Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004135 (ATM)
 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We describe MRI of the brain in 19 patients with ataxia-telangiectasia (AT) and correlate the appearances with the degree of neurologic deficit. We examined 10 male and nine female patients; 17 were aged between 2 and 12 years (mean 8 years) but a woman and her brother were 35 and 38 years old, and had a variant of AT. Ataxia was the first recognized sign of the disease in every patient. We detected the following patterns of cerebellar atrophy: in the youngest patient, aged 2 years, the study was normal; in the five next youngest patients 3-7 years of age, the lateral cerebellum and superior vermis showed the earliest changes of atrophy; and all but one of the other patients had moderate to marked diffuse atrophy of vermis and cerebellar hemispheres. There were 12 patients aged 9 years and above; one, who was normal, was 9 years old. The five patients who at the time of examination were unable to walk all had diffuse atrophy involving both vermis and cerebellar hemispheres.
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PMID:Ataxia-telangiectasia: the pattern of cerebellar atrophy on MRI. 1274 Jul 24

An autoimmune mechanism for ADEM and MS can be supported by the similar patterns of pathologic changes seen in both diseases with the animal model EAE induced by inoculating animals with nervous tissue and the occurrence of ADEM in patients exposed to nervous tissue during vaccination. Whereas there are no universally agreed-upon criteria for the diagnosis of ADEM, a combination of prodromal illness or preceding vaccination, MRI signs of demyelination, and an acute presentation of neurologic symptoms are the triad most commonly looked for in making the diagnosis of ADEM. An ever-increasing number of infections and vaccinations (nonspecific URIs being most common) has been associated with ADEM. Fever and encephalopathy are seen frequently at presentation. Seizures also are common, as are cranial nerve abnormalities and motor symptoms. A mild pleocytosis or protein elevation is found in the majority of patients with ADEM. Intrathecal IgG synthesis and oligoclonal bands are relatively infrequent but should not be considered inconsistent with the diagnosis of ADEM. White matter changes on T2 in a bilateral although asymmetric distribution with relative sparing of the periventricular region with or without deep gray matter involvement is consistent and to some a requirement for the diagnosis. Low-dose steroids have no beneficial effect in the treatment of ADEM and may be contraindicated. High-dose steroids may have a beneficial effect, particularly in more prolonged illnesses, although the evidence is primarily anecdotal. If steroids are used to improve morbidity, 30 mg/kg/d of methylprednisolone for three to five days is the dose with a six-week taper to reduce the risk of recurrence. The prodromal infection may be a major factor in the ultimate mortality and morbidity of the disease. The current mortality of ADEM is quite low. Whether or not this is an effect of different triggering agents or changes in medical care cannot be determined. In larger series of patients with ADEM, 10% to 20% of children experience some sort of recurrence with the majority occurring in the initial one to two months after the first event. This is sometimes associated with steroid withdrawal. A second group of children have a late second recurrence that clinically may not be MS but a recurrence of ADEM, although longer follow-up may change that assessment. Two months should be allowed before a second relapse is considered a manifestation of MS, whereas a second attack also may occur years after an initial attack of ADEM and still be consistent with ADEM recurrence. MS does occur during childhood, with the youngest children at the least risk, and risk increasing with age. The criteria of Poser et al can be used to diagnose MS in childhood [40]. The presentation of MS in childhood is most often sensory, motor, and brainstem signs and symptoms. A relapsing-remitting course is most common with a first relapse occurring in the year after presentation. MRI findings in MS typically show periventricular changes. Oligoclonal bands and CSF IgG synthesis are found in the majority. Treatments of childhood MS have not been studied adequately, but, when treatments studied in adults are used in children, they are well tolerated. Efficacy has not been shown. The long-term outcome of MS in childhood can be either severe or benign with no clear consensus that childhood MS is either a less or more severe disease than the adult form. ATM and ON treatments and outcomes are particularly difficult to evaluate because of the heterogeneity of populations included in case series and the small numbers reported. Steroids are used with anecdotal reports of their superiority to nontreatment. Outcome in ATM often can be poor, whereas in ON it rarely is. A multinational collaborative effort to study and collect the large numbers necessary to address the important questions in these childhood autoimmune disorders would be of great benefit and the only way likely to demonstrate good evidenced-based medicine practiced in this field.
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PMID:Childhood autoimmune neurologic diseases of the central nervous system. 1474 47

The microcirculation and oxygenation of a tumor play important roles in its responsiveness to cytotoxic treatment, and noninvasive assessments of its vascular properties may have prognostic value. Dynamic contrast-enhanced (DCE) (1)H MRI based on infusion of Gd-DTPA, and blood oxygen level-dependent (BOLD) contrast based on altering inhaled gas are both sensitive to vascular characteristics. This study compares the effects observed in eight Dunning prostate R3327-AT1 rat tumors imaged sequentially at 4.7 Tesla by echo-planar imaging (EPI). Both interventions generated a significant response, and each revealed significant differences between the center and periphery of the tumors. On a voxel-by-voxel basis across the whole tumor population, there was a close correlation between the maximum rate of signal response and the magnitude of response to each intervention (R(2) >or= 0.6, P < 0.0001). However, when the data were analyzed separately for each individual tumor, some showed a weak correlation (R(2) < 0.4), particularly for DCE, and the nature (slope) varied between separate tumors. Generally, there was a weak correlation (N = 7, R(2) < 0.5) between responses to the two interventions on a tumor-by-tumor basis, which emphasizes that the techniques are not equivalent. Both techniques revealed intra- and intertumor heterogeneity, but the BOLD response was more rapidly reversible than the DCE response. This suggests that the BOLD technique may be a useful tool for investigating interventions (such as drugs) that cause vascular disruption.
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PMID:Comparison of BOLD contrast and Gd-DTPA dynamic contrast-enhanced imaging in rat prostate tumor. 1512 77

Breast and ovarian cancers are the second and fifth leading causes of cancer death, respectively, among women in the United States. Individuals with breast cancer have a 20--30% chance of having at least one relative with the disease. However, only 5--10% of the cases are a direct result of germline mutations in highly penetrable genes, such as BRCA1 and BRCA2 (BRCA1/2) as well as genes TP53 and PTEN. Since 1996, genetic testing for these mutations has been clinically available. A strategy for the management of women at increased familial risk of breast and ovarian cancers is described, which includes genetic assessment, chemoprevention, radiologic screening, and clinical and self-examination. Genetic testing should occur within a cancer genetic clinic after genetic counseling. A blood sample allows determination of the presence of the BRCA1 and BRCA2 genes, the TP53 gene, the PTEN gene, and the ATM gene. Tumor examination has identified a growth factor receptor gene, human epidermal growth factor receptor (HER-2). With regard to diet and lifestyle, women at increased risk of breast cancer could be advised to reduce dietary fat, avoid obesity, decrease alcohol consumption, and take regular exercise. Although chemoprotection is a valuable consideration, it is important to emphasize that the use of Tamoxifen in BRCA1 and BRCA2 mutation carriers is not established, nor is the optimum duration of benefit. An overview of the main outcomes of the current published studies confirms a 38% decrease in breast cancer incidence with Tamoxifen but recommends its use be restricted to women at high risk of breast cancer and low risk for potential side effects. The role of bilateral risk-reducing mastectomy or prophylactic mastectomy has been controversial for several reasons, including the psychosocial significance of the breast in Western cultures, the wide acceptance of breast conservation in surgery for early breast cancer, and the previous lack of data on its efficacy. The surgical procedure should aim to remove substantially all at-risk breast tissue. However, there is a balance between reduction of cancer risk and cosmetic outcome. Bilateral prophylactic oophorectomy can significantly decrease ovarian cancer risk in women who carry BCRA1 mutations. Oophorectomy lowers the risk of breast cancer, even in women who have previously used hormone replacement therapy. There are no published randomized controlled trials examining the effectiveness of mammographic screening in women under 50 years of age with a family history of breast cancer. However, the published studies do suggest that mammographic screening of a high-risk group of women under 50 years of age may detect cancer at a rate equivalent to that seen in women 10 years older with normal risk. Other initial studies also support MRI as having a greater sensitivity than mammography in high-risk women. Breast clinical and self-examination is often advocated, but its effectiveness is unproved, and only one randomized study has been undertaken in women at risk. On the basis of this study as well as one nonrandomized study, it can be concluded that clinical examination as well as mammography are essential in detecting breast cancer. under 50 years of age with a family history of breast cancer. However, the published studies do suggest that mammographic screening of a high-risk group of women under 50 years of age may detect cancer at a rate equivalent to that seen in women 10 years older with normal risk. Other initial studies also support MRI as having a greater sensitivity than mammography in high-risk women. Breast clinical and self-examination is often advocated, but its effectiveness is unproved, and only one randomized study has been undertaken in women at risk. On the basis of this study as well as one nonrandomized study, it can be concluded that clinical examination as well as mammography are essential in detecting breast cancer.
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PMID:Breast cancer and ovarian cancer genetics. 1621 1

Ataxia telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectasia, immunodeficiency, elevated alpha-fetoprotein level, chromosomal instability, predisposition to cancer, and radiation sensitivity. Although a lot of mutations in the ATM gene have been described, there is still no report about ATM mutations in Chinese population. Using a molecular approach, we screened for ATM mutations in two patients from two unrelated Chinese families. 100 normal controls were analyzed to exclude possibility of polymorphism. Two novel mutations in the ATM gene were identified. The first one is a novel, homozygous, 1346G>C (Gly449Ala) missense mutation. The second one is a compound heterozygous mutation, which consists of a novel, 610G>T (Gly204Stop) nonsense mutation, combined with a previously reported, 6679C>T (Arg2227Cys) missense mutation. The transversions 1346G>C (Gly449Ala) and 610G>T (Gly204Stop) are not localized either in the conserved PI-3 kinase domain or in the other domains of the ATM protein. The phenotypic features were characterized by progressive cerebellar ataxia, ocular telangiectasia, elevated alpha-fetoprotein level, immunodeficiency (agammaglo-bulinemia and T-cell defect), and rearrangements of chromosomes 7 and 14; brain MRI showed cerebellar atrophy, brain SPECT showed cerebellar regional cerebral blood flow (rCBF) hypoperfusion. To our knowledge, this is the first report of ATM mutations in Mainland China, in which the transversions 1346G>C (Gly449Ala) and 610G>T (Gly204Stop) are two novel, disease-causing mutations.
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PMID:Mutation analysis of the ATM gene in two Chinese patients with ataxia telangiectasia. 1638 Jan 33

The aim of this study was to describe the demographic, clinical and laboratory features of idiopathic acute transverse myelitis (IATM). Patients with non-compressive ATM receiving care at Hospital da Lagoa, Rio de Janeiro (Brazil) between 2000 and 2008 were selected. Of the 70 cases of acute myelopathies, the idiopathic form was identified in 41 following exclusion of the cases associated with systemic lupus erythematosus (n = 1), Sjogren's syndrome (n = 1), herpes zoster (n = 1), cytomegalovirus in an HIV-positive patient (n = 1), Schistosoma mansoni (n = 1), actinic myelitis (n = 1), infectious myelitis of unknown etiology (n = 2) and those that, following the first attack of myelitis, converted to NMO (n = 19) or to clinically defined MS (n = 2). Of the 41 cases of IATM, the majority of patients were female (68.3%) and white (65.9%). Median age at first myelitis was 37.0 +/- 11.8 years. Over a median observation time of 36 months, 39.0% of patients remained monophasic, while recurrences occurred in 61.0% of cases. The number of ATM/patient ranged from one to seven. Among the recurrent cases the median time between the first and the second ATM was 12 months (range 1-150 months).The first myelitis was characterized mainly by partial myelitis with motor and sensorial dysfunction (63.4%). Complete and severe myelitis occurred more frequently among monophasic patients and partial myelitis with moderate dysfunction at onset in recurrent cases; however, over the long-term, dysfunction and disability were mild in both groups. Serial spine MRI confirmed spinal cord inflammation in 92.0% of cases and extensive spinal cord lesion was identified in 61.0%. Brain MRI was normal or not suggestive of MS in 94.4% of cases. CSF showed pleocytosis in 41.2%, increased IgG index in 24.0% and oligoclonal bands in 38.0% of 34 patients tested. Abnormal visual evoked potentials occurred in 11.5% of 26 patients. Positivity for anti-AQP4 was found in 23.5% of the 17 cases tested, suggesting limited forms of NMO. This study suggests some new aspects of the clinical course of IATM such as the high conversion rate to NMO, the predominance of women and a higher frequency of recurrent forms.
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PMID:The clinical course of idiopathic acute transverse myelitis in patients from Rio de Janeiro. 2012 51

To describe and compare the diagnosis, demographics and management of systemic lupus erythematosus (SLE) related versus idiopathic acute transverse myelitis during the initial presentation of the disease. We undertook a chart review of the hospital records of patients admitted to our hospital from 1994 until 2007 and had the diagnosis of SLE related and idiopathic acute transverse myelitis. Demographics, laboratory and imaging studies, diagnosis and treatment were recorded in both groups and analyzed in a case control fashion. We identified 15 patients with SLE-related acute transverse myelitis (SLE-ATM) and 39 idiopathic (I-ATM) cases between 1994 and 2007. Patients with SLE were more likely to be African American, have CNS demyelinating lesions on MRI, a high IgG% on their CSF analysis and a higher sedimentation rate on presentation. Treatment with high-dose steroids was instituted in both groups of patients, though SLE patients had a longer hospital stay by an average of 5 days. SLE-ATM patients were more likely to be African American as compared to I-ATM patients, have CNS demyelinating lesions on MRI, a high IgG% on CSF analysis and a higher sedimentation rate on presentation. The hospital stay for SLE patients was 5 days longer than the idiopathic patients. This study underlines the importance of early diagnosis of patients who develop ATM related to SLE.
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PMID:Initial presentation of acute transverse myelitis in systemic lupus erythematosus: demographics, diagnosis, management and comparison to idiopathic cases. 2183 18

A 9-year-old girl born to healthy parents showed manifestations suggestive of ataxia telangiectasia (AT), such as short stature, sudden short bouts of horizontal and rotary nystagmus, a weak and dysarthric voice, rolling gait, unstable posture, and atactic movements. She did not show several cardinal features typical of AT such as frequent, severe infections of the respiratory tract. In contrast, she showed symptoms not generally related to AT, including microcephaly, profound motor and mental retardation, small hands and feet, severely and progressively reduced muscle tone with slackly protruding abdomen and undue drooling, excess fat on her upper arms, and severe oligoarthritis. A cranial MRI showed no cerebellar hypoplasia and other abnormalities. In peripheral blood samples she carried a de novo duplication of 3.14 Mb in chromosomal region 19q12 containing six annotated genes, UQCRFS1, VSTM2B, POP4, PLEKHF1, CCNE1, and ZNF536, and a de novo mosaic inversion 14q11q32 (96% of metaphases). In a saliva-derived DNA sample only the duplication in 19q12 was detected, suggesting that the rearrangements in blood lymphocytes were acquired. These findings reinforced the suspicion that she had AT. AT was confirmed by strongly elevated serum AFP levels, cellular radiosensitivity and two inherited mutations in the ATM gene (c.510_511delGT; paternal origin and c.2922-50_2940del69; maternal origin). This case suggest that a defective ATM-dependent DNA damage response may entail additional stochastic genomic rearrangements. Screening for genomic rearrangements appears indicated in patients suspected of defective DNA damage responses.
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PMID:A girl with an atypical form of ataxia telangiectasia and an additional de novo 3.14 Mb microduplication in region 19q12. 2189 20

Familial pancreatic cancer (FPC) describes families with at least two first-degree relatives with confirmed exocrine pancreatic cancer that do not fulfil the criteria of other inherited tumour syndromes with increased risks of pancreatic cancer, such as Peutz-Jeghers syndrome, hereditary pancreatitis, and hereditary breast and ovarian cancer. The inheritance of FPC is mostly autosomal dominant and with a heterogeneous phenotype. The major gene defect is yet to be identified, although germline mutations in BRCA2, PALB2 and ATM are causative in some FPC families. Expert consensus conferences considered it appropriate to screen for pancreatic cancer in high-risk individuals using a multidisciplinary approach under research protocol conditions. However, neither biomarkers nor reliable imaging modalities for the detection of high-grade precursor lesions are yet available. Most screening programmes are currently based on findings from endoscopic ultrasonography and MRI, and data has demonstrated that precursor lesions of pancreatic cancer can be identified. No consensus exists regarding the age to initiate or stop screening and the optimal intervals for follow-up. Timing and extent of surgery as a treatment for FPC are debated. This Review focuses on the clinical phenotype of FPC, its histopathological characteristics, known underlying genetic changes and associated genetic counselling and screening.
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PMID:Familial pancreatic cancer--current knowledge. 2266 88

Ataxia telangiectasia (A-T) is a highly pleiotropic disorder. Patients suffer from progressive neurodegeneration, severe bronchial complications, immunodeficiency, hypersensitivity to radiotherapy and elevated risk of malignancies. Leukemia and lymphoma, along with lung failure, are the main causes of morbidity and mortality in A-T patients. At present, no effective therapy for A-T exists. One promising therapeutic approach is bone marrow transplantation (BMT) that is already used as a curative therapy for other genomic instability syndromes. We used an established clinically relevant non-myeloablative host-conditioning regimen and transplanted green fluorescent protein (GFP)-expressing ataxia telangiectasia mutated (ATM)-competent bone marrow-derived cells (BMDCs) into Atm-deficient mice. GFP expression allowed tracking of the potential migration of the cells into the tissues of recipient animals. Donor BMDCs migrated into the bone marrow, blood, thymus, spleen and lung tissue of Atm-deficient mice showing an ATM-competent phenotype. BMT inhibited thymic lymphomas, normalized T-lymphocyte populations, improved weight gain and rearing activity of Atm-deficient mice. In contrast, no GFP(+) cells were found in the cerebellum or cerebrum, and we detected decreased size index in MRI imaging of the cerebellum in 8-month-old transplanted Atm-deficient mice in comparison to wild-type mice. The repopulation with ATM-competent BMDCs is associated with a prolonged lifespan and significantly improved the phenotype of Atm-deficient mice.
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PMID:Bone marrow transplantation improves the outcome of Atm-deficient mice through the migration of ATM-competent cells. 2310 Mar 26


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