Ataxia Telangiectasia: Causes, Symptoms, Diagnosis and Treatment

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A man with symptoms of Ataxia Telangiectasia

1Overview

Ataxia-telangiectasia (AT or A-T), which may also be referred to as Louis–Bar syndrome, DNA damage response syndrome, or genome instability, is a  primary immunodeficiency disease that can damage different organs in the body. An immunodeficiency disease causes a breakdown in the immune system that makes the body prone to diseases. It is a rare, neurodegenerative, complex, autosomal recessive, multisystem disorder that can cause severe disability. Ataxia means poor coordination and telangiectasia means small dilated blood vessels.

This disease is defined by cerebellar ataxia, progressive difficulty with coordinating movements, impaired organ maturation, progressive neurologic impairment, recurrent respiratory and sinus infections, abnormalities of balance, dilated blood vessels on the surface of the skin and in the eyes, sensitivity to the effects of radiation treatments including medical x-rays, predisposition to malignancy, ocular and cutaneous telangiectasia, and abnormalities in the immune system.

A-T affects many parts of the body. It weakens the immune system by causing a susceptibility to infection. A lot of people affected by A-T develop chronic lung infections.
It also causes a damage to some parts of the brain which includes the cerebellum that results in difficulty with coordination and movement. It prevents repair of broken DNA which increases the risk of having cancer, particularly lymphoma or cancer of immune system cells and leukemia or cancer of blood-forming cells.

This disease usually occurs in childhood which affects between 1 in 40,000 and 1 in 100,000 people. A-T is progressive and patients of A-T are usually wheelchair-bound by their teens. This disease is generally deadly to patients by the time that they reach their twenties.

The life expectancy of individuals affected by ataxia-telangiectasia varies a lot,
but they usually live into early adulthood.

2Causes

A-T is an inherited recessive autosomal disorder, which means that this disease only occurs in an individual who acquires the same defective gene for the same attribute from each parent. An individual who only has one defective copy of the gene is known as a carrier wherein he/she will not manifest symptoms but he/she could pass on the gene mutation to his/her kids. If a couple is both carriers of the abnormal gene, the risk of having a child affected with A-T is 25% with each pregnancy. The risk of having a child who is a carrier just like the parents is 50% with each pregnancy. The child gets a 25% chance to receive normal genes from both parents and be genetically normal for that specific trait.

A-T is caused by a defect in the ATM gene, the gene responsible for managing the cell’s response to many forms of stress which includes double-strand breaks in the DNA. Mutations occur in the ATM gene that I can be found on the long arm of chromosome 11. The ATM gene controls the production of an enzyme whose role is to regulate cell division following DBA damage. ATM gene triggers the build-up of p53 protein that hinders cells from dividing. For patients of A-T, the mutations in the ATM gene cause a defect or an absence of the ATM protein and delayed aggregation of the p53 protein. This results to the dividing or replicating of the cells with DNA damage without proper repair of their DNA and this poses a higher risk of developing cancer. Around half of the cancers are defined by abnormalities or deficiencies affecting the activity of the p53 protein which is a tumor suppressor. An exposure to radiation like as medical x-rays usually strengthens the p53 directed activity of the ATM protein but in individuals affected by A-T, the deficiency of the ATM protein activity causes extreme susceptibility to radiation.

3Symptoms

The symptoms of ataxia telangiectasia usually occur in early childhood, the stage when toddlers begin to walk. Children affected by A-T usually start walking at a normal age but in some cases, there might be a delayed onset of walking. They sway, wobble, or stagger when walking, sitting, or standing still, and they may appear almost as if they are drunk.
In their early schooling age which is around three to six years old, they develop a difficulty in eye movements because, at this age, telangiectasia or visible dilated blood vessels begin in the eyes. The discolorations may spread to the eyelids, ears, face, the roof of the mouth, and possibly other body parts. Turning of the head and rapid eye movements and blinking may develop slowly. There might also be occasional nosebleeds. They develop distorted or slurred speech and swallowing problems. Other early symptoms include problems with hand coordination and balance, muscle twitches, disturbances in the nerve function, and involuntary jerking movements.

Some children with A-T have increased the number of respiratory tract infections such as sinusitis, pneumonia, bronchitis, and ear infections because of immunodeficiency which is also caused by A-T. A-T affected children have low immunoglobulin levels and problems making antibody.

A lot of children with A-T have stable neurologic symptoms for the first 4-5 years but they start showing problems as they go to school. Children with A-T normally have normal or above normal intelligence.

Patients with A-T have reduced the number of T- and B-lymphocytes that may result to having warts and a skin infection called molluscum.

It makes take years to diagnose A-T properly because some children initially show symptoms of ataxia and nothing else and another factor is that not all children develop at the same rate or in the same manner.

Other symptoms of A-T that may manifest beyond childhood are the following:

  • Premature changes in skin and hair
  • Increased risk of having cancer
  • Problems with breathing, choking and drooling
  • Delayed onset or incomplete pubertal or sexual development
  • Diabetes
  • Slowed rate of growth (height and/or weight)
  • Sensitivity to radiations including x-rays
  • Weight loss
  • Fatigue
  • Lack of appetite
  • Weakened immune system
  • Discoloration of skin when exposed to sunlight
  • Seizures
  • Premature graying of hair
  • Recurring severe respiratory infections
  • Decreased or absent deep tendon reflexes
  • Mask-like face
  • Lymph nodes, spleen, and tonsils below normal size
  • Jerky or abnormal eye movements

4Diagnosis

Ataxia Telangiectasia is diagnosed based on a detailed medical history of the patient, identification of featured symptoms, intensive clinical evaluation, and a number of specialized tests that may include MRI, karyotyping, and blood tests.

Blood tests can detect increased levels of serum alpha-fetoprotein that transpires in most cases of A-T. It may also disclose high liver enzymes.

Karyotyping detects chromosomal defects and abnormalities. A-T affected persons have a heightened frequency of these chromosomal defects.

MRI shows progressive cerebellar atrophy.

The diagnosis of A-T is suspected by a combination of neurological clinical features such as ataxia with telangiectasia which includes increased infections and is confirmed by certain laboratory abnormalities such as elevated alpha-fetoprotein levels. The diagnosis can be confirmed in the laboratory by looking for mutations in both copies of the cell’s ATM gene, a deficiency or absence of ATM function, or a deficiency or absence of ATM protein in cultured blood cells.

Since there are other rare and neurologic disorders that share similar symptoms as that of A-T, physicians should be careful in diagnosing A-T and not confuse it with other diseases. This can be done through clinical features and laboratory tests including gene sequencing.

Antenatal diagnosis is performed if the pathological ATM mutations in the family have been identified in an affected child. Antenatal diagnosis can be made by haplotype analysis if an apparent diagnosis of the affected child has been made through ATM protein analysis and/or clinical and laboratory findings.

Other tests include:

  • B and T cell screen
  • Genetic testing to look for mutations in the ATM gene
  • Carcinoembryonic antigen
  • Glucose tolerance test
  • X-rays to look at the size of the thymus gland
  • Serum immunoglobulin levels

5Treatment

There is currently no known treatment for ataxia telangiectasia. The treatment for A-T is supportive and symptomatic. Physical, speech, and occupational therapy, and also exercises may help in maintaining body functions but these treatments will not delay or stop the course of neurodegeneration.

For respiratory infections, treatment is administered through antibiotics and/or postural drainage of the lungs and bronchial tubes. Gammaglobulin injections may be effective in some cases but this should be done under the supervision of a doctor. For serious cases, physiotherapy and/or the use of a therapy vest is advised. For chronic lung diseases, antibiotic prophylaxis, supplemental oxygen therapy, and/or inhaled corticosteroids may be recommended. Patients who have a problem with swallowing may be advised to use a G-tube to intake food and drinks instead of swallowing them directly.

Vitamin E therapy has been known to provide temporary relief for some symptoms. Diazepam may also help treat involuntary muscle contractions and slurred speech. Both of these this should only be taken under doctor’s prescription.

Exposure to sunlight should be avoided to control the spreading and the severity of dilated blood vessels.

Genetic counseling may benefit individuals with A-T and their families.

There is ongoing research to develop a treatment for A-T which include gene therapy, drugs to correct the function of the mutated protein, and direct replacement of the functional protein.