Transcript Ataxia telangiectasia

Ataxia telangiectasia
Ataxia
 Ataxia describes a lack of muscle coordination during
voluntary movements, such as walking or picking up
objects.
 Ataxia can affect your movements, your speech, your
eye movements and your ability to swallow.
 Persistent ataxia usually results from damage to your
cerebellum — the part of your brain that controls muscle
coordination.
 Many conditions may cause ataxia, including alcohol
abuse, stroke, tumor, cerebral palsy and multiple
sclerosis. It's also possible to inherit a defective gene
that may cause one of many ataxia variants.
Cerebellum - function:
Cont.
 The cerebellum processes input from other
areas of the brain, spinal cord and sensory
receptors to provide precise timing for
coordinated, smooth movements of the skeletal
muscular system.
 The cerebellum is involved in the coordination of
voluntary motor movement, balance and
equilibrium and muscle tone. It is located just
above the brain stem and toward the back of the
brain. It is relatively well protected from trauma
compared to the frontal and temporal lobes and
brain stem.
Cont.
 Cerebellar injury results in movements that are
slow and uncoordinated. Individuals with
cerebellar lesions tend to sway and stagger
when walking.
 Damage to the cerebellum can lead to:
1) loss of coordination of motor movement
(asynergia).
2) the inability to judge distance and when to stop
(dysmetria).
3) the inability to perform rapid alternating
movements (adiadochokinesia).
Cont.
4) movement tremors (intention tremor).
5) staggering, wide based walking (ataxic
gait).
6) tendency toward falling.
7) weak muscles (hypotonia).
8) slurred speech (ataxic dysarthria).
9) abnormal eye movements (nystagmus).
Ataxia telangiectasia
 Ataxia telangiectasia (A-T) (Boder-Sedgwick
syndrome or Louis–Bar syndrome is a rare,
neurodegenerative, inherited disease that affects
many parts of the body and causes severe
disability. Ataxia refers to poor coordination and
telangiectasia to small dilated blood vessels,
both of which are hallmarks of the disease. A
child who has inherited A-T will display nervous
system abnormalities by age 2, and will then
progressively lose muscle control.
Genetics:
 Ataxia telangiectasia is caused by sequence
disruption in the gene ATM (Ataxia telangiectasia
mutated). It is an autosomal (relating to one of
the 23 chromosomes other than the sex
chromosome) recessive disease which means
that it will not affect the body unless it has twin
copies of the recessive genetic anomaly.
Therefore if both the parents carry one copy of
the gene, they themselves won't be affected by
it, but they will be carriers.
A-T usually runs in families. The mode of
inheritance is autosomal recessive, so in a
family with two parents who are carriers of
the A-T,there is 1 chance in 4 that each
child born to the parents will have the
disorder. Prenatal diagnosis can be carried
out in most families, but this is complex
and must be arranged before conception.
Pathophysiology
 AT is caused by a defect in the gene responsible for
recognizing and correcting errors in duplicating DNA
when cells divide. The gene normally repairs doublestranded DNA breaks.
 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 doublestranded 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.
 The majority of A-T sufferers, 65-70%, have truncating
mutations, with exon skipping mutations being
particularly common. This results in very low or
undetectable levels of ATM protein. Missense mutations
are the most common type of mutation found in carriers
with breast cancer. Individuals with two missense
mutations are believed to have a milder form of AT,
which may account for cases of attenuated A-T.
Therefore it is thought that "subtle constitutional
alterations of ATM may impart an increased risk of
developing breast cancer and therefore act as a low
penetrance, high prevalence gene in the general
population" (Maillet et al. 2002).
ATM Carriers
 Carriers of ATM missense mutations are believed to have
a 60% penetrance by age 70 and a risk of breast cancer
16 times higher that of the normal population, with a 5-8
fold increased risk of cancer. On average carriers die 7–8
years earlier than the normal population, often from heart
disease. Some papers state a lifetime risk for people with
both null and missense mutations of 10-38%, which is
still a hundredfold increase from population risk.
 Individuals with a single ATM mutation are also at a
higher risk from lung, gastric and lymphoid tumours, as
well as breast cancer. S707P is known to be particularly
common in breast cancer patients and F1463S is known
to be associated with Hodgkin’s lymphoma. If pulmonary
infections could be completely eradicated A-T is
consistent with survival into the 5th or 6th decade.
The symptoms:
At first, infants with A-T appear healthy. By
age 2, however, parents notice increased
clumsiness and balance problems. As
symptoms become progressively worse,
speech becomes slurred and difficult.
Between ages 2 to 8, the telangiectases tiny, red “spider” veins - appear on the
cheeks, ears, and in the eyes. By age 10
to 12, children with A-T lose muscle
control.
Other symptoms
can vary, but include immune system
deficiencies, low immunoglobulin
concentrations.
 missing or abnormally developed thymus
gland,
retarded growth,
 diabetes
 prematurely graying hair,
 and difficulty swallowing.
 Ocular apraxia (difficulty following objects across visual
field)
 Telangiectasias of the eyes and skin
 Chromosomal instability
 Hyper-sensitivity to ionizing radiation
 Increased incidence of malignancies (primarily
hematologic).
 Raised alpha-fetoprotein levels.
 Absent thymic shadow on X-ray.
 Ovarian dysgenesis.
Diagnosis
 Diagnosis is usually achieved clinically by examination
and identification of both ataxia and oculo-telangiectasia
or skin telangiectasia.
 This is then followed by laboratory tests for serum AFP
level,
 the response of white blood cells to X-rays and
measurement of the level of ATM protein Sufferers may
also have a low lymphocyte count and other
immunological abnormalities.
 This can then be followed by cytogenetic and
molecular testing to confirm the diagnosis.
Molecular diagnosis of A-T can be carried out by
sequencing all 66 exon of the gene or by linkage
if there is a significant family history.
 MRI and CT scans may show signs of cerebellar
atrophy. (MRI is the preferred method, as
patients should limit exposure to any radiological
diagnostic tests that use ionizing radiation)
 Protein functionality testing is also available.
 However A-T testing is usually carried out
cytogenetically as specific breakpoints and
cytogenetic instability are major characteristic
features of the disorder. This must be carried out
on lymphocytes. 10% of patients with A-T show
balanced translocations, 2/3rds of which involve
the immunoglobulin genes on chromosomes 7
and 14. Some patients show expansions in their
immunoglobulin genes, which can expand
during mitosis resulting in prolymphocyte
leukaemia.
Antenatal diagnosis can be carried out
using linkage and microsatellite markers.
However, direct gene analysis between
known sufferers and the foetus is more
common.
Histopathologic studies of the brain of an
individual with ataxia-telangiectasia have
revealed loss of Purkinji cells, granular
cells, and basket cells of cerebellar cortex.
Differential Diagnosis
Other Problems to Be Considered
- Hartnup disease
- Cockayne syndrome
- De Sanctis-Cocchione syndrome
- Friedreich ataxia
- Rendu-Osler-Weber disease
Management
 Treatment is symptomatic and supportive.
 Physical and occupational therapy may help
maintain flexibility.
 Speech therapy may also be needed.
 Gamma-globulin injections may be given to help
supplement a weakened immune system.
 High-dose vitamin regimens may also be used.
 Antibiotics are used to treat infections.
 Some physicians recommend low doses of
chemotherapy to reduce the risk of cancer but
this is controversial.
It is also recommended that heterozygote
family members are regularly monitored
for cancers.
Recently deferoxamine was shown to
increase the stability of A-T cells and may
prove to be an effective treatment for the
disorder.
People with A-T have an increased
incidence (probably 1% risk per year) of
tumours, particularly lymphomas and
leukaemia, but due to sufferers' hypersensitivity to ionising radiation,
radiotherapy and chemotherapy are rarely
used.
Prognosis
Those with A-T usually die in their teens or
early 20s although some individuals have
been known to live to over 40. Mortality is
mainly due to the compromised immune
system, which causes recurrent
respiratory infections, predisposition to
cancer, and a high rate of pulmonary
problems.
Epidemiology
 This disease has had cases all over the world in
all races and it's probable that 1 person in
100,000 will be affected by it. Also it has an
equal probability of striking in males as well as
females.
 The incidence of A-T in Caucasians is about 3
per million so the disorder is very rare, with
probably fewer than 200 affected people in the
UK.
Sex
Males and females are affected equally.
Age
The age of patients with A-T at the time of
presentation is 2.5-7 years.
Follow-up
 Further Outpatient Care
Respiratory infections should be monitored.
Physical therapy is indicated.
 Prevention
The gene responsible for A-T, the ATM gene,
was discovered in 1995. This gene makes a
protien that activates a number of the protiens
that control cell cycle, DNA repair, and cell
death. There is ongoing preclinical and early
clinical research on gene therapy to treat A-T
and other disease.
Complications
 Complications may include the following:
 Recurrent pulmonary infections.
 Progressive ataxia results in the patient being
wheelchair ridden.
 Death.
Patient Education
 Children with A-T should have psychologic
counseling ase the age because of the great
disparity between chronological age and mental
age in tests involving visual motor coordination.
References:
http://www.neuroskills.com/brain.shtml
http://www.mayoclinic.com/health/ataxia/D
S00910
http://www.umm.edu/imagepages/18008.ht
m
http://en.wikipedia.org/wiki/Ataxia_telangie
ctasia