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Ataxia telangiectasia
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Clinical signs
Ataxia-telangiectasia (AT) is a hereditary disease that mainly affects the system
that corrects spontaneously occurring chromosomal breakage, and as a result DNA
damage, in the cells of the body. Clinically it is characterized by cerebellar ataxia,
telangiectasias, immune defects, and a predisposition to malignancy.
Patients present in early childhood with progressive cerebellar ataxia and later
develop conjunctival telangiectasias, other progressive neurological degeneration,
sinopulmonary infection, and malignancies. Telangiectasias typically develop between
3 and 5 years of age. The early stages of the ataxia can be misdiagnosed as ataxic
cerebral palsy before the appearance of oculocutaneous telangiectasias. No patient
is known to have survived beyond 50 years of age.
AT cells are abnormally sensitive to being killed by ionizing radiation. All the
cases up to now have been found to be associated with mutations in the same gene
(ATM gene).
Inheritance pattern
Autosomal
recessive.
Penetrance
Full
Associated features that can be demonstrated in tests performed during pregnancy
There are no specific ultrasound signs and no associated defects.
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What is the risk of recurrence in a subsequent pregnancy?
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For a couple who has already had an affected child, the risk is 25% in every subsequent
pregnancy.
This also applies to a couple where both partners have been found to carry mutations
for Ataxia telangiectasia.
When only one parent carries the abnormal gene, there is no risk that any of their
offspring will have the disease;
however, in such families there is a 50% chance that the infant will be a carrier,
but he himself will be healthy, like the carrier parent.
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The risk for more distant relatives depends on the degree of relationship between
the relatives and the affected individuals, the ethnic groups of their partners,
the presence of family members with Ataxia telangiectasia in the partners' families,
consanguinity between the
parents, if present, etc. and is established within genetic counseling.
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Molecular genetic information
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The gene for the disease
The gene for the various types of Ataxia telangiectasia has been identified and
is called ATM
Location
On the long arm of chromosome
11.
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Genetic testing
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Diagnostic testing
In those ethnic groups in which the common disease-causing gene has been identified,
a direct gene mutation screening test can be carried out. For example, in North
African Jews, a direct test can be performed to identify the mutation in the ATM
gene - C103T - by testing for this mutation alone. See:
Testing the disease-causing gene for mutations that are common in a specific ethnic
group - autosomal recessive diseases.
Carrier testing
This can be performed only in ethnic groups where there is a known gene/mutation
that is responsible for the majority of the affected patients. The disease is common
in North African Jews, and the carrier frequency in the healthy North African Jewish
population is approximately 1:70. Unlike
cystic fibrosis, where there are a number of mutations in the gene that
causes the disease, in Ataxia telangiectasia, only one mutation common to most affected
individuals and carriers has been found in the North African Jewish population:
C103T.
In view of this, it is very important to ascertain the ethnic origins of the couple,
and it is advisable to examine (carrier DNA testing)
those couples where both partners are fully or even partially of North African Jewish
origin.
In Jews of other ethnic groups, carriers cannot be identified.
Carrier status testing in relatives of patients with Ataxia telangiectasia
It is important that relatives of patients with Ataxia telangiectasia clarify which
mutations are present in the patient or parents in their family in order to ascertain
that they are included in the battery of mutations routinely tested for - otherwise
it will be necessary to expand the list of mutations tested for and/or examine the
partner. This will be discussed in genetic counseling.
See also: "Introduction to population DNA screening for autosomal recessive diseases
such as Cystic fibrosis and others".
Fetal testing
Same as the diagnostic test.
Prenatal
diagnosis (amniocentesis) can also be offered to each couple who has had
an affected child. The best way is after identifying the mutations in the parents,
but if these are not found, indirect linkage analysis can be performed. See:
Indirect testing for genetic markers in a family that has one or more patients -
when there is only one gene that can cause the disease - autosomal recessive diseases.
Preimplantation diagnosis (before the embryonic cells implant in the uterine wall)
can also be offered for this disease - this is performed in special centers, and
in special cases this can be considered within genetic counseling.
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