A 36-year-old Han-Chinese right-handed man (patient III-10, the proband) developed anxiety, depression, sleep disorder, and tremor in his hands after a panic attack but without known medical history. His cognitive state declined, and he was unable to perform job duties due to memory loss. At 11 months after onset, the patient became withdrawn, and more deterioration of his cognitive function was observed, indicated by the difficulty in calculating, being lost at home, and frequently forgetting the names of acquaintances. Besides, the tremors spread to bilateral limbs, which led to difficulty in cake decoration (the patient's profession). After 16 months of onset, he was diagnosed with depression and anxiety and was prescribed sertraline, fluphenazine, and piracetam. At 17 months after onset, he was scored 20 of 30 on the Chinese Mini-Mental Status Examination (MMSE), and 15 of 30 on the Montreal Cognitive Assessment (MoCA Beijing Version). The Hamilton's Depression Scale was 7. At 19 months after onset, he developed hallucinations, which made him see his sons as enemies, and occasionally, he protected himself via aggressive behaviors.
In the clinic, the diagnosis of possible behavioral variant Frontotemporal Dementia (bvFTD) was considered because of the abnormal neuropsychological profile, such as early apathy and executive/gene deficits with relative sparing of memory and visuospatial functions.
A thorough neurological examination 20 months after the onset revealed a total deterioration of the cognitive state, dysarthria, slight hypermyotonia, and deep tendon hyperreflexias in the bilateral limbs, and the patient presented cogwheel-like rigidity. He had difficulty finishing the finger-to-nose test and heel-knee-tibia test due to tremors in his limbs. The patient was unsteady when walking on a straight line. No involuntary movement was observed. He scored 15 of 30 on the Chinese MMSE, and 9 of 30 on the MoCA Beijing Version. The Hamilton's Depression Scale was 7.
To our surprise, the brain MRI demonstrated abnormal intensities in the bilateral caudate nucleus, putamen, and cerebral cortex. A series of laboratory examinations were performed for the rapidly progressive early-onset dementia. The autoimmune screening and tumor marker identification were shown to be unremarkable or negative. An extensive panel for paraneoplastic antibodies including Amphiphysin, CV2, PNMA2 (Ma2/Ta), Ri, Yo, Hu, titin, SOX1, recoverin, zic4, GAD65, and Tr (DNER) were tested, and all were negative. Serology and cerebrospinal fluid (CSF) tests for HIV, cryptococcus, syphilis, tuberculosis, bacteria, fungus, and virus showed no evidence of inflammation. In addition, CSF 14-3-3 protein was tested to be negative. RT-QuIC tests of skin and CSF were also negative (Figure 2).
Diffusion-weighted imaging (DWI) sequences displayed restricted diffusion in the bilateral frontal and parietal cortex (Figures 3A-D). DWI hyperintensities were revealed in the bilateral basal ganglia, bilateral pulvinar, and dorsomedial thalamus (Figures 3E-J). Fluorodeoxyglucose PET (FDG-PET) exhibited hypometabolism in the bilateral cerebral cortex and right basal ganglia (Figure 4).
An empiric course of pulse IV gamma globulin was tried without notable improvement.
At 22 months after onset, the hypermyotonia of the patient in the bilateral limbs became more obvious. He had occasional urinary incontinence, and his ability to study was relatively reserved when he scored 21 of 30 on the Chinese MMSE. The MRC Scale score was 13 of 20. The Hamilton's Depression Scale was 6. EEG showed diffuse slow waves. MRI scanning indicated no obvious change compared to images 2 months earlier.
A follow-up study with the MRC Scale revealed gradually developed aphasia, gait disorder, and fecal incontinence 30 months after onset. The patient is still alive, 4 years after the onset, while the MRC Scale score was 2 of 20, and his swallowing function and mobility were still preserved (Table 1).
The clinical features indicated that the patient might have prion disease. To determine the etiology of the disease, we extracted genome DNA from peripheral blood leucocytes of the patient and performed a direct DNA sequencing of the PRNP coding sequence. Unexpectedly, a rare mutation of G114V and 1-OPRD of the PrP in the patient was identified (Figure 5). Given that only a few patients with gCJD were reported to carry the G114V PRNP variant, we suspected that the mutation in the patient might be inherited from his parents, and we, thus, enrolled his immediate family members in this study for a genetic investigation.
Although the medical record was not available, the maternal grandmother (patient I-2) of the proband was found to have progressive dementia in her 60s, which was within 1 year before her death, and subsequently developed a tremor in her last few months. The proband's mother (carrier II-8) received examination when she was 61 years old, but no neuropsychiatric symptoms were observed. She scored 29 of 30 on the Chinese MMSE and 21 of 30 on the MoCA (Beijing Version). Although the EEG showed slow waves in the left temporal lobe, both cranial MRI (including DWI) and FDG-PET were unremarkable. A follow-up study revealed that she suffered an acute cerebral infarction in the callosum 18 months after the first examination. No cortical ribbon was found by DWI to date (Table 2). Whereas DNA sequencing revealed a G114V mutation and 1-OPRD of PrP in this individual. The elder son of the proband (carrier IV-1) received DNA sequencing at age 10, and G114V mutation and 1-OPRD were also found, although he did not show any clinical symptoms. No further examination was performed due to his age. No autopsy or biopsy were performed on any of the patients.