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.

Identification of ATM Mutations in Korean Siblings with Ataxia-Telangiectasia

Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder. It is characterized by early-onset, progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis, conjunctival telangiectasias, immunodeficiency, and an increased risk of malignancy. Although A-T is known to be the most common cause of progressive cerebellar ataxia in childhood, there have been no confirmed cases in Korea. We report the clinical and genetic findings of Korean siblings who presented with limb and truncal ataxia, oculomotor apraxia, choreoathetosis, and telangiectasias of the eyes. Sequence analysis of the ataxia-telangiectasia mutated (ATM) gene revealed a known missense mutation (c.8546G>C; p.Arg2849Pro) and a novel intronic variant of intron 17 (c.2639-19_2639-7del13). Reverse-transcription PCR and sequencing analysis revealed that the c.2639-19_2639-7del13 variant causes a splicing aberration that potentiates skipping exon 18. Because A-T is quite rare in Korea, the diagnosis of A-T in Korean patients can be delayed. We recommend that a diagnosis of A-T should be suspected in Korean patients exhibiting the clinical features of A-T.

Identification of ATM Mutations in Korean Siblings with Ataxia-Telangiectasia

Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder. It is characterized by early-onset, progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis, conjunctival telangiectasias, immunodeficiency, and an increased risk of malignancy. Although A-T is known to be the most common cause of progressive cerebellar ataxia in childhood, there have been no confirmed cases in Korea. We report the clinical and genetic findings of Korean siblings who presented with limb and truncal ataxia, oculomotor apraxia, choreoathetosis, and telangiectasias of the eyes. Sequence analysis of the ataxia-telangiectasia mutated (ATM) gene revealed a known missense mutation (c.8546G>C; p.Arg2849Pro) and a novel intronic variant of intron 17 (c.2639-19_2639-7del13). Reverse-transcription PCR and sequencing analysis revealed that the c.2639-19_2639-7del13 variant causes a splicing aberration that potentiates skipping exon 18. Because A-T is quite rare in Korea, the diagnosis of A-T in Korean patients can be delayed. We recommend that a diagnosis of A-T should be suspected in Korean patients exhibiting the clinical features of A-T.

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.

Spectrum of primary immune deficiency at a tertiary care hospital.

OBJECTIVE: To report various primary immune deficiencies diagnosed in children at a tertiary care hospital, their clinical manifestations and laboratory profile. METHODS: Case records of children diagnosed to have primary immunodeficiency disorders over a period of 24 months at a tertiary care hospital in northern India were evaluated. RESULTS: Twenty-seven children (M: F=3.5: 1) with mean age of 5.4 +/- 4.6 yrs (2 mo-16 yr) were diagnosed to have primary immunodeficiency. Thirteen children had chronic granulomatous disease (CGD), 4 had severe combined immunodeficiency (SCID), 4 had hypogammaglobulinemia, 2 had Ataxia telangiectasia, and one each had DiGeorge syndrome, Wiskott Aldrich syndrome, hyper IgM syndrome and leukocyte adhesion defect. Common mode of presentation were recurrent/ persistent pneumonia in 19, recurrent/ persistent diarrhea in 10, deep seated abscesses in 8, allergy in 3, disseminated tuberculosis infection in 2, extensive fungal infections in 2 and 1 each of disseminated cytomegalovirus (CMV) infection, disseminated BCG disease, otitis media and meningitis. Family history of sibling deaths was elicited in 2 families. Infectious agents were isolated in 16 cases. CONCLUSION: From a single center 27 patients with primary immune deficiency could be identified by chart review, suggesting need for high index of suspicion for diagnosis of primary immune deficiency in India. Though the exact prevalence is not known there is need to make a registry to document the magnitude of problem of these disorders.

Unusual absence of neurologic symptoms in a six-year old girl with ataxia-telangiectasia.

Ataxia-telangiectasia (A-T) is a rare multisystem, neurodegenerative genetic disorder. We present a case of a 6-year-old girl who had a history of frequent respiratory infections and also had ocular and immunological features of this syndrome. The absence of neurological symptoms, which is very unusual for a patient of this age, raised many difficulties in the diagnosis of the disease. It is concluded that a normal neurological assessment must not exclude the diagnosis of A-T and delay the proper interventional measures.

Ataxica telengiectasia (Louis-Bar syndrome).

A case of ataxia telengiectasia in a 7-year-old girl with symptoms for last 3 years has been reported in detail. The necessary literature has been reviewed with proper references.

Recent advances in chromosome breakage syndromes and their diagnosis.

Chromosome instability is a characteristic cytogenetic feature of a number of genetically determined disorders collectively called as the chromosome breakage syndromes or DNA-repair disorders. They are characterized by susceptibility to chromosomal breakages, increased frequency of breaks and interchanges occurring either spontaneously or following exposure to various DNA-damaging agents. These diseases are a group of genetic disorders sharing a number of features. They are all autosomal recessive, show an increased tendency for chromosomal aberrations and to develop malignancies. The principal diseases in this group having a diverse etiology and clinical manifestations include Fanconi anemia (FA), ataxia telangiectasia (AT), Nijmegen breakage syndrome (NBS), Bloom syndrome (BS), xeroderma pigementosum (XP), Cockayne syndrome (CS) and trichothiodystrophy (TTD). The underlying defect in these syndromes is the inability to repair a particular type of DNA damage. A number of repair disorder phenotypes are caused by more than one gene. The diagnosis of these syndromes is made by the characteristic clinical features specific to each disease, but the definitive diagnosis is achieved by laboratory investigations such as cytogenetic, biochemical and molecular methods. The importance of prenatal diagnosis and our experience are discussed in this article.

Sangrado en ataxia telangiectasia. Un aspecto de la enfermedad previamente no estudiado / Bleeding in ataxia telangiectasia. An aspect of this illness wich has not been previosly studied

En un paciente con ataxia-telangiectasia se demostró la presencia de una condición hemorrágica debida a alteraciones vasculares, defectos plaquetarios funcionales múltiples y deficiencia leve de factor IX. En la revisión de 128 pacientes con ataxia-telangiectasia se encontró que 7 habían sufrido hemorragias en ausencia de alguna enfermedad subyacente capaz de provocarlas. La presencia de trastornos semejantes a los descritos en el paciente, en síndrome de Ehlers-Danlos, en osteogénesis imperfecta y en telangiectasia hemorrágica hereditaria (condiciones que tiene en común con ataxia-telangiectasia, la existencia de alteraciones vasculares), permiten plantear la existencia de alguna forma de interrelación entre el desarrollo de vasos y la síntesis de algunos factores de la coagulación y la formación de plaquetas

Ataxia-telangiectasia

El síndrome de ataxia telangiectasia antes llamado síndrome de Louis-Bar fue descrito en 1941. La enfermedad es autosómica recesiva y se cree que la anormalidad se localiza en la banda 11 del brazo corto de los cromosomas 22-23 (11a 22-23) en donde se sitúa el gen que codifica la proteína esencial en la recombinación utilizada por los genes de la familia de las inmunoglobulinas. El síndrome se caracteriza por ataxia cerebelar progresiva, telangiectasias óculo-cutáneas, enfermedad sinu-bronquial crónica, inmunodeficiencia variable y alta incidencia de tumores como leucemia, adenomas y linfoma no-Hodgkin. A continuación se describe un caso de ataxia-telangiectásica que consultó a nuestra institución.