SUMMARY

 

1. Ataxia-Telangiectasia (A-T) is an autosomal recessive chromosomal breakage syndrome characterized by progressive cerebellar neurodegeneration, immunodeficiency, radiosensitivity, and increased cancer susceptibility. This condition is caused by mutations in the ATM gene.

 

2. The defective gene in A-T encodes for the ATM (A-T mutated) kinase. ATM functions to detect double stranded DNA breaks (DSB) and to initiate cell cycle checkpoint arrest through the phosphorylation and activation of p53 and other repair proteins. The delay in cell cycle progression allows time for repair of the damage.

 

3. ATM is involved in the regulation of both non-homologous end joining (NHEJ) and homologous recombination (HR) - the two major DSB repair pathways. Defects in the NHEJ pathway can also lead to radiosensitive SCID (the NHEJ repair machinery includes DNA-PKcs, Artemis, DNA ligase IV, and Cernunnos).

 

4. Clinically, patients with A-T typically walk normally by 1 year of life. However, ataxia often develops around the second year of life and patients are generally wheelchair bound after 10 years of age. Other neurologic abnormalities include oculomotor apraxia, dysarthria, and choreoathetosis. Patients develop progressive difficulty with eating and swallowing, which increases the risk for aspiration in older patients.

 

5. Telangiectasia on the bulbar conjunctiva, ear pinna, and nose develops several years after the development of ataxia (around 3 to 5 years of age).

 

6. Patients suffer from recurrent sinopulmonary infections at high frequency. However, opportunistic infections or other invasive infections are typically not observed. Dysfunctional swallowing and aspiration can contribute to the development of pulmonary infections.

 

7. The immunodeficiency found in A-T is characterized by both humoral and cell-mediated abnormalities. It should be noted that some patients have mild or no immunodeficiency. Humoral Abnormalities include decreased IgG, IgA, IgE and decreased IgG subclasses. Serum IgM levels are normal or elevated. Decreased specific antibody responses may be present. T cell Abnormalities include T cell lymphopenia and decreased in vitro proliferation to mitogens.

 

8. In most patients with A-T, the immunodeficiency is not progressive. However, progressive deterioration of humoral immune function and lymphopenia can be seen in 5 to 10% of patients.

 

9. There is an increased risk of malignancy in patients with A-T. Approximately one-third of patients develop non-Hodgkins lymphoma (40%), leukemia (25%), or other solid malignancies (25%).

 

10. Elevation of the serum alpha-fetoprotein (AFP) level is usually found in patients with A-T and can be useful for diagnosis after the first year of age (AFP levels can be elevated in normal infants before the age of 6 months). Abnormal radiosensitivity assays can also support a diagnosis of A-T. In older patients, brain MRI may reveal cerebellar atrophy.

 

11. The absence of ATM protein on western blot or ATM gene mutation analysis confirms the diagnosis.

 

12. Unfortunately, there is no curative therapy for A-T and most patients die in the second or third decade of life from pulmonary complications or cancer. Management of immunodeficiency includes immunoglobulin replacement therapy and prophylactic antibiotic therapy.

 

13. Ataxia-Telangiectasia-Like Disorder (ATLD) is a very rare DNA repair defect that is also associated progressive cerebellar ataxia, radiosensitivity, and immunodeficiency. This condition is due to mutations in the hMRE11 gene. The hMRE11 protein is involved in the recruitment of ATM to sites of double-strand DNA break repair. Significant differences between A-T and ATLD include the following:

- ATLD patients do not have Telangiectasia

- ATLD patients do not have elevated alpha-fetoprotein levels

-Serum IgG, IgA, and IgM levels are normal but specific antibody response is defective.

- The presence of characteristic clinical features and the demonstration of increased radiosensitivity suggest the diagnosis of ATLD. Mutation analysis of the hMRE11 gene provides a definitive diagnosis.

 

 

 

 

                                                                                                                                       

 

OVERVIEW

 

          Ataxia-Telangiectasia (A-T) is an autosomal recessive chromosomal breakage syndrome characterized by progressive cerebellar neurodegeneration, immunodeficiency, radiosensitivity, and increased cancer susceptibility. This condition is caused by mutations in the ATM gene. The incidence is estimated to be 1 in 40,000 births in the U.S.

 

          Clinically, patients with A-T develop progressive ataxia. Although walking develops normally by 1 year of life, steady gait is slow to develop. Ataxia is present by around the second year of life and patients are generally wheelchair bound after 10 years of age. Other neurologic abnormalities include oculomotor apraxia (an inability to coordinate head and eye movements naturally when shifting gaze rapidly), dysarthria (abnormal speech), and choreoathetosis (involuntary uncontrolled movements). Patients develop progressive difficulty with eating and swallowing, which increases the risk for aspiration in older patients.

 

          Telangiectasias on the bulbar conjunctiva, ear pinna, and nose start to develop around 3 to 5 years of age. Thus, the onset of ataxia precedes the development of telangiectasia by a few years.

 

          Patients suffer from recurrent sinopulmonary infections at high frequency. Opportunistic infections or other invasive infections are typically not observed. Dysfunctional swallowing can contribute to the development of pulmonary infections. The immunodeficiency found in A-T is characterized by both humoral and cell-mediated abnormalities. It should be noted that some patients have mild or no immunodeficiency.

 

Humoral Abnormalities-

-Decreased serum IgG, IgA, IgE.

-Decreased IgG2 and other subclasses

-Normal or elevated IgM levels

-Decreased specific antibody responses to protein and polysaccharide antigens

 

T cell Abnormalities

-T cell lymphopenia

-Decreased T cell proliferation to mitogens

 

          In most patients with A-T, the immunodeficiency is not progressive. However, progressive deterioration of humoral immune function and lymphopenia can be seen in 5 to 10% of patients.

 

          Finally there is an increased risk of malignancy in patients with A-T. Approximately one-third of patients develop non-Hodgkins lymphoma (40%), leukemia (25%), or other solid malignancies (25%).

 

          Ataxia-Telangiectasia-Like Disorder (ATLD) is a very rare DNA repair defect disOrder that is also associated progressive cerebellar ataxia, radiosensitivity, and immunodeficiency. Significant differences between A-T and ATLD include the following:

-ATLD patients do not have Telangiectasia

-ATLD patients do not have elevated alpha-fetoprotein levels

-Serum IgG, IgA, and IgM levels are normal but specific antibody response is defective.

 

 

 

PATHOGENESIS

 

         The defective gene in A-T encodes for the ATM (A-T mutated) kinase. This gene is located on 11q22-23 and includes 66 exons. The majority of affected patients are compound heterozygotes for ATM mutations. ATM functions to detect double stranded DNA breaks (DSB) and to initiate cell cycle checkpoint arrest.

 

          DSBs are initially recognized by the MRN protein complex (includes MRE11, RAD50, and Nbs1 proteins). The MRN complex then recruits ATM to the break site. ATM is responsible for phosphorylation of proteins such as p53 that induce cell cycle arrest. The delay in cell cycle progression allows time for repair of the damage rather than transmission of the defect to daughter cells. Effective DNA repair is essential for V(D)J recombination to generate T cell/B cell diversity and for effective class-switch recombination. DSBs are repaired by non homologous end joining (a process by which two DNA ends are brought together and fused) and homologous recombination (a process that uses the homologous sister chromatin as the template for repair). ATM is involved in regulation of both NHEJ and HR. Defects in NHEJ machinery can also lead to radiosensitive SCID (the NHEJ repair complex includes DNA PKcs, Artemis, DNA ligase IV, and Cernunnos). ATM is also involved in proper class-switch recombination.

 

         ATLD is caused by mutations in the hMRE11 gene. The hMRE11 protein (which forms the MRN protein complex with Rad50 and Nbs 1) recruits ATM to sites of DSB repair as discussed above.

 

 

 

DIFFERENTIAL DIAGNOSIS

 

- Other chromosomal breakage syndromes (Nijmegen breakage syndrome, bloom syndrome)

- Other causes of ataxia (cerebral palsy, tumors, infectious processes)

- Dyskeratosis congenita - Hoyeraal-Hreidarsson variant (this can be associated with immunodeficiency, cerebellar hypoplasia, and neurologic delay)

 

 

                                           

EVALUATION

 

The diagnosis should be suspected in patients who have progressive ataxia and neurodegeneration along with a history of recurrent sinopulmonary infections. Steps should be taken to establish the diagnosis of A-T as well as an assessment of immune function.

 

 

 

Step 1: Screening for A-T and ATLD

         

                      - Serum Alpha Fetoprotein Level

- Radiosensitivity Assay

- Brain MRI (older children)

 

-The alpha fetoprotein level is usually elevated in children with A-T (the AFP level can be elevated in normal children before 1 year of age). In contrast, patients with ATLD have normal AFP levels.

 

-Radiosensitivity is assessed through a colony survival assay. A normal survival fraction is greater than 36% (A-T cells have below 21% survival). Patients with ATLD will also have increased radiosensitivity. This test is available through the UCLA medical center laboratories.

 

-In older children with A-T, a brain MRI may reveal cerebellar atrophy.

 

 

Step 2:  Additional Immune Evaluation.

The following tests may provide additional support for a diagnosis of SCID and can be helpful in certain clinical situations but not necessarily required. 

 

-ATM Protein Levels (A-T)

-ATM Mutation Analysis (A-T)

-hMRE11 Mutation Analysis (ATLD)

 

-ATM mutation analysis is available through the Johns Hopkins Medical Center laboratories.

 

-hMRE11 mutation analysis is only available through specialized research centers.

 

Step 3: Humoral and Cell-mediated Immune Evaluation

 

-Quantitative immunoglobulins (IgG, IgM, IgA)

-Antibody titers to vaccine antigens

-Flow cytometry for B cell, T cell, and NK cell enumeration

-Lymphocyte proliferation to mitogens and antigens (candida, tetanus)

 

-A-T patients can have decreased IgG and IgA but normal or elevated IgM levels. ATLD patients have normal serum immunoglobulin levels.

-Protein and polysaccharide vaccine antibody responses (ex. Tetanus, Diphtheria, and Pneumococcus) can be decreased in A-T and ATLD.

-T cell numbers can be decreased with normal B and NK cells in A-T.

-Lymphocyte proliferation to mitogens and antigens can be variably decreased in A-T.

 

 

 

 

                                                                                  

MANAGEMENT

 

          A multidisciplinary approach to help maintain the quality of life for patients is necessary. Patients with recurrent aspiration pneumonias may require thickened feeds or gastrostomy tube placement. If immunodeficiency is present, the treatment options below should be considered.

 

1. Monthly immunoglobulin (IVIG) therapy (for patients with antibody deficiency)

          -Starting doses should be 400-600mg/kg/month for IV therapy.

 

2. Antibiotic prophylaxis for sinopulmonary infections

          -Prophylaxis for Pneumocystis jiroveci pneumonia with trimethoprim-sulfamethoxazole is typically not required.

          -The following is a ample prophylaxis regimen: Amoxicillin 20mg/kg divided twice daily. Maximum of 500mg twice daily.

 

 

                                                                           

RESOURCES

 

Diagnostic Resources    

 

1. UCLA Radiosensitivity Assay 

2. Cincinnati ATM gene sequencing

 

 

Literature Resources

 

 

1.  Helleday 2007

     DNA double strand break repair review

 

2.  Perlman 2003 

     Ataxia Telangiectasisa diagnosis and treatment

 

3.  Sun 2002

    Early diagnosis of ataxia telangiectasia using radiosensitivy testing

 

4.  Reina-San Martin 2004

    ATM is required for efficient recombination between Ig switch regions

 

5.  Taylor 2004

     Ataxia telangiectasia like disorder review