1/18. A mark on the arm: myths of carrier status in sibs of individuals with ataxia-telangiectasia.The ATM gene, mutated in ataxia-telangiectasia (A-T), was identified by positional cloning. The discovery of the ATM gene now allows the identification of A-T heterozygotes [Telatar et al., 1998], who may be at increased risk of cancer. The purpose of this study was to (a) identify sib's interest in carrier testing, (b) explore perception of carrier status, and (c) assess levels of understanding of genetics of A-T. This is the sib component of a study of 103 parents and sibs (68 parents and 35 sibs) of individuals with A-T. Thirty-five sibs from 24 families, including 26 adults and 9 adolescents, drawn from the University of california, los angeles, the A-T Clinical Center at the Johns Hopkins University School of medicine, and the A-T Children's Project, were interviewed. Eighty-five percent of adult sibs stated correctly that if a child has A-T, both parents are heterozygotes; 76% knew the A-T gene had been identified. Ninety-two percent would request carrier testing for themselves if available. Seventy-nine percent would want their child tested for carrier status prior to the age of 18. Seventy-three percent believed that being a carrier is associated with increased health risks. Sibs have numerous misconceptions surrounding carrier status and genetics of A-T. Provision of factual information about genetic transmission is necessary, but unfortunately insufficient, to counter deeply held views of self and others. genetic counseling, which explores the way in which this information is filtered and interpreted, could be an effective tool in dispelling family myths. We conclude that A-T sibs need comprehensive support in relation to carrier testing.- - - - - - - - - - ranking = 1keywords = family (Clic here for more details about this article) |
2/18. High incidence of cancer in a family segregating a mutation of the ATM gene: possible role of ATM heterozygosity in cancer.ATM mutations predispose cells to malignancy by promoting chromosomal instability. We have identified a family with multiple cancers that segregates a mutant allele of ATM, IVS61 2insTA, which causes skipping of exon 61 in the mRNA, as well as a previously undescribed polymorphism, IVS61 104C(54):T(46). The mutation was inherited by two sisters, one who developed breast cancer at age 39 and the second at age 44, from their mother, who developed kidney cancer at age 67. Molecular studies were undertaken to determine the role of the ATM gene in the development of cancer in this family. Studies of irradiated lymphocytes from both sisters revealed elevated numbers of chromatid breaks, typical of A-T heterozygotes. Studies on lymphoblastoid cell lines established from these individuals revealed abnormal p53 induction and apoptosis after dna damage. Loss of heterozygosity (LOH) in the ATM region of chromosome 11q23.1 showed that the normal ATM allele was lost in the breast tumor of the older sister. LOH was not seen at the BRCA1 or BRCA2 loci. BRCA2 is not likely to be a cancer-predisposing gene in this family because each sister inherited different chromosomes 13 from each parent. The sisters share their maternal BRCA1 allele, although no mutation in this gene was detected in the family. Our findings suggest that haploinsufficiency at ATM may promote tumorigenesis, even though LOH at the locus supports a more classic two-hit tumor suppressor gene model.- - - - - - - - - - ranking = 8keywords = family (Clic here for more details about this article) |
3/18. Lymphoid malignancy as a presenting sign of ataxia-telangiectasia.Ataxia-telangiectasia (AT) is an uncommon genetic disorder characterized by cerebellar ataxia, oculocutaneous telangiectasias, progressive immunodeficiency, and a predisposition to lymphoid malignancy. The genetic defect in AT predisposes not only to malignancy but also to severe toxicity from anti-neoplastic therapies. It is important to consider the diagnosis of AT in any child with a lymphoid malignancy at a younger than expected age, or who has a pre-existing ataxia, to anticipate unusually severe toxicities from the antineoplastic therapy, to avoid confusing the development of ataxia with toxicity from therapy, and to provide appropriate genetic counseling. We describe two children at a young age with a lymphoid malignancy diagnosed before the diagnosis of AT. One patient had severe toxicity from his chemotherapy, requiring truncation of the planned course of treatment. The other child was able to tolerate his entire planned course of therapy, but ataxia that was initially interpreted as toxicity from chemotherapy rather than as a sign of his AT developed. Lymphoid malignancy may be the presenting sign of AT. Making this diagnosis may influence therapy of the malignancy. The neurologic manifestations of the disease can be misinterpreted as toxicities of the chemotherapy, and diagnosis of AT allows appropriate genetic counseling for the family.- - - - - - - - - - ranking = 1keywords = family (Clic here for more details about this article) |
4/18. dystonia as presenting manifestation of ataxia telangiectasia : a case report.ataxia telangiectasia is a genetically inherited multisystem disorder with predominant feature being telangiectasia and cerebellar ataxia. In this report, a family of three siblings suffering from ataxia telangiectasia is described. The proband presented with dystonia and dystonic myoclonus, both of which are rare presenting features of ataxia telangiectasia.- - - - - - - - - - ranking = 1keywords = family (Clic here for more details about this article) |
5/18. multiple sclerosis in a radiosensitive family with low levels of the ATM protein.multiple sclerosis (MS) is a chronic neurological disease of the central nervous system (CNS) characterized by demyelination associated with progressive disability. The mechanisms underlying the pathogenesis of MS remain a mystery. The highly pleiotropic syndrome known as ataxia telangiectasia (A-T) overlaps with MS in that it also presents with demyelination in the CNS. Whether demyelination in MS or in A-T is initiated through neuronal degeneration or immune dysfunction is not yet known. However, unlike MS, the underlying cause of A-T is known to result from mutations in the A-T gene (ATM) that often result in the complete loss of ATM protein and loss/gain of function. ATM is implicated in neurological degeneration, particularly in the cerebellum, cellular apoptosis, immunodeficiency, double stranded deoxyribonucleic acid (DNA) rejoining, VDJ antibody recombination, tumour suppression, particularly T-lymphoid malignancies, signal transduction, cell-cycle control and cellular radiohypersensitivity. In this study, we describe a case of MS in a family with cellular radiosensitivity and abnormally low postinduction levels of the ATM protein. Defective dna repair/rejoining may impact on autoimmunity.- - - - - - - - - - ranking = 5keywords = family (Clic here for more details about this article) |
6/18. Re-evaluation of CHANDS.A rare ectodermal dysplasia with the acronym CHANDS (Curly hair, Ankyloblepharon, Nail Dysplasia syndrome) was described by Baughman (1971) as being a new autosomal dominant condition. Additional pedigree data obtained after the original report indicate that the mode of inheritance is more likely to be autosomal recessive, with an instance of quasi-dominant transmission as a result of multiple consanguineous matings in the family. These data are provided in this report.- - - - - - - - - - ranking = 1keywords = family (Clic here for more details about this article) |
7/18. Extreme insulin resistance in ataxia telangiectasia: defect in affinity of insulin receptors.The syndrome of ataxia telangiectasia is associated with glucose intolerance and insulin resistance. We examined the status of insulin receptors on circulating monocytes and on cultured fibroblasts from two siblings with ataxia telangiectasia and severe insulin resistance. 125I-insulin binding to monocytes of the two patients consistently demonstrated an 80 to 85 per cent decrease in receptor affinity. In contrast, the defect in receptor affinity was not expressed on the patients' cultured fibroblasts or on monocytes or fibroblasts obtained from unaffected family members. Whole plasma and immunoglobulin-enriched fractions of plasma from the patients inhibited the normal binding of insulin to its receptors on cultured human lymphocytes (IM -9 line) and on human placental membranes. We conclude that the insulin resistance in the two siblings with ataxia telangiectasia was associated with defects in the affinity of the receptors for insulin, probably caused by circulating inhibitors of insulin binding.- - - - - - - - - - ranking = 1.0055965070108keywords = family, member (Clic here for more details about this article) |
8/18. Ataxia-without-telangiectasia. Progressive multisystem degeneration with IgE deficiency and chromosomal instability.Three of five siblings developed a progressive neurological disorder during infancy or early childhood characterized by cerebellar ataxia, choreoathetosis and peripheral neuropathy. Immunological studies revealed a marked selective deficiency of serum IgE in all three affected siblings. There was evidence of chromosomal instability in the three affected siblings and in one of the parents. One of the affected siblings also developed acute lymphoblastic leukaemia. In spite of many resemblances, this syndrome differs from classical or complete ataxia telangiectasia in that oculocutaneous telangiectases were lacking, the serum IgA and alpha-fetoprotein levels in this family were normal, there was no gonadal dysgenesis, and the cytogenetic findings were atypical.- - - - - - - - - - ranking = 1keywords = family (Clic here for more details about this article) |
9/18. Common and uncommon cutaneous findings in patients with ataxia-telangiectasia.This series describes some common and uncommon cutaneous findings in twelve patients with ataxia-telangiectasia (A-T). All patients had the characteristic telangiectasia as described previously. However, the telangiectases did not conform to a classic photodistribution . Our series did include one patient with a pathologic reaction to light-simulating hydroa aestivale or vacciniforme . In addition, there were three patients with acanthosis nigricans in two unrelated families. vitiligo, impetigo, recurrent herpetic gingivostomatitis, hirsutism, lipoatrophy, gray hair, progeroid changes and hyper- and hypopigmented macules were noted in our patients. Many of our patients had one or more caf'e au lait like-lesions in a dermatomal distribution. In addition, several of the family members showed one or more cafe au lait-like lesions, suggesting the possibility that this finding may represent a phenotypic expression in the skin of carriers of this cancer-prone syndrome.- - - - - - - - - - ranking = 1.0055965070108keywords = family, member (Clic here for more details about this article) |
10/18. chromosomal instability in ataxia telangiectasia.We have examined various aspects of lymphocyte chromosomal instability in three families comprised of five individuals affected with ataxiatelangiectasia (AT), their obligate heterozygous parents, and their unaffected sibs. We found that neither baseline sister chromatid exchanges (SCEs) nor mitomycin-C-induced increments in SCEs showed any significant differences among family members or between AT heterozygotes or homozygotes. chromosome breakage in first-division metaphases was found to be moderately elevated in three of the five AT homozygotes (range 1-12%); breakage in the six AT obligate heterozygotes was within normal limits (0-4%). Analysis of Giemsa-banded metaphases indicated the presence of a clone bearing a paracentric inversion of chromosome #14 in addition to other chromosome #14 abnormalities in one AT homozygote. The same inversion was also found in this individual's affected sister and his obligate heterozygous father. A discussion regarding the relationship of the specificity of breakage and reunion of bands q12 and q23 on chromosome #14 and the high incidence of malignancy in AT is included.- - - - - - - - - - ranking = 1.0055965070108keywords = family, member (Clic here for more details about this article) |
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