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ATAXIA-TELANGIECTASIA

Ataxia-telangiectasia
A.k.a. Louis=Bar Syndrome

A rare neurodegenerative childhood disease that affects many


parts of the body and causes severe disability.

Ataxia refers to uncoordinated movements, such as walking.


Telangiectasias are enlarged blood vessels (capillaries) just
below the surface of the skin. Telangiectasias appear as tiny,
red, spider-like veins.

Many conditions may cause ataxia, including alcohol abuse,


stroke, tumor, cerebral palsy, and multiple sclerosis. It is also
possible to inherit a defective gene that may cause one of
many ataxia variants.
Ataxia-telangiectasia
Ataxia-telangiectasia is inherited. This means it is passed
down through families. It is an autosomal recessive trait.
Both parents must provide a copy of a nonworking gene
for the child to have symptoms of the disorder.

The disease results from defects in the ataxia


telangiectasia mutated (ATM) gene. Defects in this gene
can lead to abnormal cell death around the body,
including the part of the brain that helps coordinate
movement.

Boys and girls are equally affected.


.
Ataxia-telangiectasia can best be classified, according to
its major clinical and pathologic features, as a
predominantly cerebellar form of spinocerebellar
degeneration, which is transmitted as an autosomal
recessive trait and evolves ultimately to include motor
neuron disease, with spinal muscular atrophy and
peripheral neuropathy
Function of Cerebellum
The cerebellum receives information from the sensory
systems, the spinal cord, and other parts of the brain and
then regulates motor movements.
The cerebellum coordinates voluntary movements such
as posture, balance, coordination, and speech, resulting
in smooth and balanced muscular activity.
Pathophysiology
The Ataxia-Telangiectasia Mutated (ATM) gene
encodes the protein kinase ATM, which is the key
regulator of cellular response to double-strand breaks
(DSB) in DNA. Therefore, ataxia-telangiectasia symptoms
include all the possible consequences of the perturbations
in DNA damage response (DDR).

The gene, ataxia-telangiectasia mutated (ATM),


discovered in 1995, is on chromosome 11 (11q 22-23).
. Normally, when a cell tries to duplicate damaged DNA, it
identifies the damage at several checkpoints in the cell
division cycle. It tries to repair the damage, and, if it can't
repair the damage, it commits suicide through
programmed cell death (apoptosis). The ATM gene plays
a critical role in this process. It mobilizes several other
genes try to repair the DNA damage or destroy the cell if
they can't repair it. These downstream genes include
tumor suppressor proteins p53 and BRCA1, checkpoint
kinase CHK2, checkpoint proteins RAD17 and RAD9, and
DNA repair protein NBS1.
In A-T, the pathways that control these processes are
defective. This allows cells with damaged DNA to
reproduce, resulting in chromosome instability,
abnormalities in genetic recombination, and an absence
of programmed cell death. ATM patients are particularly
sensitive to X-rays, because X-rays induce double-
stranded DNA breaks, which they are unable to repair.
They are also particularly susceptible to cancers that
result from double-stranded DNA breaks. For example,
female ATM patients have a two-fold higher risk of
developing breast cancer, often before age 50.
Mutations in the ATM gene are thought to come in two
types:

Null mutations cause complete loss of function of the


protein, and are therefore inherited in a recessive manner
and cause A-T.

Missense mutations, which produce stable, full sized


protein with reduced function, e.g., substitutions, short in-
frame insertions and deletions etc. These mutations act
by dominantly interfering with the normal copy of the
protein.
Symptoms
Decreased coordination of movements
(ataxia) in late childhood that can include
ataxic gait (cerebellar ataxia), jerky gait,
unsteadiness
Decreasing mental development, slows or
stops after age 10 to 12
Delayed walking
Discoloration of skin areas exposed to
sunlight
Discoloration of skin (coffee-with-milk-
colored spots)
Enlarged blood vessels in skin of nose,
ears, and inside of the elbow and knee
Enlarged blood vessels in the whites of the
eyes
Jerky or abnormal eye movements
(nystagmus) late in the disease
Premature graying of the hair
Seizures
Sensitivity to radiation, including x-rays
Severe respiratory infections that keep
coming back (recurring)
Diagnosis
Cytogenetic and molecular testing
MRI and CT scans
Protein functionality testing
Measurement of the alpha fetoprotein level in the blood.
Treatment
NEURODEGENERATION
>L-DOPA derivatives, Dopamine Agonists, Anticholinergic
(Basal Ganglia Dysfunction)

>Amantadine, Fluoxetine, Buspiron (Balance, Speech,


Coordination)

>Gabapentin, Donazepan, Propanalol (Tremors)


>Antioxidants
Treatment
IMMUNODEFICIENCY
>Immune globulin replacement

>Antibiotics

>Addition of thickeners to thin liquids

>Placement of gastroscopy tube


Treatment
MALIGNANCY
>High dose of vitamin regimens, folic acid, and alpha lipoic
acid (Anti-cancer properties)

Avoid X-Rays if possible


Treatment
Recently desferrioxamine was shown to increase the
stability of A-T cells and may prove to be an effective
treatment for the disorder.