[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.

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.

Different Complicated Brain Pathologies in Monozygotic Twins With Gerstmann-Sträussler-Scheinker Disease.

Gerstmann-Sträussler-Scheinker disease (GSS) is an autosomal, dominantly inherited prion disease. In this study, we present different complicated brain pathologies determined postmortem of monozygotic GSS twin sisters. Case 1 showed cerebellar ataxia at the age of 58 years, and died at 66 years. Case 2 became symptomatic at the age of 75 years, and died at 79 years. There was a 17-year difference in the age of onset between the twins. Postmortem examination revealed numerous prion protein (PrP) plaques in the brains of both cases. The spongiform change and brain atrophy in case 1 were more severe compared with those in case 2. Western-blot analysis identified proteinase-resistant PrP (PrPres) at the molecular weight of 21-30 kDa and 8 kDa in the twins. Gel filtration revealed that PrPres was mainly composed of PrP oligomer. PrPres signal patterns were similar between the twins. Additionally, case 1 showed α-synucleinopathy and case 2 showed Alzheimer disease pathology. These different proteinopathies were involved in the amyloid plaque formations of both cases. The degree of GSS pathology was mainly related to disease duration. The amyloid plaque formations could be decorated by concomitant neuropathological changes such as α-synucleinopathy and tauopathy.

A family with hereditary cerebellar ataxia finally confirmed as Gerstmann-Straussler-Scheinker syndrome with P102L mutation in PRNP gene.

Gerstmann-Straussler-Scheinker syndrome (GSS) is an exceedingly rare prion disease. There are only 3 case reports of GSS in China. Here we report the first GSS family in southern China. A 47-year-old female complained of unsteady gait and dysarthria. Seven other individuals presented similar symptoms in 3 generations of her family, and all died 4-6 years after onset. To detect causative mutations, we employed a gene analysis panel of hereditary diseases. This revealed a P102L mutation in the prion protein gene (PRNP) gene, which is commonly found in GSS featuring cerebellar ataxia. However, GSS is an uncommon cause of hereditary cerebellar ataxia that might be overlooked because many neurologists are unfamiliar with it. To avoid misdiagnosis in the patients with hereditary cerebellar ataxia, GSS should be taken into account if other causes are absent, especially in patients that have accompanying psychiatric symptoms and a short survival time.

[A case of Gerstmann-Sträussler-Scheinker disease presented with numbness in the lower extremities].

We report a patient of 68-year-old woman who developed numbness of feet in 2008. Ataxic gait disturbance, truncal ataxia, muscle weakness of lower limbs have gradually appeared and she couldn't walk without assistance in 2013. Her cognitive function declined subacutely in 2014. When she was admitted to our hospital, it was difficult to fully evaluate her neurological symptoms and cognitive function. The tendon reflex were absent and Babinski reflex showed positive in both sides of the lower limbs. Diffusion weighted image of MRI showed high intensity in cerebrocortical area, and variation P102L prion protein gene mutation was detected. We diagnosed her with Gerstmann-Sträussler-Scheinker (GSS) disease. Cerebellar symptom such as ataxic gait occurs as the initial manifestation in 90% of patients with GSS disease. Her initial symptom was numbness of lower limbs and cerebellar symptom gradually appeared during the course of disease. In addition, her cognitive function declined six years after the onset. This case presented atypical clinical course as described above. Consequently, it led to diagnostic delay in GSS disease.

A novel PRNP Y218N mutation in Gerstmann-Sträussler-Scheinker disease with neurofibrillary degeneration.

Gerstmann-Sträussler-Scheinker (GSS) disease is a prion disease associated with prion protein gene (PRNP) mutations. We report a novel PRNP mutation (Y218N) associated with GSS disease in a pathologically confirmed case and in two other affected family members. The clinical features of these cases met criteria for possible Alzheimer disease and possible frontotemporal dementia. Neuropathologic analysis revealed deposition of proteinase K-resistant prion protein (PrP(res)), widespread hyperphosphorylated tau pathology, abnormal accumulation of mitochondria in the vicinity of PrP deposits, and expression of mutant ubiquitin (UBB(+1)) in neurofibrillary tangles and dystrophic neurites. Prion protein immunoblotting using 3F4 and 1E4 antibodies disclosed multiple bands ranging from approximately 20 kd to 80 kd and lower bands of 15 kd and approximately 10 kd, the latter only seen after a long incubation. These bands were partially resistant to proteinase K pretreatment. This pattern differs from those seen in Creutzfeldt-Jakob disease andresembles those reported in other GSS cases. The approximately 10kd band was recognized with anti-PrP C-terminus antibodies but not with anti-N terminus antibodies, suggesting PrP truncation at the N terminal. This new mutation extends the list of known mutations responsible for GSS disease and reinforces its clinical heterogeneity. Genetic examination of the PRNP gene should be included in the workup of patients with poorly classifiable dementia.

A New Transgenic Mouse Model of Gerstmann-Straussler-Scheinker Syndrome Caused by the A117V Mutation of PRNP.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a genetic prion disease typified clinically by the development of progressive ataxia and dementia, and histopathologically by the presence of prion protein (PrP) amyloid plaques in the CNS, especially within the cerebellum. Several mutations of the PrP gene (PRNP) are associated with GSS, but only the P102L mutation has been convincingly modeled in transgenic (Tg) mice. To determine whether other mutations carry specific GSS phenotypic information, we constructed Tg mice that express PrP carrying the mouse homolog of the GSS-associated A117V mutation. Tg(A116V) mice express approximately six times the endogenous levels of PrP, develop progressive ataxia by approximately 140 d, and die by approximately 170 d. Compared with a mouse model of transmissible Creutzfeldt-Jakob disease (CJD), the ataxia of Tg(A116V) mice is more prominent, and the course of disease is more protracted, paralleling that observed in human disease. Neuropathology includes mild scattered vacuolation and prominent, mainly cerebellar localized, thioflavin S-positive PrP plaques comprised of full-length PrP(A116V). In some mice, more prominent vacuolation or a noncerebellar distribution of PrP plaques was evident, suggesting some variability in phenotype. The biophysical properties of PrP from Tg(A116V) mice and human GSS(A117V) revealed a similarly low fraction of insoluble PrP and a weakly protease-resistant approximately 13 kDa midspan PrP fragment, not observed in CJD. Overall, Tg(A116V) mice recapitulate many clinicopathologic features of GSS(A117V) that are distinct from CJD, supporting PrP(A116V) to carry specific phenotypic information. The occasional variation in histopathology they exhibit may shed light on a similar observation in human GSS(A117V).

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).

Gerstmann-Sträussler-Scheinker disease with P102L-V129 mutation: a case with psychiatric manifestations at onset.

Gerstmann-Sträussler-Scheinker disease (GSS) is an adult onset, rare, genetically determined autosomal dominant prion disease. Clinically, it is characterized predominantly by slowly progressive spino-cerebellar dysfunction with ataxia, absent reflexes in the legs and cognitive impairment. Onset is usually in the fifth decade and in the early phase, ataxia is predominant. Mutations in the prion protein gene (PRNP) had been identified and the most important of these is at codon 129. A genotype-phenotype relationship with genetic polymorphism at residue 129 between methionine and valine has been supposed. We describe a patient with GSS and P102L-V129 mutation in which the onset with prominent psychiatric features characterized by apathy and depression and not with cerebellar sign and the clinical course with seizures, nor observed in P102L-V129 cases, allow us to confirm observations that the GSS caused by the 102 mutation is influenced by the codon 129 polymorphism with a specific genotype-phenotype influence, but probably other additional factors might be considered as background for phenotypic variability.

Variable phenotype in a P102L Gerstmann-Sträussler-Scheinker Italian family.

BACKGROUND: Gerstmann-Sträussler-Scheinker disease is an autosomal dominant prion disease. The clinical features include ataxia, dementia, spastic paraparesis and extrapyramidal signs. METHODS: We report a new large Italian family affected by Gerstmann-Sträussler-Scheinker disease. RESULTS: The four generation pedigree includes 11 patients. The mean age at onset +/- SD was 41.4 +/- 16.2 years. Mean disease duration to death in four patients was 5.5 +/- 1.7 years. Two clinical patterns were evident: cognitive impairment with scarce neurological features or ataxia followed by cognitive impairment. Molecular analysis showed P102L mutation in PRNP gene. CONCLUSION: Three Italian families have been reported to date. The variable phenotype has already been reported, and does not appear related to the codon 129 polymorphism.

Neuropathological features of a case with schizophrenia and prion protein gene P102L mutation before onset of Gerstmann-Sträussler-Scheinker disease.

Gerstmann-Sträussler-Scheinker disease (GSS) is a hereditary transmissible spongiform encephalopathy associated with prion protein gene mutation P102L. The age of onset is roughly restricted to around the sixth decade; however, it is unclear whether the disease-specific pathology of GSS is already evident in the pre-clinical stage. We had a chance to examine an autopsy case with PRNP P102L mutation. The patient had died at 50 years of age before the clinical symptoms of GSS had appeared; neither neuronal loss, gliosis nor spongiform change was found anywhere in the brain. Immunohistochemistry failed to detect any deposition of prion protein. It is thus considered that amyloid plaque formation in GSS probably develops in a relatively rapid fashion compared with Alzheimer's disease. Although the patient suffered from schizophrenia, no significant pathological changes were detected except for astrocytic inclusion bodies in the cerebral cortex. The nature and significance of the inclusion bodies, which are not observed in patients with GSS, remain unclear.

Hyperphosphorylated tau deposition parallels prion protein burden in a case of Gerstmann-Sträussler-Scheinker syndrome P102L mutation complicated with dementia.

Hyperphosphorylated tau (p-tau) deposition has been documented in a limited population of patients with Gerstmann-Sträussler-Scheinker syndrome (GSS) with particular point mutations of the prion protein (PrP) gene. Although its pathogenesis is only poorly understood, p-tau in GSS is known to be identical to that in Alzheimer's disease (AD). We conducted immunohistochemical and quantitative image studies on the brain from a 44-year-old man with a 7-year history of dementia, diagnosed as having GSS with a point mutation of the PrP gene at codon 102 (GSS102), the commonest mutation in GSS. Severe spongiform degeneration and numerous PrP plaques were disclosed in the cerebral cortices and hippocampus, consistent with the diagnosis. However, rarely described in GSS102, prominent p-tau deposits as pretangles, neurofibrillary tangles and degenerating neurites were demonstrated adjacent to or around PrP plaques. beta-Amyloid protein (Abeta) plaques were generally sparse and appeared invariably to be of a diffuse type. Double-labeling immunohistochemistry yielded co-localization of p-tau with PrP but not with Abeta. Most PrP plaques did not contain Abeta. These results excluded a diagnosis of concomitant AD. Quantitative analysis on a fractional area density of immunoreactive pixels demonstrated that burdens of PrP and p-tau but not Abeta were significantly correlated. These results suggest that p-tau deposition in this GSS102 is secondarily induced by PrP but not by Abeta (secondary tauopathy). Our study also suggests that p-tau deposition might be a more common phenomenon in long-standing GSS.

[A case of Gerstmann-Sträussler-Scheinker disease with severe muscular atrophy and vertical gaze palsy].

Here we report a case of 56-year-old man with Gerstmann-Sträussler-Scheinker disease (GSS). He had gait disturbance, limb and truncal ataxia, dysarthria and dysphagia at the age of 53. When he developed vertical gaze palsy and dystonic posture of the neck, subcortical dementia, progressive supuranuclear palsy was suspected. Thereafter dementia rapidly progessed, and CT scan showed severe atrophy of the brain. Since severe muscular atrophy and fasciculation also appeared, and abnormality in the codon 102 of prion protein gene was found, he was diagnosed to have the classical type of GSS. GSS with vertical gaze palsy has never been reported, and involvement of the lower motor neuron is also very rare. Therefore, the present case is an atypical type of GSS.

[A case of Gerstmann-Sträussler-Scheinker syndrome (P102L) accompanied by optic atrophy].

We report a patient with Gerstmann-Sträussler-Scheinker syndrome (GSS102) who developed optic atrophy. He had been complaining of slowly progressive postural unsteadiness and pain in both legs for 3 years. Visual acuity subacutely worsened in the last half year. His father and two aunts, who already died, had been diagnosed to have dementia. It is uncertain whether they had optic atrophy or not. He was alert but apathetic. Neurological examination revealed cerebellar ataxia, painful dysesthesia and loss of deep tendon reflexes in the lower limbs. Fundoscopic examination revealed bilateral optic atrophy without retinal degeneration, which has never been reported in GSS. A brain MRI showed mild atrophy of cerebellar hemispheres without signal abnormalities of optic nerves. DNA analysis of prion gene revealed point mutation at codon 102 (P102L), which was relatively common mutation in GSS. Other mutations were not found. Only two patients of Creutzfeldt-Jakob disease with optic atrophy have been reported. This case seems to be important to investigate why optic tracts are generally spared in prion disease.

Gerstmann-Sträussler-Scheinker disease showing beta-protein type cerebellar and cerebral amyloid angiopathy.

Cerebral amyloid angiopathy is observed in several brain degenerative disorders, but this pathological condition has received little attention in Gerstmann-Sträussler-Scheinker disease (GSS). We report a 69-year-old man who showed the cardinal features of GSS together with typical and extensive congophilic angiopathy. Immunohistochemical studies revealed that the vast majority of the amyloid plaques present in the brain of this patient were consistently labeled by anti-prion protein (PrP) antibody. Double immunostaining disclosed many additional beta-protein immunoreactive plaque-like lesions, including a special type of "hybrid" plaque with colocalization of PrP and beta-protein (beta-PrP). The vascular amyloid deposits seen in both the cerebellum and cerebrum were immunoreactive only to anti-beta-protein antibody. It seems likely that the extensive deposition of beta-protein amyloid (including brain vascular amyloidosis) seen in this and other similar cases is part of pathology of GSS, although the possibility that this finding is due to ageing or concomitant Alzheimer's disease cannot be completely ruled out.

[An autopsy case of Gerstmann-Sträusser-Scheinker's disease with spastic paraplegia as its principal feature].

A 38-year-old woman developed slowly progressive gait disturbance. At age 39 years she was admitted to our department because she could not walk without assistance. On neurological examination she was alert with normal mental functions. Horizontal nystagmus on both sides, minimal clumsiness in the left upper extremity on the finger-to-nose test and moderate degree of spasticity in bilateral lower extremities without evident motor weakness were present. The gait was spastic with small steps on a wide base. There was no sensory abnormalities. The deep tendon reflexes were hyperactive on both sides, on the lower extremities, with positive Babinski's sign. The sphincter functions were intact. During the following 5 years she gradually deteriorated and pseudobulbar palsy, emotional incontinence and the progressive dementia appeared in addition to severe spastic paraplegia. At age 45 years she was admitted to our nursing home and she died 3 months later, of pneumonia, on 6 years after the onset of her illness. Two elder sisters of her 7 siblings had the similar neurologic illness. The brain weighed 1,060 g. There was mild atrophy of cerebrum, cerebellum and brainstem. There were neuronal loss and gliosis in layers IV-VI of cerebral cortex with no evidence of the spongy state. Cerebellar cortex, cerebellar peduncles and spinocerebellar tracts were preserved. There was marked degeneration of corticospinal tract from cerebral peduncle to lateral funiculus of lumbar spinal cord. The most prominent feature was appearance of numerous multicentric amyloid plaques, which were marked in layers I-III of cerebral cortex and to a lesser extent in corpus striatum, hippocampus and the white matters of cerebrum and cerebellum.(ABSTRACT TRUNCATED AT 250 WORDS)