Probable Novel APP Met671Leu Mutation in a Chinese Han Family with Early-Onset Alzheimer's Disease.

Familial Alzheimer's disease (AD) is a rare disease caused by autosomal-dominant mutations. APP (encoding amyloid precursor protein), PSEN1 (encoding presenilin 1), and PSEN2 (encoding presenilin 2) are the most common genes cause dominant inherited AD. This study aimed to demonstrate a Chinese early-onset AD pedigree presenting as progressive memory impairment, apraxia, visual-spatial disorders, psychobehavioral disorders, and personality changes with a novel APP gene mutation. The family contains four patients, three carries and three normal family members. The proband underwent brain magnetic resonance imaging (MRI), 18F-fludeoxyglucose positron emission tomography (18F-FDG-PET), cerebrospinal fluid amyloid detection, 18F-florbetapir (AV-45) Positron Emission Computed Tomography (PET) imaging, whole-exome sequencing and Sanger sequencing. Brain MRI images showed brain atrophy, especially in the entorhinal cortex, temporal hippocampus, and lateral ventricle dilation. The FDG-PET showed hypometabolism in the frontotemporal, parietal, and hippocampal regions. 18F-florbetapir (AV-45) PET imaging showed cerebral cortex Aß protein deposition. The cerebrospinal fluid amyloid protein test showed Aß42/Aß40 ratio decreases, pathological phosphor-tau level increases. Whole-exome sequencing detected a new missense mutation of codon 671 (M671L), which was a heterozygous A to T point mutation at position 2011 (c.2011A > T) in exon 16 of the amyloid precursor protein, resulting in the replacement of methionine to Leucine. The co-separation analysis was validated in this family. The mutation was found in 3 patients, 3 clinical normal members in the family, but not in the other 3 unaffected family members, 100 unrelated normal subjects, or 100 sporadic patients with AD. This mutation was probably pathogenic and novel in a Chinese Han family with early-onset AD.

Presenilin2 D439A Mutation Induces Dysfunction of Mitochondrial Fusion/Fission Dynamics and Abnormal Regulation of GTPase Activity.

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disease, and approximately 10% of AD cases are early-onset familial AD (EOFAD), which is mainly linked to point mutations in genes encoding presenilins (PS1 and PS2). Mutations in PS2 are extremely rare and have not received enough attention. Recently, studies have found that Rho GTPase activity is closely related to the pathogenesis of AD. In this study, we used transcriptome sequencing in PS2 siRNA-transfected SH-SY5Y cells and found a group of differentially expressed genes (DEGs) related to the regulation of GTPase activity. Among those DEGs, the most significantly downregulated was Rho guanine nucleotide exchange factor 5 (ARHGEF5). GTPase activity in PS2 siRNA-transfected cells was significantly decreased. Then, we found that the expression of ARHGEF5 and the GTPase activity of Mitochondrial Rho GTPase 2 (Miro2) in PS2 D439A mutant SH-SY5Y cells were significantly decreased. We found for the first time that PS2 can bind to Miro2, and the PS2 D439A mutation reduced the binding between PS2 and Miro2, reduced the expression of Miro2, and resulted in an imbalance in mitochondrial fusion/fission dynamics. In conclusion, PS2 gene knockdown may participate in the pathogenesis of AD through the regulation of GTPase activity. The imbalance in mitochondrial dynamics mediated by the PS2 D439A mutation through regulation of the expression and GTPase activity of Miro2 may be a potential pathogenic mechanism of AD.

Clinical comparative analysis of monophasic and multiphasic acute disseminated encephalomyelitis in adults.

Introduction: This study aims to explore the clinical features and prognostic factors for relapse of acute disseminated encephalomyelitis (ADEM) in adults. Material and methods: 56 patients with ADEM were retrospectively analyzed. The epidemiological characteristics, clinical manifestations, laboratory features, magnetic resonance imaging (MRI), treatment and prognosis data of these patients were analyzed using the χ2 test for categorical variables and Mann-Whitney U-test for continuous variables. Then, the clinical characteristics and recurrence factors were summarized. Results: 56 patients with ADEM, based on the criteria of the International Pediatric Multiple Sclerosis Study Group, were recruited to the study. Among these patients, 31 were male and 25 were female. Furthermore, 13 patients had multiphasic ADEM, and 29 patients (52%) had definite incentive factors before onset. The commonest presenting symptoms and signs were fever (36%), disturbance of consciousness (52%), mental disorder (38%), seizure (14%), headache and dizziness (43%), optic neuritis (34%), autonomic nervous system symptoms (43%), limb paralysis or abnormal sensation (73%), and unilateral or bilateral pyramidal tract signs (48%). Inflammatory changes in the cerebrospinal fluid were prominent. MRI T2-weighted and fluid-attenuated inversion recovery images displayed multiple or large flaky high signals, and the lesions were usually different in the number and distribution of these lesions. Intravenous corticosteroids and/or immunoglobulin were still important treatments in the acute phase. After treatment, 38 patients completely recovered, 9 patients had neurologic deficits, and 9 patients died. Conclusions: ADEM in adults is not uncommon, its clinical features are complex and varied, and some of these are multiphasic. There may be some potential clinical predictors at first onset.

Clinical, laboratory, and radiological features of cerebral amyloid angiopathy-related inflammation (CAA-ri): retrospective, observational experience of a single centre.

BACKGROUND: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a subtype of CAA with an inflammatory response to the vascular ß-amyloid deposits. Reliable and non-invasive clinical diagnostic methods may allow patients to avoid the side effects of brain biopsy. OBJECTIVE: In this observational study, we retrospectively analyzed the clinical, laboratory, radiological features, treatment, and outcome of patients diagnosed with CAA-ri. The main purpose is to enhance knowledge of CAA-ri and to avoid misdiagnosis. METHODS: We described 15 consecutive patients with probable or possible CAA-ri at Henan Provincial People's Hospital according to a validation study of proposed criteria for the diagnosis of CAA-ri. The clinical features, imaging, laboratory findings, and treatment which included the response to immunotherapy were revealed in the study. RESULTS: The median age of 15 patients was 67.0 years (range 48.0-90.0 years), and the male-to-female ratio was 7: 8. In our study, the most common clinical manifestations were cognitive decline (7/15, 46.7%), focal neurologic deficit (6/15, 40.0%), and headache (5/15, 33.3%). In terms of imaging results, white matter hyperintensity (WMH) lesions were rarely seen in the cerebellum and brainstem, while no hemorrhagic lesion was observed in the brainstem of all 15 patients. In addition, 12 patients (80.0%) showed improvement or stability for the clinical and radiological outcomes after immunotherapy. CONCLUSION: CAA-ri should be considered as a differential diagnosis when brain MRI shows typical features in the elderly. Once the diagnosis is established, immunotherapy should be initiated as early as possible to promote neurological function recovery and reduce recurrence.

Association between red blood cell distribution width-to-albumin ratio and the prognosis in patients with autoimmune encephalitis: a retrospective cohort study.

Aim: Red blood cell distribution width-to-albumin ratio (RAR) is a combined new indicator reflecting immunology and has been reported to predict the prognosis of inflammation-related diseases and brain diseases. However, the association and predictive value of RAR in the prognosis of patients with autoimmune encephalitis (AE) has not been reported. Methods: This was a retrospective cohort study, and data were collected from the Henan Provincial People's Hospital. RAR was categorized according to quartile. The prognosis was assessed using the modified Rankin Scale (mRS), and an mRS score of ≥3 was defined as a poor prognosis. The logistical regression model was used to explore the association between RAR and the prognosis, with results reported as odds ratio (OR) and 95% confidence interval (CI). The predictive value of RAR was evaluated by calculating the area under the receiving operating curve (AUC), sensitivity, specificity, and accuracy. Results: A total of 175 eligible patients were included for analysis, and 51 patients were identified as having poor prognosis. After adjusting age, cancer, other diseases, histological subtype, antiepileptic therapy, anti-tumor treatment, ICU treatment, and length of stay, RAR in the highest quartile (Q4) was found to be significantly associated with the high odds of poor prognosis (OR = 5.63, 95%CI: 1.98-16.02) compared to RAR in the lowest quartile (Q1). In addition, RAR was identified as a predictor for the prognosis of AE patients (AUC = 0.660, 95%CI: 0.574-0.746). Conclusion: This study found the close association and predictive value of RAR for the prognosis of AE patients, indicating that RAR might help clinicians identify high-risk populations.

Dietary intake of thiamine and riboflavin in relation to severe headache or migraine: A cross-sectional survey.

OBJECTIVE: The purpose of this study was to identify the prevalence of severe headache or migraine and the association between dietary thiamine and riboflavin intake with headache history using a large, nationally representative population sample. BACKGROUND: Severe headache and migraine are common and disabling neurological disorders worldwide. Previous studies revealed that the B vitamin group, as an important nutrient of diet, can reduce migraine disability. METHODS: We performed a cross-sectional study of American adults surveyed in the National Health and Nutrition Examination Survey (NHANES) 1999-2004. Information on headache history was collected in the Miscellaneous Pain section of the Questionnaire Data. Dietary intake data of thiamine and riboflavin were obtained by 24-h dietary recall interview. RESULTS: The present study included 13,439 participants and indicated that 2745/13,439 (21.6%) adults (aged ≥20 years) experienced severe headache or migraine in the past 3 months. Dietary thiamine intake was significantly inversely associated with severe headache or migraine (odds ratio [OR] = 0.93, 95% confidence interval [CI] = 0.88-1.00, p = 0.046). In the stratified analysis, the relationship was maintained in the female group (OR = 0.90, 95% CI = 0.82-0.98, p = 0.022), and the sex interaction term was significant (p = 0.020). However, no significant interaction was found between the age groups (p = 0.352). For dietary riboflavin, no significant negative association was observed between dietary riboflavin intake and headache history (OR = 0.98, 95% CI = 0.94-1.02, p = 0.367). After stratifying by sex or age, there remained no significant relationship between dietary riboflavin and migraine. CONCLUSIONS: We found that high intake of thiamine was significantly associated with lower odds of migraine, especially in females. In the future, more clinical studies are needed to confirm our conclusions, and additional experiments are needed to explore the possible mechanisms of prevention and treatment for migraine.

Novel PSEN1 (P284S) Mutation Causes Alzheimer's Disease with Cerebellar Amyloid ß-Protein Deposition.

BACKGROUND/OBJECTIVE: AD-associated PSEN1 mutations exhibit high clinical heterogeneity. The discovery of these mutations and the analysis of their associations with cases such as EOAD should be critical to understanding AD's pathogenesis. METHODS: We performed clinical analysis, neuroimaging, target region capture and high-throughput sequencing, and Sanger sequencing in a family of 3 generations. The underlying Alzheimer's pathology was evaluated using biomarker evidence obtained from cerebrospinal fluid (CSF) amyloid testing and 18F-florbetapir (AV-45) PET imaging. RESULTS: Target region capture sequencing revealed a novel heterozygous C to T missense point mutation at the base position 284 (c.850 C>T) located in exon 8 of the PSEN1 gene, resulting in a Prolineto- Serine substitution (P284S) at codon position 850. The mutation was also identified by Sanger sequencing in 2 family members, including proband and her daughter and was absent in the other 4 unaffected family members and 50 control subjects. Cerebrospinal fluid (CSF) amyloid test exhibited biomarker evidence of underlying Alzheimer's pathology. 18F-florbetapir (AV-45) PET imaging indicated extensive cerebral cortex and cerebellar Aß deposition. CONCLUSIONS: We discovered a novel PSEN1 pathogenic mutation, P284S, observed for the first time in a Chinese family with early-onset AD.

Intracranial High-Grade Stenosis and Hyperhomocysteinemia Presenting as Cortical Subarachnoid Hemorrhage Concomitant with Acute Ischemic Stroke in a Young Man.

BACKGROUND Cortical subarachnoid hemorrhage (cSAH) is a rare clinical presentation with different causes, but rarely happens along with acute ischemic stroke. Intracranial high-grade stenosis originated from brain has been regarded as an unusual cause of cSAH, especially in young adults. CASE REPORT A case of 33-year-old male presented with mild headache and spontaneous left-sided body weakness. Initial brain computed tomography (CT) showed cSAH in the right superior frontal sulcus. Further neuroimaging examinations including magnetic resonance imaging (MRI), digital subtraction angiography (DSA), transesophageal echocardiogram (TEE); in addition, lumbar puncture and blood tests were performed. Diffusion-weighted imaging (DWI) showed an acute infarction in the right frontal lobe and corona radiata of the territory of middle cerebral artery (MCA). The MR angiography (MRA) displayed no flow signal in the right middle cerebral artery M1-segment, while the DSA displayed bloodstream slowness in the right MCA M1-segment which suggested high-grade stenosis of the right MCA. The abnormal laboratory data suggested hyperhomocysteinemia, and excluded causes of thrombosis, infection, or cancer. The mechanism of cSAH may come about in severe atherosclerotic stenosis of MCAs by the broken of expanded tenuous compensatory pial vessels. The patient had good recovered at follow-up. CONCLUSIONS This case demonstrates cSAH with acute ischemic stroke, which is an uncommon complication, in a young adult stroke patient; a high-grade atherosclerotic stenosis of the MCA was identified as the etiology.

Melatonin protects blood-brain barrier integrity and permeability by inhibiting matrix metalloproteinase-9 via the NOTCH3/NF-κB pathway.

The pathophysiological mechanism of white matter hyperintensities of cerebral small vessel disease (CSVD) includes an impaired blood-brain barrier (BBB) with increased permeability. Neuroinflammation likely contributes to the disruption of the BBB in CSVD. Therefore, understanding the molecular mechanism of how neuroinflammation causes BBB damage is essential to preventing BBB disruption in CSVD. Matrix metalloproteinase 9 (MMP-9) contributes to BBB damage in neuroinflammatory diseases. In this study, we observed that interleukin-1ß (IL-1ß)-induced MMP-9 secretion in pericytes increased BBB permeability to sodium fluorescein (Na-F) by damaging the disruption of VE-cadherin, occludin, claudin-5, and zonula occludin-1 (ZO-1). Melatonin reduced BBB permeability to Na-F and inhibited the disruption of the adherens and tight junction proteins. Melatonin also downregulated MMP-9 and upregulated tissue inhibitor of metalloproteinases 1 (TIMP-1) gene expression, which decreased the MMP-9/TIMP-1 ratio. In addition, nuclear translocation of NF-κB/p65 induced by IL-1ß in pericytes upregulated MMP-9 expression, which was inhibited by the NF-κB inhibitor PDTC. However, the NOTCH3 inhibitor DAPT significantly inhibited NF-κB/p65 translocation to the nucleus, while melatonin in combination with DAPT significantly prevented NF-κB/p65 translocation than DAPT alone. Our results suggest that melatonin reduced MMP-9-induced permeability of the BBB. Melatonin reduced MMP-9 expression and activity, which was induced by IL-1ß through the regulation of the NOTCH3/NF-κB signaling pathway in pericytes, suggesting that pericytes regulate BBB integrity and function.

Clinical Features of 4 Novel NOTCH3 Mutations of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy in China.

BACKGROUND This study aimed to identify NOTCH3 mutations and describe the genetic and clinical features and magnetic resonance imaging results in 11 unrelated patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) from Henan province in China. MATERIAL AND METHODS NOTCH3 was directly sequenced in 11 unrelated patients of Chinese descent. The clinical presentations and magnetic resonance imaging features were retrospectively analyzed in the 11 index patients with a definite diagnosis. RESULTS Seven different mutations were identified in 11 unrelated patients, including 4 novel mutations (p.P167S, p.P652S, p.C709R, and p.R1100H) in China and 3 reported mutations (p.C117R, p.R578C, and p.R607C). Four novel mutations (p.P167S, p.P652S, p.C709R, and p.R1100H) were predicted to be probably pathogenic using an online pathogenicity prediction program through comprehensive analysis. Clinical presentations in symptomatic patients included stroke, cognitive decline, psychiatric disturbances, and migraine. Multiple lacunars infarcts and leukoaraiosis were detected on MRI in most symptomatic patients, while white-matter lesions were identified in the temporal pole or the external capsule in all affected patients. CONCLUSIONS The mutation spectrum of CADASIL patients from Henan province in China displayed some differences from that of those reported previously. DNA sequencing was used to diagnose all 11 patients as having CADASIL, and we found 4 novel mutations. The present results further contribute to the enrichment of NOTCH3 mutation databases.

Probable Novel PSEN1 Gln222Leu Mutation in a Chinese Family with Early-Onset Alzheimer's Disease.

BACKGROUND: The rate of occurrence of Alzheimer's disease is increasing around the world. However, there is still no significant breakthrough in the study of its etiology and pathogenesis. OBJECTIVE: To screen Alzheimer's disease pathogenic genes, which may be conducive to the elucidation of the pathogenic mechanisms of Alzheimer's disease And predict the pathogenicity by various computer software. METHODS: Clinical and neuroimaging examination, Whole Exome Sequencing, and Sanger sequencing were performed in the proband. Mutation sites were verified in 158 subjects. RESULTS: We reported a proband carrying a probably novel pathogenic mutation, which clinically manifests as progressive memory loss, visual-spatial disorders, apraxia, psychobehavioral disorders, and temperamental and personality changes. Whole Exome Sequencing detected a novel missense mutation at codon 222 (Q222L), which is a heterozygous A to T point mutation at position 665 (c.665A>T) in exon 5 of the presenilin 1 leading to a glutamine-to-leucine substitution. The mutation was also identified by Sanger sequencing in one family member; nevertheless, it was not detected in the other 7 unaffected family members, 50 sporadic Alzheimer's disease patients and 100 control subjects. CONCLUSION: A novel mutation in exon 5 of the presenilin 1 gene (Gln222Leu) in a Chinese family with early-onset Alzheimer's disease has been reported, besides， it was predicted that the missense mutation was probably a novel pathogenic mutation that was reported for the first time in a Chinese family with early-onset Alzheimer's disease.

Effect of donepezil on Hcy level in serum of Alzheimer's disease patients and correlation analysis of Hcy and dyssomnia.

Effect of donepezil on the homocysteine (Hcy) level in serum of Alzheimer's disease (AD) patients and correlation between Hcy and dyssomnia was investigated. A retrospective analysis of 124 AD patients in Zhengzhou University People's Hospital between January 2015 and October 2017 was performed, including 64 cases in the observation group and 60 cases in the control group. The control group was treated with folic acid, vitamin B12 and memantine hydrochloride tablet, and the observation group combined with donepezil on this basis, and both groups were treated for 4 months. The Hcy level before and after treatment was detected in the groups using ELISA method, dyssomnia score of patients was performed before and after treatment in the observation group according to Pittsburgh Sleep Quality Index (PSQI), and correlation analysis between the Hcy level before and after treatment and dyssomnia was performed in AD patients in the study group using Pearson's correlation analysis. The differences were statistically significant in the Hcy level before and after treatment in both groups (P<0.001). The Hcy level after treatment in the observation group was significantly lower than that in the control group (P<0.001). The dyssomnia score before treatment was higher that after treatment in the observation group (P<0.001). There was a positive correlation between the Hcy level before treatment and dyssomnia score (r=0.658, P<0.001). There was also a positive correlation between the Hcy level after treatment and dyssomnia score (r=0.670, P<0.001). Donepezil can effectively improve the sleep function of patients and reduce the Hcy level in serum in the treatment of AD patients. The application of donepezil was of great significance in the clinical treatment of AD patients.

Gene mutations in a Han Chinese Alzheimer's disease cohort.

OBJECTIVE: Alzheimer's disease (AD) is the most common form of dementia characterized by memory loss at disease onset. The gene mutations in the amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the frequent causes of AD. However, the clinical and genetic features of AD overlap with other neurodegenerative diseases. The present study aimed to identify the clinical and genetic characteristics in a Han Chinese AD cohort. METHODS: Detailed clinical assessment was applied to all the patients. We screened amyloid precursor protein (APP), PSEN1, PSEN2, and microtubule-associated protein tau (MAPT) genes were assessed in 83 sporadic AD patients by Sanger sequencing. A total of 25 probands from families with AD were subjected to next-generation sequencing on 53 dementia-associated genes to capture the target region, and Sanger sequencing was used to detect the variants in the DNA sequence. RESULTS: PSEN1 p.L226R was found in an early-onset AD (EOAD) family characterized by language impairment at disease onset, a novel probably pathogenetic variant (p.D534H) was identified in a frontal-temporal dementia gene, TANK-binding kinase 1 (TBK1) with a typical AD phenotype in a late-onset AD (LOAD) family, and a PSEN2p.H169N mutation and two benign MAPT (p.Q230R and p.V48L) mutations were detected in three EOAD patients. CONCLUSIONS: Thus, five variants were identified in a Han Chinese cohort. In the present study, a novel, probably damaging FTLD gene TBK1variant with a typical AD phenotype was detected. Also, the phenotypic characteristics of PSEN1 p.L226R, a PSEN2pathogenic mutation, and two likely benign MAPT variants were described. Hence, screening for mutations in other dementia genes could be further explored in clinically diagnosed AD patients.

The role of MAPT gene in Chinese dementia patients: a P301L pedigree study and brief literature review.

BACKGROUND AND PURPOSE: Frontotemporal dementia (FTD) is the second most common presenile dementia characterized by behavioral changes and language impairment. The diagnosis of FTD relies heavily on neuroimaging, and sometimes on genetic screening. However, the genetic components in Chinese FTD patients remain largely unknown. Only a few FTD cases with established mutations have been reported in China. This study reported the detailed clinical and neuroimaging features in a Chinese behavioral variant FTD family. The role of MAPT gene mutation in Chinese dementia patients was also reviewed. METHODS: By detailed inquiry of all affected individuals in the family, this study summarized the main clinical features of the disease. Four candidate genes (MAPT, PSEN1, PSEN2, and APP) were screened by direct sequencing. Structural magnetic resonance imaging (MRI), functional imaging of cerebral blood flow with arterial spin-labeled MRI (ASL-MRI), and cerebral metabolism with fluorodeoxyglucose positron emission tomography (FDG-PET) were collected in the proband and healthy mutation carriers. RESULTS: By direct sequencing of candidate genes (MAPT, PSEN1, PSEN2, and APP), this study identified the P301L mutation in the MAPT gene in the proband and three unaffected family members. The phenotype of the affected cases was consistent within the pedigree. In this genetically proven behavioral variant FTD (bvFTD) patient, the maps of hypoperfusion on ASL-MRI look fairly similar to the hypometabolism on FDG-PET. The clinical feature for this bvFTD was in line with the hypoperfusion or hypometabolism pattern on functional neuroimagings. The phenotype of P301L in east Asia seems similar to western countries. CONCLUSION: For the inherited FTD patients, ASL-MRI and genetic identification were strongly recommended for the final diagnosis. In case of being underestimated, the role of MAPT gene mutation in Chinese FTD patients warrants further investigation.

[CADASIL with clinical manifestations of baldness, lumbago and Parkinson's symptoms].

OBJECTIVE: To investigate a cerebral autosomal dominant arteriopathy with the subcortical infarcts and leukoencephalopathy (CADASIL) case with clinical manifestations of baldness, lumbago and Parkinson's symptoms. METHODS: Clinical and imaging data of the patient were analyzed. The patient and his family members were also subjected to genetic testing. RESULTS: The symptoms of the patient included recurrent stroke, dementia, and mood disturbance, in addition with lumbago, baldness and Parkinson's symptoms but no migraine. Cranial MRI of the patient showed bilateral symmetric leukoencephalopathy and multiple small subcortical lacunar infarcts. A point mutation in exon 11 of the NOTCH3 gene (R558C) was discovered in the proband and four asymptomatic relatives. CONCLUSION: CADASIL is characterized by recurrent subcortical ischemic stroke, dementia, pseudobulbar palsy, and mood disturbance. Baldness, lumbago and Parkinson's symptoms may also be seen in such patients.

[The study of clinical characteristics and molecular genetics in a large spinocerebellar ataxia3 pedigree].

OBJECTIVE: To investigate the clinical manifestations and gene mutations on a large spinocerebellar ataxia 3 pedigree, in order to explore the molecular genetical characteristics in this pedigree. METHODS: Blood samples from 9 patients and 27 healthy family members in the Department of Neurology of Henan Provincial People's Hospital were collected. The CAG trinucleotide repeats in SCA3 gene in each sample were amplified by polymerase chain reaction (PCR), denaturing polyacrylamide gel electrophoresis and silver staining techniques. The allele fragments were sequenced by biomedical company and the trinucleotide repeats numbers were calculated to identify the genotype. RESULTS: Nine symptomatic and 9 presymptomatic patients were detected and their CAG repeat numbers were 62-72 and 63-69, respectively. CAG repeat numbers were 12-21 in the other 18 healthy family members. CONCLUSIONS: We found a large pedigree with the diagnosis of SCA3. The genetic tests of CAG repeat numbers can contribute to clinical diagnose on symptomatic patients and provide informations for presymptomatic patients.

Probable novel PSEN2 Pro123Leu mutation in a Chinese Han family of Alzheimer's disease.

We describe a probably novel mutation in exon 5 of the presenilin 2 gene (Pro123Leu) in a Chinese familial early-onset Alzheimer's disease, which clinically manifests as progressive memory loss, cognitive impairment, parkinsonism, and myoclonic jerks. Clinical and neuroimaging examination, target region capture, and high-throughput sequencing were performed in a family of 4 generations. Cerebral perfusion and glucose metabolism were evaluated using arterial spin labeling perfusion magnetic resonance imaging and (18)F-fludeoxyglucose positron emission tomography, respectively. Target region capture sequencing yielded a novel missense mutation at codon 123 (P123L) which is a heterozygous C to T point mutation at position 368 (c.368C>T) in exon 5 of the presenilin 2 leading to a proline-to-leucine substitution. The results were also identified by Sanger sequencing in 7 family members but not in the other 9 unaffected family members and 100 control subjects. This mutation is probably pathogenic and is the first of its kind reported in an early-onset familial AD associated with atypical symptom presentation.