Octapeptide Repeat Insertions Research Articles

Four Octapeptide Repeat Insertion (4-OPRI) in PRNP Causing Huntington Disease Phenocopy.

Four Octapeptide Repeat Insertion (4-OPRI) in PRNP Causing Huntington Disease Phenocopy.

Genetic screening for Huntington disease phenocopies in Sweden: A tertiary center case series focused on short tandem repeat (STR) disorders

ObjectiveTo perform a screening for Huntington disease (HD) phenocopies in a Swedish cohort. MethodsSeventy-three DNA samples negative for HD were assessed at a tertiary center in Stockholm. The screening included analyses for C9orf72-frontotemporal dementia/amyotrophic lateral sclerosis (C9orf72-FTD/ALS), octapeptide repeat insertions (OPRIs) in PRNP associated with inherited prion diseases (IPD), Huntington's disease-like 2 (HDL2), spinocerebellar ataxia-2 (SCA2), spinocerebellar ataxia 3 (SCA3) and spinocerebellar ataxia-17 (SCA17). Targeted genetic analysis was carried out in two cases based on the salient phenotypic features. ResultsThe screening identified two patients with SCA17, one patient with IPD associated with 5-OPRI but none with nucleotide expansions in C9orf72 or for HDL2, SCA2 or SCA3. Furthermore, SGCE-myoclonic-dystonia 11 (SGCE-M-D) and benign hereditary chorea (BHC) was diagnosed in two sporadic cases. WES identified VUS in STUB1 in two patients with predominant cerebellar ataxia. ConclusionsOur results are in keeping with previous screenings and suggest that other genes yet to be discovered are involved in the etiology of HD phenocopies.

Octapeptide repeat alteration mutations of the prion protein gene in clinically diagnosed Alzheimer's disease and frontotemporal dementia.

Studies focusing on octapeptide repeat alteration mutations in PRNP in Alzheimer's disease (AD) and frontotemporal dementia (FTD) cohorts have been rare. We aim to screen sporadic AD and FTD patients with unknown etiology for the octapeptide repeat insertions and deletions in PRNP. Two hundred and six individuals were screened for alterations to the repeat region in the PRNP gene, including 146 sporadic AD and 60 sporadic FTD patients. Our study showed a 1.5% (3/206) occurrence of the octapeptide repeat alteration mutations in PRNP in a Chinese cohort of sporadic dementia. One late-onset FTD patient and one early-onset AD patient each had a two-octapeptide repeat deletion in PRNP, while one early-onset AD patient had a five-octapeptide repeat insertion mutation. PRNP octapeptide repeat alteration mutations are present in sporadic AD and FTD patients. The genetic investigation for PRNP octapeptide repeat alteration mutations in sporadic dementia patients should be carried out in future clinical studies.

Diagnostic accuracy of cerebrospinal fluid biomarkers in genetic prion diseases.

Genetic prion diseases are a rare and diverse group of fatal neurodegenerative disorders caused by pathogenic sequence variations in the prion protein gene, PRNP. Data on CSF biomarkers in patients with genetic prion diseases are limited and conflicting results have been reported for unclear reasons.Here, we aimed to analyse the diagnostic accuracy of CSF biomarkers currently used in prion clinical diagnosis in 302 symptomatic genetic prion disease cases from 11 prion diagnostic centres, encompassing a total of 36 different pathogenic sequence variations within the open reading frame of PRNP.CSF samples were assessed for the surrogate markers of neurodegeneration, 14-3-3 protein (14-3-3), total-tau protein (t-tau) and α-synuclein and for prion seeding activity through the real-time quaking-induced conversion assay. Biomarker results were compared with those obtained in healthy and neurological controls. For the most prevalent PRNP pathogenic sequence variations, biomarker accuracy and associations between biomarkers, demographic and genetic determinants were assessed. Additionally, the prognostic value of biomarkers for predicting total disease duration from symptom onset to death was investigated.High sensitivity of the four biomarkers was detected for genetic Creutzfeldt–Jakob disease associated with the E200K and V210I mutations, but low sensitivity was observed for mutations associated with Gerstmann–Sträussler–Scheinker syndrome and fatal familial insomnia. All biomarkers showed good to excellent specificity using the standard cut-offs often used for sporadic Creutzfeldt–Jakob disease. In genetic prion diseases related to octapeptide repeat insertions, the biomarker sensitivity correlated with the number of repeats. New genetic prion disease-specific cut-offs for 14-3-3, t-tau and α-synuclein were calculated. Disease duration in genetic Creutzfeldt–Jakob disease-E200K, Gerstmann–Sträussler–Scheinker-P102L and fatal familial insomnia was highly dependent on PRNP codon 129 MV polymorphism and was significantly associated with biomarker levels.In a large cohort of genetic prion diseases, the simultaneous analysis of CSF prion disease biomarkers allowed the determination of new mutation-specific cut-offs improving the discrimination of genetic prion disease cases and unveiled genetic prion disease-specific associations with disease duration.

Extra-repeat insertional mutation in the PRNP gene with cerebral amyloid angiopathy: A case report

Cerebral amyloid angiopathy (CAA), a major cause of spontaneous intracerebral haemorrhage and cognitive decline, has been documented in some forms of prion diseases (PrDs). Octapeptide Repeat Insertions (OPRIs) in the prion protein gene (PRNP) are mutations associated with genetic prion diseases (gPrDs). This is the first report of a patient with rapidly progressive dementia, carrying one OPRI in the PRNP gene and neuroimaging features consistent with CAA.

Molecular Characterization of the Danish Prion Diseases Cohort With Special Emphasis on Rare and Unique Cases.

The purpose of this study was to perform an updated reclassification of all definite prion disease cases with available fresh-frozen samples referred to the Danish Reference Center over the past 40 years, putting a special emphasis on the molecular characterization of novel disease subtypes. Investigation of the Danish prion diseases cohort revealed rare sporadic Creutzfeldt-Jakob disease cases with mixed subtypes and subtypes with previously uncharacterized white matter plaques, a new case of sporadic fatal insomnia, and 3 novel mutations, including 2 large octapeptide repeat insertions, and a point mutation in the prion protein gene. The evaluation of methionine and valine distribution at codon 129 among the prion disease patients in the cohort revealed the increased prevalence of methionine homozygotes compared to the general population. This observation was in line with the prevalence reported in other Caucasian prion disease cohort studies. Reclassification of the old prion diseases cohort revealed unique cases, the molecular characterization of which improves prion diseases classification, diagnostic accuracy, genetic counseling of affected families, and the understanding of disease biology.

A Novel Eight Octapeptide Repeat Insertion in PRNP Causing Prion Disease in a Danish Family

Octapeptide repeat insertions (OPRI) found in the prion protein gene (PRNP) constitute a subgroup of pathogenic mutations linked to inherited prion diseases, a hallmark of which is a misfolded prion protein. The number of repeats in OPRI has been associated with different disease phenotypes. However, due to the rarity of the cases and heterogenous disease manifestations, the recognition and classification of these variants has been difficult. Here, we report the first Danish family, the fifth worldwide, carrying a novel 8-OPRI with a unique sequence of the additional 8 inserts: R1-R2-R2-R3-R2-R2-R2a-R2-R3g-R2-R2-R3-R4. The mutation was found on the allele coding for methionine at codon 129 in the PRNP gene. The clinical exome sequencing revealed that no other dementia-associated genes harbored pathogenic alterations. Mutation carriers had onset of symptoms in their early thirties, but disease duration varied from 5 to 11 years. Progressive dementia with psychiatric and motor symptoms were the most prominent clinical features. Clinical, pathological, and genetic characteristics of other 4 reported families with 8-OPRI were reviewed and compared with the findings in the Danish family.

Chapter 29 - Prion disease

Genetic prion diseases (gPrDs) are caused by autosomal-dominant mutations in the prion protein gene (PRNP). Although the first PRNP mutations identified, and most since, are PRNP missense, octapeptide repeat insertions, deletion and nonsense mutations have now also been shown to cause gPrD. Based on clinicopathologic features of familial disease, gPrDs historically have been classified into three forms: familial Jakob-Creutzfeldt disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. This classification, however, occurred prior to the identification of PRNP, and although these forms are still recognized, classification now is somewhat more complex. Clinical manifestations, and even pathology, are known to be more heterogeneous and varied than the historic three phenotypic classifications. Most gPrDs either present rapidly with progression of dementia, ataxia, myoclonus, and other motor features leading to death in few months or present more slowly, declining over a few years with mild cognitive impairment, ataxia, or parkinsonism and later dementia; a few very rare mutations, however, present over years to decades with neuropsychiatric disorders and systemic symptoms (gastrointestinal disorders and neuropathy). In this chapter, we review the broad phenotypic spectrum of PRNP mutations causing gPrDs.

Genetic PrP Prion Diseases.

Genetic prion diseases (gPrDs) caused by mutations in the prion protein gene (PRNP) have been classified as genetic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, or fatal familial insomnia. Mutations in PRNP can be missense, nonsense, and/or octapeptide repeat insertions or, possibly, deletions. These mutations can produce diverse clinical features. They may also show varying ancillary testing results and neuropathological findings. Although the majority of gPrDs have a rapid progression with a short survival time of a few months, many also present as ataxic or parkinsonian disorders, which have a slower decline over a few to several years. A few very rare mutations manifest as neuropsychiatric disorders, with systemic symptoms that include gastrointestinal disorders and neuropathy; these forms can progress over years to decades. In this review, we classify gPrDs as rapid, slow, or mixed types based on their typical rate of progression and duration, and we review the broad spectrum of phenotypes manifested by these diseases.

Genetic prion disease: Experience of a rapidly progressive dementia center in the United States and a review of the literature.

Although prion diseases are generally thought to present as rapidly progressive dementias with survival of only a few months, the phenotypic spectrum for genetic prion diseases (gPrDs) is much broader. The majority have a rapid decline with short survival, but many patients with gPrDs present as slowly progressive ataxic or parkinsonian disorders with progression over a few to several years. A few very rare mutations even present as neuropsychiatric disorders, sometimes with systemic symptoms such as gastrointestinal disorders and neuropathy, progressing over years to decades. gPrDs are caused by mutations in the prion protein gene (PRNP), and have been historically classified based on their clinicopathological features as genetic Jakob-Creutzfeldt disease (gJCD), Gerstmann-Sträussler-Scheinker (GSS), or Fatal Familial Insomnia (FFI). Mutations in PRNP can be missense, nonsense, and octapeptide repeat insertions or a deletion, and present with diverse clinical features, sensitivities of ancillary testing, and neuropathological findings. We present the UCSF gPrD cohort, including 129 symptomatic patients referred to and/or seen at UCSF between 2001 and 2016, and compare the clinical features of the gPrDs from 22 mutations identified in our cohort with data from the literature, as well as perform a literature review on most other mutations not represented in our cohort. E200K is the most common mutation worldwide, is associated with gJCD, and was the most common in the UCSF cohort. Among the GSS-associated mutations, P102L is the most commonly reported and was also the most common at UCSF. We also had several octapeptide repeat insertions (OPRI), a rare nonsense mutation (Q160X), and three novel mutations (K194E, E200G, and A224V) in our UCSF cohort. © 2016 Wiley Periodicals, Inc.

Genotype-phenotype analysis in inherited prion disease with eight octapeptide repeat insertional mutation

A minority of inherited prion diseases (IPD) are caused by four to 12 extra octapeptide repeat insertions (OPRI) in the prion protein gene (PRNP). Only four families affected by IPD with 8-OPRI have been reported, one of them was a three-generation Swedish kindred in which four of seven affected subjects had chorea which was initially attributed to Huntington’s disease (HD). Following the exclusion of HD, this phenotype was labeled Huntington disease-like 1 (HDL1). Here, we provide an update on the Swedish 8-OPRI family, describe the clinical features of one of its affected members with video-recordings, compare the four 8-OPRI families and study the effect of PRNP polymorphic codon 129 and gender on phenotype. Surprisingly, the Swedish kindred displayed the longest survival of all of the 8-OPRI families with a mean of 15.1 years from onset of symptoms. Subjects with PRNP polymorphic codon 129M in the mutated allele had significantly earlier age of onset, longer survival and earlier age of death than 129V subjects. Homozygous 129MM had earlier age of onset than 129VV. Females had a significantly earlier age of onset and earlier age of death than males. Up to 50% of variability in age of onset was conferred by the combined effect of PRNP polymorphic codon 129 and gender. An inverse correlation between early age of onset and long survival was found for this mutation.

FDG-PET and PiB-PET imaging in asymptomatic at-risk carriers of a novel octapeptide repeat insertion in PRNP

FDG-PET and PiB-PET imaging in asymptomatic at-risk carriers of a novel octapeptide repeat insertion in PRNP

FDG-PET and PiB-PET imaging in asymptomatic at-risk carriers of a novel octapeptide repeat insertion in PRNP

FDG-PET and PiB-PET imaging in asymptomatic at-risk carriers of a novel octapeptide repeat insertion in PRNP

D02 A case of Huntington disease-like 1 (HDL1) with long disease duration

<h3>Summary</h3> Dynamic control of cell polarity is of critical importance for many aspects of cellular development and motility. In <i>Myxococcus xanthus</i>, a G-protein and its cognate GTPase-activating protein establish a polarity axis that defines the direction of movement of the cell and which can be rapidly inverted by the Frz chemosensory system. Although vital for collective cell behaviours, how Frz triggers this switch has remained unknown. Here, we use genetics, imaging and mathematical modelling to show that Frz controls polarity reversals via a gated relaxation oscillator. FrzX, which we newly identify as the primary Frz output, provides the gating and thus acts as the trigger for reversals. Slow relocalisation of the polarity protein RomR then creates a refractory period during which another switch cannot be triggered. A secondary Frz output, FrzZ, decreases this delay allowing rapid reversals when required. This architecture thus results in a highly tunable switch that allows a wide range of motility responses.

MRS in Early and Presymptomatic Carriers of a Novel Octapeptide Repeat Insertion in the Prion Protein Gene

To evaluate the proton magnetic resonance (MR) spectroscopy ((1) H MRS) changes in carriers of a novel octapeptide repeat insertion in the prion protein gene (PRNP) and family history of frontotemporal dementia with ataxia. Four at-risk mutation carriers and 13 controls were compared using single voxel, short TE, (1) H MRS from the posterior cingulate gyrus. The mutation carriers had an increased choline/creatine, P = .003 and increased myoinositol/creatine ratio, P = .003. (1) H MRS identified differences in markers of glial activity and choline metabolism in pre- and early-symptomatic carriers of a novel PRNP gene octapeptide insertion. These findings expand the possible diagnostic utility of (1) H MRS in familial prion disorders.

Inherited prion disease with 4-octapeptide repeat insertion linked to valine at codon 129

Sir, We have read the article by Kaski et al. (2011) with great interest, where the authors describe the results of their investigations of patients from the UK with four extra octapeptide repeat insertions (OPRIs) in the prion protein gene ( PRNP) . Herein, we would like to present a case that we had the opportunity to study with four extra OPRIs in the PRNP gene, but associated with a different genetic background at codon 129. Kaski et al . (2011) analysed 10 patients with four extra OPRIs. The predominant clinical syndrome was a rapidly progressive cortical dementia with myoclonus, motor and cerebellar signs resembling sporadic Creutzfeldt-Jakob disease (CJD). Age at onset and disease duration presented considerable variability; the mean age of onset was 60 years (range 39–85 years) with median disease duration of 414 days (range 59–2319 days). The 14-3-3 test was positive in all tested patients ( n = 4). MRI showed hyperintensities typical of sporadic CJD only in one out of five patients studied. The genetic analysis revealed that all patients have additional four R2 repeats within the repetitive part of the PRNP gene located between positions 51 and 91, and all of them were homozygous for methionine (M) at codon 129. Only one patient presented with familial history of early-onset dementia suggesting that the 4-OPRI has a very low penetrance and that, perhaps, its presence is not enough to produce the disease. We would like to report a new case with four extra OPRIs (R2R2R2R3) that, in contrast to those cases described by Kaski et al. (2011), was heterozygous valine/methionine (V/M) at codon 129. The patient was a 38-year-old male, who developed rapid progressive cognitive decline with memory impairment, inattention and spatial disorientation. The EEG registers presented slow baseline rhythm but failed to show periodic sharp wave complexes. …

A case of Gerstmann–Sträussler–Scheinker disease with a novel six octapeptide repeat insertion

Gerstmann-Straussler-Scheinker (GSS) disease is a rare inherited neurodegenerative disease due to a mutation in the prion protein (PRNP) gene, resulting in dementia and/or ataxia associated with mandatory amyloid plaques visible in the cerebral and/or cerebellar cortices on specimens stained with haematoxylin-eosin. Such amyloid plaques are dichroic in polarized light after Congo red staining and well marked by immunohistochemistry to prion protein (PrP). Almost every GSS family carries a PRNP missense mutation and almost half of them are due to a P102L mutation present in the original Austrian family [1], and also in a large family from central England [2–4]. GSS cases were also reported with a P105L mutation in Japan [5], with an A117V mutation in French-Alsacian [6], American [7] and English [8] families, and with a F198S mutation in the Indiana Kindred [9]. Other rare mutations have briefly been reported [3]. Three GSS cases due to an octapeptide repeat insertion (OPRI) in their PRNP between codons 51 and 91 [3] have also been investigated, eight in two unrelated French families [10– 13] and seven in a Dutch family [14]. We report here a French case with a novel six OPRI.

Huntington's disease like phenotype: new data from Brazil and what we know between heaven and earth

.To date, there are 4 phenocopies known as HDL1, 2, 3, and 4. HDL1 is caused by a octapeptide repeat insertion in gene en-coding prion protein, HDL2 is associated to triplet repeat expansion in gene encod-ing junctophilin-3, HDL3 is a autosomal recessive disease, which a causative muta-tion is unknown, and HDL4 or spinocere-bellar ataxia type 17 (SCA17) is caused by triplet repeat expansion in gene encoding TATA-box binding protein (TBP)

POD03 Distinct neuropsychological profiles correspond to distribution of cortical thinning in inherited prion disease caused by insertional mutation

There are at least 30 different mutations in the prion gene that cause clinical disease. Two of the most frequent in the UK are six octapeptide repeat insertion (6-OPRI) and...

PRNP allelic series from 19 years of prion protein gene sequencing at the MRC Prion Unit

Mutation of the human prion protein gene (PRNP) open reading frame (ORF) accounts for almost all reported familial concurrence of prion disease. The more common mutations globally: octapeptide repeat insertions, P102L, D178N, E200K, and V210I have occurred in large multigenerational pedigrees and display autosomal dominant inheritance, however, many rare genetic changes have been reported that are of uncertain pathogenicity. Based on 19 years of PRNP sequencing at the MRC Prion Unit, London, and analysis of 3664 samples from patients referred with suspected prion disease and healthy populations, we present novel allele combinations, healthy control population data, results of screening the PRNP ORF in DNA from the entire referral series and the CEPH human genome diversity cell line panel. Of the 10 alleles detected in patients for which detailed cases histories are presented, 4 are unreported (G54S, D167N, V209M, Q212PP), two changes are thought to be pathogenic but have not been described in our regions (P105L from the UK, G114V from India and Turkey), and the remainder reported in healthy control populations or in trans to known pathogenic mutations suggesting non- or low pathogenicity (G54S, 1-OPRI, G142S, N171S, V209M, E219K). New genotype-phenotype correlations and population frequencies presented will help the diagnosis and genetic counselling of those with suspected inherited prion disease.