A 5-year-old boy is brought to the office due to concerns about his speech and motor skills. The patient has a history of speech delay, and his parents say that his speech has become more slurred lately. He also has an unsteady, staggering gait that has progressively worsened over the past year. In addition, the mother states that the patient's eyes and head "do not move smoothly" when he looks at moving objects. Medical history is significant for recurrent ear and pulmonary infections. Vital signs are normal. Physical examination reveals numerous superficial nests of distended capillaries on the face and ears that blanch with pressure. This patient's condition is most likely due to a genetic defect affecting which of the following processes?
Ataxia-telangiectasia | |
Pathogenesis |
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Clinical features |
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Diagnosis |
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This patient has facial telangiectasias, recurrent infections, and signs of cerebellar dysfunction (eg, unsteady gait, slurred speech), findings characteristic of ataxia-telangiectasia (AT). This autosomal recessive condition is caused by a defect in the ATM (ataxia-telangiectasia mutated) gene.
ATM kinase normally plays a role in the detection of DNA damage (eg, oxidative injury) through phosphorylation of various proteins, which then halt the cell cycle to allow for DNA break repair. Without this surveillance mechanism, DNA is susceptible to ionizing radiation and prone to chromosomal breakage; accumulation of DNA mutations also increases the risk of malignant transformation.
Neurons are particularly prone to oxidative stress, and the first manifestations of AT are typically due to cerebellar degeneration. Unsteady gait progressively worsens in early childhood, and patients often display delayed and slurred (dysarthria) speech. Impaired head/eye coordination (oculomotor apraxia) is also common.
In addition, defective DNA rearrangement in developing lymphocytes often results in cellular and humoral immunodeficiency and recurrent sinopulmonary infections. Diagnosis is often delayed until characteristic telangiectasias, or superficial nests of dilated blood vessels, appear on the face and bulbar conjunctiva at age 3-5.
(Choice B) MHC class II is found on the surface of antigen-presenting cells and presents foreign protein to T-helper cells. Defective MHC class II expression (eg, bare lymphocyte syndrome) impairs T cell immune response and activation of B cells. Patients present in infancy with severe infections and failure to thrive. Ataxia does not occur.
(Choice C) Friedreich ataxia is due to a trinucleotide (GAA) repeat expansion affecting the mitochondrial protein Frataxin. Mitochondrial iron transport is impaired, leading to progressive ataxia in adolescents, as well as kyphoscoliosis, cardiomyopathy, and glucose intolerance. Immune deficiency and telangiectasias are not seen.
(Choice D) Lesch-Nyhan syndrome is a disorder of purine catabolism resulting from an X-linked recessive mutation in the gene encoding hypoxanthine-guanine phosphoribosyltransferase. This defect leads to severe hyperuricemia and gout; patients classically also exhibit self-mutilating behavior, choreoathetoid movements, and spasticity.
(Choice E) Niemann-Pick disease is an autosomal recessive disorder characterized by defective sphingolipid degradation due to a mutation in sphingomyelinase. Motor neuropathy (eg, hypotonia, areflexia) occurs rather than ataxia, and hepatosplenomegaly and a cherry-red macular spot are typical.
Educational objective:
Ataxia-telangiectasia is an autosomal recessive disorder resulting from defective DNA break repair. Classic findings include cerebellar ataxia, telangiectasias, and recurrent sinopulmonary infections.