Late onset acute Vogt-Koyanagi-Harada syndromechallenges on the way

Dear Editor,We would like to share some clinical cases of late onset acute Vogt-Koyanagi-Harada syndrome （VKH）, a rare diagnosis in this age range.

Late Onset Peripheral Spondyloarthritis in Woman with Hashimoto’s Thyroiditis: A Case Report

Late onset peripheral spondyloarthritis is a particular clinical form of spondyloarthritis, occurring at the age of 50 years or older. Hashimoto’s thyroiditis (HT) is the most frequent autoimmune thyroid disorder responsible for considerable morbidity. HT is well known to be associated with many systemic autoimmune, it is less clear whether a similar association may also be present for spondyloarthritis. Here, we report a case of late onset peripheral spondyloarthritis in a 62-year-old African woman with a 12-year history of Hashimoto’s thyroiditis, a previously undescribed association in the literature. The diagnosis of Late onset peripheral spondyloarthritis was made according to the Assessment of SpondyloArthritis international Society (ASAS) criteria for peripheral spondyloarthritis (presence of arthritis, enthesitis and Human Leukocyte Antigen B27). She was treated with methotrexate and celebid. After 6 months of treatment, the evolution was favourable with an overall improvement in her symptomatology and quality of life. The coexistence of late onset peripheral spondyloarthritis and Hashimoto’s thyroiditis may be related to the presence of a genetic background predisposing to both diseases.

Surveys of serum reproductive hormone levels and the prevalence rates of late onset of hypogonadism in Chinese aging males

Objective:To investigate the change patterns of reproductive hormones in serum of aging males and the difference among male age brackets and the prevalence rates of late onset of hypogonadism(LOH) in males in Chinese middle and aging males. Methods:Subjects included 1,498 men aged 40 to 69 from a county,and the serum reproductive hormones of 434 subjects were measured and calculated.In addition,the prevalence rates of LOH were analyzed by cut-off point of total testosterone(TT) and free testosterone(cFT),and screening scales(a questionnaire of androgen deficiency in the aging males(ADAM) and a scale of aging males’ symptoms(AMS)).TT,cFT,bio-available testosterone (Bio-T),luteinizing hormone(LH),sex hormone binding globulin(SHBG),testosterone secretion index(TSI), free testosterone index(FTD,the positive rates of LOH screening,androgen deficiency rates and the clinical prevalence rates of LOH were measured or calculated. Results:The serum TT levels did not change significantly with male aging while serum LH and SHBG levels gradually increased,but cFT,Bio-T,TSI and FTI levels gradually decreased with male aging.There was very significant difference in other six parameters of reproductive hormones(P<0.01),except for serum TT among the four age brackets(P>0.05).There was no correlation between serum TT levels and aging,LH levels(P>0.05). However,there was significantly a positive correlation between serum LH,SHBG and age(P<0.01),while there were negative correlation between cFT,Bio-T,TSI,FTI and age,LH levels(P<0.01).Moreover,SHBG level was positively correlated with LH level(P<0.01). Utilizing the Questionnaire of ADAM and AMS to screen subjects aged 40 to 69 years,mean positive rates of LOH screening were 80.77%and 32.34%respectively.Mean androgen deficiency rates were 14.02%and 43.69% by using TT and cFT cut-off point.In addition,mean LOH clinical prevalence rates of subjects on positive questionnaire results were 37.85%and 15.42%. Conclusion:The serum TT levels did not change significantly with male aging while serum LH,SHBG,cFT, Bio-T,TSI and FTI levels had the gradient change with aging.On the basis of Chinese population,however,the positive rate of LOH screening,androgen deficiency rate and clinical prevalence rate of LOH were obviously higher than that those of the other foreign studies.

Late onset fulminant Wilson's disease:A case report and review of the literature

Wilson’s disease(WD)is an autosomal recessive inherited disorder of hepatic copper metabolism.WD can be present in different clinical conditions,with the most common ones being liver disease and neuropsychiatric disturbances.Most cases present symptoms at<40years of age.However,few reports exist in the literature on patients in whom the disease presented beyond this age.In this report,we present a case of late onset fulminant WD in a 58-year-old patient in whom the diagnosis was established clinically,by genetic analysis of the ATP7B gene disclosing rare mutations(G1099S and c.1707+3ins T)as well as by high hepatic copper content.We also reviewed the relevant literature.The diagnosis of WD with late onset presentation is easily overlooked.The diagnostic features and the geneticbackground in patients with late onset WD are not different from those in patients with early onset WD,except for the age.Effective treatments for this disorder that can be fatal are available and will prevent or reverse many manifestations if the disease is discovered early.

Clinical characteristics of patients with early-and late-onset optic neuromyelitis optica spectrum disease

Objective:To analyze the different clinical features of patients with early-onset(EO-NMOSDs)and late-onset neuromyelitis optica spectrum diseases(LO-NMOSDs).Methods:A total of 51patients with neuromyelitis optica spectrum disease who were diagnosed in our hospital for the first time from January 2015 to December 2022 were included in the First Affiliated Hospital of Hainan Medical College and divided into 22 cases in the EO-NMOSDs group and 29 cases in the LO-NMOSDs group according to whether the age of onset was 50 years old.The basic data,Extended Disability Status Scale(EDSS)score,blood and cerebrospinal fluid test indicators of the two groups were statistically analyzed.Results:There were no significant differences in demographic characteristics,clinical features and serum AQP-4 antibody positivity rate between the two groups(all P>0.05),and there were significant differences in triglycerides(TG),low-density lipoprotein(LDL),apolipoprotein A(APOA),apolipoprotein B(APOB)and lipoprotein a(P=0.010,P=0.048,P=0.014,P=0.061,P=0.001,respectively),and cerebrospinal fluid LDH,There were significant differences between microprotein quantification and EDSS score(P=0.018,P=0.034,P=0.025,respectively),and the level of microprotein quantification in cerebrospinal fluid of LO-NMOSDs had a certain correlation with the degree of disability(r=0.52,P<0.03).Conclusion:LO-NMOSDs and EO-NMOSDs group patients have similar demographic characteristics,serum AQP-4 antibody positive rate and clinical features,but compared with EO-NMOSDs,patients in LO-NMOSDs group are prone to abnormal lipid metabolism,higher trace proteins in cerebrospinal fluid and more likely to be disabled,and among LO-NMOSDs,the higher the trace protein in the cerebrospinal fluid,the more severe the disability status of patients.

A Comparison between Late Preterm and Term Infants with Respiratory Distress Syndrome, Early-Onset Sepsis, and Neonatal Jaundice in Ecuadorian Newborns

Background: To examine the differences in prevalence of respiratory distress syndrome, early-onset sepsis and jaundice, between late preterm infants versus term infants in Ecuadorian newborns. Methods: Study design: Epidemiological, observational, and cross-sectional, with two cohorts of patients. Settings: IESS Quito Sur Hospital at Quito, Ecuador, from February to April of 2020. Participants: This study included 204 newborns, 102 preterm infants, 102 term infants. Results: There are significant differences between late preterm infants and term infants, with a p-value of 0.000 in the prevalence of early sepsis, 70.59% vs. 35.29%. In respiratory distress syndrome between late and term premature infants, significant differences were observed with a p-value of 0.000, the proportion being 55.58% vs. 24.51% respectively. The prevalence of jaundice is higher in term infants with a p value of 0.002, 72.55%, versus 51.96% in late preterm infants, and the mean value of bilirubins in mg/dL was higher in term infants 14.32 versus 12.33 in late preterm infants;this difference is statistically significant with a p value of 0.004. Admission to the NICU is more frequent in late preterm infants with a p-value of 0.000, being 42.16% for late preterm infants vs. 7.84% in term infants;the mean of the hospital days with p-value 0.005, was higher in late preterm infants 4.97 days vs. 3.55 days for term newborns. Conclusion: Due to the conditions of their immaturity, late preterm infants are 2.86 times more likely to present early sepsis than full-term newborns. It is shown that late preterm infants are 2.69 times more likely to have respiratory distress syndrome compared to term infants, therefore, late preterm infants have a longer hospital stay of 4.97 days versus 3.55 days in term infants. Jaundice and mean bilirubin levels are higher in term infants due to blood group incompatibility and insufficient breastfeeding.

Androgen replacement therapy improves psychological distress and health-related quality of life in late onset hypogonadism patients in Chinese population

Background Late onset hypogonadism negatively impacts on men＇s psychological well-being This study was conducted to examine the interrelationship among symptoms of testosterone deficiency, psychological well-being, and quality of life.Methods Eligible subjects were randomized into active treatment and control groups, and were asked to complete the following questionnaires at baseline and month 6： aging male＇s symptoms （AMS） rating scale,

Late-onset non-islet cell tumor hypoglycemia: A case report

BACKGROUND Hypoglycemia due to non-insulin-producing tumors is referred to as non-islet cell tumor hypoglycemia(NICTH).As NICTH is a rare lesion,the natural course of NICTH is not well understood.We report a case of NICTH that was observed 30 years before the onset of hypoglycemia.CASE SUMMARY A 50-year-old man was diagnosed with an abnormal right chest shadow during a routine X-ray examination,but no further examination was undertaken because the lesion appeared benign.Thirty years after the tumor discovery,the patient was admitted to the hospital with symptoms of severe hypoglycemia,which was diagnosed as NICTH based on a complete examination.The tumor was resected and found to be a solitary fibrous mass(15.6 cm×13.7 cm×10.4 cm);thereafter,the patient’s blood glucose levels normalized and he completely recovered.CONCLUSION NICTH can have an acute onset,even if the tumor has been present and asymptomatic over a long time period.

Survey for late-onset hypogonadism among old anti middle-aged males in Shanghai communities

This study sought to investigate late-onset hypogonadism （LOH） in old and middle-aged males in Shanghai communities, using symptom score evaluation systems and measurements of sex hormone levels. One thousand cases of males aged 40-70 years were investigated. The aging male symptoms （AMS） scale and androgen deficiency in aging males （ADAM） questionnaire were used at the beginning of the investigation, followed by measurement of the sex hormone-related factors （total testosterone （TT）, free testosterone （fT）, sex hormone-binding globulin （SHBG） and bioavailability of testosterone （Bio-T））. There were 977 valid questionnaires. The LOH-positive rates shown by AMS and ADAM were 59.88% and 84.65%, respectively; values increased with the age of the patients. There were 946 results related to sex hormone measurements, which showed the following results： TT was not related to aging （P〉O.05）; levels of SHBG increased with age; and fT and Bio-T decreased with age. There was a significant difference in fT between LOH-positive and LOH-negative patients, as shown by the ADAM. In summary, TT levels were not related to aging, even though SHBG did increase while fT and Bio-T decreased with aging. Clinically, the diagnosis of LOH cannot be based on serum TT level.

How to recognize late-onset hypogonadism in men wit sexual dysfunction

Late-onset hypogonadism （LOH） has been considered the most common form of male hypogonadism with a prevalence of approximately 1 in 100 men. Diagnosis of LOH should be made in symptomatic men with unequivocally low serum testosterone （T） levels. However, its clinical presentation is often insidious and difficult to recognize because it is characterized by nonspecific symptoms that make differential diagnosis with physiological ageing problematic. Sexual dysfunction is the most important determinant for medical consultation and the most specific symptom associated with low T. We therefore analysed a consecutive series of 1734 subjects who attended our unit for sexual dysfunction to investigate the associations between low T （different thresholds）, sexual parameters, medical history data （delayed puberty, pituitary disease or cryptorchidism） and their physical exam results. Metabolic parameters, in particular waist circumference, display the greatest accuracy in detecting low T. We found that only the association of several symptoms and signs could significantly raise the clinical suspicion of low T. Structured inventories, which cluster together symptoms and signs of hypogonadism, can help clinicians suspect androgen deficiency. In particular, structured interviews, such as ANDROTEST, have been demonstrated to have a greater accuracy when compared to self reported questionnaires in detecting low T levels.

Molecular Genetic Analysis of Autosomal Dominant Late-Onset Cataract in a Chinese Family

Congenital cataract is a highly heterogeneous disorder at both the genetic and the clinical-phenotypic levels.A unique cataract was observed in a 4-generation Chinese family,which was characterized by autosomal dominant inheritance and late-onset.Mutations in the 13 known genes (CRYAA,CRYAB,CRYBB1,CRYBB2,CRYGC,CRYBA1/A3,CRYGD,Connexin50,Connexin46,intrinsic membrane protein LIM2,cytoskeletal protein BFSP2,the major intrinsic protein-MIP and the heat shock factor HSF4) have previously been demonstrated to be the frequent reason for isolated congenital cataracts,but the exact molecular basis and underlying mechanisms of congenital cataract still remain unclear.This study was designed to find whether these 13 genes developed any mutation in the family members and to identify the disease-causing gene.Polymerase chain reaction (PCR) and direct DNA sequence analysis were carried out to detect the 13 genes.The results showed that no mutation causing amino acid alternations was found in these potential candidate genes among all patients in the family,and only several single-nucleotide polymorphisms (SNPs) were identified.A transitional mutation in the fourth intron of CRYBB2 and some silent mutations in the first exon of BFSP2 and CRYGD were found in the cataract family,but further study showed that these mutations could also be found in normal controls.It was concluded that some unidentified genes may underlie the occurrence of late-onset cataract in this family.A genome-wide screening will be carried out in the next study.

SLC26A4 gene polymorphism and late-onset Alzheimer’s disease in a Han Chinese population from Qingdao,China

In a recent genome-wide association study, the SLC26A4 gene rs2072064 polymorphism was found to be associated with late-onset Alzheimer＇s disease in Caucasians. Here, we investigated this association in a large Northern Han Chinese cohort consisting of 599 sporadic late-onset Alzheimer＇s disease patients and 598 healthy controls matched for sex and age in a Northern Han Chinese population from Qingdao, China. Genotyping by the polymerase chain reaction-ligase detection reaction revealed that there were significant differences in the genotype （P = 0.017） and allele （P = 0.007） frequencies of the rs2072064 polymorphism between late-onset Alzheimer＇s disease patients and controls. The A allele of this polymorphism was significantly associated with a reduced risk of late-onset Alzheimer＇s disease （odds ratio （OR） = 0.792, 95% confidence interval （CI） = 0.670-0.937, P = 0.007）. When the data were stratified by the apolipoprotein E E4 status, there was a significant difference only among apolipoprotein E E4 non-carriers （genotypic P = 0.001, allelic P = 0.001）. Furthermore, the association between rs2072064 and late-onset Alzheimer＇s disease remained significant by logistic regression analysis after adjustment for age, gender, and the apolipoprotein E E4 carrier status （dominant model： OR = 0.787, 95% CI = 0.619-1.000, P = 0.050; recessive model： OR = 0.655, 95% CI = 0.448-0.959, P= 0.030; additive model： OR = 0.792, 95% CI = 0.661-0.950, P = 0.012）. These findings suggest that SLC26A4 is a susceptibility gene for late-onset Alzheimer＇s disease in a Northern Han Chinese population from the Qingdao area.

A non-invasive,rapid method to genotype late-onset Alzheimer's disease-related apolipoprotein E gene polymorphisms

The apolipoprotein E gene ε4 allele is considered a negative factor for neural regeneration in late-onset Alzheimer＇s disease cases. The aim of this study was to establish a non-invasive, rapid method to genotype apolipoprotein E gene polymorphisms. Genomic DNA from mouth swab specimens was extracted using magnetic nanoparticles, and genotyping was performed by real-time PCR using TaqMan-BHQ probes. Genotyping accuracy was validated by DNA se- quencing. Our results demonstrate 100% correlation to DNA sequencing, indicating reliability of our protocol. Thus, the method we have developed for apolipoprotein E genotyping is accurate and reliable, and also suitable for genotyping large samples, which may help determine the role of the apolipoprotein E ε4 allele in neural regeneration in late-onset Alzheimer＇s disease cases.

Late-onset multiple acyl-CoA dehydrogenase deficiency with cardiac syncope: A case report

BACKGROUND Multiple acyl-CoA dehydrogenase deficiency(MADD)is an uncommon autosomal recessive disorder of mitochondrial fatty acid beta-oxidation.Syncope is a transient loss of consciousness due to acute global cerebral hypoperfusion.Late-onset MADD with syncope has not been reported previously.CASE SUMMARY We report a 17-year-old girl with exercise intolerance and muscle weakness.She felt palpitation and shortness of breath after short bouts of exercise.She also suffered from a transient loss of consciousness many times.Muscle biopsy showed lipid storage.Genetic mutation analysis indicated a compound heterozygous mutation c.250G>A(p.A84T)and c.872T>G(p.V291G)in the ETFDH gene.The results of Holter electrocardiogram monitoring showed supraventricular tachycardia when the patient experienced a loss of consciousness.After treatment with riboflavin and carnitine,muscle weakness and palpitation symptoms improved rapidly.No loss of consciousness occurred,and the Holter electrocardiogram monitoring was normal.CONCLUSION Late-onset MADD with supraventricular tachycardia can cause cardiac syncope.Carnitine and riboflavin supplement were beneficial for treating the late-onset MADD with cardiac syncope.Attention should be paid to the prevention of cardiac syncope when diagnosing late-onset MADD.

Study of Tripterygium Associated with Nicotinamide in Treating Late-onset Autoimmune Diabetes Mellitus in Adults

Objective: To explore the effect of Tripterygium polyglycoside (TP) associated with nicotinamide on the islet cell function, immune parameters and lipoperoxide (LPO) in adult patients with late-onset autoimmune diabetes mellitus (LADA). Methods: Thirty-six cases of LADA were randomly divided into three groups: TP group (n=12), treated with TP plus orally taken metformin; combined treatment group (n= 12), treated with TP combined with nicotinamide and metformin, and control group (n=12) treated with metformin alone. They were followed-up for 18 months. Results: (1) Compared with the control group after 9 months of treatment, postprandial plasma glucose and LPO in combined treatment group were decreased (P <0.05), and the postprandial C-peptide was higher (P<0.05). At the 18th month, the value of postprandial C-peptide in the TP and combined treatment group was higher than that in the control group. The slL-2R level of both TP and combined treatment groups were lowered (P<0.01); (2) Islet cell antibody (ICA) positive of 5 cases in the TP group and 6 cases in the combined treatment group got converted to the negative respectively , while only one in the control group at the time (P<0.05); (3) The level of LPO in the combined treatment group was significantly lower than that in the TP group at the 18th month of treatment (P<0. 05). Conclusion: TP combined with nicotinamide played a role in immunity regulation, decreasing the titer of islet cell antibody and slL-2R, which also reduced the production of LPO and had a tendency to improve islet cell function in early LADA patients.

Elderly patients with very late-onset schizophrenia-like psychosis and early-onset schizophrenia: Cross-sectional and retrospective clinical findings

Objectives: The aim of this study was to characterize the symptoms at onset/past and current symptoms of patients with Very Late-Onset Schizophrenia-Like Psychosis (VLOSLP;first onset of psychotic symptoms at/or after 60 years old) with those of elderly patients diagnosed with schizophrenia before the age of 40 years old (Early-Onset Schizophrenia—EOS) in order to validate the clinical nosology proposed by the International Late-Onset Schizophrenia Group. Methods: This is a between-patient comparison study with retrospective and current data taken from an historical cohort that was conducted from May/2005 to August/2008. Seventeen VLOSLP and 17 EOS were included. Schizophrenia and schizophrenia-like psychotic disorders were initially diagnosed by board-certified psychiatrists with the Diagnostic and Statistical Manual Criteria at use at onset of the disorders. Patients’ symptoms were assessed with the Scale for the Assessment of Positive Symptoms (SAPS) and the Scale for the Assessment of Negative Symptoms (SANS). The general scores on the SAPS/SANS were the primary outcomes. Results: Both groups had hallucinations and delusions at onset of the disease, but the following symptoms were more present and severe in EOS than in VLOSLP: hallucinations (p = 0.001);assiduity loss (p p = 0.001), reference (p p = 0.001) delusions. VLOSLP had mostly persecutory delusions. At current evaluation (follow-up of cohort), most patients in the two groups presented residual symptoms of anhedonia and apathy, but EOS, presented more symptoms of friendship poverty (d = 1.42, large effect size) than VLOSLP. The neuroimaging studies (when available) at follow-up demonstrated greater vascular cerebral lesions/vulnerability in VLOSLP than in EOS patients. Conclusion: This study showed that both VLOSLP and EOS had positive and negative symptoms in the past/at onset of the disease, but they were more severe in EOS than in VLOSLP. However, the positive symptoms of both groups at follow-up of the cohort (current evaluation) responded relatively well to neuroleptics.

A Rare Cause of Late-Onset Epilepsy: Linear Scleroderma en Coup de Sabre

Late-Onset Epilepsy (LOE), with onset in adult life, is often attributed to cerebrovascular disease and intracranial tumor. Herein we present a LOE patient with history of Linear Scleroderma en Coup de Sabre (LScs) and abnormal cranial MRI signs. Curiously, his band-like skin lesion, presenting on the forehead, was in line with the surface projection of the intracranial focus shown in MRI. This gave a clue of the link between the skin lesion and the intracranial focus and the epilepsy. To sum up, it exposed a rare cause of LOE. Moreover, it underlined the significance of recognizing the cause to be associated with a substantially increased risk of developing epilepsy.

高原地区卒中后癫痫的临床及预后特征

目的探讨高原地区居民卒中后癫痫(post-stroke epilepsy,PSE)的临床、治疗和预后特征,并分析影响PSE预后的风险因素,为制定高原地区PSE临床诊疗策略提供一定依据。方法回顾性连续纳入2019年1月—2023年6月在西藏自治区人民医院住院治疗的高原地区PSE患者。根据PSE类型分为早发性(卒中后≤7 d)PSE组和迟发性(卒中后>7 d)PSE组,于2023年9月通过电话和门诊相结合的方式进行随访,获取患者的功能预后(mRS评分)情况。比较两组患者的性别、年龄、卒中类型分布、卒中严重程度(发病时mRS评分)、实验室检查等基线资料,以及随访功能预后的差异,分析预后不良(随访mRS评分≥3分)的影响因素。结果共纳入符合入组标准的PSE患者89例,占同期住院高原卒中患者的4.2%,患者发病年龄中位数为55(44~69)岁,男性59例(66.3%),藏族87例(97.8%),发病时mRS评分为3(1~4)分。入组患者中早发性PSE组49例(55.1%),迟发性PSE组40例(44.9%)。卒中亚型分布中脑出血所占比例最高,为39.3%(35例)。最常见的癫痫发作类型为全面起源性发作,共69例(77.5%)。36例(40.4%)PSE患者合并癫痫持续状态。影像学检查显示卒中病灶中最常见的为皮质病灶,共48例(53.9%)。治疗方面85例(95.5%)PSE患者接受了抗癫痫药物治疗,其中79例(88.8%)患者接受单药治疗,最常应用的抗癫痫药物是奥卡西平/卡马西平(36例,40.4%)。PSE患者的院内死亡率为10.1%(9例)。随访时间中位数为27(15~40)个月,预后不良患者占56.7%(38/67),死亡率为35.8%(24/67)。与早发性PSE组相比,迟发性PSE组男性比例更高(78.6%vs.56.6%,P=0.043)且有癫痫家族史比例更高(10.0%vs.0,P=0.037)。两组间的卒中类型分布(P=0.040)和应用抗癫痫药物类型分布(P=0.047)差异有统计学意义。多因素回归分析显示,卒中症状严重(发病时mRS评分高)是PSE预后不良的独立危险因素(OR 1.691,95%CI 1.245~2.297,P<0.001)。结论PSE在高原地区住院卒中患者中的发生率为4.2%。高原地区PSE患者发病时临床症状重,40.4%的患者合并癫痫持续状态。高原地区PSE患者预后不良,致残率和死亡率高。

13例晚发型庞贝病临床特征分析

目的探讨晚发型庞贝病(LOPD)患者的临床特征和基因突变特点。方法选取2020年9月至2023年12月在浙江大学医学院附属第一医院确诊为LOPD的13例患者,对所有患者进行临床调查、GAA活性检测和GAA基因检测。结果13例患者中男7例,女6例;家系患者5例,散发患者8例;中位发病年龄17岁(8~52岁),中位就诊年龄24岁(10~52岁),中位确诊年龄31岁(14~58岁)。患者首发症状,10例患者表现为肢体无力,3例患者表现为呼吸困难。血清肌酸激酶平均水平552 U/L(55~1084 U/L),1例患者血清肌酸激酶水平正常。13例患者均有脊柱侧弯、不同程度限制性通气功能障碍。9例患者行神经电生理检查均提示肌源性损害,其中8例患者有临床下肌强直放电。GAA活性平均值0.3μmol/(L·h)[0.17~0.5μmol/(L·h)]。共检出GAA基因13个变异位点,最常见突变位点c.2238G>C(p.W746C)。发现c.543del(p.F181Lfs*40)、c.839_840insCC(p.R281Pfs*34)、c.1800_1823del(p.S601_R608del)、c.2296T>C(p.Y766H)、c.995C>A(p.S332*)共5个新变异位点。结论LOPD是一种容易延误诊断的罕见病。肢体近端无力、呼吸功能下降、肌酸激酶轻中度升高、脊柱侧弯、肌电图提示临床下肌强直放电是LOPD的高危“画像”。c.2238G>C(p.W746C)是其热点突变,新发现的5个GAA变异位点丰富了GAA基因突变谱系。

E674Q(Shanghai APP mutant),a novel amyloid precursor protein mutation,in familial late-onset Alzheimer's disease

Identified as the pathogenic genes of Alzheimer's disease(AD),APP,PSEN1,and PSEN2 mainly lead to early-onset AD,whose course is more aggressive,and atypical symptoms are more common than sporadic AD.Here,a novel missense mutation,APP E674Q(also named“Shanghai APP”),was detected in a Chinese index patient with typical late-onset AD(LOAD)who developed memory decline in his mid-70s.The results from neuroimaging were consistent with AD,where widespread amyloidβdeposition was demonstrated in 18 F-florbetapir Positron Emission Tomography(PET).APP E674Q is close to theβ-secretase cleavage site and the well-studied Swedish APP mutation(KM670/671NL),which was predicted to be pathogenic in silico.Molecular dynamics simulation indicated that the E674Q mutation resulted in a rearrangement of the interaction mode between APP and BACE1 and that the E674Q mutation was more prone to cleavage by BACE1.The in vitro results suggested that the E674Q mutation was pathogenic by facilitating the BACE1-mediated processing of APP and the production of Aβ.Furthermore,we applied an adeno-associated virus(AAV)-mediated transfer of the human E674Q mutant APP gene to the hippocampi of two-month-old C57Bl/6 J mice.AAV-E674Q-injected mice exhibited impaired learning behavior and increased pathological burden in the brain,implying that the E674Q mutation had a pathogenicity that bore a comparison with the classical Swedish mutation.Collectively,we report a strong amyloidogenic effect of the E674Q substitution in AD.To our knowledge,E674Q is the only pathogenic mutation within the amyloid processing sequence causing LOAD.