A novel phenotype in familial Creutzfeldt-Jakob disease: prion protein gene E200K mutation coupled with valine at codon 129 and type 2 protease-resistant prion protein.

A novel phenotype of familial Creutzfeldt-Jakob disease (CJD) with mutated codon 200 of the prion protein gene (PRNP) coupled with the valine codon 129 (E200K-129V haplotype) has two features never observed in subjects carrying the pathogenic mutation coupled with the methionine codon 129 (E200K-129M haplotype): (1) plaque-like prion protein (PrP) deposits in the cerebellum and (2) type 2 protease-resistant prion protein (PrP(res)). This observation further underlines the role of codon 129 on the mutated PRNP allele in modulating the phenotype of familial prion diseases.     

散发性Creutzfeldt-Jakob病患者10例prion基因研究

目的 检测10例Creutzfeldt-Jakob病（CJD）患者prion基因（PRNP）外显子突变情况.方法 抽取患者外周静脉血,提取DNA,PCR法扩增PRNP外显子后直接测序,并用限制性内切酶Nsp Ⅰ检测PRNP 129位点密码子基因型.结果 2例肯定CJD患者中,1例PRNP检测未见异常,另1例PRNP第729碱基G被C取代（729G→C）,使编码prion第211个氨基酸的密码子GAG变成了GAC,翻译后第211个氨基酸由谷氨酸变为天冬氨酸（E211D）.8例很可能CJD患者中,2例PRNP第751碱基G被A取代（751G→A）,使编码prion第219个氨基酸的密码子GAG变成了AAG,翻译后第219个氨基酸由谷氨酸变为赖氨酸（E219K）.10例CJD患者PRNP 129位点密码子基因型都是甲硫氨酸纯合型.结论 1例肯定CJD患者的prion基因外显子存在一种新的点突变E211D,这很可能是导致遗传prion病发生的原因.2例很可能CJD患者的prion基因突变E219K,与M129V同属于基因多态性,而不是致病原因.prion基因检测有助于prion病的诊断.     

Spontaneous mutations in the prion protein gene causing transmissible spongiform encephalopathy

We analyzed the prion protein gene (PRNP) region in patients with transmissible spongiform encephalopathy associated with the PRNP D178N mutation. The results suggest that the D178N chromosomes had independent origins in each affected pedigree or apparently sporadic case. A de novo spontaneous PRNP mutation was observed. We provide evidence that hereditary and apparently sporadic transmissible spongiform encephalopathy cases associated with the D178N mutation result from multiple recurrent mutational events.     

Inherited prion disease with A117V mutation of the prion protein gene: a novel Hungarian family

Three members of a family with inherited prion disease are reported. One additional family member had a progressive neurological disease without details. Two developed symptoms of ataxia, dementia, myoclonus, rigidity, and hemiparesis, and one had a different phenotype with the combination of lower motor neuron deficit, parkinsonism, intellectual decline, and ataxia. In this last patient cell loss of the anterior horn motor neurons and chronic neurogenic muscle atrophy was evident. Immunostaining for the prion protein disclosed unicentric and multicentric plaques, and coarse and fine granular positivity. Genetic analysis of the prion protein gene of the propositus showed a 117 codon alanine to valine mutation and homozygous 129 valine/valine genotype.     

Regional distribution of protease-resistant prion protein in fatal familial insomnia

Protease-resistant prion protein, total prion protein, and glial fibrillary acidic protein were measured in various brain regions from 9 subjects with fatal familial insomnia. Six were homozygotes methionine/methionine at codon 129 (mean duration, 10.7 ± 4 months) and 3 were heterozygotes methionine/valine (mean duration, 23 ± 11 months). In all subjects, protease-resistant prion protein was detected in gray matter but not in white matter and peripheral organs. Its distribution was more widespread than that of the histopathological lesions, which were observed only in the presence of a critical amount of the abnormal protein. In the mediodorsal thalamic nucleus, however, a severe neuronal loss and astrogliosis were associated with relatively moderate amounts of protease-resistant prion protein, suggesting a higher vulnerability. There was no overall correlation between amount of protease-resistant prion protein and either glial fibrillary acidic protein or total prion protein. While protease-resistant prion protein was virtually limited to subcortical areas and showed a selective pattern of distribution in the subjects with disease of the shortest duration, it was more widespread in the subjects with a longer clinical course, indicating that with time the disease process spreads within the brain. The kinetics of the accumulation of protease-resistant prion protein varied among different brain regions: While in the neocortex and to a lesser extent in the limbic lobe and in the caudate nucleus, the amount increased with disease duration, in the mediodorsal thalamic nucleus and in the brainstem it was present in comparable amounts in all subjects regardless of the disease duration. These findings indicate that in fatal familial insomnia, the pathological phenotype is the result of the variability, in different brain regions, of the (1) timing and rate of accumulation of protease-resistant prion protein, and (2) vulnerability to the presence of protease-resistant prion protein.     

Novel prion protein gene mutation presenting with subacute PSP-like syndrome

A 62-year-old Indonesian woman presenting with a progressive supranuclear palsy-like syndrome was confirmed post mortem as dying from a spongiform encephalopathy. Despite an illness duration of only 4 months, brain MRI, EEG, and CSF analysis for 14-3-3 proteins all failed to disclose changes typical of Creutzfeldt-Jakob disease. Neuropathologic examination revealed multicentric, prion protein-positive, amyloid plaques as typically seen in Gerstmann-Str?ussler-Scheinker syndrome. Prion protein gene analysis revealed a previously unreported A133V mutation.     

Novel prion protein gene mutation in an octogenarian with Creutzfeldt-Jakob disease

BACKGROUND: The transmissible spongiform encephalopathies constitute a fascinating and biologically unique group of invariably fatal neurodegenerative disorders that affect both animals and humans. Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome, and fatal familial insomnia represent the more common human phenotypes. Excluding the small number of iatrogenically transmitted cases, approximately 85% to 90% of patients develop CJD without identifiable explanation, with an increasing number of different mutations in the prion protein gene (PRNP) recognized as probably causative in the remainder. OBJECTIVE: To report on an 82-year-old woman with pathologically confirmed CJD found unexpectedly to harbor a novel mutation in PRNP. METHODS: Routine clinical investigations were undertaken to elucidate the cause of the rapidly progressive dementia and neurological decline manifested by the patient, including magnetic resonance imaging of the brain, electroencephalography, and cerebrospinal fluid analysis for the 14-3-3 beta protein. Standard postmortem neuropathological examination of the brain was performed, including immunocytochemistry of representative sections to detect the prion protein. Posthumous genetic analysis of the open reading frame of PRNP was performed on frozen brain tissue using polymerase chain reaction and direct sequencing. RESULTS: Concomitant with the exclusion of alternative diagnoses, the presence of characteristic periodic sharp-wave complexes on the electroencephalogram in combination with a positive result for 14-3-3 beta protein in the cerebrospinal fluid led to a confident clinical diagnosis of CJD, confirmed at autopsy. There was no family history of dementia or similar neurological illness, but patrilineal medical information was incomplete. Unexpectedly, full sequencing of the PRNP open reading frame revealed a single novel mutation consisting of an adenine-to-guanine substitution at nucleotide 611, causing alanine to replace threonine at codon 188. CONCLUSIONS: In addition to expanding the range of PRNP mutations associated with human prion diseases, we believe this case is important for the following reasons. First, from an epidemiological perspective, the avoidance of occasional incorrect classification of patients manifesting neurodegenerative disorders that may have a genetic basis requires systematic genotyping, particularly when there are uncertainties regarding the family history. Second, the incidence of spongiform encephalopathy in elderly patients beyond the typical age range may be underestimated and does not preclude a genetic basis. Finally, as a corollary, this case highlights problematic issues in human transmissible spongiform encephalopathies, as illustrated by disease penetrance and age of onset in genotype-phenotype correlations.     

A novel mutation (G114V) in the prion protein gene in a family with inherited prion disease

Inherited prion diseases are characterized by mutations in the PRNP gene encoding the prion protein (PrP). We report a novel missense mutation in the PRNP gene (resulting in a G114V mutation in PrP) in members of a Uruguayan family with clinical and histopathologic features of prion disease. Affected individuals were characterized by an early age at onset, initial neuropsychiatric symptoms, late dementia with prominent pyramidal and extrapyramidal symptoms, and long disease duration.     

Creutzfeldt-Jakob disease associated with the R208H mutation in the prion protein gene

The authors investigated a patient who died of apparent sporadic Creutzfeldt-Jakob disease (CJD) but carried a R208H substitution in the prion protein (PrP). The patient phenotype was indistinguishable from typical sporadic CJD (i.e., MM1 subtype). In addition, pathologic PrP, PrP(Sc), originated from both the normal and the mutated PRNP allele and had the same characteristics as PrP(Sc) type 1. The authors propose that the R208H mutation influences disease susceptibility without significantly affecting PrP(Sc) properties or disease phenotype.     

A new point mutation of the prion protein gene in Creutzfeldt-Jakob disease

Complete sequencing of the prion protein open reading frame of a 68-year-old woman affected by a familial form of Creutzfeldt-Jakob disease (CJD) revealed a new mutation at codon 210 resulting in the substitution of isoleucine for valine. Moreover, a new 24-bp deletion encompassing codons 54 to 61 or 62 to 69 was found in the other allele. Four of the 17 asymptomatic relatives tested carry the 210 mutation. Two of them were 81 and 82 years old. Four of 22 patients with CJD whose recorded familial history was negative for demented illnesses, but none of 103 healthy control subjects, tested positive for the 210 mutation. These data suggest that the 210 mutation is associated with CJD, but that environmental factors or incomplete penetrance may contribute to the development of the disease. This finding also suggests that in Italy, familial CJD is more common than previously reported.     

Creutzfeldt-Jakob disease in a patient with an R208H mutation of the prion protein gene (PRNP) and a 17-kDa prion protein fragment

A case of Creutzfeldt-Jakob disease (CJD) with a rare mutation of the prion protein (PrP) gene (PRNP) at codon 208 (R208H) is described. By comparison with two preceding reports, the case described here displayed two distinct biochemical and neuropathological features. Western blot analysis of brain homogenates showed, in addition to the commonly observed three bands of abnormal protease-resistant PrP isoform (PrP^Sc), an additional band of about 17 kDa. Neuropathological examination of the post mortem brain revealed tau pathology in the hippocampus and entorhinal cortex, as well as ballooned neurons in the cortex, hippocampus and subcortical gray matter.     

Rapidly progressive dementia syndrome associated with a novel four extra repeat mutation in the prion protein gene

OBJECTIVE: To gain a better understanding of how mutations of the prion protein (PrP) gene are responsible for progressive dementia syndrome and to clarify the correlation between genotype and phenotype, which should help to explain how the prion promotes neurological symptoms. BACKGROUND: Genetic prion diseases are associated with point or insertional mutations in the PrP gene. The insertional mutations described so far consist of one to nine extra octapeptide repeats, except three repeats. Insertions of one to four extra octapeptide repeats cause Creutzfeldt-Jakob disease (CJD) in patients without a family history of neurological disorders. CJD generally presents as progressive dementia. METHODS: Routine clinical assessment and sequence analysis of the PrP gene of DNA from a 56 year old Japanese man with progressive dementia syndrome. RESULTS: Sequence analysis disclosed a novel four octapeptide repeat insertion within the PrP gene. The patient was initially affected by progressive cerebellar and brainstem signs; a few months later myoclonus and rapidly progressive dementia appeared. These symptoms were similar to those of sporadic CJD. CONCLUSION: Taken together with previous investigations of CJD patients with insertional mutations, the current observation strengthens the notion that small octapeptide insertions from one to four extra repeats within the PrP gene cause CJD, which is characterised by late onset after the sixth decade, rapid progression, death within a few months, and lack of a family history of neurological disorders, the latter suggesting incomplete penetrance. Different patients with four extra octapeptide repeats have different patterns of extra insertions, suggesting that progression of the disease depends on the number of extra repeats.     

A new mutation in the prion protein gene: a patient with dementia and white matter changes

The authors describe the clinical characteristics, MRI abnormalities, and molecular findings in a patient with a novel variant of a two-octarepeat insertion mutation in the prion protein gene. This patient presented with moderately progressive dementia of presenile onset and gait ataxia. MRI showed extensive cortical atrophy and white matter abnormalities. The mutation consists of a two-octarepeat insertion mutation and irregularities in the nucleotide sequence of the octarepeat region.     

Familial Creutzfeldt-Jakob disease associated with a point mutation at codon 210 of the prion protein gene.

Creutzfeldt-Jakob disease (CJD), the most known human prion disease, is usually sporadic but approximately 15% of the cases are familial. To date, seven CJD cases with codon 210 mutation (GTT to ATT) have been reported in the literature. We describe a case of a 57 year-old woman who presented gait disturbances and rapidly progressive dementia, leading to death four months after onset. Electroencephalogram revealed periodic activity, diffusion-weighted magnetic resonance imaging showed hypersignal in basal ganglia, and test for 14-3-3 protein was strongly positive in the CSF. The complete prion protein gene coding region was sequenced after PCR amplification, showing a point mutation in codon 210. This is the first case of CJD with codon 210 mutation diagnosed in Brazil. We emphasize the role of genetic search for prion protein gene mutation, even in patients presenting clinical features resembling sporadic CJD.     

Diffusion-weighted MRI in familial Creutzfeldt-Jakob disease with the codon 200 mutation in the prion protein gene

Magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) has been reported to be a useful tool for early diagnosis of sporadic Creutzfeldt-Jakob disease (CJD). We report MRI findings with DWI, as well as with fluid-attenuated inversion recovery (FLAIR) and T1-weighted imaging (T1WI), in a case of familial CJD with a mutation at codon 200 of the prion protein gene. DWI in this patient showed high signal intensity in the basal ganglia and the cerebral cortex, similar to findings in sporadic CJD. In addition, T1WI showed areas of high signal intensity bilaterally in the globus pallidus. Despite the clinical diversity and atypical laboratory findings seen in familial CJD with the codon 200 mutation, these neuroimaging studies suggest that common regional distributions and a common pathogenesis might underlie the clinical progression both in sporadic CJD and in familial CJD with the codon 200 mutation in the prion protein gene. DWI abnormalities may be characteristic features that should be considered in the diagnosis of familial as well as of sporadic CJD.