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PubMed2000

The familial form of spondylarthropathy: a clinical study of 115 multiplex families. Groupe Français d'Etude Génétique des Spondylarthropathies.

OBJECTIVE: To investigate the interrelationships among different phenotypes, and their relationship to the HLA-Blocus, in multiplex families with spondylarthropathy (SpA). METHODS: We recruited 115 white French families, each of which had at least 2 members with SpA. Pedigrees were established. Clinical data and pelvic radiographs were collected. The HLA-B27 status of all patients was determined. Analysis was performed to determine the prevalence of SpA manifestations according to sex, disease duration, and HLA-B status, and to examine clustering of specific manifestations in subsets of families. RESULTS: We identified 329 SpA patients. Mean +/-SD age at onset was 24+/-9.4 years. The male:female ratio was 186:143, or 1.3, with few sex differences in disease expression. Axial manifestations and HLA-B27 were each present in 97% of the patients. Inflammatory bowel disease and HLA-B35 were overrepresented in the 7 families containing HLA-B27-negative patients. The frequency of radiographic sacroiliitis increased in parallel with disease duration. Peripheral enthesitis, radiographic sacroiliitis, and psoriasis were evenly distributed in the families. Clustering independent of age was only observed for peripheral arthritis, suggesting that specific factors may predispose individuals to this manifestation. CONCLUSION: Familial SpA appears to be homogeneous, based on the high frequencies of axial skeletal involvement and HLA-B27. The lack of clustering of most manifestations in families suggests that a predominant shared component, including HLA-B27, predisposes individuals to all forms of familial SpA, and that ubiquitous genetic or environmental factors contribute to phenotype diversity.

Adult↗
PubMed2004

Paucity of TEL-AML 1 translocation, by multiplex RT-PCR, in B-lineage acute lymphoblastic leukemia (ALL) in Indian patients.

A total of 69 patients of B lineage ALL, 35 children (32 males, 3 females) and 34 young adults (27 males, 7 females) were studied by multiplex RT-PCR to determine the relative frequency of t(9;22), t(12;21), t(1;19), and t(4;11,). Translocation (9;22) was seen in 1/35 (2.8%) and t(1;19) in 2/35 (5.7%) children. None of the children showed t(12;21) and t(4;11) translocations. In young adults, t(9;22) and t(1;19) were seen in 5/34 (14.7%) and 2/34 (5.8%) patients, respectively. None of the latter showed t(12;21) or t(4;11) translocations. Thus, there appears to be a significant under representation of the fusion transcripts for TEL-AML, a good prognostic marker, in this study, unlike in the West, where it is seen in 35% of children with ALL. This, together with the generally increased leukemic burden seen in Indian patients, may explain in part, the poor treatment outcome reported.

Adolescent↗
PubMed2001

Fine mapping places the gene for arthrogryposis multiplex congenita neuropathic type between D5S394 and D5S2069 on chromosome 5qter.

Arthrogryposis multiplex congenita (AMC) is a heterogeneous symptom complex characterized by non-progressive joint contractures from birth that involve more than one part of the body. In 1997, our group investigated a large Israeli Arab inbred kindred that showed autosomal recessive inheritance of AMC neuropathic type, and we mapped the gene to 5qter between markers D5S1456 and D5S498. Haplotype sharing studies revealed complete homozygosity in all affected individuals with marker D5S394, thus providing significant statistical evidence in favor of linkage. In this study, we have undertaken further fine mapping of this region of chromosome 5qter, and have examined several additional markers. All the affected individuals showed complete homozygosity for the marker D5S394, and also for three additional markers that are telomeric to marker D5S394 and situated 31766 bp, 58016 bp, and 58516 bp, respectively, from it. Analysis of the recombinant individuals has enabled us to narrow down the critical region to a distance of.442 Mb between markers D5S394 and D5S2069.

Alleles↗
PubMed1992

Restrictive dermopathy, a lethal form of arthrogryposis multiplex with skin and bone dysplasias: three new cases and review of the literature.

Restrictive dermopathy is a rare, lethal autosomal recessive syndrome. We report on 3 unrelated affected stillborn infants of consanguineous parents. Clinical findings include a tight, thin, translucent, taut skin, which tears spontaneously in flexion creases, arthrogryposis multiplex congenita (including the temporomandibular joint), enlarged fontanelles, typical face and dysplasia of clavicles and long bones. Histologic abnormalities include hyperplastic, abnormally keratinized epidermis, reduced tonofilaments, thin, compact dermis with hypoplasia of the elastic fibres, and abnormal subcutaneous fat. Fifteen previous cases are reviewed.

Abnormalities, Multiple↗
PubMed1995

Exclusion of linkage between alcoholism and the MNS blood group region on chromosome 4q in multiplex families.

Polymorphic DNA markers on the long arm of chromosome 4 were used to examine linkage to alcoholism in 20 multiplex pedigrees. Fifteen loci were determined for 124 individuals. Lod scores were calculated assuming both dominant and recessive disease modes of inheritance, utilizing incidence data by age and gender that allow for correction for variable age of onset and frequency of the disorder by gender. Under the assumption that alcoholism is homogeneous in this set of pedigrees, and that a recessive mode with age and gender correction is the most appropriate, the total lod scores for all families combined were uniformly lower than -2.0. This suggests an absence of linkage between the putative alcoholism susceptibility gene and markers in the region of the MNS blood group (4q28-31), a region for which we had previously found suggestive evidence of linkage to alcoholism. The 100 cM span of chromosome 4 studied includes the class I alcohol dehydrogenase (ADH) loci. Using the recessive mode, no evidence for linkage to alcoholism was found for the markers tested, which spanned almost the entire long arm of chromosome 4. Under the dominant mode, no evidence for linkage could be found for several of the markers.

Alcoholism↗
PubMed1995

Linkage analysis of chromosome 22q12-13 in a United Kingdom/Icelandic sample of 23 multiplex schizophrenia families.

A possible linkage to a genetic subtype of schizophrenia and related disorders has been reported on the long arm of chromosome 22 at q12-13. (Pulver et al., 1994: Am J Med Genet 54:36-43; Coon et al., 1994: Am J Med Genet 54:72-79; Pulver et al., 1994: Am J Med Genet 54:44-50). However formal statistical tests in a combined sample could not reject homogeneity and prove that there was a linked subgroup of families. We have studied 23 schizophrenia pedigrees to test whether some multiplex schizophrenia families may be linked to the microsatellite markers D22S274 and D22S283 which span the 22q12-13 region. Two point followed by multipoint lod and non-parametric linkage analyses under the assumption of heterogeneity provided no evidence for linkage over the relevant region.

Chromosomes, Human, Pair 22↗
PubMed2002

Lack of association between HoxA1 and HoxB1 gene variants and autism in 110 multiplex families.

A recent report suggested that the HoxA1 and/or HoxB1 genes play a role in susceptibility to autism. To determine whether these findings could be confirmed, we screened these genes for DNA polymorphisms by sequencing all exons in 24 individuals with autism. We identified the same sequence variants in the genes that appeared in this report, which include one single-base substitution variant in HoxA1 and a common haplotype in HoxB1. We performed an association study by applying the transmission disequilibrium test to detect possible association of these variants to autism in 110 multiplex families. Our results demonstrated no deviation from the null hypothesis of no association. We have also separately examined transmissions within individual mating types, for paternal versus maternal alleles, to affected versus unaffected children, and for transmission to affected boys versus girls. None of these subsets revealed significant deviation from the null expectation. Our interpretation of these findings is that it is unlikely that HoxA1 and HoxB1 play a significant role in the genetic predisposition to autism.

Autistic Disorder↗
PubMed2003

Use of a multiplex PCR/sequencing strategy to detect both connexin 30 (GJB6) 342 kb deletion and connexin 26 (GJB2) mutations in cases of childhood deafness.

Hearing loss is a common congenital disorder that is frequently associated with mutations in the Cx26 gene (GJB2). Three recent reports that found a large deletion in another DFNB1 gene, Cx30 (GJB6), suggest that this defect may cause nonsyndromic recessive hearing loss through either a homozygous deletion of Cx30, or digenic inheritance of a Cx30 deletion and a Cx26 mutation in trans. We designed a simple diagnostic strategy with multiplex PCR followed by direct sequencing to allow for the simultaneous detection of Cx26 mutations and Cx30 deletions, and evaluated its effectiveness as a clinical genetic test by examining 200 DNA samples. In the 108 samples from deaf subjects, two digenic mutations were identified in Cx26 and Cx30 (E47X/342 kb deletion and 167delT/342 kb deletion); 69 had only Cx26 mutations (29 biallelic, 40 singleton), including two novel frameshift mutations 511-512insAACG and 358-360delAG; and 37 had no detectable mutation in either Cx26 or Cx30. Our deletion mapping suggested that the proximal breakpoint of all reported Cx30 large deletions are between the nucleotide 444 and 627 at the Cx30 coding region within a maximal interval of 78 or 184 bp. This simultaneous examination of Cx26 and Cx30 is a practical and efficient diagnostic approach for patients with nonsyndromic congenital deafness.

Base Sequence↗
PubMed2005

Inheritance analysis of congenital left ventricular outflow tract obstruction malformations: Segregation, multiplex relative risk, and heritability.

The left ventricular outflow tract (LVOTO) malformations, aortic valve stenosis (AVS), coarctation of the aorta (COA), and hypoplastic left heart (HLH) constitute a mechanistically defined subgroup of congenital heart defects that have substantial evidence for a genetic component. Evidence from echocardiography studies has shown that bicuspid aortic valve (BAV) is found frequently in relatives of children with LVOTO defects. However, formal inheritance analysis has not been performed. We ascertained 124 families by an index case with AVS, COA, or HLH. A total of 413 relatives were enrolled in the study, of which 351 had detailed echocardiography exams for structural heart defects and measurements of a variety of aortic arch, left ventricle, and valve structures. LVOTO malformations were noted in 30 relatives (18 BAV, 5 HLH, 3 COA, and 3 AVS), along with significant congenital heart defects (CHD) in 2 others (32/413; 7.7%). Relative risk for first-degree relatives in this group was 36.9, with a heritability of 0.71-0.90. Formal segregation analysis suggests that one or more minor loci with rare dominant alleles may be operative in a subset of families. Multiplex relative risk analysis, which estimates number of loci, had the highest maximum likelihood score in a model with 2 loci (range of 1-6 in the lod-1 support interval). Heritability of several aortic arch measurements and aortic valve was significant. These data support a complex but most likely oligogenic pattern of inheritance. A combination of linkage and association study designs is likely to enable LVOTO risk gene identification. This data can also provide families with important information for screening asymptomatic relatives for potentially harmful cardiac defects.

Analysis of Variance↗
PubMed2005

Arthrogryposis multiplex with deafness, inguinal hernias, and early death: a family report of a probably autosomal recessive trait.

We report on three male newborn infants of a highly inbred Lebanese family presenting with a characteristic phenotype: arthrogryposis multiplex, deafness, large inguinal hernia, hiccup-like diaphragmatic contractions, and inability to suck, requiring nasogastric gavage feeding. All three boys died from respiratory failure during the first 3 months of life. Intra vitam or post mortem examinations revealed myopathic changes and elevated glycogen content of muscle tissue. This new syndrome is probably transmitted in an autosomal recessive mode, although X-linked inheritance cannot be excluded.

1,4-alpha-Glucan Branching Enzyme↗
PubMed2007

Linkage of schizophrenia with chromosome 1q32 in Korean multiplex families.

Chromosome 1q contains a few loci for which modest evidence of linkage with schizophrenia has been reported in several independent studies. However, markers showing the peak linkage signal are dispersed over a large chromosomal region. In addition, inconsistent findings have been generated from different populations or different subgroups of the same populations. The purpose of the current study is to determine whether those loci are linked to schizophrenia in the Korean population. We investigated 46 Korean multiplex schizophrenia families, initially using 11 microsatellite markers spanning around 91 cM region of 1p22 approximately 42. In a non-parametric linkage analysis, D1S249 located on 1q32.1 showed statistical evidence suggestive of linkage. At the second stage analysis for narrowing down the region, four additional nearby markers were genotyped. In the single point analysis, we found another suggestive linkage signal at D1S2891. The highest NPL score of 2.67 (P = 0.0039) was obtained in the multi-point analysis. This study provides supportive evidence for linkage of chromosome 1q32 with schizophrenia.

Chromosomes, Human, Pair 1↗
PubMed2003

Diagnostic value of electromyography and muscle biopsy in arthrogryposis multiplex congenita.

Arthrogryposis multiplex congenita (AMC), a clinical syndrome characterized by multiple congenital joint contractures, frequently is caused by lesions in the peripheral nervous system. Two standard tests for the evaluation of the motor unit are nerve conduction studies/electromyography (NCS/EMG) and muscle biopsy. We reviewed the diagnostic value of these two studies in the evaluation of AMC over a 23-year period, analyzing 38 patients with AMC who had NCS/EMG, muscle biopsy, or both. Final diagnoses were classified as neurogenic (8 patients), myopathic (10 patients), "other" (12 patients), or unknown (8 patients). Neither test alone had consistently high sensitivities, positive predictive values, or specificities. However, when NCS/EMG and muscle biopsy were concordant for neurogenic or myopathic findings, they were more accurate than either test alone, especially for neurogenic diseases. Test results were most commonly discordant in patients with "other" or unknown diagnoses. These findings suggest that when the clinical evaluation indicates a specific syndromic, developmental, or exogenous cause, NCS/EMG and muscle biopsy are not helpful and may not need to be performed. When the history, examination, and genetic evaluation are unrevealing, NCS/EMG and muscle biopsy together provide valuable diagnostic information.

Arthrogryposis↗
PubMed1987

Mononeuritis multiplex in Waldenström's macroglobulinemia.

We describe a patient with mononeuritis multiplex who had cranial nerve involvement in association with Waldenström's macroglobulinemia. Sural nerve biopsy showed abundant endoneurial granulofibrillary deposits related to microangiopathic changes. These changes were distributed in a multifocal pattern among the fascicles. Immunohistochemistry demonstrated the IgM nature of the deposit located in the endoneurial interstitium.

Biopsy↗
PubMed1997

Mononeuropathy multiplex in rhesus monkeys with chronic Lyme disease.

Peripheral neuropathy is a recognized but poorly understood manifestation of Lyme disease. We performed serial electrophysiological studies on 8 rhesus monkeys chronically infected with the JD1 strain of Borrelia burgdorferi and compared the results with those of similar studies on 10 uninfected control monkeys. Four infected and 2 uninfected animals underwent sural nerve biopsy. Five of the infected and 1 of the uninfected animals also had postmortem neuropathological examinations. Altogether, 5 of the infected monkeys demonstrated primarily axonal-loss-variety multifocal neuropathies. Only one nerve lesion exhibited findings compatible with demyelination. Pathologically, peripheral nerve specimens showed multifocal axonal degeneration and regeneration and occasional perivascular inflammatory cellular infiltrates without vessel wall necrosis. Free spirochetal structures were not seen, but several macrophages exhibited positive immunostaining with a highly specific anti-B. burgdorferi, 7.5-kd lipoprotein monoclonal antibody. In the infected animals, serial analysis of serum antibodies to B. burgdorferi showed increasing numbers of IgG specificities and new IgM specificities, suggesting persistent infection. Thus, peripheral neuropathy in the form of a mononeuropathy multiplex develops frequently in rhesus monkeys chronically infected with B. burgdorferi. The pathogenesis of these nerve lesions is not yet known, but our studies suggest an immune-mediated process perhaps driven by persistent infection with B. burgdorferi.

Animals↗
PubMed1989

Solitary plasmacytoma of the skull revealed by a mononeuritis multiplex associated with immune complex vasculitis.

We describe a patient with solitary plasmacytoma of the skull, in whom mononeuritis multiplex was the presenting manifestation. Some features of the POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal [M] protein, skin changes), including thrombocytosis, were found. Muscle and nerve biopsies disclosed a small vessel hypersensitivity-type vasculitis and complement-fixing immune complex deposits in vessel walls. Removal of the plasmacytoma resulted in clinical improvement and clearance of the vasculitis and immune complex deposits.

Adult↗
PubMed2005

Linkage at 5q14.3-15 in multiplex systemic lupus erythematosus pedigrees stratified by autoimmune thyroid disease.

OBJECTIVE: To identify genetic effects potentially shared between systemic lupus erythematosus (SLE) and autoimmune thyroiditis (AITD). METHODS: Families from the Lupus Multiplex Registry and Repository were studied in which there was at least 1 member who had both SLE and AITD (Graves' disease or Hashimoto thyroiditis). Genome scan genotyping findings in these pedigrees were evaluated for evidence of genetic linkage, by the maximum-likelihood parametric method. Nineteen pedigrees were used in the initial genome scan. Subsequently, an independent sample of 16 pedigrees was used to replicate findings. RESULTS: Studies of the first set of 19 pedigrees yielded a 2-point parametric logarithm of odds (LOD) of 4.97, which was independently confirmed in the replication sample of 16 pedigrees (LOD 2.89). For all 35 pedigrees together, the 2-point LOD was 7.86, under a dominant model used for screening with 90% penetrance and a disease allele frequency of 10%. The multipoint locus homogeneity LOD in the 35 pedigrees was 6.90 (alpha = 1.0) at 5q14.3-15 between D5S1725 and D5S1453, a 12-cM interval, with the peak at D5S1462 at 96.64 cM (nonparametric linkage P = 0.00002). Fine mapping further confirmed the genetic linkage effect and narrowed the region likely to contain the gene to approximately 5 Mb. CONCLUSION: These results suggest that stratifying SLE pedigrees by the presence of other autoimmune disorders may facilitate the discovery of genes related to SLE and that 5q14.3-15 harbors a susceptibility gene shared by SLE and AITD.

Chromosomes, Human, Pair 5↗
PubMed1998

An adult case of Kawasaki disease with multiplex coronary aneurysms and myocardial infarction: the role of transesophageal echocardiography.

Kawasaki disease (mucocutaneous lymph node syndrome) is an acute inflammatory disease that primarily affects infants and young children. In spite of proper therapy, coronary aneurysms develop in 10 to 25% of cases. Adult diagnosis of coronary aneurysm, presumably caused by Kawasaki disease, is rare. A 37-year-old male patient with previous inferior wall myocardial infarction (MI) was admitted with an acute anterior wall MI. Coronary angiography, performed 2 weeks after successful thrombolytic therapy, showed right coronary artery occlusion and multiplex (left main, left anterior descending, left circumflex, right coronary artery) giant coronary aneurysms. Transthoracic echocardiography was unable to detect the aneurysms. Transesophageal echocardiography (TEE) visualized a large left main coronary aneurysm with an occlusive thrombus and measured low flow velocity (0.2 m/s) in the proximal left anterior descending artery. At 4 weeks control, TEE showed marked regression of the thrombus, and it was not detectable after 6 months of oral anticoagulation with acenocumarol (International Normalized Ratio: 3-3.5) and standard postinfarction therapy. After 2 years of follow-up, the patient has no symptoms, and myocardial ischemia could not be provoked by stress tests [treadmill, dipyridamole single-photon emission computed tomography (SPECT)]. We conclude that, for diagnosis and follow-up of adult Kawasaki disease, transesophageal echocardiography is indicated. The importance and efficacy of long-term anticoagulant treatment should be emphasized in this disease.

Adult↗
PubMed1996

Multiplex reverse transcription polymerase chain reaction combined with temperature gradient gel electrophoresis as a tool for the normalized quantitation of intrinsic factor mRNA.

For the quantitation of intrinsic factor (IF) mRNA, an assay based on competitive reverse transcription and subsequent polymerase chain reaction (RT-PCR) combined with temperature gradient gel electrophoresis (TGGE) was established and validated with respect to precision and accuracy. IF-specific mRNA segments ("targets") were coamplified with known amounts of homologous "standard" RNA molecules, which differed from the targets by one base substitution. Following amplification, TGGE heteroduplex analysis proved to be a powerful method facilitating the efficient separation of these nearly identical target and standard DNA products. The measured absolute copy numbers of IF mRNA were put into relation to the constitutively expressed mRNA specific for glyceraldehyde-3-phosphate dehydrogenase (GAPDH), quantified simultaneously by competitive multiplex RT-PCR. The resulting normalized IF mRNA expression rate in terms of n copies of IF mRNA/copy of GAPDH mRNA is independent of the mRNA heterogeneity and the abundance of specific transcripts within the RNA population of interest. Therefore, normalization relative to the housekeeping gene GAPDH provides a widely applicable value for comparative studies of gene expression on the level of mRNA. Here, a normalized IF mRNA expression rate of three copies per GAPDH mRNA molecule was measured in human stomach mucosa.

Base Sequence↗