Background
Definition
Epidemiology
Clinical description
Ataxia and other neurological manifestations
Neuroimaging findings
Telangiectasia
Eye and vision
Immunological manifestations
Pulmonary manifestations
Cancer
Cancer in A-T carriers
Radiation sensitivity
Radiation sensitivity in carriers
Feeding, swallowing, and nutrition
• 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 min, on a regular basis | |
• Foods or drinks previously enjoyed are now refused or difficult | |
• Chewing problems | |
• Increase in the frequency or duration of breathing or respiratory problems | |
• Increase in lung infections |
Endocrine abnormalities
Hair and skin
Sleep
Cognition
Orthopedic manifestations
Manifestations in aging or older patients with A-T
• Ballistic, retropulsive or jerky movements | |
• Sensory and motor neuropathy | |
• Brain telangiectasia (observed by MRI) | |
• Restrictive lung disease | |
• Elevated cholesterol and triglyceride levels | |
• Glucose intolerance and diabetes | |
• Liver abnormalities (e.g. fatty liver; non-alcoholic cirrhosis; elevated serum transaminases) | |
• Changes in the types of malignancies (there is an increased incidence for both lymphoid and solid tumors) | |
• Osteoporosis/osteopenia and low vitamin D levels | |
• Postural scoliosis and progressive foot deformities | |
• Gastroesophageal reflux (especially if reflux was an issue in infanthood) | |
• Early menopause | |
• Depression | |
• Aging parents and caregivers |
Other manifestations of A-T
Etiology
Genetics
Genotype / phenotype correlations
Classic Form | Mild Form | |
---|---|---|
Neurological Manifestations | Neurological deficits are typically observed during the toddler years resulting in wheelchair dependency around the age of 10. | Individuals have more mild neurological deficits in childhood with slower age-related neurodegeneration. The predominant neurological symptoms or symptoms to present first may be myoclonus, dystonia, choreoathetosis or tremor with ataxia appearing later [175‐177]. Oculomotor apraxia may also appear later or not at all [95]. |
Immunodeficiencies | Roughly two-thirds of people with classic A-T suffer from some type of immunodeficiency and/or lymphopenia. | Immunodeficiencies do occur, but are less common. |
Pulmonary Disease | Relatively common. | Less common. |
Cancer | Although malignancies in these individuals tend to occur at a younger age and are often lymphoid in nature, cancers in older individuals do occur and include both hematopoietic and non-hematopoietic malignancies. | Malignancies tend to appear later in life and include a higher proportion of non-hematopoietic cancers. The diagnosis of cancer can precede the diagnosis of A-T. |
Pathophysiology: how does loss of the ATM protein create a multisystem disorder?
• 3056 amino acids | |
• Serine/Threonine protein kinase | |
• Member of the family of PI3 Kinase-like Kinases (PIKKs) | |
• Located primarily in the nucleus; smaller amounts in the cytoplasm and associated with mitochondria and peroxisomes [178] | |
• Activated primarily by DSBs and oxidative stress, but also agents affecting chromatin organization, hypoxia, hypotonic stress and hyperthermia | |
• Phosphorylates and regulates a variety of protein substrates involved in o The DNA damage response (NHEJ and HRR) to DSBso Various other genotoxic stress responseso DNA repair processeso Cell cycle checkpointso Other cell stress responseso Apoptosis |
ATM is involved in: | |
ATM deficiency results in: o Low immunoglobulin levels (particularly IgA, IgG subclasses and IgE)o Lymphopenia (particularly affecting T cell numbers)o Decreased immune repertoire diversityo Genomic instability and translocations which can result in lymphoid malignancies |
o transcription stress [119] and abortive transcription involving topoisomerase 1 cleavage complex (TOP1cc) dependent lesions [186‐189]o aneuploidy [190] |
• Defective response to oxidative stress characterized by elevated ROS and altered cellular redox status |
• Defects in neuronal function involving: o Failed cell cycle regulation resulting in the re-entry of post-mitotic (mature) neurons into the cell cycle [200]o Altered epigenetics including − HDAC4 nuclear translocation [204] − Histone H3 hypermethylation [205] and − Reduced 5-hydroxymethylcytosine [206] |
• Defects in brain vasculature [207] |
• Altered protein turnover [208] |
Diagnosis
• Elevated and slowly increasing serum alpha-fetoprotein levels after two years of age |
• Low serum levels of immunoglobulins (IgA, IgG, IgG subclasses, IgE) and lymphopenia (particularly affecting T-lymphocytes) |
• Spontaneous and X-ray induced chromosomal breaks and rearrangements in cultured lymphocytes and fibroblasts |
• Reduced survival of cultured lymphocytes and fibroblasts after exposure to ionizing radiation [209] |
• Cerebellar atrophy detected by MRI |
Differential diagnosis
Cerebral palsy (CP)
Congenital ocular motor apraxia
Friedreich’s Ataxia (FA or FRDA)
A-T | AOA1 | AOA2 | ATLD | NBS | |
---|---|---|---|---|---|
Human gene |
ATM
|
APTX
|
SETX
|
MRE11
|
NBS1
|
Radiosensitivity (type of DNA damage) | Yes (DSB) | Yes (SSB) | No (SSB?) | Yes (DSB) | Yes (DSB) |
Immune deficiency | Yes | No | No | Mild [211] | Yes |
Neurodegeneration | Yes | Yes | Yes | Yes | No |
Early Neurodevelopment | Usually Normal | Normal | Normal | Normal | Microcephaly & Cognitive Impairment |
Cancer risk | Yes | No | No | Unknown | Yes |
Albumin | Normal | Low | Normal | Normal | Normal |
AFP | High | Normal | High | Normal | Normal |
Pre-implantation genetic diagnosis, antenatal diagnosis and carrier identification
Newborn screening for SCID can detect A-T
Genetic counseling
Management
Neurologic problems
Immune problems
• If a person with A-T does not need gamma globulin replacement therapy, he/she should receive all standard childhood vaccines, including the live vaccines for measles, mumps, rubella and varicella-zoster viruses. |
• The individual with A-T and all household members should receive the influenza (flu) vaccine every fall. |
• People with A-T who are less than two years old should receive three doses of a pneumococcal conjugate vaccine (Prevnar) given at two month intervals. |
• People older than two years who have not previously been immunized with Prevnar should receive two doses of Prevnar. |
• At least 6 months after the last Prevnar has been given, and after the child is at least two years old, the 23-valent pneumococcal vaccine should be administered. Immunization with the 23-valent pneumococcal vaccine should be repeated approximately every five years after the first dose. |
Pulmonary problems
Problems with anesthesia: peri- and post-operative risks
Problems with feeding, swallowing and nutrition
Problems associated with the management of cancers
Eye and vision problems
Orthopedic problems
Education and socialization
• All children with A-T need special attention to the barriers they experience in school. In the United States, this takes the form of a formal IEP (Individualized Education Program). |
• Children with A-T tend to be excellent problem solvers. Their involvement in how to best perform tasks should be encouraged. |
• Speech-language pathologists may facilitate communication skills that enable persons with A-T to get their messages across (using key words vs. complete sentences) and teach strategies to decrease frustration associated with the increased time needed to respond to questions (e.g., holding up a hand) and inform others about the need to allow more time for responses. Traditional speech therapies that focus on the production of specific sounds and strengthening of the lip and tongue muscles are rarely helpful. |
• Classroom aides may be appropriate, especially to help with scribing, transportation throughout the school, mealtimes and toileting. The impact of an aide on peer relationships should be monitored carefully. |
• Physical therapy is useful to maintain strength and general cardiovascular health. Horseback therapy and exercises in a swimming pool are often well-tolerated and fun for people with A-T. However, no amount of practice will slow the cerebellar degeneration or improve neurologic function. Exercise to the point of exhaustion should be avoided. |
• Hearing is normal throughout life. Books on tape may be a useful adjunct to traditional school materials. |
• Early use of computers (preschool) with word completion software should be encouraged. |
• Practicing coordination (e.g. balance beam or cursive writing exercises) is not helpful. |
• Occupational therapy is helpful for managing daily living skills. |
• Allow rest time, shortened days, reduced class schedule, reduced homework, modified tests as necessary. |
• Like all children, those with A-T need to have goals to experience the satisfaction of making progress. |
• Social interactions with peers are important, and should be taken into consideration for class placement. For everyone, long-term peer relationships can be one of the most rewarding parts of life; for those with A-T establishing these connections in school years can be helpful. |