[Fluoroquinolone associated myasthenia gravis exacerbation: clinical analysis of 9 cases].

OBJECTIVE: To explore the characteristics of acute exacerbations of myasthenia gravis after fluoroquinolone exposure. METHODS: Gender, age, prior type, absolute score, concurrent disease, precipitated disease, use of antibiotic, onset/symptom/degree of exacerbation, therapeutic measures and prognosis at Month 1 were retrospectively analyzed for 9 patients after fluoroquinolone systemic exposure. RESULTS: Ciprofloxacin (n = 4), levofloxacin (n = 1) and moxifloxacin (n = 4) exposure resulted in myasthenia gravis exacerbation. Myasthenia gravis exacerbations developed at 15 minutes to 4 days post-exposure. And the clinical scores of quantitative myasthenia gravis (QMG) increased by an average of 10. The main syndromes included dyspnea, diplopia, ptosis and dysphagia. All patients improved upon the withdrawal of fluoroquinolone in conjunctions with other interventions. CONCLUSION: Fluoroquinolone exposure may result in myasthenia gravis exacerbations in patients with underlying diseases. Healthcare professionals should be aware of this serious drug-disease association.

An 85-year-old woman with Miller Fisher syndrome.

Miller Fisher's syndrome (MFS) commonly presents in the fourth and fifth decades and are rare in people over 70 years. An 85-year-old female with no significant medical history presented with upper extremity anesthesia, ptosis, and unsteady gait. The patient had a history of hypertension and diabetes mellitus. Physical examination showed bilateral total external ophthalmoplegia, areflexia, and cerebellar ataxia. Radiological and laboratory studies were unremarkable. Lumbar puncture showed albuminocytological dissociation. The combined history, physical examination, and lumbar puncture results established a presumptive diagnosis of MFS. Intravenous immunoglobulin was given for 5 days. The patient gradually improved 10 days after the onset of symptoms. Ophthalmoplegia had fully recovered after 6 months. To the best of our knowledge, this case represented the oldest patient with MFS.

[Association between vitamin D receptor gene Tru9I polymorphism and myasthenia gravis].

OBJECTIVE: To explore the associations between vitamin D receptor (VDR) gene Tru9I polymorphism and myasthenia gravis (MG). METHODS: A total of 302 MG patients, diagnosed and treated at Affiliated Hospital of Medical College, Qingdao University and Beijing Friendship Hospital from December 2006 to July 2010, were recruited. And 283 normal subjects were selected as the controls. Tru9I polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The frequencies of genotypes and alleles were compared among different MG subgroups and control group. The relationship between the genotype and susceptibility or severity of MG and immediate efficacies of glucocorticoid were explored. The SPSS17.0 was applied to statistical analysis. RESULTS: In the MG patients whose age of onset was above 15 years, the frequency of TT and tt genotypes in females was lower than that of the control group. However the frequency of Tt genotype was higher than that of the control group. And there were significant differences (χ(2) = 8.847, P = 0.012). The frequency of Tt + tt genotype in females (58/139, 41.7%) was higher than that of the control group (56/189, 29.6%). And there were also significant differences (OR = 1.70, 95% CI 1.07 - 3.41, χ(2) = 5.169, P = 0.023). Although the frequency of t alleles in females (61/278, 21.9%) was higher than that of the control group (65/378, 17.2%), no significant differences existed (P > 0.05). There were no differences in frequencies of genotypes and alleles between the patients with varying severity and different immediate efficacies of glucocorticoid (P > 0.05). CONCLUSION: VDR gene Tru9I polymorphism may be related to the risk of MG in females aged above 15 years.

Vitamin D Receptor Polymorphism and Myasthenia Gravis in Chinese Han Population.

Myasthenia gravis (MG) is an autoimmune disease in which antibodies bind to acetylcholine receptors (AChR) or other functional molecules in the postsynaptic membrane at the neuromuscular junction. Vitamin D (VD) has a number of pluripotent effects, which include immune-regulation and bone metabolism. The immunomodulatory actions of 1,25(OH)2D3 are mediated by its binding to a vitamin D receptor (VDR). In the study, we undertook a case-control study to explore the association between VDR gene polymorphism and the susceptibility and severity of MG patients. Four hundred and eighty MG patients and 487 healthy controls were included and gene polymorphisms of VDR were determined with improved multiplex ligation detection reaction technique and SNPscanTM technique. MG patients were classified into subgroups by essential clinical features and by a comprehensive classification. The frequencies of alleles and genotypes were compared between the MG group and the control group, between each MG subgroup and the control group, and between each pair of MG subgroups. There were no significant differences in frequencies of alleles and genotypes between MG patients and healthy controls, between MG subgroups and healthy controls, or between each pair of MG subgroups in the analysis of subgroups classified by essential clinical features (onset age, gender, thymoma, AChRAb positivity, onset involvement) and the maximal severity (modified Oosterhuis score). In the analysis of subgroups with a comprehensive classification, the frequencies of alleles and genotypes in rs731236 showed significant differences between adult non-thymoma AChRAb negative MG subgroup and the control group, as well as the adult non-thymoma AChRAb positive MG group. In the Chinese Han population, rs731236 was found to be possibly associated with adult non-thymoma AChRAb negative MG patients, although this needs further confirmation.

[Association of glucocorticoid receptor gene polymorphism with myasthenia gravis].

OBJECTIVE: To investigate the association of two glucocorticoid receptor (GR) polymorphisms (BclI, ER22/23EK) with Myasthenia Gravis (MG). METHODS: The genotypes of GR in 61 MG patients (MGG) and 57 age and gender-matched healthy controls (HCG) were determined by polymerase chain reaction and nucleotide sequence determination. RESULTS: The frequencies of three genotypes (GG, CG, CC) in BclIwere 3.3%, 34.4%, 62.3% in MGG and 3.5%, 38.6%, 57.9%in HCG respectively. The difference in the distribution of genotypes between MGG and HCG was statistically insignificant (P = 0.887). The frequencies of G and C allele were 20.5% vs 79.5 %in MGG, and 22.8% vs 77.2% in HCG. The difference in the distribution of alleles between MGG and HCG was statistically insignificant (P = 0.968). The genotype frequencies in two groups were both in Hardy-Weinberg equilibrium (P > 0.05). The genotypes of ER22/23EK in MGG and HCG were all GG and no mutation was detected. CONCLUSION: BclI and ER22/23EK polymorphisms of GR have no definite relationship with the risk of MG.

Association between CTLA-4 gene polymorphism and myasthenia gravis in a Chinese cohort.

Abnormal CTLA-4 expression is involved in the development of myasthenia gravis (MG), and serum CTLA-4 levels are positively correlated with serum anti-AChR antibody concentration, which might be related with the severity of MG. Polymorphism in CTLA-4 gene is associated with various autoimmune disorders. We investigated the association of polymorphism in CTLA-4 gene with the clinical variables and severity of MG. The frequencies of alleles and genotypes were compared between 480 MG patients and 487 healthy controls, as well as among subgroups of MG patients. The frequency of rs733618*C allele is significantly higher in MG group and several subgroups than in control group. Genotype is not found as independent factor for essential clinical variables of MG. The frequency of rs231775*A allele is significantly lower in ocular onset subgroup than in control group, and the frequencies of rs231775*A allele and rs3087243*A allele are significantly lower in ocular onset subgroup than in generalized onset subgroup. Genotypes of the two SNPs are found as independent factors for ocular onset. The frequency of rs231775*A allele is significantly lower in mild subgroup than that in control group. Genotype is not found as independent factor for mild severity. A haplotype containing rs733618*C, rs231775*G and rs3087243*G is identified to increase the general risk of MG by 1.278-fold and ocular onset MG subgroup by 1.362-fold. There is association of rs733618 with the general susceptibility of MG, and association of rs231775 and rs3087243 with the susceptibility of ocular onset MG, but no association with the severity of MG.

Association between Alzheimer's disease and the NOS3 gene Glu298Asp polymorphism in Chinese.

The oxidative stress caused by nitric oxide (NO) in the brain has been proposed as a pathogenic mechanism in Alzheimer's disease. Endothelial NO synthase (ecNOS) produces the majority of circulating NO. The biological functional and genetic association studies suggested that the Glu298Asp polymorphism of the ecNOS gene (NOS3) may be a genetic risk factor for late-onset Alzheimer's disease (LOAD). To investigate an association between the NOS31 Glu298Asp polymorphism and sporadic LOAD in Chinese, we examined 338 LOAD patients and 378 healthy controls. The associations of the Glu/Glu genotype and Glu allele with LOAD (chi2 = 9.12, df = 1, P = 0.003 by genotype; chi2 = 8.37, df = 1, P = 0.038 by allele) were found. After stratifying by apolipoprotein E allele 4 (APOE epsilon 4) status, increased LOAD risks associated with the Glu/Glu genotype and Glu allele only in the APOE epsilon 4 noncarriers (chi2 = 6.28, df = 1, P = 0.012 by genotype; chi2 = 5.62, df = 1, P = 0.018 by allele) were seen. These results suggest that the NOS3 gene Glu298Asp polymorphism might be a risk factor for LOAD and dependent on APOE epsilon 4 status in Chinese.

Trinucleotide expansions in the SCA7 gene in a large family with spinocerebellar ataxia and craniocervical dystonia.

Spinocerebellar ataxia type 7 is a rare autosomal dominant cerebellar ataxia (ADCA). Herein, we describe the molecular and clinical findings in patients within six generations of a large Chinese family with spinocerebellar ataxia. To identify the genetic cause(s), 4 affected patients and 26 asymptomatic relatives were recruited for the study. Molecular screening of the SCA1 and SCA7 genes was carried out by subcloning and direct PCR-sequencing methods. Both neurological and ophthalmic examinations were performed to investigate the clinical characteristics of the disease. The patients had typical cerebellar ataxia, achromatopsia and macular degeneration, and displayed a rare phenotype manifesting as a combination of cerebellar ataxia and craniocervical dystonia. Mutational analysis of the SCA7 genes demonstrated expanded CAG-repeats in the four patients. In conclusion, we identified expanded CAG-repeats in the SCA7 gene within members of a large Chinese family with spinocerebellar ataxia. The defined phenotypic characteristics of the patients may be helpful for clinical diagnosis and genetic typing of new patients.

Genetic analysis of tumor necrosis factor-alpha (TNF-alpha) G-308A and Saitohin Q7R polymorphisms with Alzheimer's disease.

Neuroinflammation and abnormal phosphorylation of TAU proteins have been implicated in the etiology of Alzheimer's disease (AD). Several studies have suggested the G-308A promoter polymorphism in one of the proinflammatory cytokine genes tumor necrosis factor-alpha (TNF-alpha) encoding TNF-alpha may be associated with AD pathogenesis. Association between the Q7R polymorphism in saitohin (STH), a gene nested within the intron of the Tau gene, has also been reported. To determine whether these two polymorphisms contribute to the risk for late-onset AD (LOAD) in Chinese, we have investigated 207 sporadic LOAD patients and 222 healthy controls. The associations of the AA genotype and A-allele with LOAD (chi(2) = 8.74, df = 1, P = 0.0031, and chi(2) = 4.47, df = 1, P = 0.035) were found. After stratifying by apolipoprotein E allele 4 (APOE epsilon4) status, increased LOAD risks associated with the AA genotype and A-allele only in the APOE epsilon4 non-carriers (chi(2) = 9.21, df = 1, P = 0.002; chi(2) = 10.02, df = 1, P = 0.0015) were seen. These results suggested that the TNF-alpha gene G-308A polymorphism might be a risk factor for LOAD and dependent on APOE epsilon4 status in Chinese. Homozygous Q/Q of STH Q7R polymorphism was the only one genotype found in either LOAD group or controls. No R allele was detected in LOAD and control groups. The extremely rare frequency of the ancestral R allele differs sharply from that observed in studies in the Caucasian population, suggesting obvious ethnic differences.

The association of mitochondrial aldehyde dehydrogenase gene (ALDH2) polymorphism with susceptibility to late-onset Alzheimer's disease in Chinese.

A functional polymorphism of mitochondrial aldehyde dehydrogenase gene (ALDH2 1/2 polymorphism) can influence the accumulation of acetaldehyde which may have a role in Alzheimer's disease (AD), and is widely prevalent among Mongoloids. Therefore ALDH2 1/2 polymorphism may represent a good candidate for genetic risk factors for AD, especially in East Asian. A case-control study from Japan found that ALDH2*2 was associated with late-onset AD (LOAD), interacting synergistically with the presence of the apolipoprotein E allele 4 (APOE epsilon4). But the subsequent studies in Koreans didn't find the similar result. To determine whether the ALDH2 gene 1/2 polymorphism contributes to the risk for LOAD in Chinese, we have investigated 188 sporadic LOAD patients and 223 healthy controls from Chinese. A significantly increased risk of AD in the carriers of ALDH2*2 allele (OR=3.11, 95% CI 2.06-4.69, P<0.001) was observed. After stratifying by APOE epsilon4 status, increased LOAD risks associated with the ALDH2 2 allele carriers only in the APOE epsilon4 non-carriers (chi2=31.79, df=1, P<0.001) and with the 2-allele in either groups (chi2=6.64 df=1, P=0.0099 and chi2=37.38, df=1, P<0.001) were seen. These results suggested that the ALDH2 gene 1/2 polymorphism might be a risk factor for LOAD and dependent on APOE epsilon4 status in Chinese.

Lack of an association between Alzheimer's disease and the cystatin C (CST3) gene G73A polymorphism in Mainland Chinese.

Alzheimer's disease (AD) is a complex multifactorial disorder involving a number of genetic and environmental factors. Cystatin C (CST3), which belongs to the type II cystatin gene family, is a potent inhibitor of lysosomal proteinases. Immunohistochemical studies have demonstrated the colocalization of the b-amyloid (A-beta) and cystatin C peptides within arteriolar walls in the AD brain. The G73A polymorphism of the CST3 genemay be associated with AD development. To investigate a possible association between the CST3 G73A polymorphism and late-onset AD (LOAD) in Mainland Chinese, we examined 281 LOAD patients and 376 healthy controls. All subjects were genotyped for CST3 and apolipoprotein E (APOE). There were no significant differences in the CST3 genotype or allele frequencies between the cases and the controls. Likewise, with the stratification of the APOE epsilon4 status, no statistical difference was observed between the cases and the controls. Our findings suggest that this polymorphism may not represent an additional genetic risk factor for LOAD in Mainland Chinese.

[The expression and clinical implications of glucocorticoid receptor isoforms in peripheral blood mononuclear cells in myasthenia gravis].

OBJECTIVE: To evaluate the expression of glucocorticoid receptor (GR) alpha and GRbeta in peripheral blood mononuclear cells (PBMC) from patients of myasthenia gravis (MG). To investigate the relationship between the expression level of GR and glucocorticoid (GC) therapeutic effects to MG patients. METHODS: The clinical score was recorded and used to assessing the therapeutic effects. Then the expression level of GRalpha and GRbeta in PBMC by immunocytochemistry was measured. We analysed the relationship of the therapeutic effects with expression level of GR. RESULTS: The scores of GRalpha positive PBMC score were same in healthy-control group, GC sensitive group, and GC dependent group. But GRalpha positive PBMC score in GC resistance group was decreased compared with the others (P < 0.01). The scores of GRbeta positive PBMC score were same in healthy-control group, GC sensitive group, and GC resistant group. But GRbeta positive PBMC score in GC dependent group was increased compared with the others (P < 0.01). CONCLUSIONS: The expression of GRalpha in GC resistant group are decreased, and the expression of GRbeta in GC dependence group is increased. The expression level of GRalpha or GRbeta is associated with the effect of GC in treatment of MG.

[HLA-DQB1 allele polymorphism and clinical characteristics of 15 familial myasthenia gravis cases in north China].

OBJECTIVE: To investigate the relationship between the HLA-DQB1 allele polymorphisms and the clinical features of 15 familial myasthenia gravis (MG) cases in north China. METHODS: By polymerase chain reaction-sequence specific primers (PCR-SSP), the HLA-DQB1 gene polymorphisms were determined in 64 MG patients (15 familial and 49 sporadic) and 52 healthy individuals as control group. The clinical characteristics of 15 familial MG patients and 49 sporadic were analyzed. The measurement data was analyzed by t test and enumeration data by chi-square test. RESULTS: The frequency of DQB1*0501 was significantly increased in familial MG, especially in the ocular type, compared with sporadic MG (P<0.05, OR=3.08) and healthy controls (P<0.01, OR=4.439). Comparing with healthy controls, the frequency of DQB1*0301/4 was increased (P<0.05, OR=2.56), while the frequency of DQB1*0601 was significantly decreased (P<0.05, OR=0.33) in sporadic MG. The familial patients had an early age of disease onset, but less severity and good prognosis. CONCLUSION: The familial MG has distinctive clinical features. DQB1*0501 allele is positively related to the genetic susceptibility to familial MG patients in north China, especially to the ocular type. DQB1*0301/4 allele is positively related to the pathogenesis of sporadic MG. DQB1*0601 may be a protecting allele for sporadic MG. The phenotype of MG may be the result of interaction of hereditary defects and environmental factors. The familial MG may be different from sporadic patients in genetic immune mechanism.

Association between HLA-DRB1 and myasthenia gravis in a northern Han Chinese population.

The cause of myasthenia gravis (MG) is unknown, but it is widely believed to be an autoimmune disease occurring in genetically susceptible individuals. The human leukocyte antigen (HLA) region is considered to be the most important genetic region for MG susceptibility genes. To investigate the association between HLA-DRB1 and myasthenia gravis (MG) in a northern Han Chinese population, a polymerase chain reaction with sequence-specific oligonucleotide probe hybridization method was used to determine the HLA-DRB1 genotypes of 91 patients with MG and 171 healthy individuals. We found that the HLA-DRB1(*)09 allele was significantly more prevalent among patients with MG than among healthy controls, especially those who experienced early onset of the disease (≤40 years), those who were seronegative for acetylcholine receptor antibody, and those with ocular MG. The prevalence of the HLA-DRB1(*)08 allele was significantly lower among patients with MG than among controls. These results indicate that HLA-DRB1(*)09 might be positively associated and DRB1(*)08 negatively associated with MG in the northern Han Chinese population.