[Clinical characteristics and diagnostics of human spongiform encephalopathies: an update]. / Klinik und Diagnostik humaner spongiformer Enzephalopathien: ein Update.

Human spongiform encephalopathies are rare transmissible neurodegenerative diseases of the brain and the nervous system that are caused by misfolding of the physiological prion protein into a pathological form and its deposition in the central nervous system (CNS). Prion diseases include Creutzfeldt-Jakob disease (CJD, sporadic or familial), Gerstmann-Straussler-Scheinker syndrome (GSS) and fatal familial insomnia (FFI). Prion diseases can be differentiated into three etiological categories: spontaneous (sporadic CJD), inherited (familial CJD, FFI, and GSS) and acquired (variant CJD and iatrogenic CJD). Most cases occur sporadically. Prion diseases can lead to a variety of neurological symptoms and always have an inevitably fatal course. Cerebrospinal fluid analysis and magnetic resonance imaging (MRI) play a crucial role in the diagnostics of prion diseases and may facilitate an early and reliable clinical diagnosis. A causal treatment or specific therapeutic agents are not yet available. In general, a palliative therapeutic concept is indicated.

NGS study in a sicilian case series with a genetic diagnosis for Gerstmann-Sträussler-Scheinker syndrome (PRNP, p.P102L).

BACKGROUND: Gerstmann Sträussler Scheinker (GSS) is an inherited, invariably fatal prion disease. Like other human prion diseases, GSS is caused by missense mutations in the prion protein (PrP) gene (PRNP), and by the formation and overtime accumulation of the misfolded, pathogenic scrapie PrP (PrPSc). The first mutation identified in the PRNP gene, and the one blamed as the main cause of the disease, is c.C305T:p.P102L. METHODS AND RESULTS: The Sanger sequencing method was performed on the PRNP gene for the detection of c.C305T:p.P102L mutations in a cohort of 10 subjects; moreover, a study was carried out, using Next Generation Sequencing (NGS), by sequencing a group of genes related to amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), movement disorders and dementia which show a phenotypic profile similar to that of GSS. The results obtained from the study using NGS indicate the potential role of other genetic variants which could contribute to the various GSS phenotypes. CONCLUSIONS: In conclusion, we highlight the large clinical variability in subjects presenting with GSS and p.P102L, as well as the hypothesis that the mutation in PrP codon 102 alone is not sufficient to trigger the cardinal clinical signs of the disease; furthermore, we do not exclude the possibility that further genetic variants play a decisive role in the aspects of the various phenotypes with which GSS manifests itself.

Gerstmann-Sträussler-Scheinker Disease Presenting as Late-Onset Slowly Progressive Spinocerebellar Ataxia, and Comparative Case Series with Neuropathology.

BACKGROUND: Genetic prion diseases, including Gerstmann-Sträussler-Scheinker disease (GSS), are extremely rare, fatal neurodegenerative disorders, often associated with progressive ataxia and cognitive/neuropsychiatric symptoms. GSS typically presents as a rapidly progressive cerebellar ataxia, associated with cognitive decline. Late-onset cases are rare. OBJECTIVE: To compare a novel GSS phenotype with six other cases and present pathological findings from a single case. METHODS: Case series of seven GSS patients, one proceeding to autopsy. RESULTS: Case 1 developed slowly progressive gait difficulties at age 71, mimicking a spinocerebellar ataxia, with a family history of balance problems in old age. Genome sequencing revealed a heterozygous c.392G > A (p.G131E) pathogenic variant and a c.395A > G resulting in p.129 M/V polymorphism in the PRNP gene. Probability analyses considering family history, phenotype, and a similar previously reported point mutation (p.G131V) suggest p.G131E as a new pathogenic variant. Clinical features and imaging of this case are compared with those six additional cases harboring p.P102L mutations. Autopsy findings of a case are described and were consistent with the prion pathology of GSS. CONCLUSIONS: We describe a patient with GSS with a novel p.G131E mutation in the PRNP gene, presenting with a late-onset, slowly progressive phenotype, mimicking a spinocerebellar ataxia, and six additional cases with the typical P102L mutation.

Structural and functional neuroimaging in human prion diseases.

INTRODUCTION: Prion diseases are neurodegenerative disorders resulting from the accumulation of a misfolded isoform of the cellular prion protein (PrPc). They can occur as acquired, sporadic, or hereditary forms. Although prion diseases show a wide range of phenotypic variations, pathological features and clinical evolution, they are all characterised by a common unfavourable course and a fatal outcome. REVIEW SUMMARY: Some variants, such as kuru, have practically disappeared, while others, for example the variant Creutzfeldt-Jakob (vCJD) or those attributable to iatrogenic causes, are still in force and pose a challenge to current medicine. There are no definitive pre-mortem diagnostic tests, except for vCJD, where a tonsil biopsy detects 100% of the cases. For this reason, diagnostic criteria dependent on statistical probability have had to be created. These require complementary examinations, such as an electroencephalogram (EEG) or the detection of 14-3-3 protein in cerebrospinal fluid (CSF). Only the pulvinar sign in magnetic resonance imaging (MRI) has been included as a vCJD diagnostic criterion. The present review discusses neuroimaging findings for each type of prion disease in patients with a definitive histopathological diagnosis. CONCLUSIONS: The aim is to define the usefulness of these complementary examinations as a tool for the diagnosis of this family of neurodegenerative diseases.

[Gerstmann-Sträussler disease: a familial case with common PRNP mutation and atypical features]. / Bolezn' Gerstmana­Shtrosslera: semeinyi sluchai s chastoi mutatsiei gena PRNP i atipichnymi proyavleniyami.

Gerstmann-Sträussler disease (GSD) is a very rare autosomal dominant late-onset neurodegenerative disorder related to prion protein gene PRNP. Mutation p.Pro102Leu produces about 80% of cases, which are often named GSD-102. DNA testing provides exact diagnosis. In the presented Russian family there were 3 patients: a female index case, age 32 years, her brother, age 37 years (age of onset in both is 27 years) and their deceased father (onset in 35 years, death in 44 years). GSD was not suspected until whole exome sequencing in the female detected PRNP mutation p.Pro102Leu confirmed in her and in the brother by Sanger sequencing. Atypical features of the case are: early onset in siblings, absence of mental and behavioral problems in the female and in the father and mild disturbances in the brother; epilepsy in the brother; atypical onset with transient signs in the brother. Other intrafamilial differences are prevailing spastic paraparesis in the female in contrast to predominant ataxia in the brother and dysarthria absence in the female. The case illustrates GSD-102 variability, complicating clinical diagnostics.

A family with mental disorder as the first symptom finally confirmed with Gerstmann-Sträussler-Scheinker disease with P102L mutation in PRNP gene - case report.

Gerstmann-Sträussler-Scheinker (GSS) disease is an autosomal dominant neurodegenerative disease, and it is characterized by progressive cerebellar ataxia. Up to now, GSS cases with the p.P102L mutation have mainly been reported in Caucasian, but rarely in Asian populations. A 54-year-old female patient presented with an unstable gait in the hospital. Last year, she was unable to walk steadily and occasionally choked, could not even walk independently gradually. After taking her medical history, we found that she was misdiagnosed with schizophrenia before the gait problems. The patient's father showed similar symptoms and was diagnosed with brain atrophy at the age of 56, but her daughter showed no similar symptoms at present. On arrival at the Neurology Department, the patient's vital signs and laboratory examinations showed no abnormality. As the proband presented with cerebellar ataxia and had an obvious family history, we were sure that she had hereditary cerebellar ataxia. Then, patient's brain MRI showed an abnormal signal in the right parietal cortex and bilateral small ischaemic lesions in the frontal lobe. A gene panel (including 142 ataxia-related genes) was performed, and a heterozygous mutation PRNP Exon2 c.305C>T p. (Pro102Leu) was identified. Her daughter had the same heterozygous mutation. The patient was diagnosed with GSS with mental disorders as initial symptoms. After 2 months of TCM treatment, the patient's walking instability decreased, and her emotional fluctuations were less than before. In conclusion, we have reported a rare case of GSS in Sichuan, China, and the family with mental disorder as the first symptom was finally confirmed with GSS PRNP P102L mutation.

Pearls & Oy-sters: Deep Phenotyping of Abnormal Eye Movements Advances the Detection of Gerstmann-Sträussler-Scheinker Syndrome.

A 58-year-old previously healthy woman presents with 3 years of rapidly progressive ataxia, parkinsonism, dysautonomia, peripheral neuropathy, leg weakness, spasticity, hyperreflexia, and mild vertical-gaze palsy. She has a matrilineal family history of neurodegenerative diseases. She was initially postulated to have spinocerebellar ataxia or atypical parkinsonism with cerebellar features. However, on closer inspection, her abnormal extraocular eye movements suggested rare mimicking disorders such as prion disease as part of the differential diagnosis, requiring further evaluation. This case highlights how deep phenotyping can open new diagnostic considerations, inform additional workup, and yield the precise diagnosis of Gerstmann-Sträussler-Scheinker syndrome (GSS).

Gerstmann-Sträussler-Scheinker syndrome misdiagnosed as cervical spondylotic myelopathy: A case report with 5-year follow-up.

RATIONALE: Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare autosomal dominant disease caused by a mutation in the prion protein gene (PRNP) that is not well known among neurologists and is therefore easily misdiagnosed. PATIENT CONCERNS: : A 49-year-old man was admitted for the first time because of an unsteady walk with mogilalia for 1 year. He underwent a cervical discectomy and a plate-screw fixation 6 months prior, although postoperative gait instability did not improve. DIAGNOSIS: Whole exome sequencing identified a pathogenic and heterozygous mutation in the PRNP 4 years after onset. The patient was eventually diagnosed with GSS. INTERVENTIONS: Symptomatic treatment to improve cerebrocirculation and cerebrometabolism was provided. OUTCOMES: The neurological decline continued. The Mini-Mental State Examination and modified Rankin Scale scores changed from 19 to 11 and 2 to 5, respectively. Progressive cerebral and cerebellar atrophy on magnetic resonance imaging was observed. LESSONS: Cerebral and cerebellar atrophy are neuroimaging features symptomatic of GSS that become more apparent as the disease progresses. This atrophy is positively correlated with the severity of symptoms and reduced quality of life. Neurologists treating middle-aged patients with progressive ataxia, cognitive impairment or dysarthria, and brain atrophy need to consider the possibility of GSS.

The first case of protease-sensitive prionopathy (PSPr) in The Netherlands: a patient with an unusual GSS-like clinical phenotype.

An atypical case of prion disease is described in a 54-year-old Dutch man, homozygous for valine at codon 129 of the prion protein gene (PRNP). The clinical phenotype was characterised by progressive dementia, spastic paraplegia and sensorimotor polyneuropathy. The disease duration was 20 months. Genetic analysis of PRNP did not reveal any abnormalities. Neuropathologically, only mild spongiform change and a coarse granular immunohistochemical staining for the abnormal prion protein, PrP(Sc), was observed, with poorly formed plaques in the molecular layer of the cerebellar cortex. However, Western blotting showed low but detectable levels of proteinase K(PK)-resistant PrP(Sc) occurring in an unusual ladder-like profile. These features define a phenotype that corresponds to the recently described protease-sensitive prionopathy (PSPr). Our report on the first Dutch patient with PSPr further expands the spectrum of prionopathies and exemplifies the need to re-evaluate cases of atypical 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.

Phenotypic heterogeneity and genetic modification of P102L inherited prion disease in an international series.

The largest kindred with inherited prion disease P102L, historically Gerstmann-Sträussler-Scheinker syndrome, originates from central England, with émigrés now resident in various parts of the English-speaking world. We have collected data from 84 patients in the large UK kindred and numerous small unrelated pedigrees to investigate phenotypic heterogeneity and modifying factors. This collection represents by far the largest series of P102L patients so far reported. Microsatellite and genealogical analyses of eight separate European kindreds support multiple distinct mutational events at a cytosine-phosphate diester-guanidine dinucleotide mutation hot spot. All of the smaller P102L kindreds were linked to polymorphic human prion protein gene codon 129M and were not connected by genealogy or microsatellite haplotype background to the large kindred or each other. While many present with classical Gerstmann-Sträussler-Scheinker syndrome, a slowly progressive cerebellar ataxia with later onset cognitive impairment, there is remarkable heterogeneity. A subset of patients present with prominent cognitive and psychiatric features and some have met diagnostic criteria for sporadic Creutzfeldt-Jakob disease. We show that polymorphic human prion protein gene codon 129 modifies age at onset: the earliest eight clinical onsets were all MM homozygotes and overall age at onset was 7 years earlier for MM compared with MV heterozygotes (P = 0.02). Unexpectedly, apolipoprotein E4 carriers have a delayed age of onset by 10 years (P = 0.02). We found a preponderance of female patients compared with males (54 females versus 30 males, P = 0.01), which probably relates to ascertainment bias. However, these modifiers had no impact on a semi-quantitative pathological phenotype in 10 autopsied patients. These data allow an appreciation of the range of clinical phenotype, modern imaging and molecular investigation and should inform genetic counselling of at-risk individuals, with the identification of two genetic modifiers.

Gerstmann-Sträussler-Scheinker syndrome misdiagnosed as conversion disorder.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare cause of genetic prion disease. Overlapping neurological, cognitive and psychiatric symptoms make GSS difficult to diagnose based on clinical features alone. We present a 40-year-old man without relevant medical or family history who developed progressive neurocognitive and behavioural symptoms over 3 years. Initial extensive diagnostic workup of his variable motor symptoms was unrevealing and he was diagnosed with conversion disorder. This diagnosis persisted for over 2 years, despite progressive neurocognitive symptoms. He eventually developed dementia and severe neurological impairment. Repeat brain MRI revealed generalised cortical volume loss, establishing the diagnosis of a rapidly progressive neurodegenerative process. He ultimately died from aspiration pneumonia at age 43. Postmortem neuropathological examination showed widespread multicentric prion protein amyloid plaques characteristic of GSS. Ultimately, genetic testing of brain tissue revealed a heterozygous A117V variant in the PNRP gene, confirming the diagnosis.

A previously undiagnosed case of Gerstmann-Sträussler-Scheinker disease revealed by PRNP gene analysis in patients with adult-onset ataxia.

Ataxia is a frequently reported symptom in prion diseases (PD) and it is characteristic of Gerstmann-Sträussler-Scheinker syndrome (GSS), a genetic PD mainly related to the P102L mutation in the PRNP gene. Our aim was to screen for the P102L and other six known PRNP gene mutations (P105L, A117V, Y145X, E200K, D202N, and V210I) a group of 206 consecutive patients diagnosed with adult-onset cerebellar ataxia of unknown origin. The patients, negative for the most common acquired and genetic forms, were analyzed using a combination of restriction endonuclease digestion and pyrosequencing; eight, affected by ataxia and cognitive dysfunction, were also sequenced for the PRNP gene. One patient resulted to be heterozygous for the P102L mutation. Retrospectively, the clinical picture was consistent with a "classical" GSS phenotype. In conclusion, the screening for the P102L mutation, or even the sequencing of the PRNP gene should be taken in consideration in patients with late-onset ataxia (>50 years).

[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.

A case of Gerstmann-Sträussler-Scheinker syndrome.

Gerstmann-Sträussler-Scheinker syndrome (GSS syndrome) is a rare hereditary disorder caused by prion protein gene mutation. We present the case of a 31-year-old man, whose signs and symptoms gradually progressed from loss of attention while driving at onset to headache, dysarthria, night sweat, fatigue, and dysgraphia. Diffusion-weighted imaging (DWI) of the brain after admission showed high signal intensities in the bilateral caudate nuclei, bilateral thalami, and cerebral cortices that suggested transmissible spongiform encephalopathy. The patient was diagnosed with GSS syndrome on genetic study. Magnetic resonance (MR) imaging of the entire period of sickbed showed gradually changing signal intensities and cerebral atrophy. We present a series of images and discuss the reasons for the abnormal intensities in GSS syndrome that vary among reported cases.

[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).

Gerstmann-Sträussler-Scheinker disease with atypical presentation.

We describe a 37-year-old woman who presented with progressive deafness, visual loss and ataxia. She latterly developed neuropsychiatric problems, including cognitive impairment, paranoid delusions and episodes of altered consciousness. She was found to be heterozygous for the Q212P mutation in the prion protein gene. She died over a decade after initial presentation and a diagnosis of prion disease was confirmed at postmortem.

Clinical features of Chinese patients with Gerstmann-Sträussler-Scheinker identified by targeted next-generation sequencing.

Gerstmann-Sträussler-Scheinker (GSS) is an autosomal dominant neurodegenerative disease due to mutations within prion protein (PRNP) gene. Clinically, it is not easy to distinguish GSS from spinocerebellar ataxia (SCA), especially in the early stage of disease. We aimed to identify genetic mutations in 8 Chinese pedigrees with dominant ataxia but excluded dynamic mutations of SCA genes. Targeted next-generation sequencing was performed in the 8 probands. A customized panel was designed to capture 24 known causative genes, including 15 autosomal dominant SCA genes and 9 dementia-related genes. A 2-year follow-up was performed in these patients who harbored mutation. Of the 8 probands, 5 were identified to harbor the p.P102L mutation within PRNP. All these 5 cases had progressive ataxia with age at onset ranging from 48 to 52 years (49.5 ± 4.51). Remarkable phenotypic heterogeneity was observed in them. Cognitive decline was found in 4/5 probands. The average duration from initial symptoms to cognitive decline is 32.5 months, ranging from 22 to 48 months. In this study, we presented the detailed clinical features of 5 GSS pedigrees with PRNP p.P102L mutation. The variable phenotypes among these GSS patients indicated other genetic or environmental factors might be involved in the phenotypic heterogeneity of GSS. Our findings also support the proposal that screening of PRNP mutations should be performed for the patients with dominant ataxia if dynamic mutations of SCA genes were excluded.