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Ataxia-telangiectasia syndrome(AT)

MedGen UID:
439
Concept ID:
C0004135
Disease or Syndrome
Synonyms: AT; AT, COMPLEMENTATION GROUP C; Ataxia-telangiectasia; ATAXIA-TELANGIECTASIA, COMPLEMENTATION GROUP A; Ataxia-telangiectasia, complementation group D; ATAXIA-TELANGIECTASIA, FRESNO VARIANT; Cerebello-oculocutaneous telangiectasia; Immunodeficiency with ataxia telangiectasia; Louis-Bar syndrome
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Sources: HPO, OMIM, Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in homozygotes. In the context of medical genetics, autosomal recessive disorders manifest in homozygotes (with two copies of the mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele). [HPO:curators]
Autosomal recessive inheritance (HPO, OMIM, Orphanet)
SNOMED CT: Ataxia-telangiectasia syndrome (68504005); Louis-Bar syndrome (68504005); Ataxia telangiectasia (68504005); Ataxia telangiectasia syndrome (68504005)
 
Gene (location): ATM (11q22.3)
OMIM®: 208900
Orphanet: ORPHA100

Definition

Ataxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. The latter trait has been used to identify complementation groups for the classic form of the disease (Jaspers et al., 1988). At least 4 of these (A, C, D, and E) map to chromosome 11q23 (Sanal et al., 1990) and are associated with mutations in the ATM gene. [from OMIM]

Additional descriptions

From GeneReviews
Classic ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between ages one and four years, oculomotor apraxia, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, frequent infections, and an increased risk for malignancy, particularly leukemia and lymphoma. Individuals with A-T are unusually sensitive to ionizing radiation. Non-classic forms of A-T have included adult-onset A-T and A-T with early-onset dystonia.  https://www.ncbi.nlm.nih.gov/books/NBK26468
From GeneReviews Overview
The hereditary ataxias are a group of genetic disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. In this GeneReview the hereditary ataxias are categorized by mode of inheritance and gene (or chromosome locus) in which pathogenic variants occur.  https://www.ncbi.nlm.nih.gov/books/NBK1138
From GHR
Ataxia-telangiectasia is a rare inherited disorder that affects the nervous system, immune system, and other body systems. This disorder is characterized by progressive difficulty with coordinating movements (ataxia) beginning in early childhood, usually before age 5. Affected children typically develop difficulty walking, problems with balance and hand coordination, involuntary jerking movements (chorea), muscle twitches (myoclonus), and disturbances in nerve function (neuropathy). The movement problems typically cause people to require wheelchair assistance by adolescence. People with this disorder also have slurred speech and trouble moving their eyes to look side-to-side (oculomotor apraxia). Small clusters of enlarged blood vessels called telangiectases, which occur in the eyes and on the surface of the skin, are also characteristic of this condition.Affected individuals tend to have high amounts of a protein called alpha-fetoprotein (AFP) in their blood. The level of this protein is normally increased in the bloodstream of pregnant women, but it is unknown why individuals with ataxia-telangiectasia have elevated AFP or what effects it has in these individuals.People with ataxia-telangiectasia often have a weakened immune system, and many develop chronic lung infections. They also have an increased risk of developing cancer, particularly cancer of blood-forming cells (leukemia) and cancer of immune system cells (lymphoma). Affected individuals are very sensitive to the effects of radiation exposure, including medical x-rays. The life expectancy of people with ataxia-telangiectasia varies greatly, but affected individuals typically live into early adulthood.  https://ghr.nlm.nih.gov/condition/ataxia-telangiectasia

Clinical features

Bronchiectasis
MedGen UID:
14234
Concept ID:
C0006267
Disease or Syndrome
Persistent abnormal dilatation of the bronchi owing to localized and irreversible destruction and widening of the large airways.
Cerebellar ataxia
MedGen UID:
849
Concept ID:
C0007758
Disease or Syndrome
Cerebellar ataxia refers to ataxia due to dysfunction of the cerebellum. This causes a variety of elementary neurological deficits including asynergy (lack of coordination between muscles, limbs and joints), dysmetria (lack of ability to judge distances that can lead to under- oder overshoot in grasping movements), and dysdiadochokinesia (inability to perform rapid movements requiring antagonizing muscle groups to be switched on and off repeatedly).
Diabetes mellitus
MedGen UID:
8350
Concept ID:
C0011849
Disease or Syndrome
A group of abnormalities characterized by hyperglycemia and glucose intolerance.
Dysarthria
MedGen UID:
8510
Concept ID:
C0013362
Mental or Behavioral Dysfunction
Disorders of speech articulation caused by imperfect coordination of pharynx, larynx, tongue, or face muscles. This may result from CRANIAL NERVE DISEASES; NEUROMUSCULAR DISEASES; CEREBELLAR DISEASES; BASAL GANGLIA DISEASES; BRAIN STEM diseases; or diseases of the corticobulbar tracts (see PYRAMIDAL TRACTS). The cortical language centers are intact in this condition. (From Adams et al., Principles of Neurology, 6th ed, p489)
Dystonia
MedGen UID:
3940
Concept ID:
C0013421
Sign or Symptom
An abnormally increased muscular tone that causes fixed abnormal postures. There is a slow, intermittent twisting motion that leads to exaggerated turning and posture of the extremities and trunk.
Hodgkin lymphoma
MedGen UID:
9283
Concept ID:
C0019829
Neoplastic Process
Classic Hodgkin lymphoma is a lymph node cancer of germinal center B-cell origin. Hodgkin lymphoma tumors consist of a minority of malignant cells, known as 'Reed-Sternberg' (RS) cells, mixed with reactive lymphocytes and other benign inflammatory cells. A defining feature of RS cells is the presence of 2 nuclei (summary by Salipante et al., 2009).
Leukemia
MedGen UID:
9725
Concept ID:
C0023418
Neoplastic Process
A cancer of the blood and bone marrow characterized by an abnormal proliferation of leukocytes.
Lymphoma
MedGen UID:
44223
Concept ID:
C0024299
Neoplastic Process
A cancer originating in lymphocytes and presenting as a solid tumor of lymhpoid cells.
Non-Hodgkin lymphoma
MedGen UID:
6160
Concept ID:
C0024305
Neoplastic Process
A typer of lymphoma characterized microscopically by the absence of multinucleated Reed-Sternberg cells.
Myoclonus
MedGen UID:
10234
Concept ID:
C0027066
Sign or Symptom
A rapid, involuntary jerk of a muscle or group of muscles.
Nystagmus
MedGen UID:
45166
Concept ID:
C0028738
Disease or Syndrome
Involuntary movements of the eye that are divided into two types, jerk and pendular. Jerk nystagmus has a slow phase in one direction followed by a corrective fast phase in the opposite direction, and is usually caused by central or peripheral vestibular dysfunction. Pendular nystagmus features oscillations that are of equal velocity in both directions and this condition is often associated with visual loss early in life. (Adams et al., Principles of Neurology, 6th ed, p272)
Sinusitis
MedGen UID:
14608
Concept ID:
C0030469
Disease or Syndrome
Inflammation of the paranasal sinuses owing to a viral, bacterial, or fungal infection, allergy, or an autoimmune reaction.
Delayed puberty
MedGen UID:
46203
Concept ID:
C0034012
Pathologic Function
Passing the age when puberty normally occurs with no physical or hormonal signs of the onset of puberty.
Seizures
MedGen UID:
20693
Concept ID:
C0036572
Sign or Symptom
Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as EPILEPSY or "seizure disorder."
Strabismus
MedGen UID:
21337
Concept ID:
C0038379
Disease or Syndrome
A misalignment of the eyes so that the visual axes deviate from bifoveal fixation. The classification of strabismus may be based on a number of features including the relative position of the eyes, whether the deviation is latent or manifest, intermittent or constant, concomitant or otherwise and according to the age of onset and the relevance of any associated refractive error.
Tremor
MedGen UID:
21635
Concept ID:
C0040822
Sign or Symptom
An unintentional, oscillating to-and-fro muscle movement about a joint axis.
Choreoathetosis
MedGen UID:
39313
Concept ID:
C0085583
Disease or Syndrome
Abnormal movement characterized by involuntary jerking and writhing affecting the limbs, trunk, and facial muscles.
Abnormality of the hair
MedGen UID:
56381
Concept ID:
C0157733
Finding
An abnormality of the hair.
Cafe-au-lait spot
MedGen UID:
113157
Concept ID:
C0221263
Finding
A light brown, sharply demarcated skin patch. It is a manifestation of neurofibromatosis type 1 and McCune-Albright syndrome.
Conjunctival telangiectasia
MedGen UID:
66780
Concept ID:
C0239105
Disease or Syndrome
The presence of small (ca. 0.5-1.0 mm) dilated blood vessels near the surface of the mucous membranes of the conjunctiva.
Female hypogonadism
MedGen UID:
75756
Concept ID:
C0271578
Disease or Syndrome
Decreased functionality of the female gonads, i.e., of the ovary.
Glucose intolerance
MedGen UID:
75760
Concept ID:
C0271650
Disease or Syndrome
A pathological state in which BLOOD GLUCOSE level is less than approximately 140 mg/100 ml of PLASMA at fasting, and above approximately 200 mg/100 ml plasma at 30-, 60-, or 90-minute during a GLUCOSE TOLERANCE TEST. This condition is seen frequently in DIABETES MELLITUS, but also occurs with other diseases and MALNUTRITION.
Short stature
MedGen UID:
87607
Concept ID:
C0349588
Finding
A height below that which is expected according to age and gender norms. Although there is no universally accepted definition of short stature, many refer to "short stature" as height more than 2 standard deviations below the mean for age and gender (or below the 3rd percentile for age and gender dependent norms).
Elevated alpha-fetoprotein
MedGen UID:
892411
Concept ID:
C0476489
Finding
An increased concentration of alpha-fetoprotein.
Abnormal spermatogenesis
MedGen UID:
488909
Concept ID:
C0520933
Finding
Incomplete maturation or aberrant formation of the male gametes.
IgA deficiency
MedGen UID:
107506
Concept ID:
C0553533
Finding
Hypoplasia of the thymus
MedGen UID:
146347
Concept ID:
C0685891
Congenital Abnormality
Underdevelopment of the thymus.
Recurrent bronchitis
MedGen UID:
148159
Concept ID:
C0741796
Disease or Syndrome
An increased susceptibility to bronchitis as manifested by a history of recurrent bronchitis.
Decreased number of CD4+ T cells
MedGen UID:
333292
Concept ID:
C1839304
Finding
A decreased proportion of circulating CD4-positive helper T cells relative to total T cell count.
Defective B cell differentiation
MedGen UID:
347920
Concept ID:
C1859624
Finding
Reduced functionality of the process in which a precursor cell type acquires the specialized features of a B cell. A B cell is a lymphocyte of B lineage with the phenotype CD19-positive and capable of B cell mediated immunity.
Reduced tendon reflexes
MedGen UID:
356648
Concept ID:
C1866934
Finding
Diminution of tendon reflexes, which is an invariable sign of peripheral nerve disease.
Immunoglobulin IgG2 deficiency
MedGen UID:
867187
Concept ID:
C4021545
Finding
A reduction in immunoglobulin levels of the IgG2 subclass.

Professional guidelines

PubMed

van de Warrenburg BP, van Gaalen J, Boesch S, Burgunder JM, Dürr A, Giunti P, Klockgether T, Mariotti C, Pandolfo M, Riess O
Eur J Neurol 2014 Apr;21(4):552-62. Epub 2014 Jan 13 doi: 10.1111/ene.12341. PMID: 24418350
Gasser T, Finsterer J, Baets J, Van Broeckhoven C, Di Donato S, Fontaine B, De Jonghe P, Lossos A, Lynch T, Mariotti C, Schöls L, Spinazzola A, Szolnoki Z, Tabrizi SJ, Tallaksen CM, Zeviani M, Burgunder JM, Harbo HF; EFNS.
Eur J Neurol 2010 Feb;17(2):179-88. Epub 2009 Dec 28 doi: 10.1111/j.1468-1331.2009.02873.x. PMID: 20050888

Recent clinical studies

Etiology

Marinău LD, Singer CE, Meşină C, Niculescu EC, Puiu I, Petrescu IO, Geormăneanu C, Enculescu AC, Tache DE, Purcaru ŞO, Răciulă S, Damian CL
Rom J Morphol Embryol 2017;58(3):1103-1108. PMID: 29250697
Choi M, Kipps T, Kurzrock R
Mol Cancer Ther 2016 Aug;15(8):1781-91. Epub 2016 Jul 13 doi: 10.1158/1535-7163.MCT-15-0945. PMID: 27413114
Marabelli M, Cheng SC, Parmigiani G
Genet Epidemiol 2016 Jul;40(5):425-31. Epub 2016 Apr 25 doi: 10.1002/gepi.21971. PMID: 27112364
Greenberger S, Berkun Y, Ben-Zeev B, Levi YB, Barziliai A, Nissenkorn A
J Am Acad Dermatol 2013 Jun;68(6):932-6. Epub 2013 Jan 27 doi: 10.1016/j.jaad.2012.12.950. PMID: 23360865
Llerena J Jr, Murer-Orlando M, McGuire M, Zahed L, Sheridan RJ, Berry AC, Bobrow M
J Med Genet 1989 Mar;26(3):174-8. PMID: 2468772Free PMC Article

Diagnosis

Marinău LD, Singer CE, Meşină C, Niculescu EC, Puiu I, Petrescu IO, Geormăneanu C, Enculescu AC, Tache DE, Purcaru ŞO, Răciulă S, Damian CL
Rom J Morphol Embryol 2017;58(3):1103-1108. PMID: 29250697
Zaki-Dizaji M, Akrami SM, Abolhassani H, Rezaei N, Aghamohammadi A
Expert Rev Clin Immunol 2017 Dec;13(12):1155-1172. Epub 2017 Oct 20 doi: 10.1080/1744666X.2017.1392856. PMID: 29034753
Greenberger S, Berkun Y, Ben-Zeev B, Levi YB, Barziliai A, Nissenkorn A
J Am Acad Dermatol 2013 Jun;68(6):932-6. Epub 2013 Jan 27 doi: 10.1016/j.jaad.2012.12.950. PMID: 23360865
Otabor IA, Abdessalam SF, Erdman SH, Hammond S, Besner GE
World J Surg Oncol 2009 Mar 12;7:29. doi: 10.1186/1477-7819-7-29. PMID: 19284625Free PMC Article
Forte WC, Menezes MC, Dionigi PC, Bastos CL
Allergol Immunopathol (Madr) 2005 Jul-Aug;33(4):199-203. PMID: 16045857

Therapy

Choi M, Kipps T, Kurzrock R
Mol Cancer Ther 2016 Aug;15(8):1781-91. Epub 2016 Jul 13 doi: 10.1158/1535-7163.MCT-15-0945. PMID: 27413114

Prognosis

Choi M, Kipps T, Kurzrock R
Mol Cancer Ther 2016 Aug;15(8):1781-91. Epub 2016 Jul 13 doi: 10.1158/1535-7163.MCT-15-0945. PMID: 27413114
Forte WC, Menezes MC, Dionigi PC, Bastos CL
Allergol Immunopathol (Madr) 2005 Jul-Aug;33(4):199-203. PMID: 16045857

Clinical prediction guides

Greenberger S, Berkun Y, Ben-Zeev B, Levi YB, Barziliai A, Nissenkorn A
J Am Acad Dermatol 2013 Jun;68(6):932-6. Epub 2013 Jan 27 doi: 10.1016/j.jaad.2012.12.950. PMID: 23360865
Forte WC, Menezes MC, Dionigi PC, Bastos CL
Allergol Immunopathol (Madr) 2005 Jul-Aug;33(4):199-203. PMID: 16045857
McKinnon PJ, Burgoyne LA
Eur J Cell Biol 1985 Nov;39(1):161-6. PMID: 3910438

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