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.

PRNP gene polymorphism frequencies for comparing possible vulnerability to BSE in Chinese bovine population.

Among the numerous transmissible spongiform encephalopathies (TSEs), bovine spongiform encephalopathy (BSE) is the most well-known TSEs. It is a potential Creutzfeldt-Jakob (CJD) disease mutation that can be transferred through cattle to humans. In several animals, the prion protein gene (PRNP) is recognized to take active part in TSE vulnerability or tolerance. Previous studies have found indels polymorphism in PRNP gene promoter and intron1 region linked to BSE vulnerability. It's linked with 23 bp indels polymorphism in putative promoter and 12 bp indel in intron 1 of the PRNP gene. The aim of this study was to compare the allele, genotype and haplotype frequencies of PRNP indel polymorphisms in Zhongdian Yak (Bos grunniens) (YK), Zhongdian Yellow cattle (Bos taurus) (YC) and Zhongdian Yakow (Bos primigenius taurus × Bos grunniens) (PK) with worldwide reported healthy or affected BSE cattle, in order to assess their potential resistance to BSE. A comparison of Chinese bovine populations with healthy and BSE-affected German and Swiss cattle from globally was conducted, and result indicating significant difference (p < .001) between healthy and affected cattle. Additionally, as compared to prior studies with Chinese bovine population, the significant results were found. In this study, the allelic frequency D23 finding high deletion in all analyzed Chinese bovine species, and haplotype D12-D23 exhibited a less significant inclination toward susceptibility to BSE.

SORL1 gene mutation and octapeptide repeat insertion in PRNP gene in a case presenting with rapidly progressive dementia and cerebral amyloid angiopathy.

BACKGROUND AND PURPOSE: Cerebral amyloid angiopathy (CAA) has been associated with a variety of neurodegenerative disorders, included prion diseases and Alzheimer's disease; its pathophysiology is still largely unknown. We report the case of an 80-year-old man with rapidly progressive dementia and neuroimaging features consistent with CAA carrying two genetic defects in the PRNP and SORL1 genes. METHODS: Neurological examination, brain magnetic resonance imaging (MRI), electroencephalographic-electromyographic (EEG-EMG) polygraphy, and analysis of 14-3-3 and tau proteins, Aß40, and Aß42 in the cerebrospinal fluid (CSF) were performed. The patient underwent a detailed genetic study by next generation sequencing analysis. RESULTS: The patient presented with progressive cognitive dysfunction, generalized myoclonus, and ataxia. Approximately 9 months after symptom onset, he was bed-bound, almost mute, and akinetic. Brain MRI was consistent with CAA. CSF analysis showed high levels of t-tau and p-tau, decreased Aß42, decreased Aß42/Aß40 ratio, and absence of 14.3.3 protein. EEG-EMG polygraphy demonstrated diffuse slowing, frontal theta activity, and generalized spike-waves related to upper limb myoclonus induced by intermittent photic stimulation. Genetic tests revealed the presence of the E270K variant in the SORL1 gene and the presence of a single octapeptide repeat insertion in the coding region of the PRNP gene. CONCLUSIONS: The specific pathogenic contribution of the two DNA variations is difficult to determine without neuropathology; among the possible explanations, we discuss the possibility of their link with CAA. Vascular and degenerative pathways actually interact in a synergistic way, and genetic studies may lead to more insight into pathophysiological mechanisms.

Detecting fecal egg count (FEC) for gastrointestinal nematodes of adult Turkish sheep with different scrapie related PRNP haplotypes.

Scrapie is a transmissible spongiform encephalopathy caused by prions and leads to neurodegeneration in the Central Nervous System (CNS) of sheep and goats. Genetic resistance/susceptibility to scrapie is well studied and it is known that the variations of 136th, 154th and 171st codons at the ovine PRNP gene have a major effect on the development of the disease. Many studies demonstrated that selection for PRNP genotypes has not influenced other performance traits, nevertheless, there is a knowledge gap about the possible link between the PRNP gene and the status of the other important diseases that affect the sheep population worldwide. In the present study, we tested whether there is an association between scrapie-related PRNP genotypes and fecal egg count (FEC) of gastrointestinal nematodes in seven adult Turkish sheep breeds. For this purpose, FEC scores of studied sheep (n = 253) were determined and the same animals were genotyped for the PRNP gene. Finally, an association analysis was performed for scrapie resistant (ARR), susceptible (VRQ), and wild-type (ARQ) haplotypes. Based on our statistical analysis, it is concluded that PRNP genotypes have no positive or negative effect on the FEC scores of adult sheep.

Mutations in Prion Protein Gene: Pathogenic Mechanisms in C-Terminal vs. N-Terminal Domain, a Review.

Inherited mutations in the Prion protein (PrP), encoded by the PRNP gene, have been associated with autosomal dominant neurodegenerative disorders, such as Creutzfeldt-Jacob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), and Fatal Familial Insomnia (FFI). Notably, PRNP mutations have also been described in clinical pictures resembling other neurodegenerative diseases, such as frontotemporal dementia. Regarding the pathogenesis, it has been observed that these point mutations are located in the C-terminal region of the PRNP gene and, currently, the potential significance of the N-terminal domain has largely been underestimated. The purpose of this report is to review and provide current insights into the pathogenic mechanisms of PRNP mutations, emphasizing the differences between the C- and N-terminal regions and focusing, in particular, on the lesser-known flexible N-terminal, for which recent biophysical evidence has revealed a physical interaction with the globular C-terminal domain of the cellular prion protein (PrPC).

Nucleotide and octapeptide-repeat variations of the prion protein coding gene (PRNP) in Anatolian, Murrah, and crossbred water buffaloes.

Resistance to bovine spongiform encephalopathy (BSE) that is significantly associated with insertion/deletion (indel) polymorphisms at two loci (putative promoter and intron 1) on the prion protein gene (PRNP) in cattle has been well documented. Studies suggest that the insertion alleles are related to BSE resistance. Until recently, BSE has never been reported in water buffaloes (unlike cattle). Previous studies have demonstrated that the PRNP gene in water buffalo consists mostly of insertion alleles at both loci; nevertheless, whether or not water buffaloes are genetically resistant to BSE and the role of indel polymorphisms in their resistance status is not clear. We examined the coding region of PRNP to determine the nucleotide and octapeptide-repeat (octarepeats) variations of Anatolian, Murrah and Murrah × Anatolian (M × A) water buffaloes. Three synonymous single nucleotide polymorphisms (SNP) at positions 126, 234, and 285, and a non-synonymous SNP at position 322 (G108S) were detected. Triplet G/A/T base substitutions were observed at position 126 and two additional genotypes, T/A and T/G, at this position were determined. We also found six octarepeats that indicated the presence of the wild-type PRNP6 allele in the coding region. To the best of our knowledge, this is the first report of the T/A and T/G genotypes in water buffaloes.

[Clinical, neuroimaging and genetic features of two Chinese families with fatal familial insomnia].

Objective: To examine clinical, neuroimaging and genetic features of two Chinese families with fatal familial insomnia (FFI). Methods: The clinical data, including case history, physical examination, biochemical analysis of blood and neuroimaging of two pedigrees with FFI who admitted to the Navy General Hospital in 2014 and 2017 were collected. The D178N prion protein (PRNP) mutation were determined by DNA sequencing among the proband and family members. Results: There were 6 patients in 2 families, 5 male and 1 female. The onset age of disease in family 1 was 47 and 60 years old respectively, and 46, 58, 58, 60 years old respectively in family 2. In terms of disease course, patients in family 1 had a rapid disease course and died half year after onset while patients in family 2 had a relatively slow disease course and survived more than 1 year after onset.The induced factors of the patients in the family 1 were fright, followed by abnormal behaviors and sleep disorders accompanied by autonomic nervous dysfunction; the clinical features of the pedigree 2 were memory loss, decreased sleep and motor disorder without obvious inducement, and the autonomic nervous dysfunction was not significant. The neuroimaging examination of 2 probands showed a mild atrophy of the whole brain and no ribbon sign. The electroencephalography (EEG) did not show typical triphasic waves. Both cases had a positive cerebrospinal fluid (CSF) 14-3-3 protein and PrP D178N /Met-129 mutation.All patients were given traditional sedatives or anti-anxiety and depression drugs which were with poor efficacy. Conclusions: The major clinical manifestations of FFI are sleep disorders accompanied by mental disorders. The clinical manifestations are similar among different individuals within one family, however, there is obvious clinical variability among different families. The neuroimaging examination shows a mild atrophy of the whole brain and no ribbon sign. There are no typical triphasic waves in EEG. Positive CSF 14-3-3 protein and PrP D178N /Met-129 mutation are common in FFI. Traditional sedatives or anti-anxiety and depression drugs may have poor efficacy.

Towards an early clinical diagnosis of sporadic CJD VV2 (ataxic type).

INTRODUCTION: Sporadic Creutzfeldt-Jakob disease (sCJD) includes a broad spectrum of clinical-pathological subtypes, which complicates the clinical differential diagnosis with other rapidly progressive neurological syndromes. AIM: To provide a better characterisation of clinical features and results of diagnostic investigations, especially at an early disease stage, in patients with sCJDVV2, the second most common sCJD subtype. METHODS: We evaluated neurological symptoms/signs, and results of brain diffusion-weighted resonance imaging (DW-MRI), electroencephalographic recordings (EEG) and cerebrospinal fluid (CSF) biomarker studies in 120 patients with a definite (n=93) or probable (n=27) diagnosis of sCJDVV2. RESULTS: All patients presented with prominent cerebellar signs, which were often associated with memory loss and/or oculomotor, visual or peripheral/spinal cord signs. In contrast, dementia was invariably a late finding. All CSF samples were positive for the 14-3-3 protein assay and had total-tau protein levels above 1250 pg/mL. Brain DW-MRI showed hyperintensity of basal ganglia, thalamus and cerebral cortex, respectively in 91.5%, 57.4% and 19.1% of cases. EEG revealed periodic sharp-wave complexes in only 17.8% of cases. CONCLUSIONS: sCJDVV2 should be considered in any patient presenting with a rapidly progressive ataxia, especially when associated with oculomotor, visual or peripheral/spinal cord signs, even in the absence of dementia or myoclonus. CSF assays and brain DW-MRI represent sensitive diagnostic tests, even at an early stage. These data strongly suggest that sCJDVV2 can be clinically diagnosed early and accurately based on clinical data, DW-MRI, CSF assays and codon 129 genotyping and provide the basis for improved and subtype-specific diagnostic criteria of sCJD.

Heidenhain variant in two patients with inherited V210I Creutzfeldt-Jakob disease.

OBJECTIVE: To report two members of the same family carrying the valine to isoleucine point mutation of the prion protein gene (PRNP) and presenting with visual symptoms as initial manifestation as in the "Heidenhain variant" of sporadic Creutzfeldt-Jakob disease (CJD). METHODS: Patients underwent neurological examination, electroencephalogram (EEG), brain magnetic resonance images (MRI) and cerebrospinal fluid (CSF) analysis including the Real Time Quaking Induced Conversion (RT-QuIC) test. Disease-specific mutations and polymorphism at codon 129 of the PRNP gene were also studied. RESULTS: Isolated visual symptoms characterized disease onset of both patients followed by progressive neurological signs, dementia and death in 3 (proband) and 9 (his aunt) months. RT-QuIC analysis of CSF samples of both patients revealed the presence of the pathological prion protein and DNA analysis the V210I point mutation of the PRNP and methionine homozygosity at the polymorphic codon 129. CONCLUSIONS: This report suggests to consider the diagnosis of V210I genetic CJD in patients presenting with the Heidenhain form of CJD and highlights the importance of genetic testing in all patients with isolated visual manifestations at onset followed by progressive neurological signs and dementia.

First report of a novel 108 bp deletion and five novel SNPs in PRNP gene of stray cats and in silico analysis of their possible relation with feline spongiform encephalopathy.

Prion diseases are fatal neurodegenerative diseases affecting humans and animals. A relationship between variations in the prion gene of some species and susceptibility to prion diseases has been detected. However, variations in the prion protein of cats that have close contact with humans and their effect on prion protein are not well-known. Therefore, this study aimed to investigate the variations of prion protein-encoding gene (PRNP gene) in stray cats and to evaluate variants detected in terms of genetic factors associated with susceptibility or resistance to feline spongiform encephalopathy using bioinformatics tools. For this, cat DNA samples were amplified by a PCR targeting PRNP gene and then sequenced to reveal the variations. Finally, the effects of variants on prion protein were predicted by bioinformatics tools. According to the obtained results, a novel 108 bp deletion and nine SNPs were detected. Among SNPs, five (c314A>G, c.454T>A, c.579G>C, c.642G>C and c.672G>C) were detected for the first time in this study. Bioinformatics findings showed that c.579G>C (Q193H), c.454T>A (Y152N) and c.457G>A (E153K) variants have deleterious effects on prion protein and c.579G>C (Q193H) has high amyloid propensities. This study demonstrates prion protein variants of stray cats and their deleterious effects on prion protein for the first time.

Novel polymorphisms in ovine prion protein gene.

The aim of this study was to identify the PRNP polymorphisms outside the standard codons 136, 154 and 171 in 1110 sheep with no clinical sign of scrapie from all 18 Turkish native sheep breeds and compare our results with published data on ovine PRNP polymorphism from other regions of the world. Among the 22 amino acid polymorphisms and three silent mutations, 10 were novel for ovine PRNP: p.Gly94Gly, p.Leu128Ile, p.Met132Leu, p.Ser135Arg, p.Met137Val, p.Asn146Lys, p.Arg159Arg, p.Tyr160Asn, p.Gln163His and p.Thr193Ser. These data reveal that sheep breeds close to the historic center of small ruminant domestication have remained highly diverse in the prion gene locus, with distinctive genetic similarities to both Asian and European sheep breeds.

Short communication: Analysis of association between the prion protein (PRNP) locus and milk traits in Latxa dairy sheep.

The purpose of this study was to analyze associations between polymorphisms in the PRNP gene and ewe milk traits. A total of 242,565 lactations of the Latxa breed were used. Milk, fat and protein yields, and fat and protein content from black-faced Latxa from Spanish Basque Country, black-faced Latxa from Navarra, and blond-faced Latxa were collected. To evaluate evidence of association, the different traits were analyzed using an animal model, where the PRNP genotype effect was included or not as a random effect. Adding the PRNP effect to the model improved the fitting for milk yield in black-faced Latxa from Spanish Basque Country and in blond-faced Latxa, for fat yield in black-faced Latxa from Navarra, and for protein yield in blond-faced Latxa. However, the proportion of the phenotypic variance explained by the PRNP effect for milk yield (1.0×10(-3)), fat yield (3.6×10(-3)) and protein yield (9.4×10(-4)) were near zero. The PRNP locus accounts for about 0.5, 1.5, and 0.4% of total genetic (PRNP and polygenic) variance in milk, fat, and protein yield. These values indicated that the PRNP effect is not relevant regarding genetic additive contribution. For breeding purposes, it is unlikely that selection for scrapie resistance will have an effect on the milk traits studied in the Latxa breed.

Comparative Analysis of PRNP Gene Indel Polymorphism and Expression among Zhongdian Yellow Cattle, Zhongdian Yak, and Their Hybrids.

Bovine spongiform encephalopathy (BSE) is a fatal disease in cattle caused by misfolded prion proteins and linked to indel polymorphisms in the promoter and intron 1 of the PRNP gene. The aim of this study was to determine the allele, genotype, and haplotype frequencies of PRNP indel polymorphisms and to investigate the effect of PRNP gene expressions of 23 bp and 12 bp indels via polymerase chain reaction (PCR) in Zhongdian Yak (Bos-grunniens) (YK), Zhongdian Yellow cattle (Bos-taurus) (YC), and Zhongdian Yakow (Bos-primigenius taurus × Bos-grunniens) (PK). Resultant high allelic frequencies were found in 23- and 12+, while haplotype frequencies were very low in 23+/12 in YK, YC, and PK. PRNP expression was higher in the +-/-- diplotype of the PK and (mean ± SE) was 3.6578 ± 1.85964. Furthermore, two variable sites were investigated-a 23 bp indel polymorphism holding AP1 binding site and a 12 bp indel polymorphism holding SP1 binding site. Additionally, reporter gene assays revealed a link between two proposed transcription factors and lower expression levels of the +/+ allele compared with the -/- allele. The expression level of PRNP was shown to be dependent on two indel polymorphisms in the bovine PRNP promoter, which includes binding sites for RP58 and SP1 transcription factors. These findings raised the possibility that the PRNP genotype may contribute to the high variation in PRNP expression.

Creutzfeldt-Jakob disease presenting as Korsakoff syndrome caused by E196A mutation in PRNP gene: A case report.

BACKGROUND: Prion diseases are a group of degenerative nerve diseases that are caused by infectious prion proteins or gene mutations. In humans, prion diseases result from mutations in the prion protein gene (PRNP). Only a limited number of cases involving a specific PRNP mutation at codon 196 (E196A) have been reported. The coexistence of Korsakoff syndrome in patients with Creutzfeldt-Jakob disease (CJD) caused by E196A mutation has not been documented in the existing literature. CASE SUMMARY: A 61-year-old Chinese man initially presented with Korsakoff syndrome, followed by rapid-onset dementia, visual hallucinations, akinetic mutism, myoclonus, and hyperthermia. The patient had no significant personal or familial medical history. Magnetic resonance imaging of the brain revealed extensive hyperintense signals in the cortex, while positron emission tomography/computed tomography showed a diffuse reduction in cerebral cortex metabolism. Routine biochemical and microorganism testing of the cerebrospinal fluid (CSF) yielded normal results. Tests for thyroid function, human immunodeficiency virus, syphilis, vitamin B1 and B12 levels, and autoimmune rheumatic disorders were normal. Blood and CSF tests for autoimmune encephalitis and autoantibody-associated paraneoplastic syndrome yielded negative results. A test for 14-3-3 protein in the CSF yielded negative results. Whole-genome sequencing revealed a disease-causing mutation in PRNP. The patient succumbed to the illness 11 months after the initial symptom onset. CONCLUSION: Korsakoff syndrome, typically associated with alcohol intoxication, also manifests in CJD patients. Individuals with CJD along with PRNP E196A mutation may present with Korsakoff syndrome.

Case report: A Chinese patient with spinocerebellar ataxia finally confirmed as Gerstmann-Sträussler-Scheinker syndrome with P102L mutation.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare genetic prion disease caused by a mutation in the prion protein (PRNP) gene. It is typically characterized by progressive cerebellar ataxia and slowly progressive dementia. We present a case study of the GSS from China in which a 45-year-old male with a progressive gait and balance disorder developed cerebellar ataxia onset but was misdiagnosed as spinocerebellar ataxia (SCA) for 2 years. The patient's clinical, electrophysiological, and radiological data were retrospectively analyzed. Examination revealed ataxia, dysarthria, muscle weakness, areflexia in lower limbs, including a pyramidal sign, whereas cognitive decline was insignificant. His late mother had a similar unsteady gait. An electroencephalogram (EEG) showed normal findings, and 14-3-3 protein was negative. A brain MRI was performed for global brain atrophy and ventricular enlargement. Positron emission tomography-computed tomography (PET-CT) (18F-fluoro-2-deoxy-d-glucose, FDG) images showed mild to moderate decreased glucose metabolism in the left superior parietal lobe and left middle temporal lobe. According to genetic testing, his younger brother also had the P102L variant in the PRNP gene. This single case adds to the clinical and genetic phenotypes of GSS.

EEG - Imaging Evolution of the MV2 Subtype of Sporadic Creutzfeldt-Jakob Disease During the two-Year Course of the Disease.

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare transmissible disease. According to molecular classification, six clinical phenotypes of sCJD have been described: MM1, MM2, MV1, MV2, VV1 and VV2. MV2 subtype comprises 9% of sCJD cases. Atypical clinical course has been reported to be the main caveat for the diagnosis of the MV2 subtype. We hereby present a rare case of MV2 subtype of sCJD, highlighting the evolution of clinical, EEG and imaging attributes over a two-year period, thus underlining the atypical course of the disease.

[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.

Thalamic-insomnia phenotype in E200K Creutzfeldt-Jakob disease: A PET/MRI study.

BACKGROUND: Insomnia and thalamic involvement were frequently reported in patients with genetic Creutzfeldt-Jakob disease (gCJD) with E200K mutations, suggesting E200K might have discrepancy with typical sporadic CJD (sCJD). The study aimed to explore the clinical and neuroimage characteristics of genetic E200K CJD patients by comprehensive neuroimage analysis. METHODS: Six patients with gCJD carried E200K mutation on Prion Protein (PRNP) gene, 13 patients with sporadic CJD, and 22 age- and sex-matched normal controls were enrolled in the study. All participants completed a hybrid positron emission tomography/magnetic resonance imaging (PET/MRI) examination. Signal intensity on diffusion-weighted imaging (DWI) and metabolism on PET were visually rating analyzed, statistical parameter mapping analysis was performed on PET and 3D-T1 images. Clinical and imaging characteristics were compared between the E200K, sCJD, and control groups. RESULTS: There was no group difference in age or gender among the E200K, sCJD, and control groups. Insomnia was a primary complaint in patients with E200K gCJD (4/2 versus 1/12, p = 0.007). Hyperintensity on DWI and hypometabolism on PET of the thalamus were observed during visual rating analysis of images in patients with E200K gCJD. Gray matter atrophy (uncorrected p < 0.001) and hypometabolism (uncorrected p < 0.001) of the thalamus were more pronounced in patients with E200K gCJD. CONCLUSION: The clinical and imaging characteristics of patients with gCJD with PRNP E200K mutations manifested as a thalamic-insomnia phenotype. PET is a sensitive approach to help identify the functional changes in the thalamus in prion disease.

Familial Creutzfeldt-Jakob Disease: The First Reported Kindred from South-East Asia.

Creutzfeldt-Jakob disease (CJD) belongs to a group of prion disease that is caused by abnormally folded proteins and is clinically characterized by rapidly progressive cognitive decline, gait abnormalities, and myoclonus. Familial CJD is very rare and is described only in few families around the world. We report a case with rapidly progressive cognitive decline, ataxia, and myoclonus, with a history of several members of his family developing similar symptoms and succumbing to it. Clinical presentation and neuroimaging were suggestive of CJD. On genetic analysis, our index case and two of his family members (younger brother and younger son) were found to have D178N mutation in PRNP gene. The polymorphism of the 129th amino acid was V/V. We report the first kindred familial CJD from South-East Asia with genetically proven D178N-129V haplotype.