Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ataxia-telangiectasia (AT) is an autosomal recessively inherited disease (one case in 40,000 to one case in 100,000 live births) whose principal features are oculocutaneous telangiectasia, progressive cerebellar ataxia, B- and T-cell immunodeficiency with recurrent sinopulmonary infections, sensitivity to ionizing radiation and cancer predisposition. The AT-gene (ATM) was recently identified by positional cloning on chromosome 11q22-23. In this paper the diagnostic, clinical and therapeutic problems of 9 AT-patients treated in our clinic are discussed in context with the current literature. Although all patients had discrete signs of cerebellar ataxia at infancy, there was a significant delay of definitive diagnosis (median 4, range 1.5-6.5). Elevated alpha fetoprotein levels clearly distinguish AT from other ataxias and immunodeficiency syndromes.
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PMID:[Pathogenesis, diagnosis, clinical and therapeutic aspects of ataxia telangiectasia]. 941 Oct 43

Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by progressive ataxia, telangiectasia, sinopulmonary infections, hypersensitivity to ionizing radiation, and combined immunodeficiency. Recently, the AT gene (ATM) was cloned and shown to be mutated in AT patients. In this report, mutation analysis of ATM was performed in a 24-year-old AT patient without immunodeficiency. ATM amplified with reverse transcriptase-polymerase chain reaction (RT-PCR) was screened with a ribonuclease (RNase) cleavage assay and auto-sequenced. This patient, a compound heterozygote, showed two mutations in ATM: one missense mutation leading to a Leu2656Pro substitution and the other to the truncation at codon 3047 (Arg-->ter). The latter mutation is within the phosphatidylinositol 3-kinase (PI 3-kinase)-like domain and the former is outside but close to the domain. The particular phenotype in our patient, no immunodeficiency, suggests incomplete functional loss of ATM protein. The clinical spectrum of AT caused by ATM mutations may be broader than previously thought. Further analysis of patients with similar phenotypes will make the relation between ATM genotype and phenotype clear.
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PMID:Ataxia-telangiectasia without immunodeficiency: novel point mutations within and adjacent to the phosphatidylinositol 3-kinase-like domain. 945 Aug 74

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity, and cancer predisposition. A-T cells are sensitive to ionizing radiation and radiomimetic chemicals and fail to activate cell-cycle checkpoints after treatment with these agents. The responsible gene, ATM, encodes a large protein kinase with a phosphatidylinositol 3-kinase-like domain. The typical A-T phenotype is caused, in most cases, by null ATM alleles that truncate or severely destabilize the ATM protein. Rare patients with milder manifestations of the clinical or cellular characteristics of the disease have been reported and have been designated "A-T variants." A special variant form of A-T is A-TFresno, which combines a typical A-T phenotype with microcephaly and mental retardation. The possible association of these syndromes with ATM is both important for understanding their molecular basis and essential for counseling and diagnostic purposes. We quantified ATM-protein levels in six A-T variants, and we searched their ATM genes for mutations. Cell lines from these patients exhibited considerable variability in radiosensitivity while showing the typical radioresistant DNA synthesis of A-T cells. Unlike classical A-T patients, these patients exhibited 1%-17% of the normal level of ATM. The underlying ATM genotypes were either homozygous for mutations expected to produce mild phenotypes or compound heterozygotes for a mild and a severe mutation. An A-TFresno cell line was found devoid of the ATM protein and homozygous for a severe ATM mutation. We conclude that certain "A-T variant" phenotypes represent ATM mutations, including some of those without telangiectasia. Our findings extend the range of phenotypes associated with ATM mutations.
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PMID:Genotype-phenotype relationships in ataxia-telangiectasia and variants. 949 52

Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectasia, immunodeficiency, elevated alpha-fetoprotein levels, chromosomal instability, predisposition to cancer, and radiation sensitivity. We report the identification of a new, double missense mutation in the ataxia telangiectasia gene (ATM) of a Dutch family. This homozygous mutation consists of two consecutive base substitutions in exon 55: a T-->G transversion at position 7875 of the ATM cDNA and a G-->C transversion at position 7876. These transversions were confirmed by polymerase chain reaction/primer-induced restriction analysis with CelII. The double base substitution results in an amino acid change of an aspartic acid to a glutamic acid at codon 2625 and of an alanine to a proline at codon 2626 of the ATM protein. Both amino acids are conserved between the ATM protein and its functional homolog, the Atm gene product in the mouse. Furthermore, the Chou-Fasman and Robson predictions both demonstrate a change in the secondary structure of the ATM protein carrying the D2625E/A2626P mutation. These findings suggest that the double base substitution in the ATM gene is a disease-causing mutation.
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PMID:A double missense mutation in the ATM gene of a Dutch family with ataxia telangiectasia. 952 87

Ataxia-Telangiectasia (A-T) is a rare autosomal recessive disease characterised by cutaneous telangiectasia, cerebellar ataxia, immunodeficiency, high sensitivity to ionising radiation, chromosomal instability and an increased risk of cancer. The gene mutated in A-T patients, ATM, is located on chromosome 11q22-23. ATM heterozygotes are thought to have a high tendency to develop malignancies, such as breast cancer. In order to determine the contribution of heterozygous ATM mutation to cancer, studies of cancer-affected patients have been undertaken in non site-specific cancer families and sporadic breast cancer cases. No evidence of an important role of ATM heterozygous mutations has been shown. In order to give another contribution to these results, we tried to define a specific family phenotype according to the most common cancers observed in ATM heterozygotes. Breast and gastric cancers appear to be the most frequent malignancies in A-T carriers and one ATM germ-line mutation has been described in a breast/gastric cancer family. Therefore we further investigated the role of ATM mutation in additional breast/gastric cancer families. In eighteen families associating these two malignancies, we used the protein transcription/translation test to detect ATM mutations in the index case from each family. We found one case of ATM mutation which did not cosegregate with the gastric cancer in the family.
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PMID:No evidence for constitutional ATM mutation in breast/gastric cancer families. 959 4

1. This manuscript describes two different strategies to progress from the clinical assessment of patients to the identification of disease-causing mutations. In the first disease, recognition of a metabolic abnormality allowed direct molecular analysis of the causal gene. In contrast, localization of the second disease gene by linkage analysis was critical to implicate a gene with a previously unsuspected disease role. 2. Two sisters with chronic respiratory disease and recurrent infections were identified as the first cases of adult onset immunodeficiency due to adenosine deaminase deficiency. Autosomal recessive inheritance of two mutations in the adenosine deaminase gene was demonstrated. Enzyme replacement therapy improved the patients' immunological and clinical status. 3. Individuals with pulmonary arteriovenous malformations were used to identify families with hereditary haemorrhagic telangiectasia (HHT, Rendu-Osler-Weber Syndrome). Linkage studies mapped the HHT disease gene in some families to chromosome 9, and demonstrated genetic heterogeneity. The chromosome 9 disease interval was refined, and several candidate genes were assessed. Following the first description of disease-segregating mutations, a complete analysis of the endoglin gene (which encodes an endothelial cell transforming growth factor-beta receptor) identified seven novel mutations. Two mutations did not produce mutant mRNA, and disease severity was comparable between families, indicating that HHT results from stoichiometric insufficiency of endoglin. 4. Each study has implications extending beyond the relatively rare disease analysed. The adenosine-deaminase-deficient patients highlight a treatable cause of HIV-negative CD4+ lymphopenia in adults, perhaps accounting for further cases of 'non-HIV AIDS'. The HHT studies have illuminated a novel area of vascular pathophysiology, with potential relevance to further disease states.
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PMID:Glaxo/MRS Young Investigator Medal. Molecular studies on adenosine deaminase deficiency and hereditary haemorrhagic telangiectasia. 961 53

Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by cerebellar ataxia, oculocutaneous telangiectasia, and variable degrees of humoral and cellular immunodeficiency. Affected individuals are known to exhibit a high incidence of lymphoma and leukemia. Because of increased chemosensitivity, the treatment of A-T patients with malignancies requires extremely careful planning and caution with respect to the use of chemotherapy. The authors report on a 12-year-old boy with A-T who developed B-cell lymphoma. He received a half-dose of the drugs administered according to the acute lymphoblastic leukemia (ALL) protocol issued by our children's cancer study group (9104 Standard Risk Protocol, Tokai Pediatric Oncology Study Group). As a result, he continues to be in complete remission and free of treatment complications 32 months after the diagnosis of B-cell lymphoma.
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PMID:Ataxia telangiectasia associated with B-cell lymphoma: the effect of a half-dose of the drugs administered according to the acute lymphoblastic leukemia standard risk protocol. 978 9

The majority of children with lethal congenital immunodeficiencies lack histocompatible related bone marrow donors. T-cell depleted haploidentical parental bone marrow transplantation has been used successfully in selected patients with severe combined immunodeficiency (SCID), but it has not benefited most patients with other immunodeficiencies when it has been tried. For these reasons, we undertook a pilot study using closely matched unrelated donors for bone marrow transplantation of children with life-threatening primary immunodeficiencies. Unrelated donor searches were performed for 24 patients and one or more suitable donors were identified for 21 patients. Unrelated donor bone marrow transplantation (URD BMT) has been performed in 18 patients with various diagnoses: SCID (8), Wiskott-Aldrich syndrome (WAS) (2), Chediak-Higashi syndrome (CHS) (2), combined immunodeficiencies (3), Ataxia Telangiectasis (AT) (2), and one patient with combined immunodeficiency and large granular lymphocytosis (1). The overall actuarial survival rate is 59% with excellent results observed for infants with SCID and children with WAS and CHS.
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PMID:Unrelated donor bone marrow transplantation for correction of lethal congenital immunodeficiencies. 1014 43

Ataxia telangiectasia is a multisystem disease with an autosomal recessive inheritance. It is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, humoral and cellular immunodeficiencies and high incidence of neoplasia and radiosensitivity. A 5 year retrospective survey included 24 patients belonging to 17 families. Cerebellar ataxia was the first clinical symptom and was usually noticed when the child began to walk. Mean age of onset was 2.9+/-1.8 years. Oculocutaneous telangiectasia was present in 17 cases and appeared between 2 and 8 years and then spread in a characteristic symmetrical pattern. When ocular telangiectasia was absent (6 cases), the diagnostic of ataxia telangiectasia was retained on oculomotor apraxia (2 cases), recurrent sinopulmonary infections (3 cases) and/or a sib with typical ataxia telangiectasia (1 case). Recurrent sinopulmonary infections, absence or low serum level of IgA (78 p.100) and lymphopenia revealed immunodeficiency. Among 12 patients, chromosomal instability was observed in 5. Balanced rearrangements involving chromosomes 2, 7, 14, 22, 1, 3 and 11. The responsible gene, ATM, encodes a large protein kinase with a phosphatidylinositol 3-kinase-like domain. Ataxia telangiectasia patients have a 100 fold higher risk of cancer than the general population. We reported, in the same family two patients who developed neoplasia, (lymphoma and leukemia). During follow-up, a progressive worsening was observed in all cases. Three patients have died.
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PMID:[Clinical, biological and genetic study of 24 patients with ataxia telangiectasia from southern Tunisia]. 1089 97

A 6-year-old girl with consanguineous parents presented with a history of progressive ataxia and patchy, segmental pigmentary changes, some reminiscent of Blaschko's lines. There was no evidence of oculocutaneous telangiectases or signs of immunodeficiency. A clinical diagnosis of ataxia--telangiectasia (AT) was suggested and confirmed by the presence of a low serum IgA, raised alpha-fetoprotein and chromosomal rearrangements of chromosomes 7 and 14. This case of AT is unique for having hypopigmentation and hyperpigmented patches adjacent to each other, which is a feature that has been described as 'cutis tricolor', and is unusual for having pigmentary skin changes, some in the lines of Blaschko without telangiectases. Clinicians should be aware that a diagnosis of AT may be made in the absence of telangiectases.
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PMID:Pigmentary anomalies in ataxia--telangiectasia: a clue to diagnosis and an example of twin spotting. 1125 75


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