Cáncer de mama y mutación del gen ataxia telangiectasia: reporte de caso

Entre las mujeres, el cáncer de mama es el más frecuente en el mundo, con el 25,7 %, lo cual hace que sea un tema de interés en salud pública. El cáncer de mama es una enfermedad genética compleja, heterogénea y, en la gran mayoría de los casos, de etiología desconocida. Alrededor del 7 % de los casos de cáncer de mama en la población general presentan alteraciones en un gen de susceptibilidad de herencia mendeliana. La mutación del gen de ataxia telangiectasia (ATM) se encuentra en menos del 1 % de la población general, y los estudios de asociación con controles han demostrado que estos alelos se caracterizan por conferir un riesgo moderado (RR: 2‐4) de padecer cáncer hereditario. Las mutaciones en ATM cosegregan de manera incompleta la enfermedad, y se estima que un 15 % de las portadoras de mutación en este gen desarrollarán el cáncer. La penetrancia incompleta de ATM, y otros genes de riesgo moderado, apoya que estos actúen siguiendo un modelo poligénico de susceptibilidad al cáncer. Se reporta el caso de una mujer de 35 años, con diagnóstico de carcinoma de mama bilateral metacrónico estadio clínico IIIB cT4b N1 M0 mama izquierda y estadio clínico I cT1c N0 mama derecha, con subtipo intrínseco luminal B y sobreexpresión HER2, y con la variante patogénica del gen ATM c.7913 G>A, p. Trp2638*. La paciente fue tratada con quimioterapia neoadyuvante, seguida de mastectomía, ganglio centinela y radioterapia. El objetivo es describir las características clínico‐patológicas y la asociación del cáncer de mama con mutaciones de genes de riesgo moderado.

Among women, breast cancer is the most common cancer in the world, accounting for 25.7 % of all cancers and thus making it a topic of interest in public health. Breast cancer is a complex, heterogeneous genetic disease and, in the vast majority of cases, of unknown etiology. Around 7 % of breast cancer cases in the general population present a susceptibility gene mutation of Mendelian inheritance. The ataxia telangiectasia mutated (ATM) gene mutation is found in less than 1 % of the general population, and association studies conducted with controls have shown that these alleles are characterized by a moderate risk (RR: 2 ‐ 4) for hereditary cancer. Mutations in ATM incompletely cosegregate the disease, with an estimated 15 % of mutation carriers in this gene developing cancer. The incomplete penetrance of ATM, as well as other moderate‐risk genes, supports that they follow a polygenic model of cancer susceptibility. We report the case of a 35‐year‐old woman diagnosed with metachronous bilateral breast carcinoma-T4b N1 M0 stage IIIB left breast and T1c N0 stage I right breast, intrinsic luminal B subtype, HER2 overexpression and pathogenic variant of ATM gene c.7913 G>A, p. Trp2638*-who was treated with neoadjuvant chemotherapy, followed by mastectomy, sentinel node biopsy and radiotherapy. The objective of this case report is to describe the clinicopathological characteristics of breast cancer and its association with moderate‐risk gene mutations.

Ataxia-telangiectasia: una revisión desde la etiopatogenia al manejo actual con descripción de casos reportados en Perú / Ataxia telangiectasia: A review from etiopathogenesis to current management with a description of reported cases in Peru

La Ataxia-Telangiectasia (AT) es una rara enfermedad de herencia autosómica recesiva y de afección multisistémica, caracterizada por ataxia progresiva, inmunodeficiencia variable con infecciones recurrentes, riesgo incrementado de neoplasias con o sin telangiectasias óculo-cutáneas. La AT es causada por variantes patogénicas bialélicas en el gen ATM. Su diagnóstico se basa en la sospecha de un cuadro clínico compatible, niveles elevados de alfafetoproteína, atrofia cerebelosa y estudios genéticos. No existe tratamiento curativo de AT y su manejo se basa en medidas de soporte y prevención de complicaciones y asesoramiento genético. En esta revisión, actualizamos la epidemiología, manifestaciones clínicas, diagnóstico y tratamiento de AT incluyendo una búsqueda de casos publicados en el Perú.

Ataxia-Telangiectasia (AT) is a rare autosomal recessive disease with multisystemic involvement, characterized by slowly progressive ataxia, variable immunodeficiency with recurrent infections, increased risk of neoplasms with or without oculocutaneous telangiectasias. AT is caused by biallelic pathogenic variants within the ATM gene. Its diagnosis is based on suspicion of a compatible clinical symptomatology, increased levels of alpha-fetoprotein, cerebellar atrophy, and genetic testing. There is no curative treatment for AT and its management is based on supportive and preventive measures of eventual complications and genetic counseling. This review updates the epidemiology, clinical manifestations, diagnosis, and treatment of AT, including a search for cases published in Peru.

Virtual screening of potential ATR kinase inhibitors based on machine learning and molecular docking / 中国药科大学学报

@#Screening potential active compounds from molecular libraries is a common method for drug discovery.However, with the continuous exploration of chemical space, there are already compound libraries with more than billions of molecules, so molecular docking is no longer enough to quickly screen specific target inhibitors from the ultra-large compound libraries.This study proposes a method for screening potential active compounds, which involves filtering and selecting compounds from a candidate compound library containing over 5.5 billion molecules through a series of steps, including calculating physical and chemical property similarities, constructing machine learning prediction models, and molecular docking.In the end, 51 compounds with potential ataxia telangiectasia-mutated and rad3-related (ATR) inhibitory activity were obtained.This method is effective for rapidly screening novel potential active compounds from large compound libraries.

Correlation analysis between ATM gene polymorphism and susceptibility of sporadic breast cancer / 中国医师杂志

Objective:To analyze the relationship between ataxia telangiectasia mutated (ATM) single nucleotide polymorphism (SNP) at rs1801516 and rs1800054 and sporadic breast cancer (SBC) in Inner Mongolia.Methods:A total of 102 patients with SBC (72 Han and 30 Mongolian) who were admitted to the Affiliated Hospital of Inner Mongolia Medical University from January 2018 to September 2019 were prospectively collected as case group and 102 healthy women (72 Han and 30 Mongolian) during the same period as control group. 2 ml of venous blood was collected to extract DNA. According to the Single Nucleotide Polymorphism Database (dbSNP), the highly polymorphic sites rs1801516 and rs1800054 of ATM gene were selected. The polymerase chain reaction (PCR) and direct sequencing were used to detect the polymorphism of the two sites, and the correlation between the single nucleotide polymorphism of the two sites and the susceptibility of SBC in Inner Mongolia was analyzed. The potential association between clinicopathological factors and ATM gene polymorphism in patients with SBC in Inner Mongolia were explored.Results:GG, GA and AA genotypes were detected in rs1801516 locus of ATM gene. Only CC genotype was detected in the rs1800054 locus of ATM gene. There was no significant difference in the distribution of genotype frequency and allele frequency between Mongolian breast cancer group and Han breast cancer group, Mongolian control group and Han control group, Mongolian breast cancer group and Mongolian control group, Han breast cancer group and Han control group (all P>0.05). Logistic regression analysis showed that allele G was the susceptibility gene of SBC in Inner Mongolia ( OR: 1.775, 95% CI: 1.04-3.03, P=0.04). ATM rs1801516 polymorphism may be associated with increased risk of breast cancer in patients with mass diameter ≤2 cm and/or without lymph node metastasis (all P<0.05). Conclusions:The polymorphism of ATM gene rs1801516 and rs1800054 may not be significantly correlated with the risk of SBC in Inner Mongolia. The rs1801516 locus may be associated with increased risk of breast cancer in patients with mass diameter ≤2 cm and/or without lymph node metastasis. Gene G may be one of the susceptible genes of SBC in Inner Mongolia.

Expression and functional SNP loci screen of ATM from coal worker's pneumoconiosis / 中华劳动卫生职业病杂志

Objective: To detect of gene expression and genotype of the ataxia telangiectasia mutated (ATM) from coal workers' pneumoconiosis (CWP) , It is explored whether CWP is related to ATM gene. Methods: In October 2020, the relevant information of 264 subjects who received physical examination or medical treatment in the Department of occupational diseases of Guiyang public health treatment center from January 2019 to September 2020 was collected. Through the occupational health examination, 67 healthy people with no history of exposure to occupational hazards were selected as the healthy control group; The coal miners with more than 10 years of coal dust exposure history and small shadow in the lung but not up to the diagnostic criteria were the dust exposure control group, a total of 66 people; The patients with the same history of coal dust exposure and confirmed stage I were coal worker's pneumoconiosis stage I group, a total of 131 people. The expression of ATM was detected by QRT PCR. ATM rs189037 and rs1801516 were genotyped by massarray. Results: There was significant difference in the expression of ATM among the groups (P<0.05) ; Compared with the healthy control group, the expression of ATM in the dust exposed control group was significantly increased (P<0.05) . With the occurrence and development of CWP, the GG of rs189037 wild type decreased, the GA of mutant heterozygote and AA of homozygote increased, but the difference was not statistically significant (P>0.05) ; Rs1801516 wild type GG and mutant heterozygote GA had no significant changes (P>0.05) . There were significant differences in age, neutrophils and basophils among rs189037 groups (all P<0.05) . There were no significant differences in blood pressure, eosinophils, lymphocytes, monocytes, smoking and drinking history among rs189037 groups (all P>0.05) . Compared with wild-type GG, the or of mutant heterozygotes and homozygotes increased, but the differences were not statistically significant (P>0.05) . Conclusion: ATM gene may be one of the early activation genes of CWP and rs189037 may be the functional loci which affects gene expression. ATM gene is related to inflammatory response, Neutrophils and basophils have an impact on the development of CWP.

Chemical screen identifies shikonin as a broad DNA damage response inhibitor that enhances chemotherapy through inhibiting ATM and ATR

DNA damage response (DDR) is a highly conserved genome surveillance mechanism that preserves cell viability in the presence of chemotherapeutic drugs. Hence, small molecules that inhibit DDR are expected to enhance the anti-cancer effect of chemotherapy. Through a recent chemical library screen, we identified shikonin as an inhibitor that strongly suppressed DDR activated by various chemotherapeutic drugs in cancer cell lines derived from different origins. Mechanistically, shikonin inhibited the activation of ataxia telangiectasia mutated (ATM), and to a lesser degree ATM and RAD3-related (ATR), two master upstream regulators of the DDR signal, through inducing degradation of ATM and ATR-interacting protein (ATRIP), an obligate associating protein of ATR, respectively. As a result of DDR inhibition, shikonin enhanced the anti-cancer effect of chemotherapeutic drugs in both cell cultures and in mouse models. While degradation of ATRIP is proteasome dependent, that of ATM depends on caspase- and lysosome-, but not proteasome. Overexpression of ATM significantly mitigated DDR inhibition and cell death induced by shikonin and chemotherapeutic drugs. These novel findings reveal shikonin as a pan DDR inhibitor and identify ATM as a primary factor in determining the chemo sensitizing effect of shikonin. Our data may facilitate the development of shikonin and its derivatives as potential chemotherapy sensitizers through inducing ATM degradation.

Role of ATR/CHK1 pathway in the occurrence and development of epithelial ovarian cancer / 中华内分泌外科杂志

Objective:To discuss the role of ataxia telangiectasia and Rad3-related kinase (ATR) /check point kinase 1 (CHK1) signaling pathway in the occurrence and development of epithelial ovarian cancer.Methods:Human epithelial ovarian cancer cells OVCAR3 cells were cultured in vitro, siRNA and VE-822 were used to interfere with ATR in OVCAR3 cells, the effectiveness of interference with ATR expression was detected by real-time fluorescence quantitative PCR (qRT-PCR) and Western blot, the cell proliferation inhibition was detect by CCK-8 method, cell cycle and apoptosis were detected by flow cytometry (FCM) , the mRNA expressions of Caspase-3, B-cell lymphoma-2 (Bcl-2) , Bcl-2-associated X protein (Bax) were detected by qRT-PCR, Western blot was used to detect the expression of ATR/CHK1 pathway related proteins.Results:After siRNA-ATR transfection and VE-822 intervention, compared with those in NC group and siRNA-sc group, the expression level of ATR mRNA [ (1.55±0.12) , (1.51±0.13) , (0.71±0.11) , (0.73±0.12) , (0.49±0.09) ] in OVCAR3 cells in siRNA-ATR group, VE-822 group and siRNA-ATR + VE-822 group was significantly lower ( P<0.05) , the inhibition rate of cell proliferation [ (0.00±0.00) %, (0.00±0.00) %, (32.84±1.08) %, (30.75±1.44) %, (43.90±1.57) %], ratio of G0/G1 phase [ (40.08±2.57) , (36.35±3.44) , (53.28±4.34) , (56.37±5.03) , (70.63±3.81) ], apoptosis rate [ (4.28±0.67) %, (5.35±0.94) %, (23.63±1.13) %, (24.57±1.20) %, (35.86±1.09) %], expression of Caspase-3 and Bax mRNA were significantly higher ( P<0.05) , and the cell proportions in S phase [ (32.93±3.02) , (35.35±2.82) , (25.79±3.61) , (23.74±3.54) , (18.04±2.37) ] and G2/M phase [ (26.99±2.84) , (28.30±2.72) , (20.93±3.01) , (19.98±2.87) , (11.33±2.11) ], Bcl-2 mRNA, ATR, p-CHK1/CHK1, cell division cycle protein 25C (CDC25C) and cyclin B1 protein expression were significantly lower ( P<0.05) . Compared with those in siRNA-ATR group, the expression of ATR mRNA in siRNA-ATR + VE-822 group was further decreased ( P<0.05) , the inhibition rate of cell proliferation, apoptosis, expression of Caspase-3 and Bax mRNA were further increased ( P<0.05) , and the expression of Bcl-2 mRNA, ATR, p-CHK1/CHK1, CDC25C and cyclin B1 protein was decreased continuously ( P<0.05) . Conclusion:ATR/CHK1 signaling pathway is activated during the proliferation of epithelial ovarian cancer OVCAR3 cells. Inhibition of ATR/CHK1 signaling pathway can inhibit the proliferation of epithelial ovarian cancer cells and induce G1/S cell cycle arrest and apoptosis.

Alterations of DNA damage response pathway: Biomarker and therapeutic strategy for cancer immunotherapy

Genomic instability remains an enabling feature of cancer and promotes malignant transformation. Alterations of DNA damage response (DDR) pathways allow genomic instability, generate neoantigens, upregulate the expression of programmed death ligand 1 (PD-L1) and interact with signaling such as cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling. Here, we review the basic knowledge of DDR pathways, mechanisms of genomic instability induced by DDR alterations, impacts of DDR alterations on immune system, and the potential applications of DDR alterations as biomarkers and therapeutic targets in cancer immunotherapy.

Phosphorylation regulates cullin-based ubiquitination in tumorigenesis

Cullin-RING ligases (CRLs) recognize and interact with substrates for ubiquitination and degradation, and can be targeted for disease treatment when the abnormal expression of substrates involves pathologic processes. Phosphorylation, either of substrates or receptors of CRLs, can alter their interaction. Phosphorylation-dependent ubiquitination and proteasome degradation influence various cellular processes and can contribute to the occurrence of various diseases, most often tumorigenesis. These processes have the potential to be used for tumor intervention through the regulation of the activities of related kinases, along with the regulation of the stability of specific oncoproteins and tumor suppressors. This review describes the mechanisms and biological functions of crosstalk between phosphorylation and ubiquitination, and most importantly its influence on tumorigenesis, to provide new directions and strategies for tumor therapy.

Ataxia telangiectasia: a diagnostic challenge. case report

ABSTRACT Introduction: Ataxia-telangiectasia (AT) is a neurodegenerative syndrome with low incidence and prevalence worldwide, which is caused by a mutation of the ATM gene. It is an autosomal recessive disorder that is associated with defective cell regeneration and DNA repair mechanisms. It is characterized by progressive cerebellar ataxia, abnormal eye movements, oculocutaneous telangiectasias and immunodeficiency. Early diagnosis is critical to initiate a timely interdisciplinary treatment, improve acute symptoms, and control the multiple comorbidities of the disease. The following is the case of a patient who presented with the aforementioned characteristics and had an adequate response to the established medical treatment. Case presentation: A 7-year-old female patient from Bogotá, who presented clinical signs of global neurodevelopmental delay, cerebellar ataxia, frequent respiratory infections and ocular telangiectasias. Symptoms were associated with elevation of alpha fetoprotein and immunodeficiency, which allowed for a diagnosis of AT and the initiation of a timely interdisciplinary treatment. Conclusion: AT is a chromosomal instability syndrome with characteristic signs and symptoms. It is essential to know the etiopathogenesis, clinical manifestations, diagnostic criteria, and therapeutic options, emphasizing that early detection and clinical suspicion could favor the proper management of the comorbidities and improve the progressive course of the disease.

RESUMEN Introducción. La ataxia-telangiectasia (AT) es un síndrome neurodegenerativo con baja incidencia y prevalencia mundial que es causado por una mutación del gen ATM, es de herencia autosómica recesiva y se asocia a mecanismos defectuosos en la regeneración y reparación del ADN. Este síndrome se caracteriza por la presencia de ataxia cerebelosa progresiva, movimientos oculares anormales, telangiectasias oculocutáneas e inmunodeficiencia. El diagnóstico oportuno de la AT es muy importante para poder iniciar un manejo interdisciplinario temprano, mejorar la sintomatología aguda y controlar las múltiples comorbilidades que causa. A continuación se presenta el caso de una paciente con las características clásicas de esta enfermedad y una adecuada respuesta y evolución al manejo médico instaurado. Presentación de caso. Paciente femenina de 7 años de edad, procedente de Bogotá, quien presentó cuadro clínico inicial de retraso global del neurodesarrollo, ataxia cerebelosa, infecciones respiratorias frecuentes y telangiectasias oculares. La sintomatología se asoció a elevación de alfa fetoproteína e inmunodeficiencia, lo que permitió plantear el diagnóstico de AT e iniciar de manera oportuna el manejo interdisciplinario. Conclusión. La AT es un síndrome de inestabilidad cromosómica con signos clínicos y síntomas característicos, por lo que es primordial conocer la etiopatogenia, el cuadro clínico, los criterios diagnósticos y las propuestas terapéuticas, pues la detección y la sospecha clínica temprana pueden favorecer el manejo precoz de las diferentes comorbilidades y mejorar el curso progresivo.

Terapia nutricional de paciente com ataxia-telangiectasia: relato de caso / Nutrition therapy of a patient with ataxia-telangiectasia: case report

Neste artigo relatamos a terapia nutricional de um paciente com ataxia-telangiectasia (A-T) utilizando a gastrostomia (GTM) como via alternativa para alimentação. Paciente do sexo masculino, 13 anos de idade, com diagnóstico clínico de A-T aos 6 anos. Aos 8 anos e 7 meses o paciente foi identificado com risco nutricional (ZIMC/I: -1,67). Após 1 ano, evoluiu de forma desfavorável (ZIMC/I: -2,51) apesar da intervenção nutricional, sendo indicada a GTM aos 9 anos e 11 meses. No entanto, em decorrência da dificuldade de aceitação dos pais, o procedimento foi realizado somente quando o adolescente completou 11 anos e 7 meses. Inicialmente foi prescrita para oferta pela GTM dieta enteral normocalórica e normoproteica, correspondendo a 45,8% da necessidade energética diária. Após um mês, com estabilidade metabólica, houve a transição para uma dieta enteral hipercalórica e hiperproteica, fornecendo 91,6% da necessidade energética diária. Após 6 meses com a GTM, verificou-se ganho de peso total de 3,3 Kg (ZIMC/I -2,97), após 1 ano de 4,7 Kg (ZIMC/I -2,59), e após 1 ano e 9 meses de 6,7 Kg (ZIMC/I -2,63). Apesar da desnutrição nos pacientes com A-T ter origem multifatorial, o uso da GTM como via alternativa para alimentação por esse paciente resultou em uma evolução favorável dos seus indicadores antropométricos, sendo relatadas poucas intercorrências com a sua utilização. Portanto, sugere-se que pacientes com A-T devam ser monitorados periodicamente por equipe multiprofissional visando à identificação precoce de potenciais agravos.

In this article we report the nutritional therapy of a patient with ataxia-telangiectasia (A-T) using percutaneous endoscopic gastrostomy (PEG) as an alternative way of feeding. The patient was a 13-year-old male diagnosed with A-T at the age of 6 years. At 8 years and 7 months, the patient was at nutritional risk (body mass index z-score [BMIZ]: -1.67). After 1 year, he had an unfavorable evolution (BMIZ: -2.51), despite nutritional intervention; then, a PEG was indicated when he was 9 years and 11 months. However, due to the difficulty of parental acceptance, the procedure was performed when the adolescent was 11 years and 7 months. At first, a standard energy and protein enteral formula was prescribed, reaching 45.8% of his daily energy requirement. After 1 month, with metabolic stability, there was a transition to a high-energy and protein enteral formula providing 91.6% of his daily energy requirement. After 6 months of PEG placement, the patient had a total body weight gain of 3.3 kg (BMIZ: -2.97); subsequently, body weight increased by 4.7 kg (BMIZ: -2.59) after 1 year, and by 6.7 kg (BMIZ: -2.63) after 1 year and 9 months. Despite the multifactorial origin of malnutrition in A-T patients, PEG placement as an alternative way of feeding for this patient resulted in favorable evolution of his anthropometric indicators, and only a few complications were reported with its use. Therefore, it is suggested that patients with A-T should be monitored periodically by a multidisciplinary team for early identification of potential damages.

Research progress on ataxia-telangiectasia / 国际儿科学杂志

Ataxia-telangiectasia (AT) is a rare autosomal recessive genetic disorder resulting from ataxia-telangiectasia mutated(ATM) gene mutation.ATM involved in DNA repair.ATM is made up of 66 exons.Its mutation forms are complex, including nonsense mutation, missense mutation, shear site mutation, insertion and deletion, etc.The patients are characterized by progressive cerebellar atrophy and ataxia, disturbance of eye movement, telangiectasia and dystonia, a high risk of cancer and immunodeficiency.These patients are also hypersensitive to radiotherapy.AT is often neglected at the early stage.As pediatricians, we should pay attention to early ataxia and conduct genetic testing as early as possible to avoid radiation exposure.

Association between single nucleotide polymorphism at rs175048 locus of ATM gene and susceptibility to lung cancer in Han population in Hengyang, Hunan / 中国肿瘤生物治疗杂志

@# Objective: To explore the association between the single nucleotide polymorphism (SNP) of rs175048 in ataxia telangiectasia mutated (ATM) gene and lung cancer susceptibility in Han population. Methods: A total of 225 cases of blood samples from lung cancer patients treated in Hospital of Traditional Chinese Medicine of Hengyang City and the Affiliated First Hospital of Nanhua University from October 2015 to August 2016 were collected as case group, and 128 cases of blood samples from healthy people were collected as the control. The polymorphisms of ATM rs175048 of above mentioned participants were detected by using the SNP sensitive On/Off Switch technique. The genotypes and allele frequencies were analyzed to compare the distribution difference between case group and control group as well as its association to the clinical features of lung cancer. Results: The genotype frequencies of AA, AT and TT of ATM rs175048 were 24.9%, 52.9%, 22.2% in case group and 42.2%, 42.2%, 15.6% in control group, respectively (all P< 0.01). Moreover, the frequencies of alleles A and T were 51.0%, 49.0% in case group, and 63.0%, 37.0% in control group (all P<0.01). Genotype TT might increase while genotype AT might decrease the risk of lung cancer. rs175048 SNP was significantly correlated with smoking, age, sex and family history (all P<0.05). Conclusion: rs175048 SNPis significantly associated with lung cancer, and TT genotype may increase the risk of lung cancer.

Research progress on ataxia-telangiectasia / 国际儿科学杂志

Ataxia-telangiectasia (AT) is a rare autosomal recessive genetic disorder resulting from ataxia-telangiectasia mutated (ATM) gene mutation.ATM involved in DNA repair.ATM is made up of 66 exons.Its mutation forms are complex,including nonsense mutation,missense mutation,shear site mutation,insertion and deletion,etc.The patients are characterized by progressive cerebellar atrophy and ataxia,disturbance of eye movement,telangiectasia and dystonia,a high risk of cancer and immunodeficiency.These patients are also hypersensitive to radiotherapy.AT is often neglected at the early stage.As pediatricians,we should pay attention to early ataxia and conduct genetic testing as early as possible to avoid radiation exposure.

Ataxia, telangiectasia con inmunodeficiencia / Ataxia, telangiectasia with immunodeficiency

La ataxia-telangiectasia es un trastorno autosómico recesivo, caracterizado por la presencia de telangiectasias oculocutáneas, ataxia cerebelosa progresiva, inmunodeficiencia e infecciones recurrentes. Además, está relacionado con neoplasias del sistema retículo-endotelial y trastornos inmunológicos. El objetivo de la presentación es destacar el papel del dermatólogo en este tipo de trastornos neurocutáneos, así como la importancia del seguimiento a largo plazo.

Ataxia telangiectasia is an autosomal recessive disorder characterized by oculocutaneous telangiectasia, progressive cerebellar ataxia, immunodeficiency, and recurrent infections. Besides, it is related to reticuloendothelial system neoplasms and immune disorders. The aim of this presentation is to emphasize the role of the Dermatologist in this type of neurocutaneous disorders and the importance of long-term follow up.

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.

Novel compound heterozygous mutations of ATM in ataxia-telangiectasia: A case report and calculated prevalence in the Republic of Korea

Ataxia-telangiectasia (AT; OMIM 208900) is a rare autosomal recessive inherited progressive neurodegenerative disorder, with onset in early childhood. AT is caused by homozygous or compound heterozygous mutations in ATM (OMIM 607585) on chromosome 11q22. The average prevalence of the disease is estimated at 1 of 100,000 children worldwide. The prevalence of AT in the Republic of Korea is suggested to be extremely low, with only a few cases genetically confirmed thus far. Herein, we report a 5-year-old Korean boy with clinical features such as progressive gait and truncal ataxia, both ankle spasticity, dysarthria, and mild intellectual disability. The patient was identified as a compound heterozygote with two novel genetic variants: a paternally derived c.5288_5289insGA p.(Tyr1763*) nonsense variant and a maternally derived c.8363A>C p.(His2788Pro) missense variant, as revealed by next-generation sequencing and confirmed by Sanger sequencing. Based on claims data from the Health Insurance Review and Assessment Service Republic of Korea, we calculated the prevalence of AT in the Republic of Korea to be about 0.9 per million individuals, which is similar to the worldwide average. Therefore, we suggest that multi-gene panel sequencing including ATM should be considered early diagnosis.

Ataxia-Telangiectasia-Mutated Protein Expression as a Prognostic Marker in Adenoid Cystic Carcinoma of the Salivary Glands

PURPOSE: Adenoid cystic carcinoma (ACC) is a high-grade malignant tumor of the salivary glands, clinically characterized by multiple recurrences and late distant metastasis. Biological markers for assessing the prognosis of ACC have remained elusive. The purpose of this study was to investigate whether the protein expressions of ataxia telangiectasia mutated (ATM), p53, and ATM-mediated phosphorylated p53 are related to patient survival in ACC. MATERIALS AND METHODS: In this study, 48 surgical samples were used to assess the expressions of ATM and its downstream target p53. Fisher's exact test and Kaplan-Meier analysis were conducted to evaluate the role of ATM, p53, and phospho-p53 (S15) protein expressions in predicting patient survival and distant metastasis. RESULTS: Myb expression was positive in 85.4% of ACCs, but did not reflect patient survival rate. In contrast, low expression of ATM in cancer cells was significantly correlated with poor survival rate (p=0.037). Moreover, under positive p53 expression, low expression of ATM was highly predictive of poor survival in ACC (p=0.017). CONCLUSION: These data indicate that combined assessment of ATM and p53 expression can serve as a useful prognostic marker for assessing survival rate in patients with ACC of the salivary glands.

A Novel Homozygous Variant of SETX Causes Ataxia with Oculomotor Apraxia Type 2

BACKGROUND AND PURPOSE: Autosomal recessive cerebellar ataxias constitute a highly heterogeneous group of neurodegenerative disorders. This study was carried out to determine the clinical and genetic causes of ataxia in two families from Pakistan. METHODS: Detailed clinical investigations were carried out on probands in two consanguineous families. Magnetic resonance imaging was performed. Exome sequencing data were examined for likely pathogenic variants. Candidate variants were checked for cosegregation with the phenotype using Sanger sequencing. Public databases including ExAC, GnomAD, dbSNP, and the 1,000 Genome Project as well as ethnically matched controls were checked to determine the frequencies of the alleles. Conservation of missense variants was ensured by aligning orthologous protein sequences from diverse vertebrate species. RESULTS: Reverse phenotyping identified spinocerebellar ataxia, autosomal recessive 1 [OMIM 606002, also referred to as ataxia oculomotor apraxia type 2 (AOA2)] and ataxia telangiectasia (OMIM 208900) in the two families. A novel homozygous missense mutation c.202 C>T (p.Arg68Cys) was identified within senataxin, SETX in the DNA of both patients in one of the families with AOA2. The patients in the second family were homozygous for a known variant in ataxia-telangiectasia mutated (ATM) gene: c.7327 C>T (p.Arg2443Ter). Both variants were absent from 100 ethnically matched control chromosomes and were either absent or present at very low frequencies in the public databases. CONCLUSIONS: This report extends the allelic heterogeneity of SETX mutations causing AOA2 and also presents an asymptomatic patient with a pathogenic ATM variant.

Bloqueo auriculoventricular completo y asistolia en un niño con ataxia-telangiectasia / Complete heart block and asystole in a child with ataxia-telangiectasia

La ataxia-telangiectasia es una entidad caracterizada por un cuadro de ataxia cerebelosa progresiva, telangiectasias, defectos inmunológicos y una mayor tendencia al desarrollo de tumores malignos. La mutación genética responsable (ataxia-telangiectasia mutada) parece jugar un papel importante en la función celular normal y el remodelado cardiovascular. Se describe la aparición de una arritmia maligna en un paciente de 14 años con un diagnóstico de ataxia-telangiectasia, en remisión completa de linfoma no Hodgkin B de alto grado. Consultó en el Servicio de Urgencias Pediátricas por episodios de presíncope, y se observó, al ingresar, bloqueo auriculoventricular completo que evolucionó hacia asistolia, por lo que requirió la colocación de un marcapasos definitivo. Las dosis acumuladas de fármacos cardiotóxicos recibidos fueron de bajo riesgo. Sin embargo, es posible que esta enfermedad degenerativa crónica afecte con el tiempo al tejido de citoconducción. En la bibliografía revisada, no existen o se desconocen reportes previos de arritmias malignas en pacientes con ataxia-telangiectasia.

Ataxia-telangiectasia is a disorder characterized by cerebellar ataxia, telangiectasia, immunodeficiency, and increased predisposition to cancer susceptibility. Mutations in the ataxia telangiectasia mutated gene seem to play an important role in normal cell function and in cardiovascular remodeling. We report a case of a 14-year-old boy with ataxia-telangiectasia and high-grade B-non-Hodgkin lymphoma who remained in continuous complete remission after chemotherapy and who was admitted into our Emergency Room presenting with episodes of presyncope. At admission he presented a complete atrioventricular block that evolved into asystole and required placement of a pacemaker. Cumulative cardiotoxic drugs received were at low risk. However, it is possible that this chronic degenerative disease may affect the cardiac conduction system over time. In the reviewed literature there are no or unknown reports of ataxia-telangiectasia with malignant cardiac arrhythmias.