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.

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.

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.

Tomada de decisão: papel do fonoaudiólogo em cuidados paliativos / Decision making: the role of the speech therapist in palliative care / Toma de decisión: papel del fonoaudiólogo en cuidados paliativos

Introdução: A tomada de decisão compartilhada é uma estratégia centrada na pessoa, procurando alinhar a comunicação entre profissionais da saúde e pacientes, conjuntamente com as preferências, valores e objetivos dos indivíduos Objetivo: Correlacionar os achados clínicos da disartria, disfagia e cognição com o processo de tomada de decisão em saúde em um paciente com diagnóstico molecular confirmado de Ataxia Telangiectasia em cuidados paliativos em fase terminal. Método: Foi realizada avaliação clínica fonoaudiológica da disartria, disfagia e cognição. À partir dos resultados apresentados na avaliação, foram abordados princípios e diretrizes do processo de tomada de decisão em saúde, a fim de auxiliar na definição do processo terapêutico em pacientes em cuidados paliativos. Resultados: Paciente apresentou disartria atáxica e disfagia orofaríngea moderada a grave, porém apesar do risco significativo de aspiração laríngea para todas as consistências alimentares, demonstrou forte desejo em manter alimentação via oral exclusiva. Com relação à cognição paciente apresentou funções cognitivas de acordo com a normalidade para idade e escolaridade. Por meio de um processo de escolha informada, discussão multidisciplinar e baseando-se em princípios da tomada de decisão compartilhada em saúde, optou-se por priorizar o desejo do paciente e indicou-se alimentação via oral. Conclusão: Partindo do processo de tomada de decisão compartilhada e buscando minimizar o sofrimento de pacientes em cuidados paliativos, o fonoaudiólogo deve assumir uma nova perspectiva às decisões terapêuticas a fim de favorecer e envolver o paciente e seus familiares desde o início do diagnóstico até as decisões de fim de vida.

Introduction: Shared decision making is a person-centered strategy, seeking to align communication between health professionals and patients, along with individuals' preferences, values and goals. Objective: To correlate the clinical findings of dysarthria, dysphagia and cognition with the health decision-making process of a patient with confirmed molecular diagnosis of Ataxia Telangiectasia, in end-stage palliative care. Method: An evaluation of dysarthria, dysphagia and cognition was performed by a speech language pathologist. Based on the results which presented in the evaluation, principles and guidelines of the health decision-making process were addressed, in order to help define the therapeutic process for patients in palliative care. Results: The patient presented ataxic dysarthria and moderate to severe oropharyngeal dysphagia. However, despite a significant risk of laryngeal aspiration for all food consistencies, the patient expressed a strong desire to maintain exclusive oral feeding. With regard to cognition, the patient presented normal cognitive functions for his age bracket and education level. Through a process of informed choice and multidisciplinary discussion, and based on principles of shared decision-making in health, we chose to prioritize the patient's desire and to support oral feeding. Conclusion: Starting from the shared decision-making process and seeking to minimize the suffering of patients in palliative care, the speech language pathologist must take a new perspective on therapeutic decisions in order to favor and involve the patient and his relatives from the beginning of the diagnosis up to end-of-life decisions.

Introduction: La toma de decisiones compartida es una estrategia centrada en la persona, buscando alinear la comunicación entre profesionales de la salud y pacientes, junto con las preferencias, valores y objetivos de los individuos. Objetivo: Correlacionar los hallazgos clínicos de la disartria, disfagia y cognición con el proceso de toma de decisión en salud en un paciente con diagnóstico molecular confirmado de Ataxia Telangiectasia en cuidados paliativos en fase terminal. Método: Se realizó una evaluación clínica fonoaudiológica de la disartria, disfagia y cognición. A partir de los resultados presentados en la evaluación se abordaron principios y directrices del proceso de toma de decisión en salud, a fin de auxiliar en la definición del proceso terapéutico en pacientes en cuidados paliativos. Resultados: Paciente presentó disartria atáxica y disfagia orofaríngea moderada a grave, pero a pesar del riesgo significativo de aspiración laríngea para todas las consistencias alimenticias, demostró fuerte deseo en mantener alimentación oral exclusiva. Con respecto a la cognición paciente presentó funciones cognitivas de acuerdo con la normalidad para edad y escolaridad. Por medio de un proceso de elección informada, discusión multidisciplinaria y basándose en principios de la toma de decisión compartida en salud, se optó por priorizar el deseo del paciente y se indicó alimentación oral. Conclusión: Partiendo del proceso de toma de decisión compartida y buscando minimizar el sufrimiento de pacientes en cuidados paliativos, el fonoaudiólogo debe asumir una nueva perspectiva a las decisiones terapéuticas a fin de favorecer e involucrar al paciente ya sus familiares desde el inicio del diagnóstico hasta las decisiones de fin de vida.

Therapeutic Targeting of the DNA Damage Response Using an ATR Inhibitor in Biliary Tract Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: The DNA damage response (DDR) is a multi-complex network of signaling pathways involved in DNA damage repair, cell cycle checkpoints, and apoptosis. In the case of biliary tract cancer (BTC), the strategy of DDR targeting has not been evaluated, even though many patients have DNA repair pathway alterations. The purpose of this study was to test the DDR-targeting strategy in BTC using an ataxia-telangiectasia and Rad3-related (ATR) inhibitor. MATERIALS AND METHODS: A total of nine human BTC cell lines were used for evaluating anti-tumor effect of AZD6738 (ATR inhibitor) alone or combination with cytotoxic chemotherapeutic agents through MTT assay, colony-forming assays, cell cycle analyses, and comet assays. We established SNU478-mouse model for in vivo experiments to confirm our findings. RESULTS: Among nine human BTC cell lines, SNU478 and SNU869 were the most sensitive to AZD6738, and showed low expression of both ataxia-telangiectasia mutated (ATM) and p53. AZD6738 blocked p-Chk1 and p-glycoprotein and increased γH2AX, a marker of DNA damage, in sensitive cells. AZD6738 significantly increased apoptosis, G2/M arrest and p21, and decreased CDC2. Combinations of AZD6738 and cytotoxic chemotherapeutic agents exerted synergistic effects in colony-forming assays, cell cycle analyses, and comet assays. In our mouse models, AZD6738 monotherapy decreased tumor growth and the combination with cisplatin showed more potent effects on growth inhibition, decreased Ki-67, and increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling than monotherapy with each drug. CONCLUSION: In BTC, DDR targeting strategy using ATR inhibitor demonstrated promising antitumor activity alone or in combination with cytotoxic chemotherapeutic agents. This supports further clinical development of DDR targeting strategy in BTC.

Frequency of Variants in DNA-Repair Genes in a Southwest Colombian Population / Frecuencia de las variantes en genes de reparación del ADN en una población del suroccidente de Colombia

Objective To describe the frequency of mutations in DNA-repair genes in a southwestern Colombian population. Methods We have designed an observational study, including 162 people from all ages from southwest Colombia. We have extracted and collected their DNA in filters. We have immersed the DNA in a phosphate buffer along with DNeasy package (Thermo Fisher Scientific, Waltham, MA, USA). The preparation process was with the TruSeq Exome Library Prep (Illumina, Inc. San Diego, CA, USA), then the obtained libraries were normalized with TruSeq Rapid Exome (Illumina, Inc. San Diego, CA, USA). We sequenced the full exome and identified the variants associated with 12 genes (ataxia telangiectasia mutated [ATM], BRCA1 DNA repair associated [BRCA1], BRCA2 DNA repair associated [BRCA2], checkpoint kinase 2 [CHEK2], epithelial cell adhesion molecule [EPCAM], homeobox protein Hox-B13 [HOXB13], mutS homolog 1, 2 and 6 [MLH1, MSH2, MSH6], nibrin [NBN], PMS1 homolog 2, mismatch repair system component [PMS2], and tumor protein p53 [TP53]). Descriptive statistics were performed with the R software (The R Foundation for Statistical Computing, Vienna, Austria). Results A total of 7,315,466 pieces of data were sequenced in this population. The most frequently mutated genes were ATM (1,221 pieces of data; 13.2%), BRCA1 (1,178 pieces of data; 12.8%), BRCA2 (1,484 pieces of data; 16.12%), and NBN (965 pieces of data; 10.42%). The most common single nucleotide polymorphisms (SNPs) in these 12 genes were the following: BRCA2 (rs169547, rs206075, rs206076); ATM (rs659243, rs228589); TP53 (rs1625895, rs1042522, rs1642785); PMS2 (rs2228006, rs1805319); NBN (rs709816); and MSH6 (rs3136367) Conclusion The BRCA2, ATM, BRCA1 and NBN DNA-repair genes were the most frequently mutated in this southwestern Colombian Population

Objetivo Describir la frecuencia de las mutaciones en los genes de reparación del ADN en una población del suroccidente de Colombia. Métodos Diseñamos un estudio observacional que incluyó a 162 personas del suroccidente de Colombia de todas las edades. Hemos extraído y recogido el ADN en filtros. Los sumergimos en tampón fosfato junto con el paquete DNeasy (Thermo Fisher Scientific, Waltham, MA, EEUU). El proceso de preparación fue realizado con TruSeq Exome Library Prep (Illumina, Inc. San Diego, CA, EEUU); luego, las bibliotecas obtenidas se normalizaron con TruSeq Rapid Exome (Illumina, Inc. San Diego, CA, USA). Secuenciamos el exoma completo e identificamos las variantes asociadas a doce genes (ataxia telangiectasia mutated [ATM], BRCA1 DNA repair associated [BRCA1], BRCA2 DNA repair associated [BRCA2], checkpoint kinase 2 [CHEK2], epithelial cell adhesion molecule [EPCAM], homeobox protein Hox-B13 [HOXB13], mutS homolog 1, 2 and 6 [MLH1, MSH2, MSH6], nibrin [NBN], PMS1 homolog 2, mismatch repair system component [PMS2], y tumor protein p53 [TP53]). La estadística descriptiva se realizó en el programa R (The R Foundation for Statistical Computing, Viena, Austria). Resultados Un total de 7.315.466 datos fueron secuenciados en esta población. Los genes más frecuentemente mutados fueron el ATM, con 1.221 datos (13,2%), el BRCA1, con 1.178 datos (12,8%), el BRCA2, con 1.484 datos (16,12%) y el NBN, con 965 datos (10,42%). Los polimorfismos de un solo nucleótido (PSN) más comunes en estos 12 genes fueron los siguientes: BRCA2 (rs169547, rs206075, rs206076); ATM (rs659243, rs228589); TP53 (rs1625895, rs1042522, rs1642785); PMS2 (rs2228006, rs1805319); NBN (rs709816) y MSH6 (rs3136367) Conclusión Los genes de reparación de ADN BRCA2, ATM, BRCA1 NBN fueron los más frecuentemente mutados en esta población del suroccidente de Colombia.

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.

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.

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.

Molecular and Cytogenetic Studies in a Child with Burkitt Lymphoma and Ataxia-Telangiectasia Syndrome Harboring MYC Overexpression and Partial Trisomy 8

No abstract available.

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.

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.

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.

ATM Signaling Pathway Is Implicated in the SMYD3-mediated Proliferation and Migration of Gastric Cancer Cells

PURPOSE: We previously found that the histone methyltransferase suppressor of variegation, enhancer of zeste, trithorax and myeloid-nervy-deformed epidermal autoregulatory factor-1 domain-containing protein 3 (SMYD3) is a potential independent predictive factor or prognostic factor for overall survival in gastric cancer patients, but its roles seem to differ from those in other cancers. Therefore, in this study, the detailed functions of SMYD3 in cell proliferation and migration in gastric cancer were examined. MATERIALS AND METHODS: SMYD3 was overexpressed or suppressed by transfection with an expression plasmid or siRNA, and a wound healing migration assay and Transwell assay were performed to detect the migration and invasion ability of gastric cancer cells. Additionally, an MTT assay and clonogenic assay were performed to evaluate cell proliferation, and a cell cycle analysis was performed by propidium iodide staining. Furthermore, the expression of genes implicated in the ataxia telangiectasia mutated (ATM) pathway and proteins involved in cell cycle regulation were detected by polymerase chain reaction and western blot analyses. RESULTS: Compared with control cells, gastric cancer cells transfected with si-SMYD3 showed lower migration and invasion abilities (P<0.05), and the absence of SMYD3 halted cells in G2/M phase and activated the ATM pathway. Furthermore, the opposite patterns were observed when SMYD3 was elevated in normal gastric cells. CONCLUSIONS: To the best of our knowledge, this study provides the first evidence that the absence of SMYD3 could inhibit the migration, invasion, and proliferation of gastric cancer cells and halt cells in G2/M phase via the ATM-CHK2/p53-Cdc25C pathway. These findings indicated that SMYD3 plays crucial roles in the proliferation, migration, and invasion of gastric cancer cells and may be a useful therapeutic target in human gastric carcinomas.

Familial Pancreatic Cancer and the Future of Directed Screening

Pancreatic cancer (PC) is the third most common cause of cancer-related death in the United States and the 12th most common worldwide. Mortality is high, largely due to late stage of presentation and suboptimal treatment regimens. Approximately 10% of PC cases have a familial basis. The major genetic defect has yet to be identified but may be inherited by an autosomal dominant pattern with reduced penetrance. Several known hereditary syndromes or genes are associated with an increased risk of developing PC and account for approximately 2% of PCs. These syndromes include the hereditary breast-ovarian cancer syndrome, Peutz-Jeghers syndrome, familial atypical multiple mole melanoma, Lynch syndrome, familial polyposis, ataxia-telangiectasia, and hereditary pancreatitis. Appropriate screening using methods such as biomarkers or imaging, with endoscopic ultrasound and magnetic resonance imaging, may assist in the early detection of neoplastic lesions in the high-risk population. If these lesions are detected and treated before the development of invasive carcinoma, PC disease morbidity and mortality may be improved. This review will focus on familial PC and other hereditary syndromes implicated in the increased risk of PC; it will also highlight current screening methods and the future of new screening modalities.

A Case of Hodgkin Lymphoma Developed in an Ataxia-telangiectasia Patient / 임상소아혈액종양

Ataxia-telangiectasia (AT) is characterized by cerebellar ataxia, progressive immunodeficiency, radiation sensitivity, telangiectasia, and predisposition to malignancy. AT patients have a 100-fold increased risk for the development of lymphoid malignancies. It is important to consider AT in a child with pre-existing ataxia, or lymphoid malignancy that was diagnosed at a younger age than expected. This consideration avoids the confusion between ataxia development and toxicity from chemotherapy. Hodgkin's lymphoma (HL) is usually treated with chemotherapy and/or radiotherapy. Unfortunately, when treated with conventional doses of radiotherapy, AT patients invariably experience devastating necrosis of their normal tissues. Therefore, a new treatment protocol for patients with HL in AT must be established. In this paper, we report the case of an 8-year-old female patient with HL in AT who was treated with chemotherapy. This patient was also treated with brentuximab (which targets CD30) for salvage therapy after the disease progressed.

A Case of Hodgkin Lymphoma Developed in an Ataxia-telangiectasia Patient / 임상소아혈액종양

Ataxia-telangiectasia (AT) is characterized by cerebellar ataxia, progressive immunodeficiency, radiation sensitivity, telangiectasia, and predisposition to malignancy. AT patients have a 100-fold increased risk for the development of lymphoid malignancies. It is important to consider AT in a child with pre-existing ataxia, or lymphoid malignancy that was diagnosed at a younger age than expected. This consideration avoids the confusion between ataxia development and toxicity from chemotherapy. Hodgkin's lymphoma (HL) is usually treated with chemotherapy and/or radiotherapy. Unfortunately, when treated with conventional doses of radiotherapy, AT patients invariably experience devastating necrosis of their normal tissues. Therefore, a new treatment protocol for patients with HL in AT must be established. In this paper, we report the case of an 8-year-old female patient with HL in AT who was treated with chemotherapy. This patient was also treated with brentuximab (which targets CD30) for salvage therapy after the disease progressed.

Pretreatment with Lycopene Attenuates Oxidative Stress-Induced Apoptosis in Human Mesenchymal Stem Cells

Human mesenchymal stem cells (MSCs) have been used in cell-based therapy to promote revascularization after peripheral or myocardial ischemia. High levels of reactive oxygen species (ROS) are involved in the senescence and apoptosis of MSCs, causing defective neovascularization. Here, we examined the effect of the natural antioxidant lycopene on oxidative stress-induced apoptosis in MSCs. Although H2O2 (200 muM) increased intracellular ROS levels in human MSCs, lycopene (10 muM) pretreatment suppressed H2O2-induced ROS generation and increased survival. H2O2-induced ROS increased the levels of phosphorylated p38 mitogen activated protein kinase (MAPK), Jun-N-terminal kinase (JNK), ataxia telangiectasia mutated (ATM), and p53, which were inhibited by lycopene pretreatment. Furthermore, lycopene pretreatment decreased the expression of cleaved poly (ADP ribose) polymerase-1 (PARP-1) and caspase-3 and increased the expression of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax), which were induced by H2O2 treatment. Moreover, lycopene significantly increased manganese superoxide dismutase (MnSOD) expression and decreased cellular ROS levels via the PI3K-Akt pathway. Our findings show that lycopene pretreatment prevents ischemic injury by suppressing apoptosis-associated signal pathway and enhancing anti-oxidant protein, suggesting that lycopene could be developed as a beneficial broad-spectrum agent for the successful MSC transplantation in ischemic diseases.

Ataxia-Telangiectasia: Reporte de caso / Ataxia-Telangiectasia: Case report

Presentamos el caso clínico de un niño de 9 años procedente de la región Cusco, con deterioro progresivo del estado neurológico caracterizado por síntomas cerebelosos, asociados a una historia de infecciones respiratorias repetidas y con hallazgos clínicos y de laboratorio que permitieron llegar al diagnóstico de Ataxia-Telangiectasia, enfermedad poco reportada en nuestro país. Se revisa la etiopatogenia, criterios diagnósticos y propuestas terapéuticas disponibles en la actualidad.

We report the case of a 9-year-old from the Cusco region, with progressive deterioration of neurological condition characterized by cerebellar symptoms associated with a history of repeated respiratory infections and clinical and laboratory features that allowed reaching the diagnosis of Ataxia-Telangiectasia, little reported disease in our country. The pathogenesis, diagnostic criteria and therapeutic approaches currently available are reviewed.