All You need to know About Ataxia Telangiectasia

Executive Summary

Ataxia telangiectasia (AT) is a rare neurological autosomal recessive illness causing severe impairment. It is mainly caused due to mutational changes in the ATM gene that contribute to detecting and repairing damaged DNA. Different age groups are affected by variations in symptoms. Difficulty with movement control, complications in the oculomotor system, infections in ears, sinuses, and lungs, delayed or incomplete pubertal development, and slower growth are the most common symptoms of ataxia telangiectasia. It is passed down through the generations in an autosomal recessive pattern. Genetic instability occurs within the ATM protein, causing radio sensitivity and cancer development. Also, AT is one of several DNA repair diseases that causes neurological degeneration or abnormalities. It is diagnosed by combining neurologic clinical features telangiectasia and occasionally increased infection and later confirmed by specific laboratory abnormalities. The laboratory findings of Ataxia Telangiectasia are considered necessary in management and determining its neurological impact. No such medication is available to date to delay or stop the progression of neurologic issues. Individuals suffering from Ataxia Telangiectasia have also faced some major immunological problems.

What is Ataxia telangiectasia?

Ataxia telangiectasia (AT or A–T), commonly known as Louis–Bar syndrome or ataxia telangiectasia syndrome, is a rare neurological autosomal recessive illness that causes severe impairment ​1​. Poor coordination is referred to as ataxia, and tiny dilated blood vessels are referred to as telangiectasia. A–T affects several sections of the body:

  •  It causes movement and coordination problems by impairing certain portions of the brain, especially the cerebellum.
  • It weakens the immune system and makes you more susceptible to illness.
  • It inhibits broken DNA from being repaired, raising the risk of cancer.

When toddlers learn to sit or walk, symptoms usually develop in early childhood (the toddler period). Kids wobble or sway when walking, standing motionless, or sitting, even though they typically begin walking at a regular age. They have trouble moving their eyes naturally from one place to the next in late preschool and early elementary school (oculomotor apraxia). They develop slurred or distorted speech, as well as difficulties swallowing. Some people have higher respiratory tract infections (ear infections, sinusitis, bronchitis, and pneumonia).

It may take several years for A–T to be fully diagnosed because not all children develop in the same way or at the same rate. For the first 4–5 years of life, most children with A–T have stable neurologic symptoms, but they start to have more issues as they become older ​2​.

A–T is caused by a mutation in the ATM gene, which is responsible for detecting and repairing damaged DNA. A–T can affect as many as one in every 40,000 people or as few as one in every 300,000 ​3​.

Also Read: Symptoms based on Cancer types.

There is a lot of variation in the intensity of A–T symptoms among people who have it and at different ages.

The following symptoms or issues are either standard or significant elements of A–T Ataxia (difficulty with movement control). 

  • A–T Ataxia (difficulty with movement control) is noticeable early but worsens in school to pre-teen years.
  • Apraxia of the oculomotor system (difficulty with coordination of head and eye movement when shifting gaze from one place to the next)
  • Uncontrollable emotions
  • Due to telangiectasia, the white (sclera) of the eyes appears bloodshot (dilated blood vessels). These appear between the ages of 5 and 8 and are not evident in infancy. Skin that has been exposed to the sun can also develop telangiectasia.
  • Infections affecting the ears, sinuses, and lungs, in particular
  • Cancer is becoming more common (primarily, but not exclusively, lymphomas and leukaemias)
  • Delayed or incomplete pubertal development, as well as menopause at a young age
  • Slowed growth (in terms of weight and height)
  • Drooling is common in young children, especially when they are weary or focused on something.
  • Dysarthria is a type of dysarthria that affects (slurred, slow, or distorted speech sounds)

Many youngsters are misdiagnosed with cerebral palsy at first. The neurologic symptoms of poor walking, hand coordination, speech, eye movement, and telangiectasia may not manifest until the preschool years when the diagnosis of A–T is made. Because A–T is so uncommon, doctors may be unfamiliar with the symptoms or diagnostic procedures. The late onset of telangiectasia might make diagnosis difficult. Because of the early stability of signs and indicators, it may take some time for doctors to explore A–T as a possibility.


A–T is passed down through the generations in an autosomal recessive pattern.

T in the ATM (ATM serine/threonine kinase or ataxia–telangiectasia mutated) gene, which was cloned in 1995, is caused by A–mutations. ATM is a 69-exon gene found on human chromosome 11 (11q22.3) that spans 150kb of genomic DNA. A–T is inherited in an autosomal recessive pattern. Each parent is a carrier, which means they each have one regular and one mutant copy of the A–T gene (ATM). A–T arises when a child gets the faulty A–T gene from both parents, so in a household with two carrier parents, a child born to the parents has a one in four chance of inheriting the disorder ​4​.

If the flaws (mutations) in an affected child’s two ATM genes have been found, prenatal diagnosis (and carrier detection) can be made in families. Getting this done can be difficult, and it should be planned ahead of time because it takes time. Finding mutations in the ATM gene of someone not related to you (for example, the spouse of a known A–T carrier) is difficult. Polymorphisms (variant spellings) in genes are familiar but do not affect function. Such variant spellings are likely to arise in a gene as vast as ATM, and clinicians cannot always anticipate whether a single mutation would cause disease or not.

Family members of A–T patients can benefit from genetic counselling to learn what can and cannot be examined and how test results should be interpreted. A–T Carriers, such as the parents of someone with A–T, have one mutant and one regular copy of the ATM gene. They are generally healthy; however, women have a higher chance of breast cancer. This discovery has been confirmed in several ways, and it is currently the topic of investigation. Unless further tests are necessary because the individual has other risk factors, routine surveillance (including monthly breast self-exams and mammography at the age-appropriate schedule) is recommended (e.g., family history of breast cancer).


What causes a multisystem disease when the ATM protein is lost?

A genomic instability disease, a DNA repair disorder, and a DNA damage response (DDR) syndrome have all been associated with the ATM protein A–T ​5​. ATM, the gene that causes this multisystem illness, codes for a protein that controls the physiological response to DNA double-strand breaks (DSBs). DSBs can be caused by radiation therapy, chemotherapy that mimics radiation (radiomimetic medicines), and specific metabolic processes and metabolites. ATM arrests the cell cycle when these breaks occur and recruits and activates other proteins to repair the damage. As a result, an ATM enables the cell to repair its DNA before cell division. ATM will mediate the process of programmed cell death (apoptosis) to remove the partition and prevent genomic instability if DNA damage is too severe.

Radio sensitivity and cancer

The ATM protein is required for cell-cycle checkpoint regulation and programmed cell death in response to DSBs. As a result, there is genetic instability, which can lead to cancer.

When an ATM is missing, DSBs are caused by irradiation and radiomimetic chemicals, not adequately repaired. As a result, such drugs can be highly hazardous to A–T cells and people who have A–T.

Pubertal development is delayed (gonadal dysgenesis)

Infertility is frequently mentioned as an Ataxia Telangiectasia symptom. This is unquestionably the case in the A–T mouse model. In humans, gonadal atrophy or dysgenesis, marked by delayed pubertal development, may accurately describe the reproductive problem. When ATM is absent, meiotic abnormalities and arrest can occur because planned DSBs are formed to initiate genetic recombination involved in creating sperm and eggs in reproductive organs (a process known as meiosis).

Immune system disorders and cancers linked to the immune system

The immune system and ATM

Lymphocytes rearrange specific DNA regions as they evolve from stem cells in the bone marrow to adult lymphocytes in the periphery [V(D)J recombination process]. This procedure necessitates the creation of DSBs, which are difficult to repair without using an ATM. As a result, most patients with A–T have fewer lymphocytes. They have some lymphocyte function impairment (such as an impaired ability to make antibodies in response to vaccines or infections). Furthermore, fragmented bits of DNA in chromosomes implicated in the rearrangements mentioned above tend to recombine with other genes (translocation).

Changes in progesterone

Genomic instability, sluggish growth and premature senescence in culture, shorter telomeres, and low-level stress response are all seen in cells from patients with A–T. These factors may have a role in the progeric (early ageing) changes in skin and hair that some persons with Ataxia Telangiectasia experience. For example, DNA damage and genomic instability trigger melanocyte stem cell (MSC) differentiation, which results in grey. ATM may thus act as a “stemness checkpoint,” preventing MSC differentiation and premature greying of the hair.


In the lack of the ATM protein, the aetiology of telangiectasia or dilated blood vessels is unknown.

Increased levels of alpha-fetoprotein (AFP)

After the age of two, approximately 95% of people with A–T have increased blood AFP levels and measured AFP levels appear to grow slowly over time. AFP levels are very high in neonates and typically decline over the first year to 18 months to adult levels. The explanation for the higher AFP levels in people with Ataxia Telangiectasia is unknown.


A–T is one of several DNA repair diseases that cause neurological degeneration or abnormalities. Progressive cerebellar degeneration, marked by the loss of and, to a lesser extent, the loss of, is thought to be one of the most devastating symptoms of A–T. (located exclusively in the cerebellum). Although several possibilities have been offered based on research performed both in cell culture and in the mouse model of A–T, the mechanism of this cell loss is unknown. The following are some of the current hypotheses for why A–T causes neurodegeneration:

Failed clearance of genomically injured neurons throughout development Transcription stress and abortive transcription, involving topoisomerase cleavage complex Defective DNA damage response in neurons can lead to (TOP1cc) lesions that are reliant.


Increased ROS and altered cellular metabolism characterize an incorrect response to oxidative stress. Mitochondrial dysfunction is a condition in which the mitochondria fail to function correctly.

Neuronal function defects:

Inappropriate re-entry of post-mitotic (mature) neurons into the cell cycle

Dysregulation of synaptic and vesicular synapses

Dysregulation of HDAC4

Hypermethylation of histones and epigenetic changes

Protein turnover changes

These possibilities may not be mutually exclusive, and when ATM is absent or deficient, neuronal cell death could be caused by more than one mechanism. Furthermore, the loss of Purkinje and granule cells. The consequences of ATM insufficiency on brain locations other than the cerebellum are currently being researched.

Exposure to radiation

Ionizing radiation sensitivity is increased in people with A–T. (X-rays and gamma rays). As a result, X-ray exposure should be confined to medically critical situations, as exposing an A–T patient to ionizing radiation might damage cells in ways that the body cannot repair. Other types of radiation, such as ultraviolet light, are generally tolerated by the cells. Therefore there is no need to take additional precautions when exposed to sunshine.

The cerebellum does not account for all neurologic problems reported in persons with Ataxia Telangiectasia.


The diagnosis of A–T is usually suspected by a combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability) combined with telangiectasia and occasionally increased infections, and confirmed by specific laboratory abnormalities (elevated alpha-fetoprotein levels, increased chromosomal breakage or cell death of white blood cells after exposure to X-rays, absence of ATM protein in white blood cells, or mutations in each of the person) and in most persons with A–T, a range of laboratory abnormalities exist, allowing a provisional diagnosis to be made in the absence of typical clinical symptoms. Not all anomalies are seen in all people ​6​.

  • After two years of age, blood alpha-fetoprotein levels are elevated and progressively increasing.
  • Low immunoglobulins (particularly IgA, IgM, IgG, and IgG subclasses) and a low number of lymphocytes in the blood indicate immunodeficiency. Chromosomal instability (broken pieces of chromosomes)
  • Cellular sensitivity to x-ray radiation has increased (cells die or develop even more breaks and other damage to chromosomes)
  • On an MRI scan, there is evidence of cerebellar atrophy.

An absence or deficit of the ATM protein in cultured blood cells, an absence or lack of ATM function (kinase assay), or mutations in both copies of the cell’s ATM gene can all be used to confirm the diagnosis in the lab.

Cogan oculomotor apraxia is a rare developmental disease. Affected children have trouble moving their eyes just to a new visual target; thus, they will swivel their heads past the mark to “drag” their eyes to the new object of interest, then turn back. This propensity emerges in late childhood and toddlerhood, and it primarily improves over time. This contrasts with the oculomotor abnormalities seen in children with A–T, which do not manifest themselves until later in infancy. Cogan’s oculomotor apraxia can be a standalone issue, or it might be linked to a more considerable developmental delay.

The most frequent hereditary cause of ataxia in children is Friedreich ataxia (FA). Like A–T, FA is a recessive disease that affects people who have never had a problem. FA is caused by a mutation in the frataxin gene, which causes an increase of a naturally occurring repetition of the three nucleotide bases GAA from the usual 5–33 repeats on each chromosome to more than 65 repeats. Between the ages of 10 and 15, ataxia is common. It is distinguished from A–T by the absence of telangiectasia and oculomotor apraxia, a normal alpha-fetoprotein, scoliosis, absent tendon reflexes, and aberrant EKG characteristics.

Other rare illnesses can be mistaken for A–T due to clinical similarities, laboratory similarities, or a combination of the two. Among them are:

Type 1 (AOA1) Ataxia–oculomotor apraxia type 2 (AOA2) (AOA2, also known as SCAR1)

A disorder that resembles ataxia telangiectasia (ATLD)

Breakdown syndrome in Nijmegen (NBS)

Clinical and laboratory characteristics of rare genetic illnesses that are similar to A–T syndrome

Ataxia–oculomotor apraxia type 1 (AOA1) is an autosomal recessive disorder that manifests increasing coordination deficits and oculomotor apraxia at a similar age to those with A–T. A mutation in the gene that codes for the protein aprataxin causes it. The absence of ocular telangiectasia, the early manifestation of peripheral neuropathy, and early in their course obvious trouble with the onset of gaze changes distinguish affected persons from those with A–T ​7​. However, laboratory findings are significant in the distinction between the two.


Ataxia and other neurologic issues

There is currently no medication available to delay or stop the progression of neurologic issues ​8​.

Immune system issues

All people with Ataxia Telangiectasia should have at least one comprehensive immunologic evaluation, which includes determining the number and type of lymphocytes in the blood (T-lymphocytes and B-lymphocytes), serum immunoglobulin levels (IgG, IgA, and IgM), and antibody responses to T-dependent (e.g., tetanus, Hemophilus influenza type B) and T-independent (23-valent pneumococcal polylactic The pattern of immunodeficiency exhibited in an A–T patient early in infancy (by age five) will, for the most part, be the same pattern seen throughout the rest of their lives. Immunization can occasionally help those with immune issues. Commercially available vaccines are against common bacterial respiratory pathogens such as Hemophilus influenza, pneumococci, and influenza virus (the “flu”). Even in people with low immunoglobulin levels, they can often aid in increasing antibody responses. Let’s say the immunizations don’t work, and the patient continues to have infection problems. Gamma globulin treatment (IV or subcutaneous infusions of antibodies taken from healthy people) may be beneficial in that instance. A tiny percentage of patients with A–T develop an anomaly in which one or more types of immunoglobulin are elevated well above normal levels. 

If a patient’s vulnerability to infection rises, it’s critical to reevaluate immune function to see if deterioration has occurred and a new treatment is needed. If a lung infection occurs, it’s also essential to look into the likelihood of a problem with swallowing that leads to aspiration into the lungs (see above sections under Symptoms: Lung Disease and Symptoms: Feeding, Swallowing and Nutrition.)The majority of persons with A–T have low blood lymphocyte counts. Although this condition appears to be essentially constant with age, a small percentage of persons experience progressively lower lymphocyte counts as they grow older.


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