Ataxia-telangiectasia (A-T)

Overview

Ataxia-telangiectasia (A-T), Bloom syndrome (BS), and Nijmegen breakage syndrome (NBS) are examples of a group of primary immunodeficiencies (PIs) called DNA breakage (or chromosomal instability) syndromes. DNA breakage syndromes are characterized by chromosomal instability and breakage, as well as a defect in the DNA repair mechanism. These syndromes are inherited in an autosomal recessive fashion. Affected individuals have varying degrees of delays in mental and physical development, organ system dysfunction, combined immunodeficiencies, and they are at high risk for various types of cancers. 

Symptoms

Individuals with A-T have an unsteady, wobbly gait (ataxia), dilated corkscrew-shaped blood vessels (telangiectasia) on the white part of the eyes and sun-exposed areas of the skin, immunodeficiency involving both B cells and T cells, and high rates of cancers. The neurologic symptoms worsen as individuals get older. 

Some individuals with A-T are identified before they have any symptoms because they have an abnormal newborn screen (TREC) test for severe combined immunodeficiency (SCID). The first symptom of A-T is generally ataxia. When children with A-T start walking, they tend to sway, stagger, or wobble and do not improve as they get older. They are usually unstable when sitting unsupported or standing in one place; for example, when standing in front of the sink to brush their hair or teeth. The ataxia is caused by abnormalities in the cerebellum, the part of the brain that controls balance and movement. Often these children are initially thought to have a neurologic condition, such as cerebral palsy. When ataxia is the only symptom present, it is sometimes hard to make a diagnosis. 

A-T causes a progressive decline in motor function, which may not become apparent until children are 4-8 years old. It is this deterioration, in addition to ataxia, which often leads to a correct diagnosis, as deterioration does not occur in children with cerebral palsy. As they get older, children with A-T develop abnormalities in eye movements (delayed onset of eye movements, jerky movements, and difficulty in eye/head coordination when tracking moving objects or following a single line of print in a book). They also develop problems with fine motor control and have problems feeding and dressing themselves. Most have enough difficulty walking that they need to use a wheelchair for at least part of the day by the time they are 10-12 years old. They develop an intention tremor (shaking when trying to use the hands), and difficulties with speaking (dysarthria) and swallowing (dysphagia). While this progressive deterioration occurs in all children, the rate of progression and severity vary widely from individual to individual. 

Telangiectasia cause the whites of the eyes to look bloodshot. It can appear as though they have pink eye (conjunctivitis) or an allergy. Telangiectasia can also develop on sun-exposed skin such as the ears, neck, arms, and legs. Most individuals with A-T have these telangiectasia but some do not, and telangiectasia are rare in infants and very young children. This is another reason why the diagnosis of A-T is sometimes delayed. 

Individuals with A-T have an increased susceptibility to infections, particularly in the lungs and/or sinuses. The reason for this susceptibility can be related to a humoral (B cell) immunodeficiency causing low immunoglobulin levels and impaired antibody responses. Approximately 2/3 of individuals with A-T have low levels or a complete absence of IgA, the immunoglobulin that protects individuals from infections on mucosal surfaces like the linings of the nose, airway, and intestines. 

Individuals with A-T can also have reduced numbers of T cells, giving them a combined (B cell and T cell) immunodeficiency. They may have problems with chronic or recurrent warts or molluscum. A small number of individuals develop chronic inflammation of the skin (granulomas) that appears to be caused by a defective response to the rubella virus in the MMR vaccine. They do not usually get opportunistic infections like pneumocystis pneumonia. However, if they are treated with steroids at high doses or over a long period of time or if they need chemotherapy to treat cancer, the T cell counts may become low enough to make individuals susceptible to opportunistic infections. 

The immunodeficiency in individuals with A-T generally remains stable over time but does worsen in approximately 15% of individuals. A thorough evaluation of humoral immune function is necessary in order to determine if there is a need for immunoglobulin (Ig) replacement therapy. 

Immunodeficiency is not the only reason for susceptibility to infection. Individuals with A-T often have neurologic problems with swallowing (dysphagia), which can cause aspiration (solid food or liquids go down the trachea and into the lungs instead of into the esophagus and stomach). They also have an ineffective cough, so they have difficulty clearing mucus and aspirated material from the airways. The ineffective clearance can lead to chronic lung infections. The use of a vibrating vest or a cough assist device several times a day may be useful to shake mucus loose and make secretions easier to cough up. Sometimes, infections related to aspiration can only be prevented by bypassing the mouth and esophagus and putting calories and nutrients directly into the stomach through a gastrostomy tube (G-tube), thereby decreasing the amount of food and liquid taken by mouth. 

Individuals with A-T are at an increased risk for developing cancers. For individuals under the age of 20 years, most cancers are lymphomas or leukemias. For individuals over the age of 20 years, there is also considerable risk for solid organ cancers including the breasts, esophagus, colon, liver, and intestines. Treatment of the cancer must be modified to account for sensitivity to radiation and certain types of chemotherapy. Cancer occurs in approximately 25% of individuals with A-T. 

Living with A-T

Unfortunately, there is no cure for A-T, and there are no specific therapies for the neurologic problems associated with the disease. The key to treatment is to anticipate that problems will occur and progress, and to deal with them proactively. For example, putting in a G-tube and getting at least part of needed calories and nutrients via G-tube feedings can prevent problems associated with malnourishment and decrease the risk of lung problems caused by aspiration. Diagnosing and treating an associated antibody disorder and instituting a regimen for airway clearance and other pulmonary care can help with infection prevention. Using a wheelchair when ambulation becomes difficult can help prevent exhaustion and other related difficulties. Addressing issues proactively will improve the quality and length of life for individuals with A-T. 

Children with A-T can and should attend school, although most will need assistive devices and full-time aides to assist with activities of daily living while the child is at school. Some academic difficulties are to be expected as progressively impaired eye movements make reading difficult. Delayed initiation of speech and problems with writing or using a computer may make it seem that there is cognitive impairment. However, cognitive function and hearing are not impaired in individuals with A-T. Early introduction and use of adaptive devices and technologies will help to mitigate some of the challenges children with A-T face at school. These children should always have an Individualized Education Program (IEP) and school personnel should be an integral part of the care team. 

A-T is a progressive disease, but the timetable of progression is not the same for all individuals. It cannot be predicted in an individual. There is great variability between affected individuals, even individuals within the same family. The key is to assemble a care team knowledgeable about the disease, tuned in to potential problems, and dealing proactively with them. For example: 

• A chronic cough may indicate a lung or sinus infection or demonstrate the need for a more effective airway clearance regimen. 
• Choking when eating or drinking may indicate aspiration. 
• Failure to grow or a child falling off their growth curve may indicate insufficient caloric intake. 
• Daily fevers, pallor, and fatigue may indicate a malignancy. 
• Infections that recur or fail to resolve when treated appropriately may indicate an immunodeficiency. 

Even if problems are addressed proactively and promptly, the reality is that there will still be neurologic deterioration. It is important to note that as research and knowledge about A-T increases, so does the hope for changing the course of the disease. In the recent past, children with A-T seldom lived to adulthood. Currently, there are individuals with A-T who are college students and able to live independently. Some individuals are living into their 50s. The goal of ongoing research is to make this the norm for individuals with A-T, rather than the exception.