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ataxia telangiectasia; Louis-Bar syndrome
Etiology: mutation in ATM gene.
Epidemiology: most common of the degenerative ataxias
Pathology:
1) defect in DNA repair
a) sensitivity to radiation
b) increased recombinase-mediated interlocus rearrangements
c) cells from patients with AT are defective at both the G1/S & G2/M checkpoints.
d) DNA repair defect may account for the high incidence of malignancy in these patients
2) loss of cerebellar Purkinje cells results in cerebellar ataxia
3) immunodeficiency
a) not all patients have immunodeficiency
b) immunological abnormalities appear to be related to aberrant development of the thymus
c) the thymus is markedly hypoplastic & similar in appearance to an embryonic thymus
d) peripheral T-cells are frequently reduced in number, especially within lymphoid tissue
e) cutaneous anergy is common.
f) the number & distribution of B-cells is usually normal; however most patients are deficient in IgE & IgA, & some in IgG particularly IgG2 & IgG4
g) IgM & IgD are usually normal
4) 2 most common causes of death
a) chronic pulmonary disease
b) malignancy.
1] lymphomas are the most common malignancy
2] brain tumors occur as well
5) insulin resistance with anti-insulin antibodies [1]
Genetics:
1) autosomal recessive
2) the responsible gene, the ATM (ataxia telangiectasia, mutated) gene has been mapped to chromosome 11q22-23
3) other implicated genes: GADD45A
Clinical manifestations:
1) cerebellar ataxia
a) generally 1st neurologic sign in patients with AT
b) progresses slowly, but relentlessly to severe disability
c) truncal ataxia in infancy
d) symptoms of ataxia manifesting at about 2 years of age, progressing to loss of ambulation by adolescence
2) oculocutaneous telangiectasias
a) telangiectasias are most obvious in the sclerae
b) other areas are also affected
c) telangiectasias may occur as early as 1 year of age or as late as 6 years
3) other skin lesions
a) hypo- & hyperpigmentation
b) atopic dermatitis
c) cutaneous atrophy simulating scleroderma
d) nummular eczema
4) oculomotor apraxia & horizontal nystagmus are common
5) variable choreoathetoid or tic-like movements
6) a mask-like facies with excessive drooling produces a remarkable similarity of appearance in affected patients
7) muscle weakness
8) poor reflexes
9) intellectual development is normal at first, but seems to stop at about 10 years in many patients
10) manifestations of immunodeficiency
a) recurrent & chronic sino-pulmonary infection leading to bronchiectasis
b) not all patients have immunodeficiency
Laboratory:
-> elevated embryonic proteins* in serum
a) elevated alpha-fetoprotein (AFP) &
b) carcinoembryonic antigen (CEA)
* seen in virtually all patients with AT (consistent with abnormalities in embryogenesis)
Related
ataxia telangiectasia-like disorder (ATLD)
General
cerebellar disease
chromosomal instability syndrome
hereditary neoplastic syndrome; cancer susceptibility syndrome
immunologic disease
Properties
THERAPY: Symptomatic treatment only.
ASSOCIATED-NEOPLASM[S]: lymphoid leukemia
lymphoma
medulloblastoma
glial neoplasm (glioma)
References
- Harrison's Principles of Internal Medicine, 13th ed.
Isselbacher et al (eds), McGraw-Hill Inc. NY,
1994, pg 1564, 1999, 2057
- NINDS Ataxia Telangiectasia Information Page
https://www.ninds.nih.gov/Disorders/All-Disorders/Ataxia-Telangiectasia-Information-Page
Databases & Figures
OMIM 208900
Human Disorders of DNA Repair