Lin Chen†‡
Yin Xu*†‡Ming-juan FangYong-guang ShiJie ZhangLiang-liang Zhang
Yu WangYong-zhu HanJi-yuan HuRen-min Yang
Xu-en Yu*- Department of Neurology, The Affiliated Hospital of Institute of Neurology, Anhui University of Chinese Medicine, Hefei, China
Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare genetic prion disease caused by a mutation in the prion protein (PRNP) gene. It is typically characterized by progressive cerebellar ataxia and slowly progressive dementia. We present a case study of the GSS from China in which a 45-year-old male with a progressive gait and balance disorder developed cerebellar ataxia onset but was misdiagnosed as spinocerebellar ataxia (SCA) for 2 years. The patient's clinical, electrophysiological, and radiological data were retrospectively analyzed. Examination revealed ataxia, dysarthria, muscle weakness, areflexia in lower limbs, including a pyramidal sign, whereas cognitive decline was insignificant. His late mother had a similar unsteady gait. An electroencephalogram (EEG) showed normal findings, and 14-3-3 protein was negative. A brain MRI was performed for global brain atrophy and ventricular enlargement. Positron emission tomography–computed tomography (PET–CT) (18F-fluoro-2-deoxy-d-glucose, FDG) images showed mild to moderate decreased glucose metabolism in the left superior parietal lobe and left middle temporal lobe. According to genetic testing, his younger brother also had the P102L variant in the PRNP gene. This single case adds to the clinical and genetic phenotypes of GSS.
Background
Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare genetic fatal prion disease with clinical heterogeneity where the prevalence ranges from 1 to 10 per 100 million individuals and is characterized by progressive cerebellar dysfunction and cognitive decline (1). GSS was initially described as a rare familial disease of the central nervous system. In 1995, a proline-to-leucine mutation at codon 102 (P102L) in the PRNP gene was identified in a family (2). Although the P102L mutation has been reported in several Chinese GSS cases, it may not be a common mutation in China (3). GSS syndrome with P102L mutation was first reported in China in 2006, and only 20 cases with P102L-associated GSS have been reported so far (Table 1) (7, 8, 12, 13, 15, 17, 18, 21, 23).
Table 1. Comparison of basic features of GSS cases with P102L mutation previously reported in Asian region.
We described a Chinese patient with GSS and a heterozygous mutation in the PRNP gene with progressive ataxia, pyramidal signs, and areflexia. The patient had a few cognitive declines previously misdiagnosed as spinocerebellar ataxia (SCA). This case report describes an unusual clinical condition with a positive family history confirmed by gene testing. Our patient and his younger brother both had heterozygous mutations in exon 2 of PRNP, located on chromosome 20. A pathogenic mutation causes the P102L mutation at codon 102 in PRNP, the most common variant associated with GSS.
Case presentation
A 41-year-old Chinese man was referred for an abnormal gait suggestive of ataxia. The patient's physical and intellectual level in early life was normal, but his family noticed decreased language fluency at the age of 40 years. One year later, he was 41-years-old, he often fell due to progressive aggravation of walking instability and decreased muscle strength in his lower limbs. He was treated at hospital at the age of 42 years for ataxia, and he was given buspirone. He deteriorated over time, when he was 44-years-old, he could not walk, and began using a wheelchair. There was no further decline in cognitive status over time.
He had a family history of similar symptoms in his mother. She presented to medical attention at the age of 55 years with an unsteady gait. She required a wheelchair by age 58 years, owing to progressive walking instability and decreased muscle strength in her lower limbs. She was subsequently bedbound but did not attend the hospital for a physical examination and finally died at the age of 60 years. During this time, her family did not realize significant cognitive difficulties. The cause of death was unknown, and her family could not provide further details.
Meanwhile, the results of SCA genetic sequencing were found negative. He was referred to our hospital in April 2022. The physical examination revealed mild dysarthria, gait ataxia, bilateral lower extremity weakness, and areflexia but with present Babinski responses bilaterally. The finger-to-nose and rapid alternating movement tests were both abnormal. Orientation, attention, calculation, comprehension, and memory were normal. Laboratory tests and cerebrospinal fluid evaluation were found normal, including the screening for paraneoplastic syndromes-related antibodies and evaluation of 14-3-3 protein levels. Blood and cerebrospinal fluid (CSF) tests were negative for neuromyelitis optica (NMO)-IgG, aquaporin 4 antibodies (AQP4-Ab), and paraneoplastic antibodies. His cognitive function was slightly impaired, and a Mini-Mental State Examination (MMSE) score of 27/30 was obtained during a neuropsychological examination. The interictal electroencephalogram (EEG) showed normal findings (Figure 1). Evoked potential: increase in the binaural threshold. The lower extremity deep sensory path revealed prolonged bilateral P40 latency with amplitude decrease. Brain MRI exhibited T2-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, as well as global brain atrophy, ventricular enlargement and cerebellar atrophy. Diffusion-weighted imaging (DWI) revealed no other abnormalities (Figure 2). PET-CT (18F-fluoro-2-deoxy-d-glucose, FDG) images showed that the left superior parietal lobe and left middle temporal lobe had mild to moderate decreased glucose metabolism, with reductions of 10 and 19%, respectively (Figure 3). We questioned the possible diagnosis of autosomal-recessive cerebellar ataxia (ARCA) before hospitalization, but not exclude a dominant ataxia. Our case was initially diagnosed with SCA. However, the genes responsible for common subtypes of SCA (including SCA1/2/3/6/7/8/12/17, FRDA, and DRPLA) were sequenced for this proband, revealing no pathogenic mutations. The patient was then suspected of having spastic paraplegia; however, areflexia was inexplicable, although later autosomal dominant spastic paraplegia type 4 had a suspected pathogenic site on chromosome 17 (c.1786G>A). The whole-exome sequencing (WES) analysis identified pathogenic heterozygous missense mutations of the PRNP gene, c.305C>T (p.Pro102Leu). The Sanger sequencing confirmed that his younger brother inherited the same mutations from his parents (Figure 4). The codon 129 genotype of the patient and his young brother were both P102L-129M/M. His younger brother inherited the same mutations from his parents at the age of 39 years. Up to now, his younger brother still has no symptoms. Then, we diagnosed a case of P102L-associated GSS. We suggested a brain biopsy before making a final diagnosis, but the patient refused. There are currently no approved treatments for GSS. He was treated with buspirone (30 mg/day). The patient's limb weakness worsened rapidly. One year after onset, he often fell due to progressive aggravation of walking instability and decreased muscle strength in his lower limbs. Then, 2 years after onset, he began using a wheelchair and was completely paralyzed in bed most of the time.
Figure 1. Video electroencephalogram (EEG) showed normal findings.
Figure 2. Magnetic resonance imaging (MRI) of the brain. Axial T2-weighted (A, B) and sagittal T2-weighted scan (C) revealed enlarged sulci in the cerebrum. Fluid-attenuated inversion recovery (FLAIR) sequences (D–F) revealed global brain atrophy, ventricular enlargement.
Figure 3. PET-CT images showed the left superior parietal lobe (A) and left middle temporal lobe (B) had mild to moderate decreased glucose metabolism, with reductions of 10 and 19%, respectively.
Figure 4. (A) Pedigree and PRNP sequences of the proband and his brother. Squares indicate men, circles indicate women, black symbols indicate affected individuals, gray indicates symptoms of presumed GSS, diagonal lines across symbols indicate deceased individuals, and the arrow indicates the proband. 
for GSS, and 
for symptoms of presumed GSS. (B) II-1: PRNP sequence of the patient reveals a heterozygous substitution from C to T at position 305 of PRNP cDNA, resulting in an amino acid change from proline to leucine at position 102 (P102L mutation). II-2: PRNP sequence of his little brother confirms the P102L mutation. The arrow indicates the mutation.
Discussion
We described a case of GSS with unusual clinical and genetic features. Since GSS is an autosomal dominant inherited disease, a single allele mutation can increase the risk of developing the disease. The duration of the disease ranges from 1 to 10 years. GSS has a relatively longer survival duration than other prion diseases. GSS with the P102L mutation is a rare genetic prion disease caused by a pathogenic mutation at codon 102 in the prion protein gene, with diverse clinical variability (7). GSS clinical symptoms include cerebellar ataxia and gait disturbance (72%), cognitive decline (80%), extrapyramidal damage (36%), psychiatric symptoms (21%), and myoclonus (15%) (24, 25). A high positivity rate (83.3%) for the family history was found in the present Chinese case of P102L-associated GSS, with slowly progressive cerebellar ataxia in 90% of patients. In contrast, visual disturbances, dystonia, and myoclonus are uncommon in patients with GSS (18). Ufkes et al. have reported a member of the GSS Indiana Kindred with supranuclear palsy, a less common feature in GSS (26). Li et al. reported five patients from China with progressive ataxia with age at onset ranging from 48 to 52 years (49.5 ± 4.51). All these patients were found to have the p.P102L mutation within PRNP (13). Of course, the vast majority of GSS cases are due to a missense mutation in the PRNP gene although there are a few other reports such as OPRI (27). From 1992 to the present, not much has been reported about Chinese cases of P102L-associated GSS (Tables 1, 2).
Table 2. Comparison of basic features of GSS cases with P102L mutation previously reported.
Genetic testing should be recommended for patients with rapidly progressing paralysis, including gait and balance disorders. Cluster analysis suggests the existence of four clinical phenotypes: typical GSS, GSS with areflexia and paresthesia, pure dementia GSS, and Creutzfeldt-Jakob disease-like GSS (43). The patient had GSS with areflexia. The symptoms at the early stage of the disease should be distinguished from those of hereditary ataxia and spastic paraplegia. Since the patient only presented with ataxia, muscle weakness, and positive family history, hereditary ataxia, such as spinocerebellar ataxia (SCA), should be distinguished.
Non-specific clinical presentation causes delays in diagnosis. Therefore, rare genetic diseases should be paid more attention especially when common causes have been excluded. The patient had no myoclonus, seizures, psychiatric symptoms, parkinsonism, and dementia. We also focused on EEG and 14-3-3 protein in the CSF because typical triphasic complexes and positivity for 14-3-3 protein in patients were useful in confirming the clinical diagnosis of prion disease. In this context, based on the analysis of 12 Chinese patients with P102L-associated GSS disease, Wang et al. found that only one-quarter and less than half of the Chinese patients had periodic sharp wave complexes (PSWC) in EEG and positivity for 14-3-3 protein in the CSF, respectively (17). Coincidental PSWC in EEG and 14-3-3 positivity in the CSF were observed in 50 and 31% of Caucasian GSS patients, respectively (24). Yazawa et al. reported a woman who developed GSS symptoms and was diagnosed with GSS due to the P102L mutation at the age of 58 years. There were no significant EEG findings during the early stage. Bilateral independent periodic discharges (BIPDs) in both temporal areas appeared at the age of 64 years (22), whereas 14-3-3 protein and EEG reports were normal for our patient, making the diagnosis more difficult.
The neuroimaging examination is an essential component in the differential diagnosis. For our patient, the MRI findings did not provide a clear diagnosis. The main imaging features of GSS are cortical atrophy (55.07%), cerebellar atrophy (42.03%), cortical hyperintensities (32.32%), and basal ganglia hyperintensities (21.54%) (43). However, an investigation based on data from the EuroCJD study found FLAIR or DWI hyperintensities in the basal ganglia in 30% of the P102L-associated GSS cases (24). Our patient revealed cortical atrophy and cerebellar atrophy, despite the absence of FLAIR or DWI hyperintensities consistent with GSS. Yoshimura et al. examined five patients from four Japanese families, and predominant abnormalities were found in the occipital and frontal lobes on SPECT and PET analyses, respectively. In SPECT analysis, the blood flow of the anterior cerebellar lobes was lower than that of the posterior cerebellar lobes (44). Hama et al. reported that a Japanese patient with 18F-2-fluorodeoxy-D-glucose (18F-FDG) PET demonstrated hypometabolism of the cerebral cortex, especially in the frontal lobes and thalamus (42). In contrast, we found reduced presynaptic dopamine transporter uptake in the left superior parietal lobe and left medial temporal lobe on PET-CT images. Thus, the significance of MRI findings in P102L-associated GSS needs further evaluation.
Among Japanese P102L-associated GSS cases, 21% presented with early and prominent dementia (45). Another study found that 40% of cases showed cognitive symptoms at the onset (18). However, unlike his mother, our patient had mild cognitive decline. More research in case studies is required to determine whether Chinese P102-associated GSS patients have a higher or lower proportion of cognitive problems. The presence of multicentric prion protein amyloid plaques in neuropathology remains the key feature of GSS that differentiates it from most other genetic prion diseases. There was no diagnosis for 3 years in the present case. Therefore, we do not have the pathological information of the patient. Nonno et al. demonstrated that GSS is a genuine prion disease characterized by both transmissibility and strain variation, expanding our understanding of the heterogeneous clinic-pathological phenotypes of GSS (46).
Our case highlights the clinical heterogeneity of GSS with the most common p.P102L mutation in the family screening. His younger brother showed no symptoms despite carrying the same P102L mutation in the PRNP gene. His mother walked unsteadily, eventually unable to walk until her death. Therefore, we inferred that his mother suffered from GSS, although the genetic screening was unavailable. His onset began earlier when he and his family refused to do a brain biopsy. His son and daughter were unaffected but did not consent to PRNP gene analysis. Therefore, we do not have full access to the genetic information of the entire family. Penetrance, age of onset, and duration of illness have been systematically characterized across PRNP variants in a global cohort. A genetic counseling session may be triggered by a symptomatic case within the family and may occur either before or after the patient has been tested. Other members of the family, including children need to be able to access clinical services for genetic counseling and testing (47). Several limitations are included in the study. Firstly, we were unable to obtain neuropathological data since the patient did not consent to brain biopsy. Secondly, we have not fully obtained the genetic information of the entire family due to the patient's compliance.
In summary, PRNP sequencing is an indispensable tool for diagnosing GSS due to the complexity of the clinical manifestations of GSS patients. The weakness of the patient's lower limbs developed rapidly, and he arrived at our hospital in a wheelchair. The patient was recently followed up, the strength of his upper limbs was still weak, and he is currently bedridden. However, the patient's younger brother remains asymptomatic.
Data availability statement
The original contributions presented in the study are included in the article/Supplementary material, further inquiries can be directed to the corresponding authors.
Ethics statement
The studies involving human participants were reviewed and approved by Ethics Committee of the Affiliated Hospital of the Institute of Neurology of Anhui University of Chinese Medicine. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.
Author contributions
LC and YX wrote the manuscripts with input from all authors. All authors contributed to data acquisition and analysis. All authors contributed to the article and approved the submitted version.
Funding
This work was supported by the Key Project of Natural Science Research Project of Universities in Anhui Province (KJ2021A0551) and Research Fund of Anhui University of Chinese Medicine (2020sjzd05).
Acknowledgments
We thank the patient and her family for placing their trust in us. We also acknowledge TopEdit LLC for linguistic editing and proofreading during the preparation of this manuscript.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Supplementary material
The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur.2023.1187813/full#supplementary-material
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Keywords: Gerstmann-Sträussler-Scheinker syndrome, PRNP gene, P102L, spinocerebellar ataxia (SCA), prion disease
Citation: Chen L, Xu Y, Fang M-j, Shi Y-g, Zhang J, Zhang L-l, Wang Y, Han Y-z, Hu J-y, Yang R-m and Yu X-e (2023) Case report: A Chinese patient with spinocerebellar ataxia finally confirmed as Gerstmann-Sträussler-Scheinker syndrome with P102L mutation. Front. Neurol. 14:1187813. doi: 10.3389/fneur.2023.1187813
Received: 19 April 2023; Accepted: 13 July 2023;
Published: 03 August 2023.
Edited by:
Huifang Shang, Sichuan University, ChinaReviewed by:
Ahmet Burak Caglayan, Istanbul Medipol University, TürkiyeJifeng Bian, Agricultural Research Service (USDA), United States
Christopher D. Stephen, Massachusetts General Hospital and Harvard Medical School, United States
Copyright © 2023 Chen, Xu, Fang, Shi, Zhang, Zhang, Wang, Han, Hu, Yang and Yu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Yin Xu, fmrixuy@126.com; Xu-en Yu, yuxuen1746@163.com
†These authors share first authorship
‡ORCID: Lin Chen orcid.org/0009-0007-9449-2876
Yin Xu orcid.org/0000-0002-3123-561