Yi-Min Sun

Spinocerebellar ataxia: relationship between phenotype and genotype – a review

Spinocerebellar ataxia (SCA) comprises a large group of heterogeneous neurodegenerative disorders inherited in an autosomal dominant fashion. It is characterized by progressive cerebellar ataxia with oculomotor dysfunction, dysarthria, pyramidal signs, extrapyramidal signs, pigmentary retinopathy, peripheral neuropathy, cognitive impairment and other symptoms. It is classified according to the clinical manifestations or genetic nosology. To date, 40 SCAs have been characterized, and include SCA1–40. The pathogenic genes of 28 SCAs were identified. In recent years, with the widespread clinical use of next‐generation sequencing, the genes underlying SCAs, and the mutants as well as the affected phenotypes were identified. These advances elucidated the phenotype–genotype relationship in SCAs. We reviewed the recent clinical advances, genetic features and phenotype–genotype correlations involving each SCA and its differentiation. The heterogeneity of the disease and the genetic diagnosis might be attributed to the regional distribution and clinical characteristics. Therefore, recognition of the phenotype–genotype relationship facilitates genetic testing, prognosis and monitoring of symptoms.

PICALM and CR1 Variants are not Associated with Sporadic Alzheimer's Disease in Chinese Patients

Alzheimers disease (AD) is the most common form of senile dementia, and the overall prevalence increases exponentially with age. It is well known that genetic variants may play an important role in the pathogenesis of this disorder. Recently, two independent large-scale genome-wide association studies (GWAS) identified 3 novel single nucleotide polymorphisms (SNPs) (rs11136000 within CLU, rs3851179 within PICALM and rs6656401 within CR1) that are associated with late-onset AD (LOAD), and these results have been replicated by other studies performed in the Caucasian population. Recently, an independent study failed to verify the association for the SNP within CLU in a Han Chinese population, indicating that there may be genetic heterogeneity in this association. In the present study, we studied the SNPs within PICALM and CR1 in 474 sporadic AD patients (SAD) and 591 unrelated age- and sex-matched healthy controls of Han Chinese descent. Our data revealed that the frequencies of both of these SNPs were not significantly difference between the SAD and control groups. Thus, the association between SNPs within PICALM, CR1, and SAD should be studied further in different ethnic groups.

Clusterin variants are not associated with southern Chinese patients with Alzheimer's disease

Recent genome-wide association studies identified clusterin (CLU) to be associated with sporadic Alzheimers disease. To help clarify the relevance of CLU as genetic determinant of AD, we analyzed its association in southern Chinese Han population. This study comprised 499 sporadic Alzheimers disease patients and 592 unrelated age- and sex-matched healthy controls. Four single-nucleotide polymorphisms (rs2279590, rs9331888, rs11136000, and rs1532278) within CLU were selected for genotyping. No positive association was found between the CLU variants and AD. Our study suggests that CLU variants may not be an AD susceptibility factor in southern Chinese Han population.

The Polymorphism of the ATP-Binding Cassette Transporter 1 Gene Modulates Alzheimer Disease Risk in Chinese Han Ethnic Population

BACKGROUND Recent studies highlight a potential role of cholesterol metabolic disturbance in the pathophysiology of Alzheimer disease (AD). The adenosine triphosphate (ATP)-binding cassette transporter 1 (ABCA1) gene resides within proximity of linkage peaks on chromosome 9q influence AD and plays a key role in cellular cholesterol efflux in the brain. METHODS We studied the role of R219K and V825I polymorphisms of ABCA1 in modulating the risk of AD in 321 AD patients and 349 comparisons of Chinese Han. Genotyping of R219K and V825I were performed by PCR-restriction fragment length polymorphism analysis. RESULTS The genotype distribution of R219K was different with more RK in total AD group (χ(2) = 8.705, df = 2, p = 0.013), late-onset AD (LOAD) group (χ(2) = 10.636, df = 2, p = 0.005), APOE non-ε4ε4 group (χ(2) = 9.900, df = 2, p = 0.007), and female AD group (χ(2) = 8.369, df = 2, p = 0.015). Logistic regression manifested the risk of AD increased in RK carriers in total AD group (Wald = 6.102, df = 1, p = 0.014, odds ratio [OR]: 1.546, 95% confidence interval [95% CI]: 1.094-2.185), LOAD group (Wald = 7.746, df = 1, p = 0.005, OR: 1.921, 95% CI: 1.213-3.041), and APOE non-ε4ε4 group (Wald = 6.399, df = 1, p = 0.011, OR: 1.586, 95% CI: 1.109-2.266). K allele (RK + KK) also increased the risk of AD compared with RR allele in LOAD group (Wald = 4.750, df = 1, p = 0.029, OR: 1.619, 95% CI: 1.050-2.497). However, no discrepancy was found in V825I. In R219K, age at onset (AAO) was significantly lower by 4.9 years on average in patients of KK genotype than those of RK in APOE ε4 carrying group and higher by 5.5 years in patients of KK genotype than those of RR in APOE ε4 noncarrying group. In V825I, AAO was diseased by 4.3 years in II genotype compared with VV genotype in APOE ε4 noncarrying group and 3.4 years in APOE ε4ε4 noncarrying group. CONCLUSION The results indicated that the RK genotype or K allele (RK + KK) of R219K may relate to the development of AD in the east of China.

Association study of ABCA7 and NPC1 polymorphisms with Alzheimer's disease in Chinese Han ethnic population.

Department of Neurology and Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai and Department of Neurology, General Hospital of Ningxia Medical University, Ningxia, China Correspondence to Zhi-Ying Wu, MD, PhD, Department of Neurology and Institute of Neurology, Huashan Hospital, Institutes of Brain Science and State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, China Tel/fax: + 86 21 62483421; e-mail: zhiyingwu@fudan.edu.cn

Chinese patients with Huntington's disease initially presenting with spinocerebellar ataxia

Recent studies have described Huntingtons disease (HD) patients with atypical onset of ataxia. Symptoms in these patients can overlap with those of spinocerebellar ataxia (SCA). We retrospectively examined clinical data for 82 HD probands and found 7 had initially been clinically diagnosed as SCA cases. Clinical features in these patients were further investigated and the number of CAG repeats in the huntingtin (HTT) gene was determined by direct sequencing. Genetic screenings for SCAs in the 7 patients were all negative. By contrast, HTT was heterozygous in each patient. The distribution of CAG number in the 7 patients was statistically the same as that in the other 75 patients. Each of 7 HD patients had presented with atypical onset of ataxia. The mean time from onset to HTT genetic testing was 5.6 ± 5.52 years. Three of the patients developed chorea, but the others did not. Our observations confirm the clinical heterogeneity of HD in Han Chinese. Based on these findings, testing for HTT expansions should be considered for clinically diagnosed SCA patients who test negatively in genetic screening of SCA genes.

The LRRK2 R1628P variant plays a protective role in Han Chinese population with Alzheimer's disease.

Alzheimers disease (AD) and Parkinsons disease (PD) are the most prevalent neurodegenerative disorders that may share some overlapping etiologies. Mutations within leucine‐rich repeat kinase 2 (LRRK2) have been reported to be responsible for PD, and the location of LRRK2 is within a linkage peak for sporadic AD (SAD). The aim of this study was to investigate two Asian‐specific LRRK2 variants, R1628P and G2385R, with the association of Han Chinese SAD.

Common variants at Bin1 are associated with sporadic Alzheimer's disease in the Han Chinese population.

Objectives Recent genome-wide association studies identified bridging integrator 1 (Bin1) to be associated with sporadic Alzheimer’s disease (SAD). To clarify the relevance of Bin1 as a genetic determinant of AD, we analyzed its association in a Han Chinese population from the South East part of mainland China. Methods This study investigated 427 SAD patients and 451 unrelated age-matched and sex-matched healthy controls. Two single nucleotide polymorphisms (rs7561528 and rs744373) adjacent to Bin1 that emerged from previous genome-wide association studies were genotyped using the MassARRAY Analyzer 4 Sequenom platform. Results As expected, the genotype distribution of rs7561528 was significantly different between the SAD group and the controls, with more AG in controls [odds ratio (OR) 0.605, 95% confidence interval (CI) 0.429–0.854, P=0.004], and the difference increased using an additive genetic model (OR 0.593, 95% CI 0.425–0.828, P=0.002). However, we did not observe a difference in the genotype distribution of the rs744373 between the SAD and the control group (OR 1.189, 95% CI 0.809–1.747, P=0.378). Conclusions To the best of our knowledge, our study is the first to confirm the association of the variant rs7561528 adjacent to Bin1 with SAD in a Han Chinese Population.

Associations between apolipoprotein E gene polymorphisms and Alzheimer's disease risk in a large Chinese Han population.

Objective Apolipoprotein E gene (APOE) polymorphisms contributing to the risk of sporadic Alzheimer’s disease (AD) have been identified for decades, but it has not been investigated in large AD samples of Chinese Han population. Methods We performed a cross-sectional study to explore the effect of APOE polymorphisms on sporadic AD in 875 sporadic AD patients and 1,195 cognitive normal controls of Chinese Han. Genotyping of APOE was determined by multiplex amplification refractory mutation system polymerase chain reaction. Results APOE ε3ε4 and ε4ε4 genotypes increased AD risk with dosage effect. The odds ratio (OR) of ε3ε4 was 1.89 and the OR of ε4ε4 was 15.64 compared with that of ε3ε3 in all the subjects. E2ε3 genotype decreased AD risk in all the subjects (OR=0.64), female subgroup (OR=0.57), and late-onset AD subgroup (OR=0.60). However, neither ε2ε2 nor ε2ε4 affected AD risk. About the age at onset (AAO), the influence of APOE ε4 was only exhibited in late-onset AD subgroup, with 1 year lower in ε4-positive ones than negative ones. Further analysis did not show the dosage effect of ε4 pertinent to AAO, though the AAO of ε4ε4 patients decreased by 2 years. E2 did not affect the AAO of AD. Conclusion APOE ε4 is a strong risk factor of AD risk in Chinese Han population, and APOE ε4ε4 genotype might be related to the AAO of late-onset AD.

Clinical features of Chinese patients with Huntington’s disease carrying CAG repeats beyond 60 within HTT gene

Patients with Huntingtons disease (HD) carrying CAG repeats beyond 60 are less frequently seen and clinical features of them have been rarely reported. We identified four unrelated patients carrying CAG repeats beyond 60 (84.0 ± 13.76, ranging from 74 to 104) from 119 Chinese HD patients via direct sequencing. These four were all early onset with a mean age at presenting symptom of 9.8 ± 1.71 years. Paternal transmission was found in three of them and the fourth was apparently sporadic. In addition, they had atypical onset symptoms including epilepsy, intellectual decline, tics and walking instability, which might lead the clinicians to make the wrong diagnosis in the early stage of disease. Our work explores clinical features of Chinese HD patients with an expanded CAG repeat over 60 and may help the clinicians make a correct diagnosis in the early stage of disease.