Fatal familial insomnia
Fatal familial insomnia (FFI) is a rare and devastating genetic prion disease characterized by a progressive inability to sleep. It is caused by a mutation in the prion protein gene (PRNP) located on chromosome 20, inherited in an autosomal dominant manner. Individuals with the affected gene have a 50 percent chance of passing it on to their offspring, and those who inherit the mutation are likely to develop the disease. Symptoms typically manifest in middle to late adulthood and can include severe insomnia, impaired motor functions, difficulty speaking and swallowing, and cognitive decline. The disease leads to significant degeneration of neurons in the thalamus, which plays a critical role in regulating sleep-wake cycles and autonomic functions, contributing to the hallmark insomnia and chronic stress experienced by patients. Unfortunately, FFI is untreatable, with only palliative care options available. Diagnosis is often confirmed postmortem, as earlier detection methods lack sensitivity. Genetic counseling is available for those concerned about the hereditary nature of the disease.
Fatal familial insomnia
- ANATOMY OR SYSTEM AFFECTED: Brain, central nervous system, muscles, musculoskeletal system
Definition
Fatal familial insomnia (FFI) is a rare, genetic prion disease transmitted as an autosomal dominant trait. The responsible mutation causes prions (proteins found extensively in the body) to assume abnormal shapes and become pathogenic. A nongenetic form of the disease, sporadic fatal insomnia, also exists.
Causes
The cause of FFI has been identified as a mutation at codon 178 of the prion protein gene (PRNP) on chromosome 20. A polymorphism at codon 129 of the PRNP gene determines disease characteristics, such as duration. Additional but rare mutations in the PRNP gene have also been associated with FFI.
Risk Factors
Each offspring of an affected parent has a 50 percent risk of inheriting the highly penetrant mutant gene; as far as is known, those who inherit the gene will express the disease. Sporadic cases have no known risk factors.
Symptoms
The hallmark of this disease is insomnia, although it is not invariably present in the earliest stages. Symptoms are best understood in the context of the histopathology of FFI, primarily involving degeneration and loss of neurons in the thalamus. The thalamus has a crucial integrative function in the brain, relaying sensory information to the cerebral cortex. The role of the thalamus in regulating autonomic functions and vital circadian rhythms is consistent with prominent FFI symptoms. Twenty-four-hour circadian patterns comprise the sleep-wake cycle and the normal ebb and flow of hormone secretions.
Other symptoms include severely impaired motor functions, uncoordinated and jerky muscle movements, and difficulty speaking and swallowing. Autonomic dysregulation also manifests as fever and sweating. Affected persons are often described as inattentive, restless, and unable to concentrate. Cognition may also be affected.
Adrenocortical hormones are secreted more frequently. These hormones are involved in the body’s stress reaction, and those affected experience chronic stress. The insomnia that characterizes this disease is progressive and untreatable, leading to the ultimate absence of any sleep patterns or responses.
The first reported case, in 1986, was that of a fifty-three-year-old man. The onset of FFI is most often in middle to late adulthood, although it has been reported in some patients in their early twenties. The duration of the disease, from less than one year to several years, largely depends on genetic factors.
Screening and Diagnosis
Neither careful clinical examination nor standard sleep response tests can identify carriers of the FFI mutation before symptoms become apparent. Findings of routine laboratory tests are generally normal. However, positron emission tomography (PET), which can measure the brain’s consumption of glucose, has shown thalamic changes in an asymptomatic gene carrier. Postmortem examination confirms the diagnosis.
Treatment and Therapy
Palliative treatment has been the only reported treatment. Attempts to alter the disease course with medications have been unsuccessful. Drugs that promote sleep or manage symptoms, such as muscle spasms and anxiety, can be temporarily helpful. Nutritional support for symptoms such as difficulty swallowing or loss of appetite, physical therapy for muscle weakness, and psychological therapy may also be suggested. However, fatal familial insomnia is considered untreatable.
Prevention and Outcomes
There is no known way to prevent the disease in a carrier. Prenatal diagnosis is theoretically possible but is accompanied by ethical considerations. Still, genetic counseling is an option. Further, treatments and means of prevention of FFI are being researched.
Bibliography
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