%), actually limited to the anterior thalamus; the other 2 cases of metabolic decline also exist in the cerebral cortex (especially the frontal lobe and Parietal) (-40%), hippocampus, basal ganglia and cerebellum, but the thalamus is the most severe.

5.PrPsc detects the variability of phenotypes between different FFI families. FFI is a well-defined disease with different phenotypes and genotypes. The variability of this disease phenotype is very small among all FFI families, and the PRNP genotypes are identical. The patient (codon 129 is homozygous for Met) is particularly evident (Table 2). However, phenotypes similar to FFI may be associated with similar but different genotypes. In 1992, Bosque et al. reported a codon 82 and There is a family of 24bp intermediate deletion between 91, the mutant haplotype of this family is equivalent to FFI, 129Met and 178 Asn are all on the PRNP mutation allele, but there is another 24bp deletion, unfortunately, this family expresses this disease The phenotype was unclear. Three patients reported insomnia in 3 cases, but no polysomnography was performed. [18F] Fluorodeoxyglucose showed a slightly lower degree of cerebral cortex metabolism than the thalamus. Histopathological findings Also consistent with this finding, cerebral cortical lesions were significantly more severe than the thalamus, but the dorsal medial nucleus of the thalamus was not examined; the amount of PrPsc in the cerebral cortex was greater than that in the thalamus.

Diagnosis and diagnosis of fatal familial insomnia

Diagnostic criteria

In 1993, Gambetti et al. proposed the following diagnostic criteria:

1. Frequently stained dominant disease, adulthood, with a course of 6 to 32 months.

2. Presenting ineffective intractable insomnia, familial autonomic dysfunction, memory impairment, ataxia and/or myoclonus, pyramidal tract and extrapyramidal signs.

3.129Met and 178Asn haplotypes.

Any two of the criteria 15 can be used for suspicious diagnosis of FFI, and standard 6 can have any other criteria to confirm FFI.

Differential diagnosis

Like CJD, in addition to fatal familial insomnia, there may be sporadic fatal insomnia.

In 1988, Mizusawa et al reported a case of sporadic fatal insomnia, 37 years old, male, 30 months of insomnia, dementia, myoclonus, ataxia, nocturnal agitation and autonomic dysfunction, organization Pathological examination revealed that the dorsolateral side of the thalamus, the dorsal medial side, the dorsolateral nucleus and the occipital nucleus were severely atrophied, the cerebral cortex was slightly edema of the cerebral cortex, and there were scattered 'torpedoes' in the cerebellar cortex. The loss of the olive body neurons was severe. For PrPSC examination and PRNP gene analysis, PrPSC was positive, but PRNP was not mutated. From 1939 to 1975, Stem et al., Schulman et al., Garcin et al. and Martin et al. reported cases of thalamic atrophy or thalamic CJD. It may also be sporadic fatal insomnia.

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