A 53-year-old man was hospitalized in the neurology department in June 2023. The main complaint was “10 days of mental state change and 6 days of progressive memory disorder”. Ten days before admission, he had dizziness for no obvious cause and then lost consciousness and fell down. The first cranial CT scan done in a local hospital showed “chronic subdural hematoma in the left parietal bone area”. The local hospital gave him symptomatic treatment, and then his consciousness level improved compared with before, and he was discharged from the hospital. However, 6 days before admission, he began to show a significant decline in cognitive ability especially short-term memory, so the patient came to our neurology department for further evaluation and treatment. The patient's past medical history includes 6 months of bronchitis and pharyngitis and 1 month of involuntary limb tremor. Neurological examination: clear consciousness, average mental state, clear speech, memory loss. The bilateral pupils are equal in size, round, and sensitive to light reflection. Lingual muscle tremor. The muscle strength and tension of the limbs are normal, and the limbs tremble involuntarily. The double upper limb finger nose test is unstable and inaccurate. There was no abnormality in the sensory examination, and the pathological signs on both sides were negative. On the second day of hospitalization, the laboratory results showed a mild elevation of creatine kinase (581 U/L). Lumbar puncture showed that the pressure of cerebrospinal fluid (CSF) was 110 mmH2O, and the results of routine analysis, biochemical analysis, cytology and pathogen detection were normal. On the 7th day of hospitalization, the patient's reaction was still slow and his memory was reduced. The test results of external autoimmune encephalitis antibodies are all negative. The neuropsychological evaluation showed that the MOCA score was 11, which was consistent with obvious cognitive dysfunction, and the MMSE score was 23, suggesting mild cognitive impairment. The HAMD-17 score is 20 points, suggesting mild to moderate depression; the HAMA score is 22 points, suggesting obvious anxiety. Brain MRI enhancement, DWI, SWI, and MRS (Figure 1) show left parietal subdural hematoma. During hospitalization, patients were observed shouting in their sleep. Combined with symptoms such as rapidly progressive dementia, muscle convulsions, and sleep abnormalities, the possibility of prion disease was considered; the cerebrospinal fluid 14-3-3 protein was sent for examination, and the test result was negative. On the 10th day of hospitalization, we continued to ask about the relevant medical history. The patient began to have a progressive memory decline since April. He was often forgetful at work. In May, he took medical leave due to worsening cognitive symptoms. Notably, both the patient's father and paternal uncle had histories of similar neuropsychiatric manifestations, including sleep disturbances and behavioral changes, and both died around the age of 50. Given this strong familial pattern of early-onset neurodegenerative presentation, a hereditary etiology is highly suspected. Sleep monitoring and genetic testing are recommended for further evaluation. On day 15 of hospitalization, polysomnography (Figure 2) revealed the following findings: Markedly reduced sleep efficiency, severe obstructive and central breathing disturbances, and severe periodic limb movements during sleep. Due to poor sleep quality and short total sleep time during monitoring, combined with the family's request to continue follow-up outpatient management while awaiting genetic testing results, the patient was discharged on 1 July 2023. In December 2023, the patient was readmitted due to progressive cognitive decline and chronic sleep disturbances lasting six months, with recent deterioration over one month including urinary and fecal incontinence. At this stage, neurological symptoms had advanced to include dysarthria and oropharyngeal dysphagia. Genetic analysis (Figure 3) found heterozygous mutations at PRNP gene codon 178 (c. 532G> a, p. Asp178Asn), and methionine pure fusion was found at codon 129 (129MM), which was confirmed as fatal familial insomnia (FFI). The family survey (Figure 4) showed autosomal dominant inheritance and found that one of the patients' daughters carried the same mutation. Neurological examination: The mind is blurred, the mind is depressed, the speech is slurred, the reaction is dull, the bilateral pupils are large and equally round, the light reflection is sensitive, the tongue is in the middle, the tongue muscle is trembling, the muscle strength and muscle tone of the limbs are normal, the limbs are involuntary, the compatibility and the physical examination is not cooperative, and the bilateral pathological signs are negative. During this hospitalization, symptomatic support treatment, including airway management, anti-infection and trying a variety of sedatives (benzodiazepines, zopidine, chloraldehyde hydroly), could not effectively induce sleep. The patient's condition continues to deteriorate, and the family is required to be discharged automatically on 26 December 2023. Brain magnetic resonance imaging results of a proband with fatal familial insomnia. This image displays the brain MRI of the FFI proband, including T1, T2, and SWI sequences. It presents six consecutive brain images. The images reveal that the T1 signal in the subdural region of the left parietal bone is uneven and of equal intensity with a slightly longer T2 signal accompanied by strip-like low signal intensity areas (magnetization effect). Additionally, adjacent brain parenchyma is visible to be compressed, indicating a subdural hematoma. Polysomnography results of a proband with fatal familial insomnia. This figure presents the results of a polysomnography monitoring conducted on a proband with fatal familial insomnia (FFI) during the night. The x-axis represents the monitoring time (from D1 22: 00 to D2 5: 00), and the y-axis sequentially displays sleep stages (W = wakefulness, N1 = nonrapid eye movement sleep stage I, N2 = nonrapid eye movement sleep stage II, N3 = nonrapid eye movement sleep stage III, R = rapid eye movement sleep stage), blood oxygen saturation (SaO2, %), heart rate (Heart Rate, bpm), and sleep-related events (hypopnea, RERA, obstructive sleep apnea, periodic limb movements (PLM), arousals). The monitoring revealed that: (1) Markedly reduced sleep efficiency (15. 8%), prolonged sleep latency, disrupted sleep architecture, increased proportion of stage 1 sleep, decreased proportions of stage II and slow-wave (stage III) sleep, reduced REM sleep percentage, shortened REM sleep latency, and frequent arousals; (2) severe obstructive and central breathing disturbances consistent with severe sleep-disordered breathing, predominantly hypopnea events, accompanied by mixed, central, and obstructive apneas. The apnea-hypopnea index (AHI) was 45. 6 events per hour, the lowest oxygen saturation reached 85%, and the longest recorded duration of a single hypopnea event was 62. 8 s; (3) severe periodic limb movements during sleep with a PLM index of 95. 2, meeting criteria for clinically significant periodic limb movement disorder. Analysis of mutation in the PRNP gene forward sequencing peak map of a fatal familial insomnia pedigree. This figure displays the PRNP gene forward sequencing results of the proband and two of her daughters with fatal familial insomnia (FFI). The red arrow and gray box indicate the mutation hotspot region at codon 178 of the PRNP gene (c. 533C > T). The numbers on the x-axis represent the base positions (90–120 bp). A: The sequencing peak map of the proband shows a double peak of cytosine (C) and thymine (T) at this site, indicating a heterozygous mutation type (PRNP c. 533C > T, p. D178N) ; B: The sequencing peak map of daughter 1 shows only a single peak of cytosine (C) at this site, indicating a wild-type; C: The sequencing peak map of daughter 2 shows a double peak of C/T at this site, indicating a heterozygous mutation type. Family Tree of fatal familial insomnia. This figure illustrates the disease and genetic relationships among members of four generations in a family with fatal familial insomnia (FFI). It is drawn using standard pedigree symbols in human genetics: squares represent males, and circles represent females; symbols filled with black indicate individuals with FFI, whereas those filled with white indicate individuals with normal phenotype; a slash inside the symbol indicates deceased individuals; the male in generation III pointed by the red arrow is the proband of this family; the phenotype of the parents in generation I is marked with a “? , ” indicating that their disease status has not been definitively confirmed. Two males in generation II (the proband's father and uncle), the proband in generation III, and one female in generation IV all exhibit the FFI phenotype, whereas the remaining members have normal phenotype. Familial fatal insomnia (FFI) is a rare and highly characteristic neurodegenerative disease caused by pathogenic misfolding and aggregation of prion proteins. 1 Globally, only dozens of genealogies have been reported, and the average age of onset is about 50 years old. The exact incidence and prevalence are still unknown, and it is often manifested as family gathering. 2, 3 This case report describes a middle-aged man who, with sudden fainting and loss of consciousness as the initial symptoms, rapidly developed into a typical clinical process, characterized by intractable insomnia, autonomic dysfunction, obvious motor ataxia and cognitive and mental disorders. Although this atypical pathogenesis is not common in FFI, it has important clinical warning significance because it can easily lead to initial misdiagnosis (such as cardiogenic syncope, epilepsy or cerebrovascular events), thus delaying the identification of underlying neurodegenerative diseases. Its positive family history provided important clues for diagnosis. Finally, it was found through genetic testing that the PRNP gene D178N (c. 532G > A) mutation was accompanied by 129 methionine monozygates (129MM) and confirmed. 4 This genotype is a highly specific molecular marker of FFI. The diagnosis process of this case highlights several key characteristics of FFI. First of all, the gradually aggravated sleep disorder is the core symptom of FFI. The early difficulty of falling asleep, sleep fragmentation, and inability to take a nap in the early stage of the patient progressed into almost complete sleep deprivation. Polysomnography (PSG) can objectively record the characteristic disorders of sleep structure, manifested as severe loss or complete disappearance of slow-wave sleep (N3 phase) and rapid eye movement sleep as well as extremely low sleep efficiency, 5 as shown in Figure 2. Secondly, autonomic dysfunction is another core aspect that runs through the whole course of the disease, including unexplained tachycardia, hypertension, body temperature fluctuations, and constipation. 6, 7 In addition, rapidly progressing neuropsychic symptoms, such as ataxia, dysphony, cognitive decline, and hallucinations, are also important diagnostic basics. Finally, the positive family history provides a key direction for the diagnosis of hereditary prion diseases. In this case, due to early cognitive and motor symptoms, it was considered autoimmune encephalitis, which shows the confusion of FFI in the early stage. In the differential diagnosis, familial fatal insomnia (FFI) needs to be distinguished from other prion diseases especially sporadic Creutzfeldt–Jakob disease (sCJD). The key to distinguishing between the two lies in the differences in clinical manifestations and auxiliary examinations. sCJD is predominantly characterized by rapidly progressive dementia, whereas prominent insomnia is typically absent in the early stages of the disease. From a neuroimaging perspective, brain MRI in sCJD commonly reveals characteristic hyperintensities on diffusion-weighted imaging (DWI), including cortical “cortical ribboning” and abnormal signals in the basal ganglia. 8 In contrast, the conventional brain MRI of early fatal familial insomnia (FFI) usually shows no specific abnormalities or only nonspecific brain atrophy. However, fluorodeoxyglucose positron emission tomography (FDG-PET) usually shows a significant decrease in the metabolism of the thalamus, cerebral cortex, and cerebellar, which is the core and highly suggestive neuroimaging feature of FFI. 9, 10 Quantitative MRI studies show that both sCJD and FFI are associated with significant atrophy of the thalamus and cerebellum. It is worth noting that in sCJD, the average diffusion rate (MD) of the striatum is reduced, whereas the MD of the subcortical white matter is increased; while in FFI, the diffusion rate of the thalamus and cerebellar increases specifically. 11 In addition, the detection of cerebrospinal fluid (CSF) 14-3-3 protein is highly sensitive in sCJD, whereas it is often negative in FFI—this finding is consistent with the results observed in this case. 12 From the perspective of pathophysiology, the D178N mutation in the prion gene (PRNP gene) 3, 13 will induce the conformational transformation of cell prion (PrPC^) into an isomer (PrPSc^) associated with disease and resistant to protease. This misfolded protein will accumulate abnormally in the thalamus and other selectively susceptible brain areas, 14 thus triggering neuronal apoptosis and glial proliferation. The polymorphism of 129-bit codons (methionine M or valine V) is an important phenotypic regulator. When the D178N mutation is combined with the 129M allele (i. e. , 178Asn-129M haploid type), the phenotype is characterized by fatal familial insomnia (FFI). On the contrary, when the same mutation is associated with the 129V allele, it can lead to hereditary crest disease (gCJD), a disease mainly manifested as rapidly progressive dementia. 15 This “genotype-phenotype” association explains the relative consistency of FFI clinical manifestations. The lesions of FFI are highly concentrated in the thalamus especially the anterior ventral lateral nucleus and the dorsal medial nucleus of the thalamus, which are the key hubs that produce sleep spindle waves and regulate the sleep–awake cycle. 16 Their progressive degeneration directly leads to the collapse of the sleep structure, which explains why traditional GABAergic sedative hypnotics (such as eszopiclone used in this case) have little effect on insomnia caused by FFI–they cannot replace the damaged thalamic nuclear function. Furthermore, the thalamus is not only the center of sleep regulation, but also the key node of consciousness integration. Severe thalamocortical circuit dysfunction may be a potential mechanism of fluctuations in the level of consciousness or even loss of consciousness in FFI patients. The sudden disturbance of consciousness in this case may be an acute and severe interference with the thalamus-cortical network in the early stage of the disease. In addition, the later involvement of the structure of regulating alertness such as the brain stem, and the deterioration of the cognitive and conscious state caused by severe sleep deprivation itself have aggravated the overall consciousness disorder. The emergence of respiratory disorders (such as sleep apnea and stridor) in the terminal stage is related to the involvement of the respiratory center in the brainstem. 17, 18 Therefore, proactive airway management is crucial for preserving comfort and quality of life during the terminal phase of the illness. At present, FFI is still a terminal disease with no effective disease-modifying therapy. Management is entirely palliative and supportive aimed at mitigating specific symptoms—such as pharmacological control of autonomic instability (e. g. , blood pressure and heart rate fluctuations) and treatment of intercurrent infections. With regard to insomnia, despite trials of multiple therapeutic strategies, interventions have shown minimal efficacy. Moreover, sedative agents must be used cautiously due to the risk of worsening cognitive confusion or paradoxical agitation. In recent years, targeted treatment strategies such as prion reduction therapy, gene therapy, and mTOR signaling pathway19, 20 are being explored in the experimental stage bringing hope for the future. This case is a typical example of fatal familial insomnia. It warns clinicians. For patients with progressive and intractable insomnia as the core, accompanied by autonomic nerve and motor dysfunction, even if the conventional imaging is normal, FFI must be included in the differential diagnosis. Detailed family history inquiries, characteristic multilead sleep diagrams, brain metabolic imaging showing low thalamic metabolism, and decisive PRNP gene detection are the keys to the diagnosis of this disease. Raising awareness of FFI is not only conducive to early diagnosis and avoiding unnecessary examination and treatment, but more importantly, it can provide accurate genetic counseling and prenatal diagnosis opportunities for patient families and fulfill the important role of modern medicine in the management of rare diseases. Wenyan Liu: Conceptualization; investigation; writing—original draft; methodology; writing—review and editing; project administration. Xinyue Xing: Conceptualization; methodology; project administration. Xiaoming Wang: Investigation; methodology. Xuqian Liu: Conceptualization; methodology. Mingyue Liu: Project administration; investigation. Wei Shang: Supervision; resources; project administration. Zhaohong Xie: Supervision; resources; project administration; conceptualization; funding acquisition; methodology. We would like to thank all members of the Department of Neurology of the second hospital of Shandong University for their guidance and support. We also sincerely thank the patient's family members for their understanding and support during the writing of this case report. The studies involving humans were approved by research ethics committee of the Qilu Second Hospital of Shandong University (approval number: KYLL202602067). The studies were conducted in accordance with the local legislation and institutional requirements. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Liu et al. (Tue,) studied this question.