Assessing cardiovascular risk in ATM heterozygotes / Avaliação do risco cardiovascular de ATM heterozigotos

Summary Objective: To evaluate the carotid intima-media complex (CIMC) thickness and lipid metabolism biomarkers associated with cardiovascular risk (CR) in parents of patients with ataxia-telangiectasia and verify an association with gender. Method: A cross-sectional and controlled study with 29 ATM heterozygotes and 14 healthy controls. Biochemical tests and CIMC thickness measurement were performed. Results: The mean CIMC measurement in heterozygous ATM was 0.72 ± 0.1 mm (minimum: 0.5 mm and maximum: 1.0 mm). Noticed high percentage of amounts above 75 percentile compared to the population referential (16 [76.2%]), without any significant statistical differences between the female and the male gender (11/15 [73.3%] vs. 5/6 [83.3%]; p=0.550). The comparison between heterozygous and controls, stratified by gender, showed that in heterozygous ATMs, women had higher concentrations of HDL-c compared to men, as well as higher values of hs-CRP in relation to the control women. In heterozygous ATMs, stratified by gender, the correlation between HDL-c and hs-CRP was inversely proportional and stronger among women, with a tendency to statistical significance. Conclusion: Heterozygous ATMs did not differ from controls in relation to the biomarkers studied related to CR. However, most of them presented increased CIMC, independent predictor of death, risk for myocardial infarction and stroke, compared to the referential for the same age group. This finding suggests CR in the heterozygous ATM and shows to the need to monitor CIMC thickness and nutritional orientations.

Resumo Objetivo: Avaliar a espessura do complexo médio-intimal da carótida (CMIC) e os biomarcadores do metabolismo lipídico associados ao risco cardiovascular (RC) em pais de pacientes com ataxia-telangiectasia (AT) e verificar associação com gênero. Método: Estudo transversal prospectivo e controlado com 29 ATM heterozigotos e 14 controles saudáveis. Foram realizados exames bioquímicos e a espessura do CMIC por ultrassonografia. Resultados: A média da medida do CMIC nos ATM heterozigotos foi de 0,72± 0,1 mm (mínimo: 0,5 mm e máximo: 1,0 mm). Observou-se elevado percentual de valores acima do percentil 75 em relação ao referencial populacional (16 [76,2%]), sem diferença estatisticamente significante entre o gênero feminino e o masculino (11/15 [73,3%] vs. 5/6 [83,3%]; p=0.550). A comparação entre os ATM heterozigotos e os controles, estratificados por gênero, mostrou que, nos ATM heterozigotos, as mulheres tinham maiores concentrações de HDL-c em comparação aos homens, e valores mais elevados de PCR-us em relação às mulheres controle. Nos ATM heterozigotos, estratificando segundo gênero, a correlação entre HDL-c e PCR-us foi inversamente proporcional e mais forte entre as mulheres, com tendência à significância estatística. Conclusão: Os ATM heterozigotos não diferiram dos controles em relação aos biomarcadores estudados relacionados ao RC. Entretanto, a maioria deles apresentou aumento na espessura do CMIC, preditor independente de morte, risco para infarto do miocárdio e AVC, quando comparado ao referencial para a mesma faixa etária. Esse achado sugere RC nos ATM heterozigotos e aponta para a necessidade de monitoramento da espessura do CMIC e de orientações nutricionais.

Nueva mutación en el gen ATM en paciente con ataxis telangiectasia: Caso clínico / New mutation in ATM gen in patient whith Ataxia Telangiectasia: Clinical case

Introducción: El síndrome de ataxia telangiectasia (AT) es una enfermedad genética autosómica recesiva de compromiso multisistémico, con un espectro clínico amplio, ocasionada por la mutación del gen ATM, lo que causa la disminución o ausencia de la proteinkinasa ATM, por lo que se alteran procesos del ciclo celular, reparación del ADN y apoptosis. El objetivo de este artículo es el de reportar el caso de una paciente con síndrome de AT causada por una mutación no reportada previamente en la literatura. Caso clínico: Paciente originaria de Colombia, de 14 años de edad, con manifestaciones clínicas y fenotípicas clásicas del síndrome de AT a partir de los 6 años de edad, con alteración pondoestatural, infecciones respiratorias a repetición, telangiectasias oculocutáneas y compromiso neurológico progresivo, caracterizado por regresión en su desarrollo psicomotor, ataxia y apraxia oculomotora. Se realizó secuenciación del gen ATM que demostró mutación en homocigosis no reportada previamente en la literatura. Discusión: En Latinoamérica son escasos los reportes de pacientes con AT y pocos aquellos en donde se describen los hallazgos moleculares. Los estudios moleculares son una herramienta que facilita el diagnóstico y permite orientar mejor el manejo y pronóstico de pacientes con enfermedades neurodegenerativas. El reporte de variantes moleculares no descritas es de gran importancia para establecer la causa etiológica de este tipo de patologías en grupos poblacionales diversos, como lo son los países de Latinoamérica.

Introduction: The ataxia telangiectasia syndrome (AT) is a genetic disease with an autosomal recessive inheritance pattern, with multisystem involvement and a broad clinical spectrum. It is caused by the mutation of the ATM gene, causing reduction or absence of the ATM proteinkinase, altering processes in the cell cycle, DNA repair and apoptosis. The objective of this article is to report the case of a patient with ataxia telangiectasia syndrome, caused by a mutation not previously reported in the literature. Case report: A 14 year-old patient native to Colombia, with classic clinical and phenotypical manifestations of AT syndrome, which started at 6 years of age with pondostatural alteration, recurrent respiratory infections, oculocutaneus telangiectasias and progressive neurological disorder that included: regression in her psychomotor development, ataxia and oculomotor apraxia. ATM gene sequencing is performed evidencing a homozygous mutation not reported in literature. Discussion: In Latin America are sparse the number of reports of patients with ataxia telangiectasia and only few of these describe their molecular findings. Molecular studies allow the diagnosis and a better orientation in the management and prognosis of patients with neurodegenerative diseases. The report of undescribed molecular variants is of great importance to establish the etiology of such diseases in diverse population groups, such as the countries of Latin America.

Ataxia-Telangiectasia with Novel Splicing Mutations in the ATM Gene

No abstract available.

Síndrome de ataxia telangiectasia (enfermedad de Louis Barr): una rara facomatosis / Syndrome of ataxia telangiectasia (Louis Barr disease): a rare facomatosis

La ataxia telangiectasia o síndrome de Louis Barr es un raro desorden neurodegenerativo de carácter autosómico recesivo, caracterizado por afectación multisistémica: neurológica, oftalmológica, inmunológica, endocrina, hepática y cutánea. El complejo clínico comprende la presencia de ataxia cerebelosa progresiva, telangiectasias oculocutáneas, enfermedad sinopulmonar crónica, elevada incidencia de neoplasias y una inmunodeficiencia combinada. Es causada por mutación en el gen ataxia telangiectasia, localizado en el locus 11 q22-23, lo que da lugar a deficiencias en su expresión. Su frecuencia se calcula en 1:80.000 y 1,4 % de la población es portadora del gen. Se presenta el caso de una paciente con documentación fotográfica.

The syndrome of ataxia telangiectasia or Louis Barr disease is a rare neurodegenerative disorder autosomal recessive, characterized by multisystem involvement: neurological, immunological, endocrine, ophthalmological, hepatic and cutaneous. The clinical complex includes the presence of progressive cerebellar ataxia, ocular and cutaneous telangiectasia, chronic sinopulmonar disease, high incidence of neoplasms and combined immunodeficiency. It is caused by mutation in the gene for ataxia telangiectasia, located in the q22-23 11 locus, which leads in its expression to numerous deficiencies. Its frequency is calculated in 1:80.000, and 1,4% of the population is a carrier of the gene. The case of a patient with photographic documentation is presented.

Ataxia telangiectasia: Family management.

Ataxia telangiectasia (AT) is a rare autosomal recessive disease resulting in progressive degeneration of multiple systems in the body. Both A-T homozygote and heterozygote are at increased risk of developing malignancy. We report a family in which three generations were affected by this disorder. Our index case is a 12-year-old female child, born of second degree consanguineous marriage diagnosed to have ataxia telangiectasia at the age of four years, now presented with fever and neck swelling of one month duration. Family history suggestive of ataxia telangiectasia in maternal uncle and younger sibling was present. History of premature coronary artery disease and death in paternal grandfather was present. On evaluation, child was diagnosed to have Alk negative anaplastic large T cell lymphoma. Management included genetic counseling, examination of all the family members, identification of A-T homozygote and providing appropriate care, regular surveillance of the heterozygote for malignancy.

Roles of nibrin and ATM/ATR kinases on the G2 checkpoint under endogenous or radio-induced DNA damage

Checkpoint response to DNA damage involves the activation of DNA repair and G2 lengthening subpathways. The roles of nibrin (NBS1) and the ATM/ATR kinases in the G2 DNA damage checkpoint, evoked by endogenous and radio-induced DNA damage, were analyzed in control, A-T and NBS lymphoblast cell lines. Short-term responses to G2 treatments were evaluated by recording changes in the yield of chromosomal aberrations in the ensuing mitosis, due to G2 checkpoint adaptation, and also in the duration of G2 itself. The role of ATM/ATR in the G2 checkpoint pathway repairing chromosomal aberrations was unveiled by caffeine inhibition of both kinases in G2. In the control cell lines, nibrin and ATM cooperated to provide optimum G2 repair for endogenous DNA damage. In the A-T cells, ATR kinase substituted successfully for ATM, even though no G2 lengthening occurred. X-ray irradiation (0.4 Gy) in G2 increased chromosomal aberrations and lengthened G2, in both mutant and control cells. However, the repair of radio-induced DNA damage took place only in the controls. It was associated with nibrin-ATM interaction, and ATR did not substitute for ATM. The absence of nibrin prevented the repair of both endogenous and radio-induced DNA damage in the NBS cells and partially affected the induction of G2 lengthening.

Ataxia telangietasia [about 11 cases]

Ataxia telangiectasia [AT] is an autosomal recessive disorder, caracterized by progressive cerebellar ataxia, oculocutaneos telangiectasia, immunological abnormalities and increased susceptibility of malignancies. Our study objectives are to provide the last data in genetic, clinical and therapeutic fields concerning AT in order to help our doctors to establish the diagnosis in the first stages and so participite to the diagnosis of the primary immunodeficiency diseases. Our 11 patients are from 7 families and the consanguinity was found in 8 cases. The median age of diagnosis is about 7 years and 7 months. The clinical study had found out eight cases of manifest ataxia, nine times bulbar telangiectasias and eight cases of bronchectasias. On the immunological side, the serum IgA deficiency was found 5 times and one case had showed lymphopenia. The taking in charge consisted in infectious episodes treatement and continuous antibiotic prophylaxis, IGIV infusion was used only four times. The course of our patients was characterized by regression of infectious signs in five cases and the death of five others. One patient had never been seen again. Our set was charactezed by the heterogenecity of the features. In one hand we had severe form with a very soon start and in the other hand we had a mild clinical form with a late start

Cytogenetic studies in ataxia telangiectasia & their use in prenatal diagnosis.

Cytogenetic studies were carried out in obligate ataxia telangiectasia (AT) heterozygotes, AT homozygotes and control subjects. Rate of chromosomal aberrations and the frequency of micronuclei were examined before and after radiation (100 rads). Significant differences in the rate of chromosomal aberrations and micronuclei were observed among heterozygotes, homozygotes and controls. The same methods were then applied for prenatal diagnosis of AT using amniotic cell culture in two families.

Detección de heterocigotos de ataxia telangiectasia por la sensibilidad a la radiación ionizante / Detection of heterocygotic with patients with ataxia telangiectasia show chromosomic rupture

Investigaciones recientes han demostrado que los pacientes homocigotos y heterocigotos de ataxia telangiectasia (AT) tienen rompimientos cromosómicos. De acuerdo con esta característica se diseñó el estudio inducido rompimientos cromosómicos en células granulocíticas de pacientes con diagnóstico de AT, heterocigotos obligados de AT y comparados con un grupo de individuos sanos. A todos los pacientes se les cuantificó el número de rompimientos cromosómicos con 14 dosis de radiación 125 kv, 125 mA. Los resultados sugieren diferencias significativas en el número de alteraciones estructurales cromosómicas inducidas por la radiación en los granulocitos de heterocigotos de ataxia telangiectasia similares a las alteraciones estructurales de los linfocitos de pacientes con AT y se demuestra que estas alteraciones se presentan preferentemente en un cromosoma del grupo C de homocigotos y heterocigotos de AT