ataxia telangiectasia; Louis-Bar syndrome

Etiology

mutation in ATM gene

Epidemiology

most common of the degenerative ataxias

Pathology

• defect in DNA repair
  • sensitivity to radiation
  • increased recombinase-mediated interlocus rearrangements
  • cells from patients with AT are defective at both the G1/S & G2/M checkpoints.
  • DNA repair defect may account for the high incidence of malignancy in these patients
• loss of cerebellar Purkinje cells results in cerebellar ataxia
• immunodeficiency
  • not all patients have immunodeficiency
  • immunological abnormalities appear to be related to aberrant development of the thymus
  • the thymus is markedly hypoplastic & similar in appearance to an embryonic thymus
  • peripheral T-cells are frequently reduced in number, especially within lymphoid tissue
  • cutaneous anergy is common.
  • the number & distribution of B-cells is usually normal; however most patients are deficient in IgE & IgA, & some in IgG particularly IgG2 & IgG4
  • IgM & IgD are usually normal
• 2 most common causes of death
  • chronic pulmonary disease
  • malignancy.
    • lymphomas are the most common malignancy
    • brain tumors occur as well
• insulin resistance with anti-insulin antibodies

Genetics

• autosomal recessive
• the responsible gene, the ATM (ataxia telangiectasia, mutated) gene has been mapped to chromosome 11q22-23
• other implicated genes: GADD45A

Clinical manifestations

• cerebellar ataxia
  • generally 1st neurologic sign in patients with AT
  • progresses slowly, but relentlessly to severe disability
  • truncal ataxia in infancy
  • symptoms of ataxia manifesting at about 2 years of age, progressing to loss of ambulation by adolescence
• oculocutaneous telangiectasias
  • telangiectasias are most obvious in the sclerae
  • other areas are also affected
  • telangiectasias may occur as early as 1 year of age or as late as 6 years
• other skin lesions
  • hypo- & hyperpigmentation
  • atopic dermatitis
  • cutaneous atrophy simulating scleroderma
  • nummular eczema
• oculomotor apraxia & horizontal nystagmus are common
• variable choreoathetoid or tic-like movements
• a mask-like facies with excessive drooling produces a remarkable similarity of appearance in affected patients
• muscle weakness
• poor reflexes
• intellectual development is normal at first, but seems to stop at about 10 years in many patients
• manifestations of immunodeficiency
  • recurrent & chronic sino-pulmonary infection leading to bronchiectasis
  • not all patients have immunodeficiency

Laboratory

• elevated embryonic proteins* in serum
  • elevated alpha-fetoprotein (AFP) &
  • carcinoembryonic antigen (CEA)

* seen in virtually all patients with AT (consistent with abnormalities in embryogenesis)

More general terms

• hereditary neoplastic syndrome; cancer susceptibility syndrome
• chromosomal instability syndrome
• cerebellar disease
• immunologic disease

Additional terms

• ataxia telangiectasia-like disorder (ATLD)

Patient information

ataxia telangiectasia (Louis-Bar syndrome) patient information

Database

• OMIM: https://mirror.omim.org/entry/208900