Distribution of codon 129 genotype in human growth hormone-treated CJD patients in France and the UK

Since homozygosity MM at codon 129 of the prion protein gene is a recognised risk factor in all forms of Creutzfeldt-Jakob disease (CJD), we studied the distribution of codon 129 polymorphism in patients in France and in the UK with CJD transmitted iatrogenically by human growth hormone. The overall frequencies of codon 129 genotypes in these patients differed from those in the population unaffected by CJD. An excess of VV homozygotes was noted among those with iatrogenic CJD compared with sporadic CJD cases. The proportion of MM genotype in UK patients was surprisingly low (4%) compared with that in French patients (62%). There is no evident explanation for this different distribution, which might be due to infection with different strains of prion in human growth hormone.     

V180I genetic Creutzfeldt-Jakob disease with cardiac sympathetic nerve denervation masquerading as Parkinson's disease: A case report

Rationale:Creutzfeldt-Jakob disease (CJD) with a point mutation of valine to isoleucine at codon 180 of the prion protein gene (V180I) is the most frequent form of genetic CJD in Japan. However, peripheral nerve involvement, especially cardiac sympathetic denervation, has not been investigated in cases with V180I genetic CJD.We herein report a genetically confirmed case of V180I genetic CJD presenting with parkinsonism and cardiac sympathetic nerve denervation.Patient concerns:The patient was a 79-year-old Japanese woman who presented with subacute progressive gait disturbance and cognitive impairment. Clinical diagnosis of Parkinson''s disease (PD) with mild cognitive impairment was initially suspected based on parkinsonism, such as bradykinesia, rigidity and tremor, and reduced accumulation of cardiac meta-iodobenzylguanidine (MIBG) scintigraphy.Interventions:Based on parkinsonism and impaired cardiac MIBG findings, levodopa/decarboxylase inhibitor was administered up to 300 mg/day; however, her symptoms were not improved.Outcomes:Her motor and cognitive function progressively deteriorated.Diagnosis:Although the patient had no family history of CJD, genetic CJD was diagnosed according to extensive hyperintensities in the bilateral cortices on diffusion-weighted magnetic resonance images, positive tau protein and 14-3-3 protein in the cerebrospinal fluid and a V180I mutation with methionine homozygosity at codon 129 by prion protein gene analysis.Lessons:We should be aware that reduced uptake of cardiac MIBG scintigraphy in patients presenting with parkinsonism cannot confirm a diagnosis of PD. CJD should be considered when patients show a rapid progressive clinical course with atypical manifestations of PD.     

Mutations at codons 178, 200-129, and 232 contributed to the inherited prion diseases in Korean patients

Background

Polymorphisms of the human prion protein gene (PRNP) contribute to the genetic determinants of Creutzfeldt-Jakob disease (CJD). Numerous polymorphisms in the promoter regions as well as the open reading frame of PRNP were investigated. Greater than 90% of Korean, Chinese, and Japanese carry the homozygote 129 MM codon. In Korea, polymorphisms have not been comprehensively studied, except codons 129 and 219 in PRNP among Korean CJD cases. Although polymorphisms at codons 129 and 219 play an important role in susceptibility to sporadic CJD, patients with other polymorphisms in PRNP exhibited critical distinctions of clinical symptoms.

Methods

The genetic analyses of PRNP were carried out among probable CJD patients in comparison with the results from magnetic resonance imaging (MRI) and electroencephalogram (EEG).

Results

The molecular analyses revealed that three mutations at codons D178N, E200K, and M232R in heterozygosity. Patients with the D178N and M232R mutations had a 129MM codon, whereas the patient with the E200K mutation showed 129MV heterozygosity. They all revealed strong 14-3-3 positive signals. The 67-year-old patient with the D178N-129M mutation showed progressive gait disturbance and dysarthria was in progress. The 58-year-old patient with the E200K mutation coupled to the 129MV codon had gait disturbance, dysarthria, agitation, and ataxic gait, and progressed rapidly to death 3 months from the first onset of symptoms. The 65-year-old patient with the M232R mutation showed rapidly progressive memory decline and gait disturbance, and died within 16 months after onset of symptoms.

Conclusion

Despite differences in ethnicity, the clinical and pathological outcomes were similar to the respective mutations around the world, except absence of insomnia in D178N-129M subject.     

A case of Creutzfeldt-Jakob disease with codon 129 polymorphism and codon 180 point mutation

We report a 79-year-old Japanese man with histlogically-diagnosed Creutzfeldt-Jakob disease (CJD) with codon 129 polymorphism and codon 180 point mutation. At the time of the first examination, we diagnosed and treated as Alzheimer's disease with cerebrovascular disease because of laterality of cortex accumulation and an accumulation decrease of perforating branch areas at the SPECT ((123)I-IMP). His status rapidly progressed to an apallic state and died of lung abscess 12 months later. None of the members of his family had neuromuscular disorders. EEG (electroencephalogram) did not reveal periodic synchronous discharges (PSD). Prion protein gene analysis showed Codon 129 polymorphism (Met/Val) and codon 180 point mutation (Val/Ile). The autopsy findings revealed spongiform changes and numerous senile plaque formation in the cerebral cortex. The hippocampus and the cerebellar cortex were well preserved and did not show lacunar infarctions. CJD patients with combination of the codon 180 point mutation and codon 129 polymorphism of the PrP gene have rarely been reported.     

贵州省2010-2015年克-雅病病例监测结果分析

目的 分析2010-2015年贵州省克-雅病(Creutzfeldt-Jakob disease,CJD)监测病例流行病学、临床特征、以及病例转归情况.方法 对贵州省克-雅病监测网络发现的疑似病例的流行病学、临床特征以及随访资料进行分析,同时结合病例脑脊液、血液标本的实验室检测结果.结果 2010-2015年贵州省报告的23例CJD疑似病例中发现CJD病例11例,其中sCJD临床诊断病例8例,sCJD临床疑似病例2例,gCJD确诊诊断病例1例.11例病例中,首发症状以快速进行性痴呆为主要表现,其次是精神症状、锥体外系症状、小脑症状和皮质性失明;临床症状中进行性痴呆为主要症状,其次是视觉或小脑障碍、肌阵挛、锥体系/锥体外系功能异常、无动性缄默;辅助检查以头颅核磁共振(MRI)异常为主(45.45％);实验室检测脑脊液14-3-3蛋白阳性率较高(70％),血液标本中朊蛋白基因(PRNP)检测129位氨基酸多态性均为M/M型,除1例gCJD确诊诊断病例PRNP基因检测发现D178N突变外,均未发现其它位点突变.11例CJD病例无季节、地区聚集性和职业倾向,以男性为主,年龄中位数在65岁,主要为汉族.流行病学史无特殊.对所有CJD病例在报告当年进行随访,失访率27％,大多数病例均在1年内死亡.结论 2010-2015年贵州省CJD病例中以sCJD为主,其流行病学特征与同期全国监测情况相符.首次在贵州省发现1例gCJD病例,其PRNP基因突变与2011-2014年全国CJD监测网络发现的gCJD突变位点均不相同,与河南2011-2013年间报告的2例遗传型朊蛋白病病例在临床表现及PRNP基因突变位点相似.     

Familial Creutzfeldt-Jakob Disease with a codon 200 mutation presenting as thalamic syndrome: diagnosis by single photon emission computed tomography using (99m)Tc-ethyl cysteinate dimer

The clinical features of familial Creutzfeldt-Jakob disease with a codon 200 point mutation [fCJD (E200K)] are similar to those of sporadic CJD (sCJD). MRI diffusion-weighted imaging (MRI-DWI) has been reported to be useful for the early diagnosis of CJD. We describe a Japanese fCJD (E200K) case in which thalamic symptoms were the initial manifestations. On admission, electroencephalography (ECG) showed no periodic synchronous discharge (PSD), and MRI showed no abnormalities. However, single photon emission computed tomography (SPECT) using (99m)Tc-ethyl cysteinate dimer ((99m)Tc-ECD) revealed hypoperfusion in the right thalamus. We conclude that the thalamic form of CJD tends to show no high-intensity area (HIA) by MRI-DWI, and that SPECT may be more useful for visualizing the affected area responsible for the thalamic symptoms at an early stage.     

2009-2018年安徽省克-雅病病例监测特征分析

目的 分析2009-2018年安徽省克-雅病(Creutzfeldt-Jackob Disease,CJD)病例流行病学、临床特征、以及病例转归情况。方法 结合病例脑脊液、血液标本的实验室检测结果,对安徽省克-雅病监测的疑似病例的流行病学、临床特征以及随访资料进行分析。结果 2009-2018年安徽省报告的29例CJD病例中临床诊断CJD病例17例,疑似病例CJD病例9例,遗传或家族型CJD病例3例。病例报告无季节聚集性,长久居住地呈散在分布,职业分布广泛。临床资料分析,进行性痴呆为最常见的首发症状,占全部的65.52%(19/29);散发型CJD临床诊断病例发病年龄中位数为61.11岁,男女比例1.23∶1,均是汉族。辅助检查以头颅核磁共振(MRI)异常为主(80.00%)。实验室检测脑脊液14-3-3蛋白阳性10例,阳性率37.93%;血标本中PRNP检测129位氨基酸多态性均为M/M型;PRNP基因检测与遗传型相关的基因突变有3例,基因突变位点T188K、D178N和R208H各1例。结论 2009-2018年安徽省CJD 病例流行病学特征与同期全国监测情况相符合。首次在安徽发现第一例以R208H为基因突变位少见的遗传型CJD病例。     

Phenotypic Heterogeneity of Variably Protease-Sensitive Prionopathy: A Report of Three Cases Carrying Different Genotypes at PRNP Codon 129

Variably protease-sensitive prionopathy is an exceedingly rare, likely underestimated, sporadic prion disease that is characterized by heterogeneous and often non-specific clinical and pathological features posing diagnostic challenges. We report the results of a comprehensive analysis of three emblematic cases carrying different genotypes at the methionine (M)/valine (V) polymorphic codon 129 in the prion protein gene (PRNP). Clinical, biochemical, and neuropathological findings highlighted the prominent role of the host genetic background as a phenotypic modulator. In particular, the PRNP codon 129 showed a remarkable influence on the physicochemical properties of the pathological prion protein (PrP^Sc), especially on the sensitivity to proteinase K (PK) digestion (VV > MV > MM), which variably affected the three main fragments (i.e., of 19, 17, and 7 kDa, respectively) comprising the PrP^Sc profile after PK digestion and immunoblotting. This, in turn, correlated with significant differences in the ratio between the 19 kDa and the 7 kDa fragments which was highest in the MM case and lowest in the VV one. The relative amount of cerebral and cerebellar PrP mini-plaques immunohistochemistry showed a similar association with the codon 129 genotype (i.e., VV > MV > MM). Clinical manifestations and results of diagnostic investigations were non-specific, except for the detection of prion seeding activity by the real-time quaking-induced conversion assay in the only cerebrospinal fluid sample that we tested (from patient 129VV).     

Creutzfeldt-Jakob disease in patients before and after 80 years of age

The frequency of sporadic CJD is maximum in the 70 to 79 years age group and decreases later. Clinical signs of CJD after the age of 80 do not differ from those before 80 excepted for myoclonia and cerebellar symptoms that are less frequently observed. The results of surrogate markers, neuropathological and biochemical examinations are comparable before or after 80 years old. This last result suggests that the causal event of the disease, potentially the conversion of PrP(c) into PrP(sc), is not qualitatively regulated by brain aging.     

A Japanese patient of congenital hypothyroidism with cerebellar atrophy

We encountered a Japanese patient of congenital hypothyroidism with severe cerebellum atrophy. The boy was born after 40 weeks of gestation by normal vaginal delivery from nonconsanguineous parents. There were no abnormal physical findings; however neonatal mass screening for congenital hypothyroidism at 5 days of age demonstrated elevated thyrotropin (TSH) level (15.5 microU/ml, normal range 0.54-10.0 microU/ml). He was suspected to have subclinical or mild congenital hypothyroidism (CH). Thus he was treated with L-thyroxine using a regimen that rendered his serum TSH concentration within normal range from 27 days of age. Despite early and adequate treatment, he showed signs of global developmental delay and became gradually hypotonic and exhibited a staggering gait at 3 years of age. Brain magnetic resonance imaging (MRI) demonstrated marked cerebellar atrophy with an intact brainstem. Thyroidal uptake of radioiodide and thyroid gland size were normal, indicating a functional defect only. The relation between congenital hypothyroidism and severe cerebellar atrophy in our patient is not clear. As only a few cases of the combination of CH and cerebellar anomalies have been described previously, cerebellar symptoms in CH should be examined carefully.     

Sporadic Creutzfeldt-Jakob disease and isolated dementia. Contribution of brain MRI

Creutzfeldt-Jakob disease (CJD) is the most frequent transmissible spongiform encephalopathy. Its definite diagnosis is ascertained by cerebral neuropathological exam. However, diagnosis of a probable or possible case of CJD can be evoked on the basis of Masters'classification which is based on the association of different clinical and electroencephalographical criteria. We report the case of a 58-year-old woman who died in a geriatric unit of autopsy proven sporadic CJD. The clinical course over 15 months was rapidly progressive dementia without characteristic clinical and EEG signs. The case presentation did not meet the criteria of probable or possible CJD, according to Masters'classification. However, 4 months after the onset of the disease, t-Flair MRI revealed an increased signal intensity in the right frontal and occipital cortex which could suggest the diagnosis of CJD. This case therefore stresses the contribution of MRI, especially diffusion-weighted imaging, for early diagnosis of CJD. It shows also the short comings of Masters'classification which does not always enable diagnosis of CJD even though control measures would have to be rapidly undertaken, specially the decontamination of medico-surgical equipment. Finally, this case illustrates the great importance of post mortem exam in such context. In light of this clinical observation, we discuss this rare diagnosis which should be considered in geriatrics when confronted with a rapidly progressive dementia     

A unique case of sporadic Creutzfeldt-Jacob disease presenting as progressive supranuclear palsy

We report a Japanese case of sporadic Creutzfeldt-Jakob disease (CJD) presenting as progressive supranuclear palsy. For 2 years after onset, neurological deficits had slowly progressed but neither myoclonus nor periodic synchronous discharge was observed. Diffusion-weighted image (DWI) showed unique high signal lesions in the bilateral frontal cortex, left parietooccipital and occipital cortices, but there was nearly no change eight months later. Needle biopsy revealed deposition of prion protein of a patchy/perivacuolar type with spongiform degeneration. Thus, the phenotype of sporadic CJD seems variable and DWI should be performed, even in atypical cases lacking the characteristics of CJD.     

Vision loss due to coincident ocular and central causes in a patient with Heidenhain variant Creutzfeldt-Jakob disease

Creutzfeldt-Jakob disease (CJD) is a degenerative disease of the brain associated with a rapidly progressive spongiform encephalopathy. Visual symptoms and neuro-ophthalmological signs are not infrequent, and presentation to an ophthalmologist may result. A case is reported of an 89-years-old gentleman who presented with a short history of isolated deterioration in vision. He underwent ocular intervention but subsequently developed progressive dementia, asterixis, myoclonus, cerebellar and extrapyramidal signs, and cortical blindness. An electroencephalogram was consistent with CJD. The patient progressively deteriorated and died 9 weeks after symptom onset. Limited post-mortem examination confirmed CJD.     

Pellagra encephalopathy as a differential diagnosis for Creutzfeldt-Jakob disease

In the present study we evaluated cases referred as suspected Creutzfeldt-Jakob disease (CJD). Five out of 59 without prion disease showed neuropathological features of pellagra encephalopathy with widespread chromatolytic neurons (age range 40–48 years at death; one woman). These patients presented with a progressive neuropsychiatric disorder lasting for 2 to 24 months. Common symptoms included gait disorder, para- or tetraspasticity, extrapyramidal symptoms, incontinence, and myoclonus. Protein 14-3-3 in the cerebrospinal fluid was examined in a single patient and was positive, allowing the clinical classification as probable sporadic CJD. Pellagra encephalopathy may be considered as a differential diagnosis of CJD including detection of protein 14-3-3.     

Activating and dominant inactivating c-KIT catalytic domain mutations in distinct clinical forms of human mastocytosis

Human mastocytosis is characterized by increased mast cells. It usually occurs as a sporadic disease that is often transient and limited in children and persistent or progressive in adults. The c-KIT protooncogene encodes KIT, a tyrosine kinase that is the receptor for mast cell growth factor. Because mutated KIT can transform cells, we examined c-KIT in skin lesions of 22 patients with sporadic mastocytosis and 3 patients with familial mastocytosis. All patients with adult sporadic mastocytosis had somatic c-KIT mutations in codon 816 causing substitution of valine for aspartate and spontaneous activation of mast cell growth factor receptor (P = 0.0001). A subset of four pediatric onset cases with clinically unusual disease also had codon 816 activating mutations substituting valine, tyrosine, or phenylalanine for aspartate. Typical pediatric patients lacked 816 mutations, but limited sequencing showed three of six had a novel dominant inactivating mutation substituting lysine for glutamic acid in position 839, the site of a potential salt bridge that is highly conserved in receptor tyrosine kinases. No c-KIT mutations were found in the entire coding region of three patients with familial mastocytosis. We conclude that c-KIT somatic mutations substituting valine in position 816 of KIT are characteristic of sporadic adult mastocytosis and may cause this disease. Similar mutations causing activation of the mast cell growth factor receptor are found in children apparently at risk for extensive or persistent disease. In contrast, typical pediatric mastocytosis patients lack these mutations and may express inactivating c-KIT mutations. Familial mastocytosis, however, may occur in the absence of c-KIT coding mutations.     

Surveillance of Creutzfeldt Jakob disease in the United Kingdom

By the end of May 2000, 54 definite cases and 13 probable cases of vCJD had been notified in the United Kingdom by the National CJD Surveillance Unit set up in 1990. All definite cases for whom data are available are methionine homozygous at codon 129 of     

Mutations in the genes for sarcomeric proteins in Japanese patients with onset sporadic hypertrophic cardiomyopathy after age 40 years

This study was conducted to assess the hypothesis that mutations in the genes for sarcomeric proteins are the molecular cause for older-onset sporadic hypertrophic cardiomyopathy (HC) in Japanese patients. Molecular genetic approaches have demonstrated that familial HC is caused by mutations in genes encoding sarcomeric proteins. Recent studies have shown that sarcomeric gene mutations can also be a molecular cause of older-onset and/or sporadic HC. However, genetic studies to date have examined only a limited number of older Caucasian patients with HC. Clinical evaluations were performed in patients with HC onset after 40 years of age, and the sequence encoding the beta-cardiac myosin heavy chain, cardiac troponin T, cardiac troponin I, cardiac myosin binding protein-C, myosin ventricular regulatory light chain, and myosin ventricular essential light chain genes was analyzed. When a putative mutation was identified, clinical evaluations and genetic studies were subsequently performed on all first-degree relatives. Forty-one patients with sporadic HC onset after 40 years of age (31 men, 10 women; mean age 63+/-10 years at the time of study) were studied. Four novel missense mutations in the cardiac myosin binding protein-C gene (arginine to tryptophan at codon 160, glutamic acid to lysine at codon 334, glycine to arginine at codon 507, and threonine to methionine at codon 1,046) and a previously reported missense mutation in the beta-cardiac myosin heavy chain gene (arginine to histidine at codon 663) were identified in 5 of the 41 patients. No family members carried these mutations or had clinical evidence of HC. In conclusion, mutations in the cardiac myosin binding protein-C are the most common cause of older-onset sporadic HC in Japan.     

朊蛋白基因129密码子多态性与阿尔茨海默病的关系

目的探讨朊蛋白基因（PRNP）129密码子多态性与阿尔茨海默病（AD）的关联性。方法以AD组和健康对照组基因型分布的OR值为统计量进行荟萃。全面检索相关文献并应用Review Manager 4．2软件对各研究结果进行一致性检验和数据合并。结果4个相关文献结果差异无统计学意义。研究共包括AD组1095例,健康对照组940例,校正后包括3个研究AD组972例,健康对照658例。携带至少一个缬氨酸等位基因（V^＊）的基因型相对于甲硫氨酸纯合子（MM）（即V^＊／MM的合并,OR为0．80,95％C10．65—0．98,P=0．03）。携带至少一个甲硫氨酸等位基因（M^＊）的基因型相对于缬氨酸纯合子（VV）,即M^＊／VV的合并（OR为1．38,95％CI1．01—1．89,P=0．04）。纯合子基因型相对于杂合子,即（MM＋VV）／MV的合并（OR为1．10.95％C10．89—1．35,P=0．38）。结论欧洲人群PRNP129密码子纯合子发生AD的危险性增高,但无统计学意义。MM纯合子AD风险增加,M^＊基因型与AD发病风险增加有关联,V^＊基因型与AD发病风险减少有关联。     

Phenotype-genotype studies in kuru: Implications for new variant Creutzfeldt–Jakob disease

The PRNP polymorphic (methionine/valine) codon 129 genotype influences the phenotypic features of transmissible spongiform encephalopathy. All tested cases of new variant Creutzfeldt–Jakob disease (nvCJD) have been homozygous for methionine, and it is conjectural whether different genotypes, if they appear, might have distinctive phenotypes and implications for the future “epidemic curve” of nvCJD. Genotype-phenotype studies of kuru, the only other orally transmitted transmissible spongiform encephalopathy, might be instructive in predicting the answers to these questions. We therefore extracted DNA from blood clots or sera from 92 kuru patients, and analyzed their codon 129 PRNP genotypes with respect to the age at onset and duration of illness and, in nine cases, to detailed clinical and neuropathology data. Homozygosity at codon 129 (particularly for methionine) was associated with an earlier age at onset and a shorter duration of illness than was heterozygosity, but other clinical characteristics were similar for all genotypes. In the nine neuropathologically examined cases, the presence of histologically recognizable plaques was limited to cases carrying at least one methionine allele (three homozygotes and one heterozygote). If nvCJD behaves like kuru, future cases (with longer incubation periods) may begin to occur in older individuals with heterozygous codon 129 genotypes and signal a maturing evolution of the nvCJD “epidemic.” The clinical phenotype of such cases should be similar to that of homozygous cases, but may have less (or at least less readily identified) amyloid plaque formation.     

Two kindreds with familial Alzheimer's disease--analysis of the APP717 mutation and the mutated genes for the prion protein]

Numerous Caucasian familial Alzheimer's disease (FAD) pedigrees have been described in the literature, while only 21 Japanese FAD families have been reported to date. Here we report the clinical findings and the result of molecular genetic analysis of 4 patients from two FAD kindreds, OS-2 and OS-3. The proband in OS-2 family has developed loss of recent memory and place disorientation age at 43. A brain CT showed severe diffuse cortical atrophy. Her younger brother had dementia at 42 years and her mother and other 3 siblings had also dementia symptoms suspected to be Alzheimer's disease. The proband in OS-3 family showed declining recent memory at 49 years and developed dysphagia, gait disturbance and emotional incontinent with cerebral atrophy at 52 years. His father and elder brother demonstrated dementia signs at 60 and 54 years old, respectively. Recently it was reported that affected members from 2 Caucasian kindreds with FAD had missense mutation in exon 17 of the gene for amyloid precursor protein (APP). Patients from three different Japanese kindreds with FAD also showed the same mutation on the APP gene. Amino acid substitution (Val-Ile) at codon 717 by this mutation is responsible for FAD in at least some kindreds. We used genomic DNA from 4 affected members of 2 families to determine whether the disease in these families is associated with a APP717 mutation and the mutated codons, 102, 117, 129, 178 and 200, on the gene for protease-resistance prion protein (PrP) which cause transmissible dementia, Creutzfelt-Jacob disease (CJD) and Gerstmann-Strausler syndrome (GSS).(ABSTRACT TRUNCATED AT 250 WORDS)