IVIg therapy in autoimmunity and related disorders: our experience with a large cohort of patients

Intravenous immunoglobulin (IVIg) is used to treat a number of immune-deficiencies and autoimmune diseases. It has been shown that IVIg contains anti-idiotypic antibodies, which explains its immunomodulatory action.In murine models, recent investigations have demonstrated that IVIg can prevent and reduce the affliction by systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS) and scleroderma. Relevant disease-specific fractions of IVIg were able to reproduce and even enhance the therapeutic effect in a murine model.IVIg treatment before tumor resection in rodents inoculated with melanoma and sarcoma cells dramatically improved the cure rate (50%) in comparison to the control group (0%).In patients affected by SLE, several clinical manifestations responded to IVIg treatment including serositis, hematological manifestations, treatment-resistant nephritis and central nervous system involvement. Similarly, in women with recurrent fetal loss due to APS, IVIg was able to diminish the abortion rate. Vasculitides such as Churg-Strauss' and Wegener's and skin fibrosis in patients affected by scleroderma improved after IVIg treatment. In agreement with in vitro investigations, prolonged survival has been noted in cancer patients treated with IVIg.We suggest that in the presence of a steroid and immunosuppressive-resistant autoimmune disease, IVIg is a rational and safe choice.     

IVIg therapy in autoimmunity and related disorders: our experience with a large cohort of patients

Intravenous immunoglobulin (IVIg) is used to treat a number of immune-deficiencies and autoimmune diseases. It has been shown that IVIg contains anti-idiotypic antibodies, which explains its immunomodulatory action.

In murine models, recent investigations have demonstrated that IVIg can prevent and reduce the affliction by systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS) and scleroderma. Relevant disease-specific fractions of IVIg were able to reproduce and even enhance the therapeutic effect in a murine model.

IVIg treatment before tumor resection in rodents inoculated with melanoma and sarcoma cells dramatically improved the cure rate (50%) in comparison to the control group (0%).

In patients affected by SLE, several clinical manifestations responded to IVIg treatment including serositis, hematological manifestations, treatment-resistant nephritis and central nervous system involvement. Similarly, in women with recurrent fetal loss due to APS, IVIg was able to diminish the abortion rate. Vasculitides such as Churg–Strauss' and Wegener's and skin fibrosis in patients affected by scleroderma improved after IVIg treatment. In agreement with in vitro investigations, prolonged survival has been noted in cancer patients treated with IVIg.

We suggest that in the presence of a steroid and immunosuppressive-resistant autoimmune disease, IVIg is a rational and safe choice.     

Analysis of the DYSF mutational spectrum in a large cohort of patients

Dysferlinopathies belong to the heterogeneous group of autosomal recessive muscular dystrophies. Mutations in the gene encoding dysferlin (DYSF) lead to distinct phenotypes, mainly Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and Miyoshi myopathy (MM). Here, we analysed the mutational data from the largest cohort described to date, a cohort of 134 patients, included based on clinical suspicion of primary dysferlinopathy and/or dysferlin protein deficiency identified on muscle biopsy samples. Data were compiled from 38 patients previously screened for mutations in our laboratory (Nguyen, et al., 2005; Nguyen, et al., 2007), and 96 supplementary patients screened for DYSF mutations using genomic DHPLC analysis, and subsequent sequencing of detected variants, in a routine diagnostic setting. In 89 (66%) out of 134 patients, molecular analysis identified two disease causing mutations, confirming the diagnosis of primary Dysferlinopathy on a genetic basis. Furthermore, one mutation was identified in 30 patients, without identification of a second deleterious allele. We are currently developing complementary analysis for patients in whom only one or no disease-causing allele could be identified using the genomic screening procedure. Altogether, 64 novel mutations have been identified in this cohort, which corresponds to approximately 25% of all DYSF mutations reported to date. The mutational spectrum of this cohort significantly shows a higher proportion of nonsense mutations, but a lower proportion of deleterious missense changes as compared to previous series. (c) 2008 Wiley-Liss, Inc.     

单纯降压和降尿酸治疗高尿酸血症合并原发性高血压疗效分析

目的 探讨单纯合理降压治疗和降尿酸治疗高尿酸血症合并原发性高血压患者的临床疗效.方法 将284例高尿酸血症合并原发性高血压患者随机分为降压组、降尿酸组.降压组给予合理抗高血压药物治疗,降尿酸组严格控制尿酸.所有患者分别在治疗前后检测血尿酸水平和血压水平,并进行统计学分析.结果 降压组尿酸值明显低于治疗前,差异有统计学意义(P＜0.01),降尿酸组收缩压和舒张压值低于治疗前,但无统计学意义.结论 单纯合理有效控制血压可以改善血尿酸水平,单纯降尿酸治疗不能明显改善血压水平,对高尿酸血症合并原发性高血压患者需严格控制血压和血尿酸.     

Evaluating the monogenic contribution and genotype–phenotype correlation in patients with isolated thoracic aortic aneurysm

Thoracic aortic aneurysm with or without dissection (TAAD) can be broadly categorized as syndromic TAAD (sTAAD) and isolated TAAD (iTAAD). sTAAD and is highly correlated with genetics. However, although the incidence of iTAAD is much higher, its monogenic contribution is not yet clear. Here, we sequenced 15 known TAAD genes for 578 iTAAD cases from four cardiac centers in China and found that 10.6% patients with a pathogenic/likely pathogenic (P/LP) variant. Other 7.27% of patients carried variants of uncertain significance in these target genes. We further investigated the correlations among genetics, clinical features, and long-term outcomes. Genetic patients showed younger onset ages (P = 1.31E-13) and larger aortic diameter (P = 1.00E-6), with the youngest age in patients with FBN1 P/LP variants. Monogenic variants were also associated with more aortic segments involved (P = 0.043) and complicated with initial dissection (P = 4.50E-5), especially for genetic patients with non-FBN1 P/LP variants. MACEs occurred in 14.9% patients during follow-up of median 55 months. Genetic status (P = 0.001) and initial dissection (P = 3.00E-6) were two major risk factors for poor prognosis. Early onset age was associated with MACEs in non-genetic cases without initial dissection (P = 0.005). Our study revealed the monogenic contribution in known TAAD genes to iTAAD patients. The genotype–phenotype correlations may complement the risk stratification of iTAAD patients and identification of higher risk subgroups, as well as assist the development of tailored precision medicine in iTAAD.Subject terms: Aneurysm, Genetics research     

Identification and characterization of seven novel mutations of elastin gene in a cohort of patients affected by supravalvular aortic stenosis

Supravalvular aortic stenosis (SVAS) is a congenital narrowing of the ascending aorta, which can occur sporadically as an autosomal dominant condition or as one component of the Williams–Beuren syndrome, a complex developmental genomic disorder associated with cardiovascular, neurobehavioral, craniofacial, and metabolic abnormalities, caused by a microdeletion at 7q11.23. We report the identification of seven novel mutations within the elastin gene in 31 familial and sporadic cases of nonsyndromic SVAS. Five are frameshift mutations within the coding region of the ELN gene that result in premature stop codons (PTCs); the other two mutations abolish the donor splice site of introns 3 and 28, respectively, and are predicted to alter splicing efficiency resulting in the generation of a PTC within the same introns of the gene. In vitro analysis using minigenes and cycloheximide showed that some selected frameshift mutant alleles are substrates of nonsense-mediated mRNA decay (NMD), confirming that the functional haploinsufficiency of the ELN gene is the main pathomechanism underlying SVAS. Interestingly, molecular analysis on patient fibroblasts showed that the c.2044+5G>C mutant allele encodes for an aberrant shorter form of the elastin polypeptide that may hamper the normal assembly of elastin fibers in a dominant-negative manner.     

Presenting phenotype and clinical evaluation in a cohort of 22 Williams-Beuren syndrome patients

Williams-Beuren syndrome (WS) is a rare multi-system genomic disorder, caused by 7q11.23 microdeletion with a prevalence of 1/7500-1/20,000 live births. Clinical phenotype includes typical facial dysmorphism (elfin face), mental retardation associated with a peculiar neuropsychological profile and congenital heart defects. We investigated 22 WS patients (mean age of 9.7 years, range 1 day to 39 years) with a multi-specialist follow-up protocol comprehensive of neuropsychological, cardiologic, nephrologic, ophthalmologic, endocrinologic, gastroenterologic, odontostomatologic and orthopaedic evaluations. The mean age at diagnosis was 5.38 years, being 1.02 years when genetic evaluation was requested for congenital heart defects (CHD) and 10.68 years in case of mental retardation and/or abnormal neuropsychological profile without an evident CHD. All patients showed facial dysmorphisms, with supravalvular aortic stenosis (SVAS) as the most common cardiovascular anomaly (12/22), followed by peripheral pulmonary stenosis (9/22); interestingly, in one patient we detected a total anomalous pulmonary venous return (TAPVR), confirming the possible association of this rare CHD with WS. Hypertension was detected by 24-h ambulatory blood pressure monitoring in 7/22 cases. A cognitive assessment was performed in 13 patients older than 6 years, showing various degrees of mental retardation in 12 and a normal intelligence quotient (IQ) in a single patient; evaluation of developmental milestones revealed various grades of developmental delay in all the patients younger than 6 years. Chiari malformation type 1 was found in 3 patients. Our study underlines a remarkable diagnostic delay in patients who present to genetic evaluation because of mental retardation and/or peculiar neuropsychological profile lacking an evident cardiopathy and confirms the multi-systemic nature of WS leading to a high clinical presentation's variability and complex follow-up strategies.     

Andersen-Tawil syndrome: prospective cohort analysis and expansion of the phenotype

Andersen-Tawil syndrome (ATS) is an autosomal dominant multisystem disorder characterized by developmental, cardiac, and neuromuscular abnormalities. Approximately 70% of patients have mutations in KCNJ2, resulting in dysfunction of the inward-rectifying potassium channel Kir2.1. Variable expression complicates the diagnosis of ATS, which in many cases, is not made until years after the first recognized symptom. To better define the distinctive clinical features of ATS and facilitate earlier diagnosis, we conducted a prospective, standardized evaluation of 10 subjects with confirmed KCNJ2 mutations. Detailed anthropometric, neurological, and cardiac evaluations were performed. Using this approach, we identified novel skeletal and dental findings and proposed additional diagnostic criteria for ATS dysmorphology.     

Comprehensive genotype‐phenotype correlation in AP‐4 deficiency syndrome; Adding data from a large cohort of Iranian patients

Mutations in adaptor protein complex‐4 (AP‐4) genes have first been identified in 2009, causing a phenotype termed as AP‐4 deficiency syndrome. Since then several patients with overlapping phenotypes, comprised of intellectual disability (ID) and spastic tetraplegia have been reported. To delineate the genotype‐phenotype correlation of the AP‐4 deficiency syndrome, we add the data from 30 affected individuals from 12 out of 640 Iranian families with ID in whom we detected disease‐causing variants in AP‐4 complex subunits, using next‐generation sequencing. Furthermore, by comparing genotype‐phenotype findings of those affected individuals with previously reported patients, we further refine the genotype‐phenotype correlation in this syndrome. The most frequent reported clinical findings in the 101 cases consist of ID and/or global developmental delay (97%), speech disorders (92.1%), inability to walk (90.1%), spasticity (77.2%), and microcephaly (75.2%). Spastic tetraplegia has been reported in 72.3% of the investigated patients. The major brain imaging findings are abnormal corpus callosum morphology (63.4%) followed by ventriculomegaly (44.5%). Our result might suggest the AP‐4 deficiency syndrome as a major differential diagnostic for unknown hereditary neurodegenerative disorders.     

Analysis of neutralizing antibodies to therapeutic interferon-beta in multiple sclerosis patients: a comparison of three methods in a large Australasian cohort

Persistent high-titre neutralizing antibodies (NAB) to therapeutic interferon-β (IFNβ) in multiple sclerosis patients reduce therapeutic efficacy. Difficulties in standardization of cell-based bioactivity assays have hindered interlaboratory comparison of NAB titres and the determination of a clinically relevant definition of seropositivity. We determined NAB status in Australasian multiple sclerosis patients receiving IFNβ using both the antiviral cytopathic effect (CPE) assay (n = 227) and the more specific ELISA for the type I interferon-inducible MxA protein (n = 350). While the log₁₀ titres determined in the two assays were highly correlated (p < 0.0001; r = 0.967) with similar distributions, the MxA assay was more sensitive, detecting lower concentrations of NAB than the CPE assay. The range of titres determined in the CPE assay was 10 to > 7290; and 9 to 53,700 in the MxA assay, with ranked titre distribution highlighting the arbitrary nature of currently accepted definitions of NAB seropositivity. Bioactivity of injected IFNβ  was significantly reduced in NAB-positive patients (p = 0.006; NAB MxA titres = 184 to 5340) compared to NAB-negative patients as assessed ex vivo using real-time RT-PCR analysis of MxA gene induction. The range of MxA mRNA levels in healthy controls was remarkably consistent with previously published results, regardless of the assay standardization method [Gilli, F., Sala, A., Marnetto, F., Lindberg, R.L., Leppert, D. and Bertolotto, A. (2003) Comparison of IFNbeta bioavailability evaluations by MxA mRNA using two independent quantification methods. Abstract, ECTRIMS Meeting, Milan, Italy; Pachner, A., Narayan, K., Price, N., Hurd, M. and Dail, D. (2003a) MxA Gene Expression Analysis as an Interferon-beta Bioactivity Measurement in Patients with Multiple Sclerosis and the Identification of Antibody-Mediated Decreased Bioactivity. Mol. Diagn. 7, 17–25]. Assessment of IFNβ response ex vivo accounts for both circulating factors and the cellular response to IFNβ, and the data support the development of the MxA gene induction assay for the routine screening of patients receiving IFNβ.     

Czech dysplasia: report of a large family and further delineation of the phenotype

Czech dysplasia (OMIM 609162) is a recently delineated COL2A1 disorder characterized by early-onset progressive pseudorheumatoid arthritis, platyspondyly, short third and fourth metatarsals, normal height, and the absence of ophthalmological problems or cleft palate. Czech dysplasia is caused by a specific missense mutation (R275C, c.823C > T) in the triple helical domain of the COL2A1 gene. We report on a large family with 11 patients with typical Czech dysplasia and sensorineural hearing loss. Hearing loss has hitherto not been considered as a major manifestation of Czech dysplasia. Mutation analysis documented the COL2A1 c.823C > T (R275C) mutation in all affected individuals. Thus, Czech dysplasia is possibly caused exclusively by the R275C mutation, which is a unique situation among the COL2A1 disorders. The family provides further evidence for the remarkably uniform manifestation of the clinical and radiological abnormalities and adds hearing loss to the list of major anomalies of Czech dysplasia.     

C9ORF72 repeat expansion in a large Italian ALS cohort: evidence of a founder effect

A hexanucleotide repeat expansion (RE) in C9ORF72 gene was recently reported as the main cause of amyotrophic lateral sclerosis (ALS) and cases with frontotemporal dementia. We screened C9ORF72 in a large cohort of 259 familial ALS, 1275 sporadic ALS, and 862 control individuals of Italian descent. We found RE in 23.9% familial ALS, 5.1% sporadic ALS, and 0.2% controls. Two cases carried the RE together with mutations in other ALS-associated genes. The phenotype of RE carriers was characterized by bulbar-onset, shorter survival, and association with cognitive and behavioral impairment. Extrapyramidal and cerebellar signs were also observed in few patients. Genotype data revealed that 95% of RE carriers shared a restricted 10-single nucleotide polymorphism haplotype within the previously reported 20-single nucleotide polymorphism risk haplotype, detectable in only 27% of nonexpanded ALS cases and in 28% of controls, suggesting a common founder with cohorts of North European ancestry. Although C9ORF72 RE segregates with disease, the identification of RE both in controls and in patients carrying additional pathogenic mutations suggests that penetrance and phenotypic expression of C9ORF72 RE may depend on additional genetic risk factors.     

大脑中动脉狭窄患者血管内支架植入术治疗前后脑电图动态观察

目的:采用定量脑电图(EEG)动态观察大脑中动脉(MCA)狭窄在透视下经皮血管内支架植入术(PBI)后对病人脑功能的改善作用.方法:对37例MCA狭窄患者PBI术前、术后第一、第三个月的脑电功率谱主频、β、θ、δ频段相对功率值进行动态比较.结果:术后MCA狭窄血管相应供血区域主频率比术前明显增加,β、θ、δ频段相对功率谱值比术前明显降低,其间的差异有显著意义(P<0.05).结论:MCA狭窄患者PBI术前和术后脑电活动存在明显的差异,因此定量EEG可作为评价脑动脉狭窄PBI术后脑功能改善的一种安全、有效的方法之一.     

Decreased coronary reserve: a mechanism for angina pectoris in patients with aortic stenosis and normal coronary arteries

The pathogenesis of angina pectoris in patients with aortic stenosis and normal coronary arteries remains uncertain. Using a specially designed Doppler probe, we measured the maximal velocity of coronary blood flow in the left-anterior descending coronary artery at the time of elective open-heart surgery in 14 patients with aortic stenosis and left ventricular hypertrophy (13 had angina) and in 8 controls without left ventricular hypertrophy. The ratio peak velocity of coronary blood flow, after a 20-second occlusion, to resting velocity was decreased by more than 50 per cent (P less than 0.05) in the patients with aortic stenosis. In 7 of the patients this ratio was decreased by more than 75 per cent. Studies of the velocity of coronary blood flow in vessels perfusing the right ventricle in these patients showed only mild abnormalities. These data demonstrate a selective and marked decrease in coronary reserve to the hypertrophied left ventricle in patients with severe aortic stenosis. The impairment in coronary reserve is probably an important contributor to the pathogenesis of angina pectoris in these patients.