Lethal Congenital Muscular Dystrophy with Arthrogryposis Multiplex Congenita: Three New Cases and Review of the Literature

Congenital muscular dystrophy (CMD) comprises a heterogeneous group of muscle disorders. We report on two stillborn sibs with early lethal CMD and a prematurely born boy who died within minutes after birth. The pregnancies were complicated by polyhydramnios. All presented with arthrogryposis multiplex congenita, severe muscle wasting, lung hypoplasia, and hydrops. The muscle biopsies showed fibrosis, variation in fiber size, and extensive fat replacement compatible with muscular dystrophy. Fatal CMD seems to be distinct from CMD with survival after birth and is probably autosomal recessively inherited.     

High-risk AML evidenced by a monoclonal antibody

A monoclonal antibody has been raised against a surface membrane antigen present on leukemic myeloblasts. In 52 consecutive patients with acute myeloid leukemia treated in a standardized fashion with intensive chemotherapy the immunologic subclass with respect to this antigen was correlated to the clinical outcome. We found the expression of this antigen to predict a poor prognosis, when measured as survival of CR-patients and as survival after 1st relapse.     

The ordered transmission disequilibrium test: detection of modifier genes

We consider the problem of detection of modifier genes that lead to variations in a disease‐related continuous variable (DRCV), such as the age of onset or a measure of disease severity, in a strategy of candidate genes. We propose a novel method, the ordered transmission disequilibrium test (OTDT), to test for a relation between the clinical heterogeneity expressed by a DRCV and marker genotypes of a candidate gene. The OTDT applies to trio families with one patients and his parents, all three genotyped at a bi‐allelic marker M. The OTDT aims to find a critical value of the DRCV which separates the sample of families in two subsamples in which the transmission rates are significantly different. We investigate the power of the method by simulations under various genetic models and covariate distributions and compare it with a linear regression analysis. Genet. Epidemiol. 2008. ©2008 Wiley‐Liss, Inc.     

Rh phenotype prediction by DNA typing and its application to practice

The complexity of the RHD and RHCE genes, which is the greatest of all blood group systems, confounds analysis at the molecular level. RH DNA typing was introduced in 1993 and has been applied to prenatal testing. PCR-SSP analysis covering multiple polymorphisms was recently introduced for the screening and initial characterization of partial D. Our objective is to summarize the accrued knowledge relevant to the approaches to Rh phenotype prediction by DNA typing, their possible applications beyond research laboratories and their limitations. The procedures, results and problems encountered are highly detailed. It is recommended that DNA typing comprises an analysis of more than one polymorphism. We discuss future directions and propose a piecemeal approach to improve reliability and cost-efficiency of blood group genotyping that may eventually replace the prevalent serology-based techniques even for many routine tasks. Transfusion medicine is in the unique position of being able to utilize the most extensive phenotype databases available to check and develop genotyping strategies.     

基因分型技术首次应用于类孟买型家系ABO基因的研究

目的 探计将基因分型技术用于解决临床输注中血型血清学难题。方法 报告首次在国内用基因分型技术用于一个类孟买型家系5口人ABO基因多态性的研究。在吸收放散试验、唾液血型物质凝集抑制等血清学试验基础上，采用快速盐析法提取外周血中的DNA，用PCR—SSP法扩增ABO血型等位基因。结果 一家5人中，兄弟3人均为类孟买型，ABO基因分型分别为A102B、A102B、Al20O1，而其父母血型基因与血清学血型相符合。结论 ABO PCR—SSP基因分型是一种方便、快速、可靠的技术，与血型血清学相比有着显优势。     

肝豆状核变性ATP7B基因Arg778Leu突变型与临床表现的相关性研究

目的:探讨肝豆状核变性(Hepatolenticular Degeneration,HLD)患者ATP7B基因Arg778Leu突变型与临床表现之间的相关性。方法:采用PCR和DNA测序技术检测91例HLD患者ATPTB基因8号外显子Arg778Leu突变,将91例患者分为纯合突变组、杂合突变组和无突变组,并与临床表现(性别、起病年龄、临床表型)进行相关分析。结果:在91例HLD患者中检出26例Arg778Leu纯合子和40例杂合子,其余25例无此突变。患者性别、起病年龄、临床表型与该突变型均无相关性。结论:Arg778Leu突变与患者性别、起病年龄及临床表型无关。     

Genetically determined N-acetylation and oxidation capacities in Japanese patients with non-occupational urinary bladder cancer

Summary Genetically determined polymorphisms of N-acetylation and oxidative capacity have been studied using dapsone and metoprolol in 51 Japanese patients with spontaneous bladder cancer and 203 healthy control subjects.The results for N-acetylation pharmacogenetics were against the initial expectation that there would be a preponderance of slow acetylators in the cancer group, as 3 such patients (5.9%) were found as compared to 13 (6.4%) in the healthy group. There was no poor metabolizer (PM) of metoprolol in the cancer group, whereas in the healthy group one (0.5%) was a PM. There were no significant differences between the groups in the frequency of slow acetylator and poor oxidiser phenotypes, or in the frequency distribution profiles of acetylation (monoacetyldapsone/dapsone) and oxidative metabolic ratio (log metoprolol/-hydroxymetoprolol).The results indicate that neither N-acetylation nor the debrisoquine/sparteine-type oxidative phenotype and/or capacity represent a genetic predisposition to spontaneous bladder carcinogenesis in Japanese patients. In the normal Japanese population there is a great predominance of rapid acetylators and extensive oxidisers.     

Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases

Unrelated patients with achromatopsia, macular degeneration with onset under age 50 years, cone degeneration or dysfunction, cone-rod degeneration, or macular malfunction were screened for mutations in the three genes known to be associated with achromatopsia: the GNAT2 gene encoding the alpha subunit of cone transducin and the CNGA3 and CNGB3 genes encoding the alpha and beta subunits of the cone cGMP-gated cation channel. We found no examples of patients with GNAT2 mutations. Out of 36 achromats, 12 (33%) had mutations in CNGA3 (13 different mutations including five novel mutations) and 12 (33%) had mutations in CNGB3 (six different mutations including four novel mutations). All achromats with CNG mutations had residual, presumably cone function as determined by computer-averaged 30-Hz electroretinograms (ERGs). There was considerable variability in acuity and color vision, with most patients having acuities of 20/200-20/400 and complete absence of color perception, and others having acuities of 20/25-20/40 and some color vision. Two pseudodominant achromatopsia cases were uncovered, both with CNGA3 mutations, including one family in which some compound heterozygotes with achromatopsia mutations were clinically unaffected. We found two novel CNGB3 changes in three patients with juvenile macular degeneration, a phenotype not previously associated with mutations in the cone channel subunits. These patients had subnormal acuity (20/30-20/60), normal to subnormal color vision, and normal to subnormal full-field cone ERG amplitudes. Our results indicate that some patients with channel protein mutations retain residual foveal cone function. Based on our findings, CNGB3 should be considered as a candidate gene to be evaluated in patients with forms of cone dysfunction, including macular degeneration.     

The molecular basis of classic Ehlers-Danlos syndrome: a comprehensive study of biochemical and molecular findings in 48 unrelated patients

Classic Ehlers-Danlos syndrome (EDS) is characterized by fragile and hyperextensible skin, atrophic scarring, and joint hypermobility. Mutations in the COL5A1 and the COL5A2 gene encoding the alpha1(V) and the alpha2(V) chains, respectively, of type V collagen have been shown to cause the disorder, but it is unknown what proportion of classic EDS patients carries a mutation in these genes. We studied fibroblast cultures from 48 patients with classic EDS by SDS-PAGE for the presence of type V collagen defects. An abnormal collagen pattern was detected in only 2 out of 48 cell lines, making this a poor method for routine diagnostic evaluation. A total of 42 out of 48 (88%) patients were heterozygous for an expressed polymorphic variant in COL5A1. cDNA from 18 (43%) of them expressed only one COL5A1 allele. In 37 patients, the COL5A1/A2 genes were then analyzed by SSCP and conformation sensitive gel electrophoresis (CSGE). A total of 26 patients that were mutation-negative after SSCP/CSGE screening were reanalyzed by dHPLC. In addition, 11 other patients were analyzed by dHPLC only. In total, 17 mutations leading to a premature stop codon and five structural mutations were identified in the COL5A1 and the COL5A2 genes. In three patients with a positive COL5A1 null-allele test, no causal mutation was found. Overall, in 25 out of 48 patients (52%) with classic EDS, an abnormality in type V collagen was confirmed. Variability in severity of the phenotype was observed, but no significant genotype-phenotype correlations emerged. The relatively low mutation detection rate suggests that other genes are involved in classic EDS. We excluded the COL1A1, COL1A2, and DCN gene as major candidate genes for classic EDS, since no causal mutation in these genes was found in a number of patients who tested negative for COL5A1 and COL5A2.     

Genotypic and phenotypic variability of 22q11.2 microduplications: An institutional experience

Duplications in the 22q11.2 region can cause 22q11.2 duplication syndrome and encompass a variety of phenotypes including developmental delays, facial abnormalities, cardiovascular defects, central nervous system delays, and other congenital abnormalities. However, the contribution of these contiguous duplicated regions to the clinical phenotypes has not been fully elucidated. In this study, we identified nine patients carrying different 22q11.2 microduplications detected by chromosomal microarray. Of these patients, seven pediatric patients presented with various clinical features including two neonate cases died shortly after birth, and two healthy adults. We examined region specific genotype–phenotype associations and found unpredictability associated with 22q11.2 duplications in these nine patients.