Clinical features and genetic characteristics of two Chinese pedigrees with fatal family insomnia.

Background: Fatal familial insomnia (FFI) is a rare autosomal-dominant inherited prion disease characterized clinically by severe sleep disorder, motor signs, dysautonomia and abnormal behaviour. FFI is caused by a missense mutation at codon 178 of the prion protein gene (PRNP). Our study is aimed to explore typical clinical and genetic features of two Chinese pedigrees with FFI and review the related literatures. Methods: Two FFI cases with family histories were recruited in our study. The main clinical features, genetic features and possible pathophysiologic mechanisms of these two FFI cases were analysed. Results: The foremost symptoms seemed to be sleep disturbances and psychosis. Progressive sympathetic symptoms, movement disturbances and memory loss were frequently observed as well. Electroencephalography (EEG) showed a minor slowing without periodic triphasic waves. Polysomnography (PSG) showed reduction in total sleep time and disturbance of sleep-related respiratory. Brain magnetic resonance imaging (MRI) did not reveal obvious abnormality. Genetic analysis disclosed the prion protein gene mutation at codon 178 (D178N), with methionine (Met) homozygosity at the polymorphic position 129 (Met129Met). Conclusions: The major clinical features of Chinese FFI are sleep dysfunction, psychiatric symptoms and sympathetic symptoms. Our patients have similar clinical characteristics as that of the typical FFI cases.

Fatal familial insomnia and Agrypnia Excitata: Autonomic dysfunctions and pathophysiological implications.

Fatal Familial Insomnia (FFI) is a hereditary prion disease caused by a mutation at codon 178 of the prion-protein gene leading to a D178N substitution in the protein determining severe and selective atrophy of mediodorsal and anteroventral thalamic nuclei. FFI is characterized by physiological sleep loss, which polygraphically appears to be a slow wave sleep loss, autonomic and motor hyperactivation with peculiar episodes of oneiric stupor. Alteration of autonomic functions is a great burden for FFI patients consisting in sympathetic overactivation, dysregulation of its physiological responses and disruption of circadian rhythms. The cardiovascular system is the most frequently and severely affected confirming the increased sympathetic drive with preserved parasympathetic responses. Sleep loss, autonomic and motor hyperactivation define Agrypnia Excitata (AE), which is not exclusive to FFI, but it has been canonically described also in Morvan Syndrome and Delirium Tremens. These three conditions present different pathophysiological mechanisms but share the same thalamo-limbic impairment of which AE is one of the possible clinical presentations. FFI, and consequently also AE, is a model for the investigation of the essential role of the thalamus in the organization of body homeostasis, integrating both sleep and autonomic function control.

Fatal familial insomnia with abnormal signals on routine MRI: a case report and literature review.

BACKGROUND: Fatal familial insomnia (FFI) is a rare autosomal dominant disease caused by the PRNP D178N/129 M mutation. Routine brain CT and MRI usually reveal non-specific features. We report a patient with FFI presenting with diffuse abnormal signals on MRI, later confirmed as combined with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). CASE PRESENTATION: The patient was a 58-year-old female, whose main clinical manifestations were insomnia, movement disorders, autonomic hyperactivity and mental deterioration. The patient also suffered a typical episode of transient global amnesia. MRI indicated a diffuse white matter abnormality and microbleeding on the susceptibility-weighted imaging. On biopsy, the brain tissue sections showed spongiform changes with gliosis, neuronal degeneration, and prion protein deposition in a portion of the neurons. In addition, arteriosclerosis was prominent. Transmission electron microscopy showed osmiophilic particle deposition in the matrix of medial smooth muscle cells. Gene sequencing confirmed a diagnosis of FFI with CADASIL. CONCLUSIONS: This case is a compelling example that even with evidence of leukoencephalopathy, prion disease should be an important differential diagnosis of rapidly progressive dementia and related diseases. In cases of genetic diseases with atypical manifestations, the coexistence of two or even more diseases should be considered as a possible explanation.

Sporadic fatal insomnia in an adolescent.

The occurrence of sporadic prion disease among adolescents is extremely rare. A prion disease was confirmed in an adolescent with disease onset at 13 years of age. Genetic, neuropathologic, and biochemical analyses of the patient's autopsy brain tissue were consistent with sporadic fatal insomnia, a type of sporadic prion disease. There was no evidence of an environmental source of infection, and this patient represents the youngest documented case of sporadic prion disease. Although rare, a prion disease diagnosis should not be discounted in adolescents exhibiting neurologic signs. Brain tissue testing is necessary for disease confirmation and is particularly beneficial in cases with an unusual clinical presentation.

Insomnio y muerte de Marilyn Monroe. Parte II: muerte / No disponible

Objetivo: Evaluar las circunstancias de la muerte de Marilyn Monroe (MM) desde un punto de vista médico, e intentar reconstruir el tratamiento prescrito para su insomnio crónico. Material y métodos: Documentación original de la investigación policial y médico-forense sobre su muerte, recetas de medicamentos y otros documentos de interés, testimonios directos de los testigos principales y valoración de conflictos de intereses. Resultados: MM falleció la noche del sábado 4 de agosto de 1962 a causa de una sobredosis de fármacos hipnóticos. Existió una divergencia entre la investigación policial, que valoró la muerte como accidental, y la forense, que prevaleció, y que la clasificó de "probable suicidio". Este dictamen se apoyó en una "autopsia psicológica", externa a la investigación oficial, llevada a cabo por especialistas en salud mental relacionados profesionalmente con el Dr. Greenson, psiquiatra de MM y fuente principal de esta investigación, la cual ignoró los hallazgos policiales. Parece probable que sus médicos mintieran sobre la hora y circunstancias de la muerte y retrasaran el aviso a la policía, que el cuerpo fuera cambiado de posición durante ese tiempo y que se intentara justificar la presencia de una cantidad de pentobarbital que no figuraba en ninguna parte. El Dr. Engelberg prescribió al menos diez fármacos psicoactivos en los dos últimos meses de vida de MM, aunque después lo negaría. Las conclusiones de la investigación forense parecen contaminadas por un problema de corporativismo médico. El tratamiento prescrito para el insomnio fue inadecuado, incluso para los estándares de la época (AU)

Objective: To evaluate the circumstances of Marilyn Monroe’s death from a medical perspective, and to try to reconstruct the treatment prescribed to her for chronic insomnia. Material and methods. Original documents from the police and forensic investigations on her death, drug prescriptions and other valuable documents, direct accounts from the main witnesses and assessment of conflicts of interest. Results. MM died on the night of August 4, 1962 from an overdose of hypnotic drugs. There was a divergence between the police investigation, which labelled the death as accidental, and the forensic one, which prevailed and described it as a ‘probable suicide’. This opinion relied on a ‘psychological autopsy,’ external to the official investigation, carried out by mental health specialists professionally related to Dr. Greenson, MM’s psychiatrist and the major source for this investigation, which ignored police findings. It seems likely that her doctors lied about the hour and circumstances of her death, and delayed the call to the police, that the position of the body was changed during this time, and that they tried to justify the presence of an unaccounted for quantity of pentobarbital. Dr. Engelberg prescribed al least ten different psychoactive drugs during the last two months of MM’s life, although he would later deny it. The conclusions of the forensic investigation seem contaminated by a problem of medical corporatism. The treatment prescribed for insomnia was inadequate, even for the period standards (AU)

Agrypnia excitata.

Agrypnia (from the Greek: to chase sleep) excitata (AE) is a syndrome characterized by loss of sleep and permanent motor and autonomic hyperactivation (excitata). Disruption of the sleep-wake rhythm consists in the disappearance of spindle-delta activities, and the persistence of stage 1 non-rapid eye movement (NREM) sleep. Rapid eye movement (REM) sleep persists but fails to stabilize, appearing in short recurrent episodes, isolated, or mixed with stage 1 NREM sleep. Diurnal and nocturnal motor, autonomic and hormonal overactivity is the second hallmark of AE. Of particular interest is the finding that norepinephrine secretion is extremely elevated at all hours of the day and night whereas the nocturnal melatonin peak is lacking. Oneiric stupor is probably an exclusive sign of AE and consists in the recurrence of stereotyped gestures mimicking simple daily life activities. Agrypnia excitata aptly defines 3 different clinical conditions, fatal familial insomnia (FFI), an autosomal dominant prion disease, Morvan syndrome (MS), an autoimmune encephalitis, and delirium tremens (DT), the alcohol withdrawal syndrome. Agrypnia excitata is due to an intralimbic disconnection releasing the hypothalamus and brainstem reticular formation from cortico-limbic inhibitory control. This pathogenetic mechanism is visceral thalamus degeneration in FI, whereas it may depend on autoantibodies blocking voltage-gated potassium (VGK) channels within the limbic system in MS, and in the sudden changes in gabaergic synapses down-regulated by chronic alcohol abuse within the limbic system in DT.

Prionpatías: las encefalopatías por priones / Prion diseases: prion encephalopathies

Las prionpatías o encefalopatías por priones son un grupo de enfermedades poco frecuentes que comparten una fisiopatología similar con distintas características clínicas. La enfermedad de Creutzfeldt-Jakob (ECJ) esporádica es la más conocida. Se manifiesta con una demencia rápidamente progresiva, ataxia y sintomatología extrapiramidal. Aunque el diagnóstico de certeza es anatomopatológico se puede llegar al diagnóstico probable empleando los criterios establecidos por la Organización Mundial de la Salud. Se está discutiendo en la actualidad la posibilidad de integrar la resonancia magnética nuclear en dichos criterios para aumentar la sensibilidad del diagnóstico. Las técnicas moleculares de estudio de proteínas en el líquido cefalorraquídeo tienen un peso creciente y colaboran en el diagnóstico. El diagnóstico de las otras encefalopatías por priones no es tan avanzado como el de la ECJ. El tratamiento de todas estas enfermedades continúa siendo paliativo (AU)

Prion diseases or prion encephalopathies are a group of rare disorders that share a similar pathophysiology with different clinical characteristics. Sporadic Creutzfeldt-Jakob disease (CJD) is best known. It presents as a rapidly progressive dementia, ataxia and extrapyramidal symptoms. Although accurate diagnosis is by histopathological examination, a diagnosis can be probably achieved using the criteria established by the World Health Organization. We are currently discussing the possibility of integrating the nuclear magnetic resonance into this criteria for increasing the sensitivity of diagnosis. Molecular techniques for studying proteins in cerebrospinal fluid have an increasingly significant role in aiding diagnosis. The diagnosis of other prion encephalopathies is not as advanced as that of CJD. The treatment of these diseases remains palliative (AU)

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)

Rare genetically defined causes of dementia.

Several genetic disorders, though rare, are associated or present with dementia. Developments in the field of genetics are contributing to clarify and expand our knowledge of the complex physiopathological mechanisms leading to neurodegeneration and cognitive decline. Disorders associated with misfolded and aggregated proteins and lipid, metal or energy metabolism are examples of the multifarious disease processes converging in the clinical features of dementia, either as its predominant feature, as in cases of Alzheimer's disease (AD) or frontotemporal dementia (FTD), or as part of a cohort of accompanying or late-developing symptoms, as in Parkinson's disease (PD) or amyotrophic lateral sclerosis with dementia (ALS-D). Awareness of these disorders, allied with recent advances in genetic, biochemical and neuroimaging techniques, may lead to early diagnosis, successful treatment and better prognosis.

Insomnio familiar fatal y enfermedades priónicas. Anatomía clínica / No disponible

Las encefalopatías espongiformes transmisibles (EET) son enfermedades priónicas provocadas por el depósito de una o varias isoformas anormales o scrapie (PrPSc) de la proteína priónica celular (PrPC), abundante en el sistema nervioso central (SNC) y necesaria para la replicación de aquélla. Se estudia el posible papel funcional de la PrPC y su relación con el insomnio familiar fatal (FFI), que cursa con alteraciones del ritmo vigilia-sueño (imposibilidad de instaurarse la fase de sueño de ondaslentas, graves alteraciones del sueño REM) y de otros ritmos circadianos. Las alteraciones anatomopatológicas primarias del FFI se encuentran en el núcleo dorsomedial (DM) y núcleos anteriores (A) del tálamo. Estudios experimentales en gato, rata y vaca, nos hacen sospecharque las enfermedades priónicas producen una alteración de los mecanismos nitrérgicos encefálicos. Una vez instaurada la enfermedad, la transmisión de la PrPSc se realizaría de forma retrógrada dentro del encéfalo. La mayor presencia de la PrPC en determinadas zonas del SNC significa que la PrPSc se transmite y replica con más intensidad en dichas zonas. Por otra parte, la lesión de células parvalbúmina (PV) positivas (que probablemente contengan PrPC) podría explicar los mecanismos de desinhibición que se dan por ejemplo en el FFI

Transmissible spongiform encephalopathies (EET) are prion diseases caused by the deposition of the abnormal or scrapie isoform (PrPSc) of the cellular or host encoded prion protein (PrPC). This cellular form is especially abundant in the central nervous system (SNC) and itspresence is necessary for the replication of the abnormal form of the protein.This paper reviews the functional role of PrPC and its relationship with fatal familial insomnia (FFI), a prion disease accompanied by alterations in the sleep-waking cycle (impossibility to establish slowwave sleep, enacted dreams during REM sleep) as well as of some other circadian rhythms. The primary anatomopathological alterations of FFI are due to damage to mediodorsal (DM) and anterior (A) thalamic nuclei. Animal models such us rat, cat, and cow allow us to infer that priondiseases produce alterations of the nitrergic mechanisms in affected brains. Once the disease is set, PrPSc might spread retrogradely within the brain. The higher expression of PrPC in specific brain regions determines the degree of replication and transmission of PrPSc withinthese areas. Notwithstanding, lesion of parvalbumin- (PV-) containing neurons (probably expressing PrPC) might explain some disinhibiting mechanisms in FFI (AU)