462Ataxia-telangiectasia (A-T) is an autosomal recessive genomic instability syndrome characterized by progressive cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, hypersensitivity to ionizing radiation, and cancer predisposition, with lymphoid malignancies predominating in the first two decades of life [1][2][3][4][5][6][7][8][9][10] . Mutations in the Ataxiatelangiectasia mutated (ATM) gene result in markedly decreased or absent levels of ATM kinase, a protein that phosphorylates many downstream targets. A deficiency of ATM kinase leads to cell cycle defects, faulty repair of DNA damage, defective apoptosis, and poor responses to oxidative stress 1,3,11 .ABSTRACT: Background: The onset of progressive cerebellar ataxia in early childhood is considered a key feature of ataxiatelangiectasia (A-T), accompanied by ocular apraxia, telangiectasias, immunodeficiency, cancer susceptibility and hypersensitivity to ionizing radiation. Methods: We describe the clinical features and course of three Mennonite children who were diagnosed with A-T following the completion of therapy for lymphoid malignancies. Results: Prior to cancer therapy, all had non-progressive atypical neurological abnormalities, with onset by age 30 months, including dysarthria, dyskinesia, hypotonia and/or dystonia, without telangiectasias. Cerebellar ataxia was noted in only one of the children and was mild until his death at age eight years. None had severe infections. All three children were "cured" of their lymphoid malignancies, but experienced severe adverse effects from the treatments administered. The two children who received cranial irradiation developed supratentorial primitive neuroectodermal tumors of the brain, an association not previously described, with fatal outcomes. Conclusions: The range of neurological presentations of A-T is broad. Ataxia and telangiectasias may be minimal or absent and the course seemingly non-progressive. The diagnosis of A-T should be considered in all children with neuromotor dysfunction or peripheral neuropathy, particularly those who develop lymphoid malignancies. The consequences of missing the diagnosis may be dire. Radiation therapy and radiomimetic drugs should be avoided in individuals with A-T. RÉSUMÉ: Mode de présentation atypique et toxicité du traitement anticancéreux chez les patients atteints d'ataxie-télangiectasie. Contexte :L'apparition d'une ataxie cérébelleuse progressive dans la petite enfance est considérée comme une manifestation clé de l'ataxie-télangiectasie (A-T), accompagnée d'apraxie oculaire, de télangiectasies, d'un déficit immunitaire, de susceptibilité au cancer et d'hypersensibilité aux radiations ionisantes. Méthodes : Nous décrivons les manifestations cliniques et l'évolution chez trois enfants mennonites chez qui un diagnostic d'A-T a été posé après un traitement pour cancer lymphoïde. Résultats : Avant le traitement anticancéreux, tous présentaient des anomalies neurologiques atypiques non évolutives, dont l'âge de début se situait vers 30 mois, soit de ...
Abstract:We describe eleven mid-western Canadian aboriginal infants with a unique, progressive muscle disorder. All except one had muscle biopsy and/or autopsy. The infants were normal newborns who rapidly developed rigidity of all skeletal muscles, with early, respiratory insufficiency. Death occurred before 18 months of age. Electromyography showed increased insertion activity and profuse fibrillation potentials; motor unit potentials and interference pattern are normal until late in the course. Pathologic features include progressive, granular to powdery Z-band transformation, myofibrillar loss, and muscle regeneration. SDS-gel electrophoresis of one muscle sample revealed increased 54kDa and reduced 80kDa protein fractions. This disease differs from other conditions with Z-band alterations because of continuous muscle activity and relentless clinical progression. The clinical features, elevated serum creatine kinase, electromyographic and muscle biopsy findings suggest a dystrophic process. The recognition of this condition as an autosomal recessive disorder allows appropriate genetic counselling.Resume: Dystrophic musculaire hypertonique infantile fatale dont l'heredite est autosomale recessive chez les autochtones. Nous decrivons onze nourrissons autochtones de l'ouest canadien atteints d'une affection musculaire progressive. Tous sauf un ont eu une biopsie musculaire et/ou une autopsie. Les nourrissons 6taient normaux a la naissance. lis ont deVeloppe rapidement de la rigiditd de tous les muscles squelettiques avec une insuffisance respiratoire pr6coce et sont ddcfides avant Page de 18 mois. L'electromyographie a montre 1 une activity d'insertion augmentee et des potentiels de fibrillation en abondance; les potentiels de plaques motrices et le trace 1 interfdrentiel fitaient normaux jusqu'a un stade avance de la maladie. A l'anatomopathologie, on remarque une transformation progressive de granulaires a poudreuses des bandes en Z, une perte neurofibrillaire et une regeneration musculaire. L'electrophorese sur gel SDS d'un echantillon musculaire a reVele une augmentation de la fraction protdique de 54kD et une diminution de la fraction de 80kD. Cette maladie est diffeYente des autres affections ou Ton observe des alterations des bandes en Z a cause de Pactivite musculaire continue et de la progression clinique inexorable. Les caracteristiques cliniques, I'elevation de la creatine-kinase, les observations electromyographiques et anatomopathologiques suggerent qu'il s'agit d'un processus dystrophique. L'identification de cette affection comme etant une maladie autosomale recessive permet d'offrir une conseil gdn&ique approprie.
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