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Fatal familial insomnia cases1/17/2024 As the thalamus has been shown to exhibit damage first, even before clinical symptoms surface, the authors speculate that this brain structure plays a paramount role in motor control of the eyes. The most prominent and consistent findings were saccadic intrusions. All patients experienced disturbance in vision, including binocular horizontal diplopia and blurred vision, as well as irregular eye movements. analyzed neuro-ophthalmological manifestations in six patients with early FFI, with early stage defined as within six months of onset of insomnia. In addition, administration of mydriatic agents including 4% cocaine and 5% homatropine demonstrated parasympathetic hyperactivity of the pupils. described a 52-year-old male with transient diplopia six months after the onset of nocturnal insomnia and saccadic ocular movements another month later. One of the earliest symptoms of FFI is fluctuating diplopia. Of the clinical signs discussed in detail below, sleep-related changes plus either progressive autonomic dysfunction or somatomotor manifestations must be present for a diagnosis of probable FFI. In addition, electroencephalogram (EEG) depicts surplus theta and delta frequencies and cerebrospinal fluid (CSF) analysis may demonstrate increased protein levels. Polysomnography is remarkably useful, showing a loss of sleep spindles and K-complexes. PET may show hypometabolism of the thalamus and other affected areas. Imaging modalities including brain magnetic resonance imaging (MRI) and diffusion-weighted imaging (DWI) reflect mild cortical atrophy and hyperintense signals in gray matter areas. Molecular analysis can identify the GAC to AAC genetic variant of PRNP and atargeted PRNP gene test can confirm FFI. However, these latter changes are not as severe and less often described. Neuropathological analysis of other areas of the brain may find reactive gliosis in the cerebral cortex, cerebellar cortex and olives as well as rare spongiosis of the cerebral cortex. 2-fluoro-2-deoxy-D-glucose (FDG) and positron emission tomography (PET) imaging confirms a substantial decrease in metabolism, most notably in these particular thalamic regions. This selective reduction in neural cells can range from over 50% to almost 80% and corresponds with a two to three-fold increase in reactive astrocytes. These lesions are characterized by a significant loss in the number of large neurons and astrogliosis. Autopsy examination of brain specimens reveals microscopic abnormalities in the anterior and dorsomedial thalamic nuclei bilaterally. Īs FFI progresses specific neurodegenerative changes occur. This proliferation allows for the accumulation of insoluble PrP, which is resistant to degradation by proteases. PathophysiologyĪ conformational change in the normal PrP protein results in a deviant isoform that acts as a template for self-propagation. Therefore, heterozygosity for the methionine residue (Met-Val) at codon 129 may provide a protective effect against developing FFI. The homozygous presence of methionine (Met-Met), most common in East Asians, may shorten the duration of disease or hasten the onset of disease. The substituted amino acid at position 178 interacts with a nonmutated methionine residue at the polymorphic position 129 to form the abnormal PrP isoform responsible for this distinct disease. This uniformly fatal illness is passed from parent to offspring in an autosomal dominant fashion with high phenotypic penetrance. In FFI, a missense mutation at codon 178 of the PRNP gene located on chromosome 20 results in the substitution of asparagine for aspartic acid (D178N). Loss of wild type function due to misfolding and aggregation of insoluble PrP triggers inevitable neurodegeneration and plays a central role in prion disease. While details of the physiological role of PrP remains unclear, this protein is highly expressed in the nervous system. An increased number of FFI cases have been reported in Han Chinese, more so that other Asian regions (including Japan and Korea). The mean age of onset is about 50 years old. EpidemiologyįFI affects both male and females equally with onset typically occurring between the third through sixth decades of life. The sporadic form, termed sporadic fatal insomnia (SFI), presents with similar clinical features as FFI. in 1986, this disorder causes intractable insomnia, dysautonomia and motor system abnormalities. 2.1 Neuro-ophthalmic Symptoms and Signsįatal Familial Insomnia (FFI) is an inherited prion disease produced by a genetic variant of the prion-protein (PrP) gene (PRNP).
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