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Ataxia telangiectasia

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					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 double-
  stranded 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 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.
 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' hyper-
 sensitivity 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.h
 tm
http://en.wikipedia.org/wiki/Ataxia_telangie
 ctasia

				
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posted:8/31/2011
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