Ataxia–telangiectasia (AT or A–T), also referred to as ataxia–telangiectasia syndrome or Louis-Bar syndrome, is a rare, neurodegenerative disease causing severe disability. Ataxia refers to poor coordination and telangiectasia to small dilated blood vessels, both of which are hallmarks of the disease. A–T affects many parts of the body: It impairs certain areas of the brain including the cerebellum, causing difficulty with movement and coordination. It weakens the immune system, causing a predisposition to infection. It prevents the repair of broken DNA, increasing the risk of cancer.
Symptoms most often first appear in early childhood (the toddler stage) when children begin to sit or walk. Though they usually start walking at a normal age, they wobble or sway when walking, standing still, or sitting. In late preschool and early school age, they develop difficulty naturally moving their eyes from one place to the next (oculomotor apraxia). They develop slurred or distorted speech and swallowing problems. Some have an increased number of respiratory tract infections (ear infections, sinusitis, bronchitis, and pneumonia). Since children develop differently, it may be some years before A–T is properly diagnosed. Most children with A–T have stable neurologic symptoms for the first 4–5 years of life, but begin to show increasing problems in early school years.
Causes A–T has an autosomal recessive pattern of inheritance.
A–T is caused by a defect in the ATM gene, named after this disease, which is involved in the recognition and repair of damaged DNA. Heterozygotes will not experience the characteristic symptoms, but it has been reported that they have higher risks of cancer and heart disease. The prevalence of A–T is estimated to be as high as 1 in 40,000 to as low as 1 in 300,000 people.
Signs and symptoms There is substantial variability in the severity of the signs and symptoms of A–T among affected individuals, and they may appear at different ages. The following symptoms or problems are either common or important features of A–T: Ataxia (difficulty with control of movement) that is apparent early but worsens in school to pre-teen years Oculomotor apraxia (difficulty with coordination of head and eye movement when shifting gaze from one place to the next) Involuntary (extrapyramidal) movements Telangiectasia (dilated blood vessels) over the white (sclera) of the eyes, making them appear bloodshot. These are not apparent in infancy and may first appear between the ages of 5–8 years. Telangiectasia may also appear on sun-exposed areas of skin. Problems with infections, especially of the ears, sinuses, and lungs Increased incidence of cancer (primarily, but not exclusively, lymphomas and leukemias) Delayed onset or incomplete pubertal development, and very early menopause Slowed rate of growth (weight and/or height) Drooling, particularly in young children, when they are tired or concentrating on activities Dysarthria (slurred, slow, or distorted speech) Diabetes in adolescence or later on in disease progression Premature changes in hair and skin
Many children are initially misdiagnosed as having cerebral palsy. The diagnosis of A–T may not be made until the preschool years when the neurologic symptoms of impaired gait, hand coordination, speech, and eye movement appear or worsen, and the telangiectasia first develops. Because A–T is so rare, doctors may not be familiar with the symptoms or methods of making a diagnosis. The late appearance of telangiectasia may be a barrier to the diagnosis. It may also take some time before doctors consider A–T as a possibility because of the early stability of symptoms and signs. Some patients have been diagnosed with A-T only in adulthood due to an attenuated form of the disease, and this has been correlated with the type of their gene mutation.
Ataxia and other neurologic problems The first indications of A–T usually occur during the toddler years. Children start walking at a normal age, but may not improve much from their initial wobbly gait. Sometimes they have problems standing or sitting still and tend to sway backward or from side to side. During the primary school years, walking becomes more difficult, and children will use doorways and walls for support. Children with A–T often appear better when running or walking quickly in comparison to when they walk slowly or stand still. Around the beginning of their second decade, children with the more severe ("classic") form of A–T start using a wheelchair for long distances. During school years, children may have increasing difficulty with reading because of impaired coordination of eye movement. At the same time, other problems with fine motor functions (writing, coloring, and using utensils to eat) and with speech (dysarthria) may arise. Most of these neurologic problems stop progressing after the age of about 12 – 15 years, though involuntary movements may start at any age and may worsen over time. These extra movements can take many forms, including small jerks of the hands and feet that look like fidgeting (chorea), slower twisting movements of the upper body (athetosis), adoption of stiff and twisted postures (dystonia), occasional uncontrolled jerks (myoclonic jerks), and various rhythmic and non-rhythmic movements with attempts at coordinated action (tremors).
Telangiectasia
Prominent blood vessels (telangiectasia) over the white (sclera) of the eyes usually occur by the age of 5–8 years, but sometimes appear later or not at all. The absence of telangiectasia does not exclude the diagnosis of A–T. Potentially a cosmetic problem, the ocular telangiectasia does not bleed or itch, though they are sometimes misdiagnosed as chronic conjunctivitis. It is their constant nature, not changing with time, weather, or emotion, that marks them as different from other visible blood vessels. Telangiectasia can also appear on sun-exposed areas of skin, especially the face and ears. They occur in the bladder as a late complication of chemotherapy with cyclophosphamide, have been seen deep inside the brain of older people with A–T, and occasionally arise in the liver and lungs.
Immune problems About two-thirds of people with A–T have abnormalities of the immune system. The most common abnormalities are low levels of one or more classes of immunoglobulins (IgA, IgM, and IgG subclasses), not making antibodies in response to vaccines or infections, and having low numbers of lymphocytes (especially T-lymphocytes) in the blood. Some people develop frequent infections of the upper (common colds, sinus, and ear infections) and lower (bronchitis and pneumonia) respiratory tract. All children with A–T should have their immune systems evaluated to detect those with severe problems that require treatment to minimize the number or severity of infections. Some people with A–T need additional immunizations (especially with pneumonia and influenza vaccines), antibiotics to provide protection (prophylaxis) from infections, and/or infusions of immunoglobulins (gamma globulin). An expert in the field of immunodeficiency or infectious diseases should determine the need for these treatments.
Cancer People with A–T have a highly increased incidence (approximately 25% lifetime risk) of cancers, particularly lymphomas and leukemia, but other cancers can occur.
Women who are A–T carriers (who have one mutated copy of the ATM gene) have approximately a two-fold increased risk for the development of breast cancer compared to the general population. This includes all mothers of A–T children and some female relatives. The current consensus is that enhanced screening consisting of annual mammographies and frequently, an annual breast MRI should be used for patients carrying ATM mutations.
Skin A–T can cause features of early aging, such as premature graying of the hair. It can also cause vitiligo (an autoimmune disease causing loss of skin pigment resulting in a blotchy "bleach-splashed" look), and warts, which can be extensive and recalcitrant to treatment. A small number of people develop a chronic inflammatory skin disease (granulomas).
Lung disease Chronic lung disease develops in more than 25% of people with A–T.
Lung function tests (spirometry) should be performed at least annually in children old enough to participate, influenza and pneumococcal vaccines given to eligible individuals, and sinopulmonary infections treated aggressively to limit the development of chronic lung disease.
Feeding, swallowing, and nutrition Feeding and swallowing can become difficult for people with A–T as they age.
Involuntary movements may make feeding difficult or messy and may excessively prolong mealtimes. It may be easier to finger feed than use utensils (e.g., spoon or fork). For liquids, it is often easier to drink from a closed container with a straw than from an open cup. Caregivers may need to provide foods or liquids so that self-feeding can occur, or they may need to hand-feed the person with A–T. In general, meals should be completed within approximately 30 minutes. Longer meals may be stressful, interfere with other daily activities, and limit the intake of necessary liquids and nutrients.
If swallowing problems (dysphagia) occur, they typically present during the second decade of life. Difficulty swallowing is common because of the neurological changes that interfere with the coordination of mouth and pharynx (throat) movements that are needed for safe and efficient swallowing. Coordination problems involving the mouth may make chewing difficult and increase the meal duration. Problems involving the pharynx may cause liquid, food, and saliva to be inhaled into the airway (aspiration). People with dysphagia may not cough when they aspirate (silent aspiration). Swallowing problems, especially difficulties with silent aspiration, can lead to lung diseases due to the inability to cough and clear food and liquids from the airway.
Warning signs of a swallowing problem Choking or coughing when eating or drinking Poor weight gain (during ages of expected growth) or weight loss at any age Excessive drooling Mealtimes longer than 40–45 minutes, regularly Foods or drinks previously enjoyed are now refused or difficult to consume Chewing problems Increase in the frequency or duration of breathing or respiratory problems Increase in lung infections
Eye and vision Most people develop telangiectasia (prominent blood vessels) in the membrane that covers the white part (sclera) of the eye. Vision (ability to see objects in focus) is normal. Control of eye movement is often impaired, affecting visual functions that require fast, accurate eye movements from point to point (e.g., reading). Eye misalignments (strabismus) are common but may be treatable. There may be difficulty in coordinating eye position and shaping the lens to see objects up close.
Orthopedics Many individuals with A–T develop foot deformities that compound the difficulty they have with walking due to impaired coordination. Early treatment may slow the progression of this deformity. Bracing or surgical correction may improve ankle stability, thereby allowing the individual to walk with support or bear weight during assisted standing transfers from one seat to another. Severe scoliosis is relatively uncommon, but probably does occur more often than in those without A–T. Spinal fusion is only rarely indicated.
Genetics
A–T is caused by mutations in the ATM (ATM serine/threonine kinase or ataxia–telangiectasia mutated) gene, which was cloned in 1995. ATM is located on human chromosome 11 (11q22.3) and is made up of 69 exons spread across 150kb of genomic DNA.