Ataxia teleangiectatica G11.3

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 25.11.2022

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Synonym(s)

cerebello-oculocutaneous telangiectasia; Louis Bar Syndrome; telangiectasia cerebello-oculocutaneous; Teleangiectasia-Ataxia Syndrome

History
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Syllaba and Henner, 1926; Louis-Bar, 1941

Definition
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Autosomal recessive, radiosensitive chromosome breakage syndrome with cerebellar ataxia, canities (premature graying), hirsutism, keratosis follicularis, seborrheic eczema, telangiectasias, ephelioid hyperpigmentation, and varioliform atrophies of the face, associated with a T-cellular immunodeficiency and an increased risk of neoplasia (cf.u. Immunodeficiencies, T-cellular, primary).

Etiopathogenesis
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Genetically heterogeneous, autosomal recessive inherited disease (5 complementation groups known so far). The mutations affect the AT gene located on chromosome 11q22.3 (the mutated gene is called the ATM gene ). The gene locus is in the region of important genes for T cell functions(CD3, THY1, NCAM). The mutations cause disruption of phosphatidylinositol 3-kinase.

Upon detection of double-strand breaks (DSBs), the wild-type kinase encoded by ATM initiates the DNA damage response by phosphorylating histone H2AX and subsequently several other proteins such as BRCA1 (see BRCA1 gene below) and the MRE11-RAD50-NBS1 (MRN) complex, which are placed at the damaged site. In addition, the ATM protein phosphorylates p53, leading to expression of the cyclin-dependent kinase inhibitor p21 and consequent senescence or apoptosis .

The AT gene defect causes, among other things, increased radiosensitivity.

Caution. Iatrogenic tumor induction during extensive radiographic diagnosis. Recombination defect during T cell maturation?

Manifestation
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Early childhood, predominantly 4th-8th LJ.

Localization
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Head: Conjunctival, nose, cheeks, auricles and neck; also elbows, hollow of the knees, back of the hands and feet.

Clinical features
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Integument: Canities (premature graying); hirsutism, keratosis follicularis; seborrheic eczema. Teleangiectasias, ephelioid hyperpigmentation, varioliform atrophies of the face.

Neurologic: Progressive cerebellar ataxia, trunk and extremities affected; oculomotor apraxia, typically sloping shoulders, head tilt to one side, generalized muscle weakness, dysarthritic speech, strabismus, nystagmus, peripheral neuropathy, absent tendon reflexes. CT: cerebral atrophy; mental retardation in about one-third, usually not marked until 10 years of age.

Immunological: Decreased cellular immune defense (IgA deficiency) leads to decreased resistance to infection with recurrent bacterial infections especially of maxillary sinuses and lungs. Hypoplasia or agenesis of the thymus, hypoplasia of the lymphoid tissue.

Pesons with ataxia telangiectasia have a higher incidence of T-cell prolymphocytic leukemia (former median age between 25-30 years, compared to the "non-Louis Bar collective - Suarez F et al. 2015).

Laboratory
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Decrease in serum immunoglobulins. Lymphopenia, reduced IgA and IgE; in women ovary, in men testicular insufficiency or aplasia. Genetic laboratory findings: Increased chromosomal fragility; characteristic clonal translocations between the T-cell receptor loci on chromosomes 7 and 14; greatly reduced stimulability of T-lymphocytes. Cell cycle block in the G2 phase characteristic of peripheral mononuclear blood cells after in vitro X-ray irradiation (1.5 Gy) as an expression of increased radiation sensitivity; increased alpha-fetoprotein.

Diagnosis
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X-ray of the thorax: thymus hypo- or aplasia; pneumo-encephalography: cerebellar atrophy.

Differential diagnosis
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Hartnup syndrome, brain tumor.

Therapy
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Symptomatic, infection prophylaxis with broad-spectrum antibiotic. Genetic counseling!

Progression/forecast
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Life expectancy shortened by a tendency to infection or malignancy development. Premature death, usually between the ages of 20 and 30; maximum survival is about 50 years. Body growth and intelligence reduced.

Literature
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  1. Louis-Bar D (1941) Sur un syndrome progressif comprenant des télangiectasies capillaires cutanées et conjonctivales, à disposition naevoide et des troubles cérébelleux. Confin Neurol 4: 32-42
  2. McKinnon PJ (1987) Ataxia-teleangiectasia: an inherited disorder of ionizing-radiation sensivity in man. Progress in the elucidation of the underlying biochemical defect. Hum Genet 75: 197-208
  3. Perlman S et al (2003) Ataxia-telangiectasia: diagnosis and treatment. Semin Pediatr Neurol 10: 173-182
  4. Seyschab H et al (1992) Simultaneous measurement of radiosensitivity and defective mitogen response in ataxia telangiectasia and related syndromes. Eur J Pediatr 151: 756-760
  5. Suarez F et al. (2015) Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: a report from the French national registry of primary immune deficiencies. J Clin Oncol 33:202-208.
  6. Syllaba L, Henner K (1926) Contribution a l'independence de l'athetose double idiopathique et congenitale. Rev Neurol 1: 541-562
  7. Takagi M et al (2004) Identification and characterization of polymorphic variations of the ataxia telangiectasia mutated (ATM) gene in childhood Hodgkin disease. Blood 103: 283-290

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Last updated on: 25.11.2022