Appearance of bitemporal periodic EEG activity in the last stage of Gerstmann-Sträussler-Scheinker syndrome (Pro102Leu): A case report.

EEG findings in advanced Gerstmann-Sträussler-Scheinker syndrome (GSS) are shown. A 56-year-old woman developed GSS symptoms and was diagnosed as having GSS with the P102L mutation at age 58. During the early stage, there were no significant EEG findings. Her clinical condition worsened and she developed akinetic mutism at age 62. The patient died of pneumonia at age 65. EEGs were recorded annually from age 61 to 65. Bilateral independent periodic discharges (BIPDs) in both temporal areas appeared at age 64. No clinical seizures were noticed. MEG showed the sharp waves of BIPDs originated independently in each temporal lobe. Other causes of BIPDs were absent.

Clinical Variability in P102L Gerstmann-Sträussler-Scheinker Syndrome.

Gerstmann-Sträussler-Scheinker syndrome (GSS) with the P102L mutation is a rare genetic prion disease caused by a pathogenic mutation at codon 102 in the prion protein gene. Cluster analysis encompassing data from 7 Czech patients and 87 published cases suggests the existence of 4 clinical phenotypes (typical GSS, GSS with areflexia and paresthesia, pure dementia GSS, and Creutzfeldt-Jakob disease-like GSS); GSS may be more common than previously estimated. In making a clinical diagnosis or progression estimates of GSS, magnetic resonance imaging and real-time quaking-induced conversion may be helpful, but the results should be evaluated with respect to the overall clinical context. ANN NEUROL 2019;86:643-652.

Correlation between clinical and radiologic features of patients with Gerstmann-Sträussler-Scheinker syndrome (Pro102Leu).

BACKGROUND AND PURPOSE: Gerstmann-Sträussler-Scheinker syndrome is a rare hereditary neurodegenerative disorder with clinical heterogeneity. This study is aim to demonstrate the clinical spectrum and radiologic characteristics of patients caused by Pro102Leu mutation in PRNP. MATERIALS AND METHODS: We retrospect clinical manifestations of five patients from four Japanese families, and comprehensively analyzed their brain MRI, SPECT (N-isopropyl-p-[123I] iodoamphetamine), and PET (18F-2-fluoro-2-deoxy-d-glucose) images. RESULTS: All patients developed ataxia of lower limbs and trunk, gait disturbance, dysesthesia in legs, and lower limb hyporeflexia. In the early clinical stage before dementia began, no noticeable abnormalities could be observed from brain MRI, but SPECT and PET revealed mosaic-like pattern of blood flow and glucose metabolism of the brain. Predominant abnormalities were found in the occipital and frontal lobes on SPECT and PET analysis, respectively. In SPECT analysis, blood flow of the anterior cerebellar lobes was lower than that of the posterior cerebellar lobes. CONCLUSIONS: Clinical symptoms resulting from failure of dorsal horn of spinal cord and spinocerebellar tracts were observed in all cases. Radiologic findings revealed individual differences of involved region in their brain, which could produce clinical diversity. We identified a downtrend of blood flow in the anterior cerebellar lobes, a projection field of the spinocerebellar tracts, which is an important feature of Gerstmann-Sträussler-Scheinker syndrome.

Differential overexpression of SERPINA3 in human prion diseases.

Prion diseases are fatal neurodegenerative disorders with sporadic, genetic or acquired etiologies. The molecular alterations leading to the onset and the spreading of these diseases are still unknown. In a previous work we identified a five-gene signature able to distinguish intracranially BSE-infected macaques from healthy ones, with SERPINA3 showing the most prominent dysregulation. We analyzed 128 suitable frontal cortex samples, from prion-affected patients (variant Creutzfeldt-Jakob disease (vCJD) n = 20, iatrogenic CJD (iCJD) n = 11, sporadic CJD (sCJD) n = 23, familial CJD (gCJD) n = 17, fatal familial insomnia (FFI) n = 9, Gerstmann-Sträussler-Scheinker syndrome (GSS)) n = 4), patients with Alzheimer disease (AD, n = 14) and age-matched controls (n = 30). Real Time-quantitative PCR was performed for SERPINA3 transcript, and ACTB, RPL19, GAPDH and B2M were used as reference genes. We report SERPINA3 to be strongly up-regulated in the brain of all human prion diseases, with only a mild up-regulation in AD. We show that this striking up-regulation, both at the mRNA and at the protein level, is present in all types of human prion diseases analyzed, although to a different extent for each specific disorder. Our data suggest that SERPINA3 may be involved in the pathogenesis and the progression of prion diseases, representing a valid tool for distinguishing different forms of these disorders in humans.

Quantitative, functional MRI and neurophysiological markers in a case of Gerstmann-Sträussler-Scheinker syndrome.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is an inherited autosomal dominant prion disease, caused by a codon 102 proline to leucine substitution (P102L) in the prion protein gene (PRNP). We describe the case of a 40-year-old male, affected by a slowly progressive gait disturbance, leg weakness and cognitive impairment. Genomic DNA revealed a point mutation of PRNP at codon 102, resulting in P102L, and the diagnosis of GSS was confirmed. Somatosensory evoked potentials showed alterations of principal parameters, particularly in the right upper and lower limbs. Laser-evoked potentials were indicative of nociceptive system impairment, especially in the right upper and lower limbs. Conventional magnetic resonance imaging (MRI) revealed marked atrophy of the vermis and cerebellar hemispheres and mild atrophy of the middle cerebellar peduncles and brainstem, as confirmed by a brain volume automatic analysis. Resting-state functional MRI showed increased functional connectivity in the bilateral visual cortex, and decreased functional connectivity in the bilateral frontal pole and supramarginal and precentral gyrus. Albeit limited to a single case, this is the first study to assess structural and functional connectivity in GSS using a multimodal approach.

Reversible symptoms and clearance of mutant prion protein in an inducible model of a genetic prion disease in Drosophila melanogaster.

Prion diseases are progressive disorders that affect the central nervous system leading to memory loss, personality changes, ataxia and neurodegeneration. In humans, these disorders include Creutzfeldt-Jakob disease, kuru and Gerstmann-Straüssler-Scheinker (GSS) syndrome, the latter being a dominantly inherited prion disease associated with missense mutations in the gene that codes for the prion protein. The exact mechanism by which mutant prion proteins affect the central nervous system and cause neurological disease is not well understood. We have generated an inducible model of GSS disease in Drosophila melanogaster by temporally expressing a misfolded form of the murine prion protein in cholinergic neurons. Flies accumulating this mutant protein develop motor abnormalities which are associated with electrophysiological defects in cholinergic neurons. We find that, upon blocking the expression of the mutant protein, both behavioral and electrophysiological defects can be reversed. This represents the first case of reversibility reported in a model of genetic prion disease. Additionally, we observe that endogenous mechanisms exist within Drosophila that are capable of clearing the accumulated prion protein.

Atypical parkinsonism due to a D202N Gerstmann-Sträussler-Scheinker prion protein mutation: first in vivo diagnosed case.

BACKGROUND: Parkinsonism with dopa-sensitivity and a correlating DaTSCAN turned out to be due to a D202N mutation which is associated with the Gerstmann-Sträussler-Scheinker (GSS) disease. METHODS/RESULTS: We report a 51-year old female who presented with left-dominant parkinsonism and a positive DaTSCAN. She was diagnosed with idiopathic Parkinson's syndrome. Dopaminergic medication reduced her symptoms. In addition, punding-like behavior, deficits in organizing daily life and abnormal sleep behavior were reported. Neuropsychological testing, EEG, polysomnography as well as PET imaging with fluorodexyglucose (FDG), [F-18]-desmethoxyfallypride (DMFP), and [C-11]-6-OH-BTA-1 (PIB) were not diagnostic. Cerebral spinal fluid analysis revealed no 14-3-3 protein, but elevated neuron-specific enolase (NSE) and S100-beta and a very low phospho-tau/total-tau ratio. Analysis of the prion gene disclosed the rare D202N mutation. CONCLUSIONS: The D202N prion mutation has been associated with GSS pathology and up to now was only reported post mortem. Our patient is the very first case diagnosed in vivo.

Spontaneous generation of anchorless prions in transgenic mice.

Some prion protein mutations create anchorless molecules that cause Gerstmann-Sträussler-Scheinker (GSS) disease. To model GSS, we generated transgenic mice expressing cellular prion protein (PrP(C)) lacking the glycosylphosphatidyl inositol (GPI) anchor, denoted PrP(ΔGPI). Mice overexpressing PrP(ΔGPI) developed a late-onset, spontaneous neurologic dysfunction characterized by widespread amyloid deposition in the brain and the presence of a short protease-resistant PrP fragment similar to those found in GSS patients. In Tg(PrP,ΔGPI) mice, disease onset could be accelerated either by inoculation with brain homogenate prepared from spontaneously ill animals or by coexpression of membrane-anchored, full-length PrP(C). In contrast, coexpression of N-terminally truncated PrP(Δ23-88) did not affect disease progression. Remarkably, disease from ill Tg(PrP,ΔGPI) mice transmitted to mice expressing wild-type PrP(C), indicating the spontaneous generation of prions.

A second case of Gerstmann-Sträussler-Scheinker disease linked to the G131V mutation in the prion protein gene in a Dutch patient.

A rare case of Gerstmann-Sträussler-Scheinker disease in a 36-year-old Dutch man is reported. The clinical phenotype was characterized by slowly progressive cognitive decline, later followed by ataxia and parkinsonism. Neuropathologic findings consisted of numerous amyloid plaques in the cerebellum, which showed positive staining for the abnormal prion protein (PrP(Sc)). In addition, there were tau accumulations around numerous amyloid deposits in the cerebral cortex, striatum, hippocampal formation, and midbrain. There was no spongiform degeneration. Western blot analysis showed the co-occurrence of 2 distinct abnormal prion protein species comprising an unglycosylated, protease-resistant fragment of approximately 8 kd, which was found to be truncated at both N- and C-terminal ends by epitope mapping, and a detergent-insoluble but protease-sensitive form of full-length PrP(Sc). Sequence analysis disclosed a mutation at codon 131 of the prion protein gene (PRNP), resulting in a valine-for-glycine substitution (G131V). The patient was heterozygous at the polymorphic codon 129 and carried the mutation on the methionine allele. To our knowledge, this is the second family worldwide in which this mutation has been identified. Gerstmann-Sträussler-Scheinker disease should be considered in patients with a clinical diagnosis of familial frontotemporal dementia.

Lower limb areflexia without central and peripheral conduction abnormalities is highly suggestive of Gerstmann-Sträussler-Scheinker disease Pro102Leu.

Gerstmann-Sträussler-Scheinker disease Pro102Leu (GSS102) is a rare autosomal dominant inherited prion disease due to a substitution of proline for leucine at codon 102 in the Prion Protein gene, and characterized by early walking difficulties and much later occurring dementia. We report clinical, electrophysiological and neuroradiological features of seven novel Italian cases of GSS102. The findings in our series support the thesis that early signs of GSS102 (including areflexia, ataxia, lower limb weakness, and painful dysesthesias) are likely due to a caudal myelopathic process, and suggest that GSS102 should be included among the causes of ataxia with areflexia. Moreover, our observations show that in patients with GSS102, as opposed to Friedreich's ataxia and other forms of ataxia with areflexia, nerve conduction studies and somato-sensory evoked potentials are normal, despite the presence of lower limb areflexia. Hence, in subjects with walking difficulties, the presence of lower limb areflexia without central and peripheral conduction abnormalities is highly suggestive or possibly pathognomonic of GSS102, and can easily guide the clinicians to make the diagnosis of this rare neurodegenerative disease.

A distinct phenotype of leg hyperreflexia in a Japanese family with Gerstmann-Sträussler-Scheinker syndrome (P102L).

Gerstmann-Sträussler-Scheinker Syndrome (GSS) is an inherited prion disease characterized by midlife onset and slowly progression of cerebellar ataxia and dementia. We report a distinct phenotype of leg hyperreflexia in a Japanese family with GSS. A 38-year-old woman noticed unsteady gait at 33 years of age. Afterwards, dysarthria and writing difficulty were appeared. Her family history revealed that her grandfather and her mother had a clinical history of unsteadiness and mental changes. At 1 year after clinical onset, neurological examination showed cerebellar ataxia and leg hyperreflexia. At 4 years after onset, she suddenly developed insomnia and nocturnal howling. Her mental status disclosed marked disorientation, anxiety and irritability. Muscle stretch reflexes were increased in four extremities with Babinski's signs. Remarkable dysarthria and cerebellar ataxia were presented. Brain diffusion weighted imaging showed extensive hyperintensity signal areas in the cerebral cortex. A point mutation of the prion protein gene (PRNP) at codon 102 resulting in the substitution of proline by leucine (P102L) was identified. PRNP polymorphism exhibited homozygous methionine at codon 129 and homozygous glutamate at codon 219. She had verbal perseveration, somnolence and myoclonus of lower limbs, leading to akinetic mutism at 4 months after neuropsychiatric events. Phenotypic hallmark of our patient indicates leg hyperreflexia from an early disease course. This neurological sign differs from the previously reported clinical expression of Japanese and foreign patients with GSS (P102L). Thus, physicians should pay more attention to phenotypic heterogeneity in this prion disease.

Sleep and temperature rhythms in two sisters with P102L Gerstmann-Sträussler-Scheinker (GSS) disease.

BACKGROUND: Sleep disorders are increasingly recognized in the symptomatology of many neurodegenerative diseases. Gerstmann-Sträussler-Scheinker (GSS) disease is a hereditary prion disease featuring cerebellar ataxia, akinetic parkinsonism, pyramidal signs and cognitive decline. METHODS: We performed a polysomnographic study (PSG) of sleep and body core temperature (BcT degrees ) in two sisters with GSS. RESULTS: Our study showed protracted nocturnal awakenings, reduced sleep efficiency and brief daytime naps but also qualitatively preserved slow-wave and REM sleep and substantially normal arousal and periodic limb movements in sleep indices and BcT degrees rhythm. CONCLUSIONS: These findings conflict with those in multiple system atrophy and other prion diseases such as fatal familial insomnia, which enter the differential diagnosis of GSS and are characterized by prominently disrupted sleep-wake and BcT degrees cycles.

Atypical frontotemporal dementia as a new clinical phenotype of Gerstmann-Straussler-Scheinker disease with the PrP-P102L mutation. Description of a previously unreported Italian family.

OBJECTIVE: To describe a new dementia phenotype of Gerstmann-Straussler-Scheinker disease (GSS) in a previously unreported Italian family. Design Longitudinal clinical and neuropsychological assessment, combined with magnetic resonance imaging (MRI), single positron emission tomography (SPECT) and molecular genetic studies. Setting Neuropsychology Laboratory, and Division of Neuropathology and Neurology, "C. Besta" National Neurological Institute. Patients and participants Three members of the family. Measurements and results. Standardised neuropsychological tests were used to determine cognitive patterns. The proband had a history of primary dementia characterised by loss of initiative, planning, behaviour control, awareness, language and memory; the two relatives suffered from progressive ataxia. MRI of the demented patient revealed brain atrophy with a hyperintense signal in the frontal cortex; SPECT revealed decreased perfusion in the left temporal and parietal cortex and left thalamus. The two ataxic patients showed cerebellar atrophy with no signs of altered perfusion. Analysis of the PRNP gene showed a proline/leucine substitution at codon 102 in all three patients, associated with methionine/valine heterozygosity at the polymorphic codon 129. Conclusions Primary dementia with prominent frontotemporal signs is a new phenotypical expression of P102L-related GSS that coexists in the same family with the ataxic form of the disease. This remarkable variability suggests that still unidentified genetic or acquired factors may modulate the manifestations of GSS. Genetic examination of the PRNP should be included in the diagnostic work-up of patients with poorly classifiable dementia.

[Case of Gerstmann-Sträussler-Scheinker syndrome (GSS-P102L) mimicking variant Creurtzfeldt-Jakob disease in clinical manifestation and MRI findings].

We reported a 51-year-old woman with Gerstmann-Sträussler-Scheinker syndrome (GSS P102L) manifesting characteristic MRI findings. At the age of 45, She developed gait disturbance with muscle atrophy in the lower limbs and positive plantar flexor sign. Subsequently, sensory disturbance such as refractory pain in the lower limbs and ataxic gait were developed at the age of 49. Following these clinical symptoms, she finally demonstrated rapid progressive cognitive dysfunction. Just after presenting cognitive dysfunction, cranial MRI was performed. Cranial MRI with diffusion-weighted imaging and FLAIR imaging demonstrated abnormal high intensity lesions in the bilateral pulvinar, caudate nuclei and cerebral cortex. The degree of high signal at the pulvinar was less than those of the cortex and caudate nuclei. A proline-for-leucine substitution at codon 102 of the prion protein gene was demonstrated. These results allowed the diagnosis of GSS (P102L). This is a rare case of GSS (P102L) presenting with high intensity lesions in the bilateral pulvinar on MRI.

[Familial prion disease (GSS, familial CJD, FFI)].

We described clinically features of inherited prion disease (GSS, familial CJD and FFI). In addition, we found new useful findings of GSS patients for early diagnosis. Generally, clinicians believe that the main features of GSS (P102L) are cerebellar symptoms and dementia; however, our patients showed other features. Most showed mild gait disturbance, dysesthesia and hyporeflexia of the lower legs, proximal leg muscle weakness, and truncal ataxia during the early stage of the disease. Dementia was not a main symptom during the early stage. The key features for the early diagnosis of GSS102 are truncal ataxia, dysesthesia and hyporeflexia of the lower legs, and mild dysarthria. Normal cerebellar MRI and abnormal cerebral SPECT findings should be useful for early diagnosis of GSS (P102L).

The epsilon isoform of 14-3-3 protein is a component of the prion protein amyloid deposits of Gerstmann-Sträussler-Scheinker disease.

The 14-3-3 proteins are highly conserved, ubiquitous molecules involved in a variety of biologic events, such as transduction pathway modulation, cell cycle control, and apoptosis. Seven isoforms have been identified that are abundant in the brain, preferentially localized in neurons. Remarkable increases in 14-3-3 are seen in the cerebrospinal fluid of patients with Creutzfeldt-Jakob disease (CJD), and it has been found in pathologic inclusions of several neurodegenerative diseases. Moreover, the zeta isoform has been detected in prion protein (PrP) amyloid deposits of CJD patients. To further investigate the cerebral distribution of 14-3-3 in prion-related encephalopathies, we carried out an immunohistochemical and biochemical analysis of brain tissue from patients with Gerstmann-Sträussler-Scheinker disease (GSS) and sporadic, familial and acquired forms of CJD, using specific antibodies against the seven 14-3-3 isoforms. The study showed a strong immunoreactivity of PrP amyloid plaques of GSS patients for the 14-3-3 epsilon isoform, but not for the other isoforms. The epsilon isoform of 14-3-3 was not found in PrP deposits of CJD. These results indicate that the epsilon isoform of 14-3-3 is a component of PrP amyloid deposits of GSS and suggest that this is the sole 14-3-3 isoform specifically involved in the neuropathologic changes associated with this disorder.