Ataxia telangiectasia

Ataxia telangiectasia (A-T) is an autosomal recessive disorder caused by mutations in the gene ATM (ataxia-telangiectasia mutated)(11q22.3). This gene is expressed commonly and encodes a protein kinase (ATM kinase) which plays a key role in the control of double-strand-break DNA repair. A-T is a progressive, multisystem disease that has a large number of complex and diverse manifestations that vary with age. The clinical picture of this condition can be very variable and the severity of the pulmonary, immunological and neurological manifestations varies widely between patients and is related to the severity of the underlying mutations and any residual ATM kinase activity. It has been recently suggested that the name A-T should be replaced by ATM syndrome. ATM syndrome represents a neurodegenerative disorder with multisystem involvement due to the absence or reduced levels of ATM protein and kinase activity. The syndrome is characterised by the presence of movement disorders, such as cerebellar ataxia, dystonia, chorea and myoclonus, in association with systemic abnormalities such as immunodeficiency, malignancies, oculocutaneous telangiectasias and an increase in α-fetoprotein levels. The disease most commonly presents with ataxia during the third or fourth year of life. The important first step in the evaluation of young children presenting with ataxia should be α-fetoprotein testing. The diagnosis should then be confirmed by genetic testing to identify the mutations and measure the product of the ATM gene, the protein kinase ATM. This diagnostic test is likely to be available in specialised laboratories only. Patients with A-T die prematurely, the leading causes of death being respiratory diseases and cancer. A minimally estimated annual mortality rate for white patients is 19.5/1000 for ages 15–19 years and reportedly three-fold higher for African-American patients.

The term Ataxia-Telangiectasia was initially advanced by Boder and Sedgwick in 1957,in which described eight patients with classical A-T, while in 1958 Centerwall and Miller entitled it Louis-Bar syndrome which relates to Madame Louis-Bar, a Belgian neurologist who published a case report of a 9 year-old boy with cutaneous telangiectasia and progressive cerebellar ataxia. She initially classified this new disease in the group of phacomatosis PPV. In 1993, a case report was published about a 17 year-old boy with cerebellar ataxia concomitant dystonia, myoclonus, pyramidal signs, pulmonary infection, persistent lymphopenia, immunoglobulin deficiency and rising alpha-fetoprotein, termed as ataxia with immune deficiency.^[1] In 1995, the responsible gene for A-T(ATM) was identified by Savitsky et al. In 2001, Stewart found a correlation with ATM kinase activity levels in cells and the degree of neurological symptoms in A-T patients.^[2]

• The ataxias can be divided into:^[3]
  • Genetic (with or without a family history) and those that are acquired/degenerative.
  • Sporadic ataxia implies there is no family history.
  • Acquired progressive ataxias can be:
    • Immune mediated (paraneoplastic spinocerebellar degeneration, gluten ataxia)
    • Degenerative (cerebellar variant of multiple systems atrophy (type C))
    • Caused by deficiency states (vitamin B12, vitamin E)
    • Toxicity (eg, alcohol-related ataxia, phenytoin)
    • Associated with infections (HIV, sporadic Creutzfeldt-Jakob disease, progressive multifocal leukoencephalopathy).
  • Inherited ataxias can have autosomal dominant, autosomal recessive, X-linked or mitochondrial (maternal) inheritance.
  • Metabolic disorders (Niemann-Pick type C, Tay-Sachs disease).

• There is no established system for the classification of Ataxia Telangiectasia.

The responsible gene in AT, ataxia-telangiectasia mutated (ATM), was discovered in 1995 by Savitsky et al.,^[4] a team led by Yosef Shiloh of Tel Aviv University in Israel. Researchers linked the hyper-sensitivity of AT patients to ionizing radiation (IR) and predisposition to cancer, to “chromosomal instability, abnormalities in genetic recombination, and defective signaling to programmed cell death and several cell cycle checkpoints activated by DNA damage”.^[5] Earlier observations predicted that the gene altered in AT played a role in DNA damage recognition. These predictions were confirmed when a single gene on chromosome 11 (11q 22-23) was discovered.^[4][6] Since its discovery, the protein product of the ATM gene has been shown to be a part of eukaryotic cell cycle control, DNA repair, and DNA recombination (Lavin, 2004). Specifically, the AT gene serves as a tumor suppressor gene by contributing to a network of genes that link double stranded breaks in DNA to cell cycle arrest and apoptosis (programmed cell death). Patients with ATM have a defective AT gene, which leaves them susceptible to contracting cancer. For example, female ATM patients have a two-fold higher chance of ever having breast cancer, which often occur before the age of 50. ATM patients must try avoiding x-rays at all costs since the radiation induces double-stranded breaks.

• AT is an autosomal recessive disorder caused by mutations in the ATM gene located on chromosome 11q22-23. ^[7]
• It was characterised in June of 1995 and is made up of 66 exons spread across 150kb of genomic DNA.
• It encodes a 13kb mature transcript with an open reading frame of 9168 nucleotides.
• The ATM protein is about 370kDa and is ubiquitously expressed and is localised to the cell nucleus.
• The ATM protein is a large serine-threonine kinase thought to play a role in regulating cell cycle checkpoints, repair of double stranded DNA and meiosis (similar to the BRCA genes).
• ATM is also known to play a role in regulating p53, BRCA1 and CHEK2.
• Part of ATM’s role in DNA repair is known to be that of telomere repair as telomeres degrade more rapidly in people affected with AT.

• Mutations in the ATM gene are thought to come in two types:
  • Null mutations are those which cause complete loss of function of the protein and are therefore inherited in a recessive manner and cause AT.
  • ‘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 AT 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 AT.
• 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).

• Oculo–cutaneous telangiectasia combined with ataxia are the defining features of the condition.
• Some patients with AT, even those with two null mutations who produce no ATM protein at all, may never present with oculo–cutaneous telangiectasia.

• Ataxia-telangiectasia is inherited, which means it is passed down through families. It is an autosomal recessive trait. This means that both parents must provide a defective gene for the child to have symptoms of the disorder.

• The disease results from defects in the ataxia telangiectasia mutated (ATM) gene. The ATM gene is involved in making protein that control cell division and DNA repair. The ATM protein helps cells to identify damaged and broken DNA and activates enzymes which fix the broken parts.^[8]. Defects in this gene can lead to abnormal cell death in various places of the body, including the part of the brain that helps coordinate movement.

• Boys and girls are equally affected.

Ataxia telangiectasia like disorder (ATLD) is an extremely rare condition which could be considered as a differential diagnosis to AT. ATLD patients are very similar to AT patients in showing a progressive cerebellar ataxia, hypersensitivity to ionising radiation and genomic instability. However, ATLD can be distinguished from AT by the absence of telangiectasias, normal immunoglobulin levels, a later onset of the condition and a slower progression of the disease. It is not known whether ATLD individuals are also predisposed to tumors. The gene mutated in ATLD is hMre11 and is located on chromosome 11q21.

Nijmegen breakage syndrome (NBS), also known as ataxia telangiectasia variant 1, is a very rare syndrome which could be considered as a differential diagnosis to AT. People with Nijmegen breakage syndrome show the same immunodeficiency, radiosensitivity and risk of cancer as AT but do not have any ataxia or oculo–cutaneous telangiectasia. Nijmegen breakage syndrome sufferers also show microcephaly. The gene associated with Nijmegen breakage syndrome (NBS) is known to be located on 8q21.

Interestingly, the proteins expressed by the hMre11 and Nbs1 genes exist in the cell as a complex, along with a third protein expressed by the hRad50 gene. This complex, known as the MRN complex, plays an important role in DNA damage repair and signaling and is required to recruit ATM to the sites of DNA double strand breaks. Mre11 and Nbs1 are also targets for phosphorylation by the ATM kinase. Thus, the similarity of the three diseases can be explained in part by the fact that the protein products of the three genes mutated in these disorders interact in common pathways in the cell.

In the early ataxic stages children may be diagnosed with cerebral palsy.

Other differential diagnoses are:

• Ataxia oculomotor apraxia type 1
• Ataxia oculomotor apraxia type 2
• Gaucher disease
• Hartnup disease
• Niemann-Pick disease
• Refsum disease

Ataxia telangiectasia must be differentiated from other diseases that cause neurological manifestations in infants.

Comparison of the clinical features, biomarkers and brain imaging between ataxia telangiectasia (AT), ataxiatelangiectasia-like disorder type 1 (ATLD1) and ataxia telangiectasia-like disorder type 2 (ATLD2)

AT, ataxia telangiectasia; ATLD1, ataxia telangiectasia-like disorder type 1; ATLD2, ataxia telangiectasia-like disorder type 2.

Epidemiology:

Ataxia-Telangiectasia prevalence is estimated between 1 in 40,000 and 1 in 100,000.^[9] Some studies have shown that the prevalence of A-T among adults younger than age 50 is approximately 1 in 500,000. Some mutations are more common than others is certain geographical regions for example, the 7636del9 mutation is a common mutation in European populations which has been shown to increase the risk of breast cancer in carriers.

Etiology:

Ataxia-Telangiectasia is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene which encodes a protein of the same name. The primary role of the ATM protein is coordination of cellular signaling pathways in response to DNA double strand breaks, oxidative stress and other genotoxic stress.

• There are no established risk factors for Ataxia Telangiectasia.

• Ataxia Telangiectasia patients are at 40% risk of developing cancer, especially leukemia and lymphoma (85%).
• They are also have increasing risk of developing breast cancer, ovarian, stomach, skin, bone and soft tissue cancers. Lifestyle changes to reduce the risk of cancer are important to A-T patients.

• A carrier of the ATM gene has been linked to a high rate of breast cancer in some families as per the American Cancer Society.
• A 2021 review study identified a specific mutation or ATM variant associated with increased breast cancer risk called the V2424G mutation.

• General risk factors for cancer include:
  • Older age
  • Family history of cancer
  • Tobacco
  • Obesity
  • Alcohol
  • Viral infections, such as human papillomavirus (HPV)
  • Specific chemicals
  • Exposure to radiation, such as ultraviolet radiation (UV)

One of the defective screening test for newborn is severe combined immunodeficiency (SCID), which detect T cells and B cells deficiency or absence from infant dried blood spots. Although there is no modifying therapy or cure for A-T recently, SCID screening test allows for early family education and genetic counseling.
Pre-implantation genetic diagnosis (PGD) can avoid the birth of an affected child. By this screening test, parents who have an affected child (or children) with [[A-T take its advantages.
Antenatal diagnosis can also be performed using haplotype analysis if a diagnosis has been made for the affected child. In this case, DNA polymorphisms within and around the ATM gene can be utilized even if the pathogenic mutations are not known. ^[10]

The outlook for AT patients is not good, mainly due to the compromised immune system which results in recurrent respiratory infections. Neurological features are progressive as is deterioration and aging of the skin and hair with ataxia usually seen in the first year of life. Patients are usually wheelchair bound by the age of 10 or 11. Telangiectasias are not seen in the early stages of the disease and begin to appear after a few years i.e. between 3-6 years of age, in the corners of the eyes, ears and cheeks. Individuals are also at a 10% risk of developing cancer, usually lymphomas and often breast cancer. However due to patients hyper-sensitivity to ionizing radiation, radiotherapy and chemotherapy must be used with extreme caution. Oculo–cutaneous telangiectasia is often not obvious in the early stages of the disease. Other features of the disease may include mild diabetes mellitus, premature graying of the hair, dysphagia, and delayed physical and sexual development. People with the disease usually have normal intelligence. Mental retardation is uncommon in people with A-T.^[11]

Carriers of any type of ATM mutation have a 5-8 fold increased risk of cancer and on average die 7-8 years earlier than the normal population, often from heart disease. 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. A recent study suggests that the majority of AT sufferers die from pulmonary infections (46%), with 21% dying from malignancies and 28% from malignancies and pulmonary infection. If pulmonary infections could be completely eradicated AT is consistent with survival into the 5th or 6th decade.

The prognosis for AT sufferers is not good. Those with the disease usually die in their teens or early 20s although some individuals have been know to live to over 40. Carriers of ATM missense mutations are believed to have a 60% penetrance by age 70 and a risk of breast cancer 16x that of the normal population. Some papers state a lifetime risk for people with both null and missense mutations of 10-38%, which is still a hundred fold increase from population risk.

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Case #1

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