Ataxia–telangiectasia - Knowledge (XXG)

850:

Hemophilus influenzae b) and T-independent (23-valent pneumococcal polysaccharide) vaccines. For the most part, the pattern of immunodeficiency seen in an A–T patient early in life (by age five) will be the same pattern seen throughout the lifetime of that individual. Therefore, the tests need not be repeated unless that individual develops more problems with infection. Problems with immunity sometimes can be overcome by immunization. Vaccines against common bacterial respiratory pathogens such as Hemophilus influenzae, pneumococci and influenza virus (the "flu") are commercially available and often help to boost antibody responses, even in individuals with low immunoglobulin levels. If the vaccines do not work and the patient continues to have problems with infections, gamma globulin therapy (IV or subcutaneous infusions of antibodies collected from normal individuals) may be of benefit. A small number of people with A–T develop an abnormality in which one or more types of immunoglobulin are increased far beyond the normal range. In a few cases, the immunoglobulin levels can be increased so much that the blood becomes thick and does not flow properly. Therapy for this problem must be tailored to the specific abnormality found and its severity.

870:

managed with prophylactic antibiotics and minimized exposure to infection. If antibody function is normal, all routine childhood immunizations including live viral vaccines (measles, mumps, rubella and varicella) should be given. In addition, several "special" vaccines (that is, licensed but not routine for otherwise healthy children and young adults) should be given to decrease the risk that an A–T patient will develop lung infections. The patient 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.

711:(CP) describes a non-progressive disorder of motor function stemming from malformation or early damage to the brain. CP can manifest in many ways, given the different manner in which the brain can be damaged; in common to all forms is the emergence of signs and symptoms of impairment as the child develops. However, milestones that have been accomplished and neurologic functions that have developed do not deteriorate in CP as they often do in children with A–T in the late pre-school years. Most children with ataxia caused by CP do not begin to walk at a normal age, whereas most children with A–T start to walk at a normal age even though they often "wobble" from the start. Pure ataxia is a rare manifestation of early brain damage or malformation, however, and the possibility of an occult genetic disorder of brain should be considered and sought for those in whom ataxia is the chief manifestation of CP. Children with ataxic CP will not manifest the laboratory abnormalities associated with A–T. 942:

text that is read to them. Delays in speech initiation and lack of facial expression make it seem that they do not know the answers to questions. Reduction of the skilled effort needed to answer questions, and an increase of the time available to respond, is often rewarded by real accomplishment. It is important to recognize that intellectual disability is not regularly a part of the clinical picture of A–T although school performance may be suboptimal because of the many difficulties in reading, writing, and speech. Children with A–T are often very conscious of their appearance, and strive to appear normal to their peers and teachers. Life within the ataxic body can be tiring. The enhanced effort needed to maintain appearances and increased energy expended in abnormal tone and extra movements all contribute to physical and mental fatigue. As a consequence, for some a shortened school day yields real benefits.

887:(greater than 7 days), even following what was presumed to have been a viral infection. To help prevent respiratory illnesses from common respiratory pathogens, annual influenza vaccinations should be given and pneumococcal vaccines should be administered when appropriate. Antibiotic treatment should also be considered in children with chronic coughs that are productive of mucous, those who do not respond to aggressive pulmonary clearance techniques and in children with muco-purulent secretions from the sinuses or chest. A wet cough can also be associated with chronic aspiration which should be ruled out through proper diagnostic studies, however, aspiration and respiratory infections are not necessarily exclusive of each other. In children and adults with bronchiectasis, chronic antibiotic therapy should be considered to slow chronic lung disease progression. 866:

risk for infection. Such individuals develop complications from live viral vaccines (measles, mumps, rubella and chickenpox), chronic or severe viral infections, yeast infections of the skin and vagina, and opportunistic infections (such as pneumocystis pneumonia). Although lymphocyte counts are often as low in people with A–T, they seldom have problems with opportunistic infections. (The one exception to that rule is that problems with chronic or recurrent warts are common.) The number and function of T-lymphocytes should be re-evaluated if a person with A–T is treated with corticosteroid drugs such as prednisone for longer than a few weeks or is treated with chemotherapy for cancer. If lymphocyte counts are low in people taking those types of drugs, the use of prophylactic antibiotics is recommended to prevent opportunistic infections.

272:(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 have frequent infections of the upper (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). The need for these treatments should be determined by an expert in the field of immunodeficiency or infectious diseases. 755: 938:), abnormalities of eye control (oculomotor apraxia), and impaired fine motor control. Despite these problems, children with A–T often enjoy school if proper accommodations to their disability can be made. The decision about the need for special education classes or extra help in regular classes is highly influenced by the local resources available. Decisions about proper educational placement should be revisited as often as circumstances warrant. Despite their many neurologic impairments, most individuals with A–T are very socially aware and socially skilled, and thus benefit from sustained peer relationships developed at school. Some individuals are able to function quite well despite their disabilities and a few have graduated from community colleges. 260:) 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 do 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. 206:. 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 appear. 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. There are patients who 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. 487:, the gene responsible for this multi-system disorder, encodes a protein of the same name which coordinates the cellular response to DNA double strand breaks (DSBs). Radiation therapy, chemotherapy that acts like radiation (radiomimetic drugs) and certain biochemical processes and metabolites can cause DSBs. When these breaks occur, ATM stops the cell from making new DNA (cell cycle arrest) and recruits and activates other proteins to repair the damage. Thus, ATM allows the cell to repair its DNA before the completion of cell division. If DNA damage is too severe, ATM will mediate the process of programmed cell death (apoptosis) to eliminate the cell and prevent genomic instability. 765:(AOA1) is an autosomal recessive disorder similar to A–T in manifesting increasing problems with coordination and oculomotor apraxia, often at a similar age to those having A–T. It is caused by mutation in the gene coding for the protein aprataxin. Affected individuals differ from those with A–T by the early appearance of peripheral neuropathy, early in their course manifest difficulty with initiation of gaze shifts, and the absence of ocular telangiectasia, but laboratory features are of key importance in the differentiation of the two. Individuals with AOA1 have a normal AFP, normal measures of immune function, and after 10–15 years have low serum levels of albumin. 789:(NBS) is a rare genetic disorder that has similar chromosomal instability to that seen in people with A–T, but the problems experienced are quite different. Children with NBS have significant microcephaly, a distinct facial appearance, short stature, and moderate cognitive impairment, but do not experience any neurologic deterioration over time. Like those with A–T, children with NBS have enhanced sensitivity to radiation, disposition to lymphoma and leukemia, and some laboratory measures of impaired immune function, but do not have ocular telangiectasia or an elevated level of 249: 721:(FA) is the most common genetic cause of ataxia in children. Like A–T, FA is a recessive disease, appearing in families without a history of the disorder. FA is caused by mutation in the frataxin gene, most often an expansion of a naturally occurring repetition of the three nucleotide bases GAA from the usual 5–33 repetitions of this trinucleotide sequence to greater than 65 repeats on each chromosome. Most often the ataxia appears between 10 and 15 years of age, and differs from A–T by the absence of telangiectasia and oculomotor apraxia, a normal 775:(AOA2) is an autosomal recessive disorder also similar to A–T in manifesting increasing problems with coordination and peripheral neuropathy, but oculomotor apraxia is present in only half of affected individuals. Ocular telangiectasia do not develop. Laboratory abnormalities of AOA2 are like A–T, and unlike AOA1, in having an elevated serum AFP level, but like AOA1 and unlike A–T in having normal markers of immune function. Genetic testing of the senataxin gene (SETX) can confirm the diagnosis. There is no enhanced risk for cancer. 476: 2790: 895:

physiotherapy vest. Chest physiotherapy can help bring up mucous from the lower bronchial tree, however, an adequate cough is needed to remove secretions. In people who have decreased lung reserve and a weak cough, use of an insufflator-exsufflator (cough-assist) device may be useful as a maintenance therapy or during acute respiratory illnesses to help remove bronchial secretions from the upper airways. Evaluation by a Pulmonology specialist, however, should first be done to properly assess patient suitability.

783:

those with A–T by the absence of telangiectasia, normal immunoglobulin levels, a later onset, and a slower progression of the symptoms. Because of its rarity, it is not yet known whether or not ATLD carries an increased risk to develop cancer. Because those mutations of Mre11 that severely impair the MRE11 protein are incompatible with life, individuals with ATLD all have some partial function of the Mre11 protein, and hence likely all have their own levels of disease severity.

518: 428: 526:

lymphocytes and some impairment of lymphocyte function (such as an impaired ability to make antibodies in response to vaccines or infections). In addition, broken pieces of DNA in chromosomes involved in the above-mentioned rearrangements have a tendency to recombine with other genes (translocation), making the cells prone to the development of cancer (lymphoma and leukemia).

725:, and the frequent presence of scoliosis, absent tendon reflexes, and abnormal features on the EKG. Individuals with FA manifest difficulty standing in one place that is much enhanced by closure of the eyes (Romberg sign) that is not so apparent in those with A–T – even though those with A–T may have greater difficulty standing in one place with their eyes open. 215:

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 are walking slowly or standing in one place. Around the beginning of their second decade, children with the more severe ("classic") form of A–T start using a

715:

infancy and toddler years, and mostly improves with time. This contrasts to the oculomotor difficulties evident in children with A–T, which are not evident in early childhood but emerge over time. Cogan's oculomotor apraxia is generally an isolated problem, or may be associated with broader developmental delay.

450:. Each parent is a carrier, meaning that they have one normal copy of the A–T gene (ATM) and one copy that is mutated. A–T occurs if a child inherits the mutated A–T gene from each parent, so in a family with two carrier parents, there is 1 chance in 4 that a child born to the parents will have the disorder. 573:(located exclusively in the cerebellum). The cause of this cell loss is not known, though many hypotheses have been proposed based on experiments performed both in cell culture and in the mouse model of A–T. Current hypotheses explaining the neurodegeneration associated with A–T include the following: 941:

Many of the problems encountered will benefit from special attention, as problems are often related more to "input and output" issues than to intellectual impairment. Problems with eye movement control make it difficult for people with A–T to read, yet most fully understand the meaning and nuances of

873:

In people with A–T who have low levels of IgA, further testing should be performed to determine whether the IgA level is low or completely absent. If absent, there is a slightly increased risk of a transfusion reaction. "Medical Alert" bracelets are not necessary, but the family and primary physician

631:

People with A–T have an increased sensitivity to ionizing radiation (X-rays and gamma rays). Therefore, X-ray exposure should be limited to times when it is medically necessary, as exposing an A–T patient to ionizing radiation can damage cells in such a way that the body cannot repair them. The cells

622:

These hypotheses may not be mutually exclusive and more than one of these mechanisms may underlie neuronal cell death when there is an absence or deficiency of ATM. Further, cerebellar damage and loss of Purkinje and granule cells do not explain all of the neurologic abnormalities seen in people with

327:

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

214:

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. In primary school years, walking

125:

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 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

1955:

Renwick A, Thompson D, Seal S, Kelly P, Chagtai T, Ahmed M, North B, Jayatilake H, Barfoot R, Spanova K, McGuffog L, Evans DG, Eccles D, Easton DF, Stratton MR, Rahman N, et al. (Breast Cancer Susceptibility Collaboration, (UK)) (August 2006). "ATM mutations that cause ataxia–telangiectasia are

964:

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

1106:

studying the use of red blood cells (erythrocytes) loaded with dexamethasone sodium phosphate found that this treatment improved symptoms and appeared to be well tolerated. This treatment uses a unique delivery system for medication by using the patient's own red blood cells as the delivery vehicle

890:

Culturing of the sinuses may be needed to direct antibiotic therapy. This can be done by an Ear Nose and Throat (ENT) specialist. In addition, diagnostic bronchoscopy may be necessary in people who have recurrent pneumonias, especially those who do not respond or respond incompletely to a course of

869:

If the tests show significant abnormalities of the immune system, a specialist in immunodeficiency or infectious diseases will be able to discuss various treatment options. Absence of immunoglobulin or antibody responses to vaccine can be treated with replacement gamma globulin infusions, or can be

865:

Most people with A–T have low lymphocyte counts in the blood. This problem seems to be relatively stable with age, but a rare number of people do have progressively decreasing lymphocyte counts as they get older. In the general population, very low lymphocyte counts are associated with an increased

853:

If an individual patient's susceptibility to infection increases, it is important to reassess immune function in case deterioration has occurred and a new therapy is indicated. If infections are occurring in the lung, it is also important to investigate the possibility of dysfunctional swallow with

714:

Cogan occulomotor apraxia is a rare disorder of development. Affected children have difficulty moving their eyes only to a new visual target, so they will turn their head past the target to "drag" the eyes to the new object of interest, then turn the head back. This tendency becomes evident in late

508:

Infertility is often described as a characteristic of A–T. Whereas this is certainly the case for the mouse model of A–T, in humans it may be more accurate to characterize the reproductive abnormality as gonadal atrophy or dysgenesis characterized by delayed pubertal development. Because programmed

957:

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 increase time needed to respond to questions (e.g., holding up a hand

782:

gene, that could be considered in the differential diagnosis of A–T. Patients with ATLD are very similar to those with A–T in showing a progressive cerebellar ataxia, hypersensitivity to ionizing radiation and genomic instability. Those rare individuals with ATLD who are well described differ from

534:

Cells from people with A–T demonstrate genomic instability, slow growth and premature senescence in culture, shortened telomeres and an ongoing, low-level stress response. These factors may contribute to the progeric (signs of early aging) changes of skin and hair sometimes observed in people with

525:

As lymphocytes develop from stem cells in the bone marrow into mature lymphocytes in the periphery, they rearrange special segments of their DNA . This process requires them to make DSBs, which are difficult to repair in the absence of ATM. As a result, most people with A–T have reduced numbers of

219:

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

898:

Children and adults with chronic dry cough, increased work of breathing (fast respiratory rate, shortness of breath at rest or with activities) and absence of an infectious process to explain respiratory symptoms should be evaluated for interstitial lung disease or another intrapulmonary process.

886:

Recurrent sinus and lung infections can lead to the development of chronic lung disease. Such infections should be treated with appropriate antibiotics to prevent and limit lung injury. Administration of antibiotics should be considered when children and adults have prolonged respiratory symptoms

677:

The diagnosis can be confirmed in the laboratory by finding an absence or deficiency of the ATM protein in cultured blood cells, an absence or deficiency of ATM function (kinase assay), or mutations in both copies of the cell's ATM gene. These more specialized tests are not always needed, but are

461:

Carriers of A–T, such as the parents of a person with A–T, have one mutated copy of the ATM gene and one normal copy. They are generally healthy, but there is an increased risk of breast cancer in women. This finding has been confirmed in a variety of different ways, and is the subject of current

339:

is common because of the neurological changes that interfere with 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 duration of meals. Problems involving the

83:

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 pre-school and early school age, they develop difficulty moving their

457:

Looking for mutations in the ATM gene of an unrelated person (for example, the spouse of a known A–T carrier) presents significant challenges. Genes often have variant spellings (polymorphisms) that do not affect function. In a gene as large as ATM, such variant spellings are likely to occur and

907:

Oral intake may be aided by teaching persons with A–T how to drink, chew and swallow more safely. The propriety of treatments for swallowing problems should be determined following evaluation by an expert in the field of speech-language pathology. Dieticians may help treat nutrition problems by

1197:

Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S, Ashkenazi M, Pecker I, Frydman M, Harnik R, Patanjali SR, Simmons A, Clines GA, Sartiel A, Gatti RA, Chessa L, Sanal O, Lavin MF, Jaspers NG, Taylor AM, Arlett CF, Miki T, Weissman SM, Lovett M,

328:

foods or liquids so that self-feeding is possible, or they may need to 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.

849:

All individuals with A–T should have at least one comprehensive immunologic evaluation that measures the number and type of lymphocytes in the blood (T-lymphocytes and B-lymphocytes), the levels of serum immunoglobulins (IgG, IgA, and IgM) and antibody responses to T-dependent (e.g., tetanus,

827:

Differentiation of these disorders is often possible with clinical features and selected laboratory tests. In cases where the distinction is unclear, clinical laboratories can identify genetic abnormalities of ATM, aprataxin and senataxin, and specialty centers can identify abnormality of the

418:

Many individuals with A–T develop deformities of the feet that compound the difficulty they have with walking due to impaired coordination. Early treatment may slow progression of this deformity. Bracing or surgical correction sometimes improves stability at the ankle sufficient to enable an

291:

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. Current consensus is that special

894:

Clearance of bronchial secretions is essential for good pulmonary health and can help limit injury from acute and chronic lung infections. Children and adults with increased bronchial secretions can benefit from routine chest therapy using the manual method, an a cappella device or a chest

877:

People with A–T also have an increased risk of developing autoimmune or chronic inflammatory diseases. This risk is probably a secondary effect of their immunodeficiency and not a direct effect of the lack of ATM protein. The most common examples of such disorders in A–T include immune

555:

levels after the age of two, and measured levels of AFP appear to increase slowly over time. AFP levels are very high in the newborn, and normally descend to adult levels over the first year to 18 months. The reason why individuals with A–T have elevated levels of AFP is not yet known.

100:). Because not all children develop in the same manner or at the same rate, 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. 640:

The diagnosis of A–T is usually suspected by the combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability) with telangiectasia and sometimes increased infections, and confirmed by specific laboratory abnormalities (elevated

315:

Lung function tests (spirometry) should be performed at least annually in children old enough to perform them, influenza and pneumococcal vaccines given to eligible individuals, and sinopulmonary infections treated aggressively to limit the development of chronic lung disease.

899:

Evaluation by a Pulmonologist and a CT scan of the chest should be considered in individuals with symptoms of interstitial lung disease or to rule other non-infectious pulmonary processes. People diagnosed with interstitial lung disease may benefit from systemic steroids.

220:

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 (

986:

Social interactions with peers are important, and should be taken into consideration for class placement. For everyone long-term peer relationships can be the most rewarding part of life; for those with A–T establishing these connections in school years can be

462:

research. Standard surveillance (including monthly breast self-exams and mammography at the usual schedule for age) is recommended, unless additional tests are indicated because the individual has other risk factors (e.g., family history of breast cancer).

454:(and carrier detection) can be carried out in families if the errors (mutation) in an affected child's two ATM genes have been identified. The process of getting this done can be complicated and, as it requires time, should be arranged before conception. 419:

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.

304:(an auto-immune 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). 5011: 4996: 535:

A–T. For example, DNA damage and genomic instability cause melanocyte stem cell (MSC) differentiation which produces graying. Thus, ATM may be a "stemness checkpoint" protecting against MSC differentiation and premature graying of the hair.

458:

doctors cannot always predict whether a specific variant will or will not cause disease. Genetic counseling can help family members of an A–T patient understand what can or cannot be tested, and how the test results should be interpreted.

648:

A variety of laboratory abnormalities occur in most people with A–T, allowing for a tentative diagnosis to be made in the presence of typical clinical features. Not all abnormalities are seen in all patients. These abnormalities include:

564:

A–T is one of several DNA repair disorders that result in neurological abnormalities or degeneration. Arguably some of the most devastating symptoms of A–T are a result of progressive cerebellar degeneration, characterized by the loss of

4846:

Chessa L, Leuzzi V, Plebani A, Soresina A, Micheli R, D'Agnano D, Venturi T, Molinaro A, Fazzi E, Marini M, Ferremi Leali P, Quinti I, Cavaliere FM, Girelli G, Pietrogrande MC, Finocchi A, Tabolli S, Abeni D, Magnani M (January 2014).

3220:

Inomata K, Aoto T, Binh NT, Okamoto N, Tanimura S, Wakayama T, Iseki S, Hara E, Masunaga T, Shimizu H, Nishimura EK (June 2009). "Genotoxic stress abrogates renewal of melanocyte stem cells by triggering their differentiation".

6940: 344:

may not cough when they aspirate (silent aspiration). Swallowing problems and especially swallowing problems with silent aspiration may cause lung problems due to inability to cough and clear food and liquids from the airway.

157:(dilated blood vessels) over the white (sclera) of the eyes, making them appear bloodshot. These are not apparent in infancy and may first appear at age 5–8 years. Telangiectasia may also appear on sun-exposed areas of skin. 6684: 3078:

Bredemeyer AL, Helmink BA, Innes CL, Calderon B, McGinnis LM, Mahowald GK, Gapud EJ, Walker LM, Collins JB, Weaver BK, Mandik-Nayak L, Schreiber RD, Allen PM, May MJ, Paules RS, Bassing CH, Sleckman BP (December 2008).

2977:

Bredemeyer AL, Sharma GG, Huang CY, Helmink BA, Walker LM, Khor KC, Nuskey B, Sullivan KE, Pandita TK, Bassing CH, Sleckman BP (July 2006). "ATM stabilizes DNA double-strand-break complexes during V(D)J recombination".

1018:(EMA) for the treatment of various genetic diseases, including Ataxia-Telangiectasia. N-Acetyl-Leucine has also been granted Orphan Drug Designations in the US and EU for related inherited cerebellar ataxias, such as 958:

and informing others about the need to allow more time for responses). Rarely helpful are traditional speech therapies that focus on the production of specific sounds and strengthening of the lip and tongue muscles.

509:

DSBs are generated to initiate genetic recombinations involved in the production of sperm and eggs in reproductive organs (a process known as meiosis), meiotic defects and arrest can occur when ATM is not present.

2037:

McGrath-Morrow SA, Gower WA, Rothblum-Oviatt C, Brody AS, Langston C, Fan LL, Lefton-Greif MA, Crawford TO, Troche M, Sandlund JT, Auwaerter PG, Easley B, Loughlin GM, Carroll JL, Lederman HM (September 2010).

495:

In the absence of the ATM protein, cell-cycle check-point regulation and programmed cell death in response to DSBs are defective. The result is genomic instability which can lead to the development of cancers.

6259: 499:

Irradiation and radiomimetic compounds induce DSBs which are unable to be repaired appropriately when ATM is absent. Consequently, such agents can prove especially cytotoxic to A–T cells and people with A–T.

5598: 443:(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. 4214:

Chun HH, Sun X, Nahas SA, Teraoka S, Lai CH, Concannon P, Gatti RA (December 2003). "Improved diagnostic testing for ataxia–telangiectasia by immunoblotting of nuclear lysates for ATM protein expression".

961:

Classroom aides may be appropriate, especially to help with scribing, transportation through the school, mealtimes and toileting. The impact of an aide on peer relationships should be monitored carefully.

686:

There are several other disorders with similar symptoms or laboratory features that physicians may consider when diagnosing A–T. The three most common disorders that are sometimes confused with A–T are:

134:

There is substantial variability in the severity of features of A–T among affected individuals, and at different ages. The following symptoms or problems are either common or important features of A–T:

824:

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.

4179:

Sun X, Becker-Catania SG, Chun HH, Hwang MJ, Huo Y, Wang Z, Mitui M, Sanal O, Chessa L, Crandall B, Gatti RA (June 2002). "Early diagnosis of ataxia–telangiectasia using radiosensitivity testing".

6677: 5984: 5979: 645:

levels, increased chromosomal breakage or cell death of white blood cells after exposure to X-rays, absence of ATM protein in white blood cells, or mutations in each of the person's ATM genes).

5996: 5974: 2157:

Gatti RA, Berkel I, Boder E, Braedt G, Charmley P, Concannon P, Ersoy F, Foroud T, Jaspers NG, Lange K (December 1988). "Localization of an ataxia–telangiectasia gene to chromosome 11q22-23".

2087:

Lefton-Greif MA, Crawford TO, Winkelstein JA, Loughlin GM, Koerner CB, Zahurak M, Lederman HM (February 2000). "Oropharyngeal dysphagia and aspiration in patients with ataxia–telangiectasia".

3185:

Shiloh Y, Tabor E, Becker Y (July 1982). "Colony-forming ability of ataxia–telangiectasia skin fibroblasts is an indicator of their early senescence and increased demand for growth factors".

1007:

is an orally administered, modified amino acid that is being developed as a novel treatment for multiple rare and common neurological disorders by IntraBio Inc (Oxford, United Kingdom).

6955: 5147: 3136:

Callén E, Jankovic M, Difilippantonio S, Daniel JA, Chen HT, Celeste A, Pellegrini M, McBride K, Wangsa D, Bredemeyer AL, Sleckman BP, Ried T, Nussenzweig M, Nussenzweig A (July 2007).

1124:

Louis-Bar D (1941). "Sur un syndrome progressif cormprenant des télangiectasies capillaires cutanées et conjonctivales symétriques, à disposition naevoïde et des troubles cérébelleux".

828:

proteins of potentially responsible genes, such as ATM, MRE11, nibrin, TDP1, aprataxin and senataxin as well as other proteins important to ATM function such as ATR, DNA-PK, and RAD50.

6670: 1505:

van Os NJ, Chessa L, Weemaes CM, van Deuren M, Fiévet A, van Gaalen J, Mahlaoui N, Roeleveld N, Schrader C, Schindler D, Taylor AM, Van de Warrenburg BP, Dörk T, Willemsen MA (2019).

6252: 951:

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).

3350:

Herzog KH, Chong MJ, Kapsetaki M, Morgan JI, McKinnon PJ (May 1998). "Requirement for Atm in ionizing radiation-induced cell death in the developing central nervous system".

728:

There are other rare disorders that can be confused with A–T, either because of similar clinical features, a similarity of some laboratory features, or both. These include:

1999:

Paller AS, Massey RB, Curtis MA, Pelachyk JM, Dombrowski HC, Leickly FE, Swift M (December 1991). "Cutaneous granulomatous lesions in patients with ataxia–telangiectasia".

1865:

Reiman A, Srinivasan V, Barone G, Last JI, Wootton LL, Davies EG, Verhagen MM, Willemsen MA, Weemaes CM, Byrd PJ, Izatt L, Easton DF, Thompson DJ, Taylor AM (August 2011).

4718: 6245: 5343: 3274:

Stray-Pedersen A, Borresen-Dale AL, Paus E, Lindman CR, Burgers T, Abrahamsen TG (November 2007). "Alpha fetoprotein is increasing with age in ataxia–telangiectasia".

1151: 1415:"ATM mutations and phenotypes in ataxia-telangiectasia families in the British Isles: expression of mutant ATM and the risk of leukemia, lymphoma, and breast cancer" 6960: 2702:

Plug AW, Peters AH, Xu Y, Keegan KS, Hoekstra MF, Baltimore D, de Boer P, Ashley T (December 1997). "ATM and RPA in meiotic chromosome synapsis and recombination".

1639:

Crawford TO, Mandir AS, Lefton-Greif MA, Goodman SN, Goodman BK, Sengul H, Lederman HM (April 2000). "Quantitative neurologic assessment of ataxia–telangiectasia".

754: 5338: 6950: 5140: 3442:

Sordet O, Redon CE, Guirouilh-Barbat J, Smith S, Solier S, Douarre C, Conti C, Nakamura AJ, Das BB, Nicolas E, Kohn KW, Bonner WM, Pommier Y (August 2009).

3395:"Ataxia telangiectasia mutated-dependent apoptosis after genotoxic stress in the developing nervous system is determined by cellular differentiation status" 874:

should be aware that if there is elective surgery requiring red cell transfusion, the cells should be washed to decrease the risk of an allergic reaction.

6477: 6325: 6160: 4743:

Strupp M, Bayer O, Feil K, Straube A (February 2019). "Prophylactic treatment of migraine with and without aura with acetyl-DL-leucine: a case series".

3581:

Alexander A, Cai SL, Kim J, Nanez A, Sahin M, MacLean KH, Inoki K, Guan KL, Shen J, Person MD, Kusewitt D, Mills GB, Kastan MB, Walker CL (March 2010).

3542:"Increased chromosome instability dramatically disrupts neural genome integrity and mediates cerebellar degeneration in the ataxia–telangiectasia brain" 1771:

Rothblum-Oviatt, Cynthia; Wright, Jennifer; Lefton-Greif, Maureen A.; McGrath-Morrow, Sharon A.; Crawford, Thomas O.; Lederman, Howard M. (2016-11-25).

1413:

Stankovic T, Kidd AM, Sutcliffe A, McGuire GM, Robinson P, Weber P, Bedenham T, Bradwell AR, Easton DF, Lennox GG, Haites N, Byrd PJ, Taylor AM (1998).

2852:

Franco S, Alt FW, Manis JP (September 2006). "Pathways that suppress programmed DNA breaks from progressing to chromosomal breaks and translocations".

1094:

Individuals of all races and ethnicities are affected equally. The incidence worldwide is estimated to be between 1 in 40,000 and 1 in 100,000 people.

1033:

Published case series studies have demonstrated the positive clinical benefit of treatment with N-Acetyl-Leucine various inherited cerebellar ataxias.

6930: 6818: 6514: 5966: 1867:"Lymphoid tumours and breast cancer in ataxia telangiectasia; substantial protective effect of residual ATM kinase activity against childhood tumours" 88:). They develop slurred or distorted speech, and swallowing problems. Some have an increased number of respiratory tract infections (ear infections, 6206: 1462:

Dörk T, Bendix-Waltes R, Wegner RD, Stumm M (2004). "Slow progression of ataxia-telangiectasia with double missense and in frame splice mutations".

268:

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

1370:

Cabana MD, Crawford TO, Winkelstein JA, Christensen JR, Lederman HM (July 1998). "Consequences of the delayed diagnosis of ataxia–telangiectasia".

399:

Control of eye movement is often impaired, affecting visual functions that require fast, accurate eye movements from point to point (e.g. reading).

5956: 5133: 934:

Most children with A–T have difficulty in school because of a delay in response time to visual, verbal or other cues, slurred and quiet speech (

632:

can cope normally with other forms of radiation, such as ultraviolet light, so there is no need for special precautions from sunlight exposure.

6641: 6077: 5936: 5609: 1830:

Nowak-Wegrzyn A, Crawford TO, Winkelstein JA, Carson KA, Lederman HM (April 2004). "Immunodeficiency and infections in ataxia–telangiectasia".

6343: 5961: 5593: 2887:

Callén E, Jankovic M, Wong N, Zha S, Chen HT, Difilippantonio S, Di Virgilio M, Heidkamp G, Alt FW, Nussenzweig A, Nussenzweig M (May 2009).

812:

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.

772: 762: 738: 732: 6945: 6226: 5799: 5787: 5249: 4849:"Intra-erythrocyte infusion of dexamethasone reduces neurological symptoms in ataxia teleangiectasia patients: results of a phase 2 trial" 2803:

Lumsden JM, McCarty T, Petiniot LK, Shen R, Barlow C, Wynn TA, Morse HC, Gearhart PJ, Wynshaw-Boris A, Max EE, Hodes RJ (November 2004).

2122:

Farr AK, Shalev B, Crawford TO, Lederman HM, Winkelstein JA, Repka MX (December 2002). "Ocular manifestations of ataxia–telangiectasia".

6646: 5026: 2352:"ATM, the Mre11/Rad50/Nbs1 complex, and topoisomerase I are concentrated in the nucleus of Purkinje neurons in the juvenile human brain" 2653:

Barlow C, Hirotsune S, Paylor R, Liyanage M, Eckhaus M, Collins F, Shiloh Y, Crawley JN, Ried T, Tagle D, Wynshaw-Boris A (July 1996).

6018: 5951: 5506: 2515:

Bakkenist CJ, Kastan MB (January 2003). "DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation".

1023: 1011: 6725: 5721: 5524: 1275: 6779: 3311:"Nuclear ataxia–telangiectasia mutated (ATM) mediates the cellular response to DNA double strand breaks in human neuron-like cells" 3031:"Aberrant V(D)J recombination in ataxia telangiectasia mutated-deficient lymphocytes is dependent on nonhomologous DNA end joining" 1040: 6581: 6905: 6498: 6409: 4122:"A novel role for ATM in regulating proteasome-mediated protein degradation through suppression of the ISG15 conjugation pathway" 2402:

Valentin-Vega YA, Maclean KH, Tait-Mulder J, Milasta S, Steeves M, Dorsey FC, Cleveland JL, Green DR, Kastan MB (February 2012).

4722: 6828: 5840: 3689:

Biton S, Barzilai A, Shiloh Y (July 2008). "The neurological phenotype of ataxia–telangiectasia: solving a persistent puzzle".

623:

A–T. The effects of ATM deficiency on the other areas of the brain outside of the cerebellum are being actively investigated.

6965: 6701: 6651: 6521: 6393: 5355: 5331: 5161: 4069:"Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency" 996:

No curative medication has been approved for the treatment of inherited cerebellar ataxias, including Ataxia-Telangiectasia.

6884: 6107: 5547: 4953: 4515: 4491: 4467: 4442: 954:

Children with A–T tend to be excellent problem solvers. Their involvement in how to best perform tasks should be encouraged.

6034: 5919: 5835: 5777: 5326: 1060: 821: 248: 6388: 6165: 483:

A–T has been described as a genome instability syndrome, a DNA repair disorder and a DNA damage response (DDR) syndrome.

6662: 6003: 5377: 4967: 1548:"Severe reaction to radiotherapy provoked by hypomorphic germline mutations in ATM (ataxia-telangiectasia mutated gene)" 670:

Increased sensitivity of cells to x-ray exposure (cells die or develop even more breaks and other damage to chromosomes)

6134: 1036:

A multinational clinical trial investigating N-Acetyl-L-Leucine for the treatment Ataxia-Telangiectasia began in 2019.

6693: 6501: 6353: 6320: 6145: 5513: 1103: 440: 120: 6221: 2263:

Kurz EU, Lees-Miller SP (Aug–Sep 2004). "DNA damage-induced activation of ATM and ATM-dependent signaling pathways".

1507:"Genotype-phenotype correlations in ataxia telangiectasia patients with ATM c.3576G>A and c.8147T>C mutations" 6851: 6806: 6767: 6070: 5991: 5541: 5213: 786: 747: 6102: 6487: 6382: 6377: 6372: 6367: 6362: 6297: 6190: 5941: 5909: 5861: 5710: 5289: 3444:"Ataxia telangiectasia mutated activation by transcription- and topoisomerase I-induced DNA double-strand breaks" 1027: 1015: 50: 6900: 2938:"Regulation of oxidative stress responses by ataxia–telangiectasia mutated is required for T cell proliferation" 61:

to small dilated blood vessels, both of which are hallmarks of the disease. A–T affects many parts of the body:

6536: 6284: 6185: 6008: 5782: 5196: 5037: 1198:

Collins FS, Shiloh Y (June 1995). "A single ataxia telangiectasia gene with a product similar to PI-3 kinase".

475: 6823: 6013: 2747:"ATM promotes the obligate XY crossover and both crossover control and chromosome axis integrity on autosomes" 6237: 4540: 280:

People with A–T have a highly increased incidence (approximately 25% lifetime risk) of cancers, particularly

6970: 6935: 6636: 6621: 6617: 5946: 5702: 5520: 5372: 5362: 5206: 2789: 6746: 6216: 6130: 5878: 5870: 5825: 5501: 5473: 5321: 2889:"Essential role for DNA-PKcs in DNA double-strand break repair and apoptosis in ATM-deficient lymphocytes" 1064: 1019: 718: 696: 584: 3726:"Reducing mitochondrial ROS improves disease-related pathology in a mouse model of ataxia–telangiectasia" 2303:"Analysis of the ataxia telangiectasia mutated-mediated DNA damage response in murine cerebellar neurons" 1048: 968:

Hearing is normal throughout life. Books on tape may be a useful adjunct to traditional school materials.

543:

The cause of telangiectasia or dilated blood vessels in the absence of the ATM protein is not yet known.

6789: 6611: 6591: 6312: 6211: 6063: 5893: 5767: 5585: 5563: 5478: 5401: 5311: 5298: 5223: 5113: 1145: 4972: 4962: 1914:

Thompson D, Duedal S, Kirner J, McGuffog L, Last J, Reiman A, Byrd P, Taylor M, Easton DF (June 2005).

983:

Like all children, those with A–T need to have goals to experience the satisfaction of making progress.

980:

Allow rest time, shortened days, reduced class schedule, reduced homework, modified tests as necessary.

758:

Comparison of clinical and laboratory features of rare genetic disorders than can be confused with A–T

6631: 6335: 5830: 5647: 5536: 4133: 3922:"Nuclear accumulation of HDAC4 in ATM deficiency promotes neurodegeneration in ataxia telangiectasia" 3594: 3359: 3092: 2987: 2524: 2463: 2454:

Guo Z, Kozlov S, Lavin MF, Person MD, Paull TT (October 2010). "ATM activation by oxidative stress".

2166: 1259: 1247: 1207: 804:(defective in NBS) genes exist in the cell as a complex, along with a third protein expressed by the 778:

Ataxia–telangiectasia like disorder (ATLD) is an extremely rare condition, caused by mutation in the

148:(difficulty with coordination of head and eye movement when shifting gaze from one place to the next) 4564:

Strupp M, Teufel J, Habs M, Feuerecker R, Muth C, van de Warrenburg BP, et al. (October 2013).

3491:

Das BB, Antony S, Gupta S, Dexheimer TS, Redon CE, Garfield S, Shiloh Y, Pommier Y (December 2009).

595:

Defective response to oxidative stress characterized by elevated ROS and altered cellular metabolism

142:(difficulty with control of movement) that is apparent early but worsens in school to pre-teen years 6888: 6810: 5759: 5406: 5261: 5201: 5015: 1039:

IntraBio is also conducting two parallel clinical trials with N-Acetyl-L-Leucine for the treatment

517: 432: 340:

pharynx may cause liquid, food, and saliva to be inhaled into the airway (aspiration). People with

109: 3493:"Optimal function of the DNA repair enzyme TDP1 requires its phosphorylation by ATM and/or DNA-PK" 409:

There may be difficulty in coordinating eye position and shaping the lens to see objects up close.

6483: 6358: 6125: 5929: 5914: 5902: 5652: 5603: 5440: 5303: 5191: 4768: 4706: 4688: 4670: 3256: 3167: 3011: 2727: 2684: 2632: 2548: 2497: 2190: 1981: 1664: 1487: 1395: 1068: 1056: 1044: 451: 145: 85: 5125: 3081:"DNA double-strand breaks activate a multi-functional genetic program in developing lymphocytes" 4299:

Anheim M, Tranchant C, Koenig M (February 2012). "The autosomal recessive cerebellar ataxias".

3773:

Sharma NK, Lebedeva M, Thomas T, Kovalenko OA, Stumpf JD, Shadel GS, Santos JH (January 2014).

300:

A–T can cause features of early aging such as premature graying of the hair. It can also cause

6775: 6452: 6443: 6428: 6272: 6177: 5692: 5658: 5630: 5621: 5553: 5529: 5396: 5244: 5077: 5048: 4929: 4880: 4828: 4810: 4760: 4646: 4615:"Acetyl-DL-leucine improves gait variability in patients with cerebellar ataxia-a case series" 4595: 4424: 4375: 4324: 4281: 4232: 4196: 4161: 4098: 4049: 4000: 3951: 3902: 3853: 3804: 3755: 3706: 3671: 3622: 3563: 3522: 3473: 3424: 3375: 3332: 3291: 3248: 3202: 3159: 3118: 3060: 3003: 2959: 2918: 2869: 2834: 2778: 2719: 2676: 2624: 2589: 2540: 2489: 2433: 2381: 2332: 2280: 2242: 2182: 2139: 2104: 2069: 2016: 1973: 1937: 1896: 1847: 1812: 1794: 1750: 1701: 1656: 1621: 1577: 1528: 1479: 1444: 1387: 1349: 1281: 1271: 1223: 1174: 919:

A child cannot eat enough to grow or a person of any age cannot eat enough to maintain weight;

790: 722: 654: 642: 552: 6550: 6531: 6462: 6276: 6268: 6150: 5815: 5686: 5681: 5466: 5461: 4919: 4911: 4870: 4860: 4818: 4802: 4752: 4636: 4626: 4585: 4577: 4414: 4406: 4365: 4355: 4316: 4308: 4271: 4263: 4224: 4188: 4151: 4141: 4088: 4080: 4039: 4031: 3990: 3982: 3941: 3933: 3892: 3884: 3843: 3835: 3794: 3786: 3745: 3737: 3698: 3661: 3653: 3612: 3602: 3553: 3512: 3504: 3463: 3455: 3414: 3406: 3367: 3322: 3283: 3238: 3230: 3194: 3149: 3108: 3100: 3050: 3042: 2995: 2949: 2908: 2900: 2861: 2824: 2816: 2768: 2758: 2711: 2666: 2616: 2579: 2532: 2479: 2471: 2423: 2415: 2371: 2363: 2322: 2314: 2272: 2232: 2224: 2174: 2131: 2096: 2059: 2051: 2008: 1965: 1927: 1886: 1878: 1839: 1802: 1784: 1740: 1732: 1691: 1648: 1611: 1567: 1559: 1518: 1471: 1434: 1426: 1379: 1339: 1263: 1215: 1133: 1083:

Median survival in two large cohorts studies was 25 and 19 years of age, with a wide range.

1052: 809: 4344:"Safety and caregiver satisfaction with gastrostomy in patients with Ataxia Telangiectasia" 3824:"Loss of neuronal cell cycle control in ataxia–telangiectasia: a unified disease mechanism" 3642:"ATM activates the pentose phosphate pathway promoting anti-oxidant defence and DNA repair" 1546:

Asadollahi R, Britschgi C, Joset P, Oneda B, Schindler D, Meier UR, Rauch A (August 2020).

6879: 6709: 6697: 6573: 6155: 5737: 5428: 4957: 1299: 909: 766: 661: 183:

Drooling particularly in young children when they are tired or concentrating on activities

2607:

Shiloh Y (March 2003). "ATM and related protein kinases: safeguarding genome integrity".

1684:"Current and potential therapeutic strategies for the treatment of ataxia–telangiectasia" 705:

Each of these can be distinguished from A–T by the neurologic exam and clinical history.

664:(especially IgA, IgM, IgG, and IgG subclasses) and low number of lymphocytes in the blood 4137: 4020:"EZH2-mediated H3K27 trimethylation mediates neurodegeneration in ataxia–telangiectasia" 3598: 3363: 3096: 2991: 2528: 2467: 2170: 1326:

Swift M, Morrell D, Cromartie E, Chamberlin AR, Skolnick MH, Bishop DT (November 1986).

1211: 974:

Practicing coordination (e.g. balance beam or cursive writing exercises) is not helpful.

841:

There is no treatment known to slow or stop the progression of the neurologic problems.

292:

screening tests are not helpful, but all women should have routine cancer surveillance.

236:), and various rhythmic and non-rhythmic movements with attempts at coordinated action ( 6895: 6874: 6796: 6626: 6526: 6348: 6140: 5794: 5743: 5571: 5280: 5157: 4924: 4899: 4875: 4848: 4823: 4790: 4641: 4614: 4590: 4565: 4419: 4394: 4393:

Ilg W, Bastian AJ, Boesch S, Burciu RG, Celnik P, Claaßen J, et al. (April 2014).

4370: 4343: 4276: 4251: 4156: 4121: 4093: 4068: 4044: 4019: 3995: 3970: 3946: 3921: 3897: 3872: 3848: 3823: 3799: 3774: 3750: 3725: 3666: 3641: 3617: 3582: 3517: 3492: 3468: 3443: 3419: 3410: 3394: 3113: 3080: 3055: 3030: 2913: 2888: 2829: 2804: 2773: 2746: 2428: 2403: 2376: 2351: 2327: 2302: 2237: 2212: 2064: 2039: 1891: 1866: 1807: 1772: 1745: 1720: 1572: 1547: 1439: 1414: 1344: 1327: 769:

of the aprataxin gene can confirm the diagnosis. There is no enhanced risk for cancer.

708: 691: 566: 386: 203: 154: 58: 5020: 2671: 2654: 2135: 2100: 2012: 1616: 1599: 1267: 971:

Early use of computers (preschool) with word completion software should be encouraged.

6924: 6868: 6784: 5820: 5772: 5642: 5411: 5367: 5218: 4705:

for "N-Acetyl-L-Leucine for GM2 Gangliosdisosis (Tay-Sachs and Sandhoff Disease)" at

3198: 2501: 1004: 570: 73: 17: 4772: 3260: 3171: 2688: 2636: 1668: 1491: 1399: 6602: 6414: 6094: 6086: 5316: 5186: 5169: 5088: 4342:

Lefton-Greif MA, Crawford TO, McGrath-Morrow S, Carson KA, Lederman HM (May 2011).

3839: 3015: 2552: 2318: 2194: 1985: 324:

Feeding and swallowing can become difficult for people with A–T as they get older.

4701: 4683: 4665: 3920:

Li J, Chen J, Ricupero CL, Hart RP, Schwartz MS, Kusnecov A, Herrup K (May 2012).

3371: 3138:"ATM prevents the persistence and propagation of chromosome breaks in lymphocytes" 2731: 2228: 1523: 1506: 1086:

Life expectancy does not correlate well with severity of neurological impairment.

5042: 4950: 4446: 4146: 3790: 3702: 2904: 2865: 2763: 2419: 2367: 2276: 6838: 5275: 5236: 5178: 5097: 5072: 4566:"Effects of acetyl-DL-leucine in patients with cerebellar ataxia: a case series" 4228: 3046: 2954: 2937: 1843: 1328:"The incidence and gene frequency of ataxia–telangiectasia in the United States" 113: 5102: 3587:

Proceedings of the National Academy of Sciences of the United States of America

3287: 3234: 3154: 3137: 6758: 6735: 6607: 6568: 5386: 5256: 5091: 5053: 5005: 4756: 4631: 4581: 4410: 4018:

Li J, Hart RP, Mallimo EM, Swerdel MR, Kusnecov AW, Herrup K (December 2013).

3986: 3888: 1789: 935: 403: 216: 186: 93: 66: 4814: 4613:

Schniepp R, Strupp M, Wuehr M, Jahn K, Dieterich M, Brandt T, Feil K (2016).

2805:"Immunoglobulin class switch recombination is impaired in Atm-deficient mice" 1798: 1010:

N-Acetyl-Leucine has been granted multiple orphan drug designations from the

915:

A feeding (gastrostomy) tube is recommended when any of the following occur:

6117: 5496: 5447: 5435: 5418: 5350: 5083: 4806: 4267: 4192: 4117: 3607: 3583:"ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS" 2475: 1219: 447: 341: 336: 332: 281: 233: 225: 175: 97: 89: 4933: 4884: 4832: 4764: 4650: 4599: 4428: 4379: 4360: 4328: 4285: 4236: 4200: 4165: 4102: 4084: 4053: 4004: 3955: 3906: 3857: 3808: 3759: 3710: 3675: 3657: 3626: 3567: 3526: 3508: 3477: 3428: 3336: 3327: 3310: 3295: 3252: 3163: 3122: 3064: 3029:

Bredemeyer AL, Huang CY, Walker LM, Bassing CH, Sleckman BP (August 2008).

3007: 2963: 2922: 2873: 2838: 2782: 2745:

Barchi M, Roig I, Di Giacomo M, de Rooij DG, Keeney S, Jasin M (May 2008).

2628: 2593: 2544: 2493: 2437: 2385: 2336: 2284: 2246: 2143: 2108: 2073: 1977: 1941: 1900: 1851: 1816: 1754: 1705: 1660: 1581: 1532: 1483: 1285: 427: 357:

Poor weight gain (during ages of expected growth) or weight loss at any age

4865: 4312: 3459: 3379: 3206: 2723: 2680: 2186: 2020: 1932: 1915: 1652: 1625: 1448: 1391: 1383: 1353: 1227: 1178: 372:

Increase in the frequency or duration of breathing or respiratory problems

6740: 6719: 6558: 6293: 5676: 5668: 5634: 5488: 5391: 5108: 3558: 3541: 2820: 2584: 2567: 2040:"Evaluation and management of pulmonary disease in ataxia–telangiectasia" 1882: 1696: 1683: 1475: 1072: 301: 285: 269: 229: 192: 168: 164: 4320: 3741: 3309:

Biton S, Dar I, Mittelman L, Pereg Y, Barzilai A, Shiloh Y (June 2006).

3104: 2999: 2536: 2715: 2055: 1736: 925:

Mealtimes are stressful or too long, interfering with other activities.

4988: 4915: 3724:

D'Souza AD, Parish IA, Krause DS, Kaech SM, Shadel GS (January 2013).

3243: 1563: 1137: 389:(prominent blood vessels) in the membrane that covers the white part ( 6433: 6302: 5715: 5456: 5423: 5000: 3775:"Intrinsic mitochondrial DNA repair defects in Ataxia Telangiectasia" 2484: 2449: 2447: 2178: 1365: 1363: 1248:"ATM: genome stability, neuronal development, and cancer cross paths" 813: 797: 779: 587:

including topoisomerase 1 cleavage complex (TOP1cc) dependent lesions

390: 257: 237: 221: 139: 54: 4035: 3937: 3540:

Iourov IY, Vorsanova SG, Liehr T, Kolotii AD, Yurov YB (July 2009).

2620: 908:

recommending dietary modifications, including high calorie foods or

5971:

Spinal muscular atrophy with lower extremity predominance (SMALED)

4687:

for "N-Acetyl-L-Leucine for Niemann-Pick Disease, Type C (NPC)" at

4067:

Jiang D, Zhang Y, Hart RP, Chen J, Herrup K, Li J (December 2015).

2213:"Multiple roles of ATM in monitoring and maintaining DNA integrity" 1969: 1430: 312:

Chronic lung disease develops in more than 25% of people with A–T.

160:

Problems with infections, especially of the ears, sinuses and lungs

4395:"Consensus paper: management of degenerative cerebellar disorders" 1916:"Cancer risks and mortality in heterozygous ATM mutation carriers" 1055:

Disease) Future opportunities to develop N-Acetyl-Leucine include

878:

thrombocytopenia (ITP), several forms of arthritis, and vitiligo.

805: 753: 604:

Inappropriate cell cycle re-entry of post-mitotic (mature) neurons

580:

Failed clearance of genomically damaged neurons during development

516: 474: 426: 335:) occur, they typically present during the second decade of life. 247: 6941:

Systemic atrophies primarily affecting the central nervous system

977:

Occupational therapy is helpful for managing daily living skills.

174:

Delayed onset or incomplete pubertal development, and very early

5031: 817: 801: 79:

It prevents repair of broken DNA, increasing the risk of cancer.

6666: 6241: 6059: 6055: 5129: 366:

Foods or drinks previously enjoyed are now refused or difficult

163:

Increased incidence of cancer (primarily, but not exclusively,

1721:"Cerebral abnormalities in adults with ataxia–telangiectasia" 4669:

for "N-Acetyl-L-Leucine for Ataxia-Telangiectasia (A-T)" at

1719:

Lin DD, Barker PB, Lederman HM, Crawford TO (January 2014).

2568:"ATMINistrating ATM signalling: regulation of ATM by ATMIN" 2350:

Gorodetsky E, Calkins S, Ahn J, Brooks PJ (November 2007).

577:

Defective DNA damage response in neurons which can lead to

471:

How loss of the ATM protein creates a multisystem disorder

2655:"Atm-deficient mice: a paradigm of ataxia telangiectasia" 678:

particularly helpful if a child's symptoms are atypical.

551:

Approximately 95% of people with A–T have elevated serum

363:

Mealtimes longer than 40 – 45 minutes, on a regular basis

256:

Prominent blood vessels (telangiectasia) over the white (

3873:"Cytoplasmic ATM in neurons modulates synaptic function" 2032: 2030: 1165:

Boder E (1985). "Ataxia–telangiectasia: an overview".

667:

Chromosomal instability (broken pieces of chromosomes)

84:

eyes in a natural manner from one place to the next (

4978: 3871:

Li J, Han YR, Plummer MR, Herrup K (December 2009).

2404:"Mitochondrial dysfunction in ataxia–telangiectasia" 2206: 2204: 1241: 1239: 1237: 854:

aspiration into the lungs (see above sections under

69:, causing difficulty with movement and coordination. 65:

It impairs certain areas of the brain including the

6860: 6837: 6805: 6766: 6757: 6708: 6590: 6567: 6549: 6497: 6427: 6402: 6334: 6311: 6292: 6283: 6199: 6176: 6116: 6093: 5892: 5869: 5860: 5853: 5808: 5758: 5730: 5701: 5667: 5629: 5618: 5584: 5562: 5487: 5297: 5288: 5274: 5234: 5177: 5168: 5063: 4982: 4973:

Replication-Independent Double-Strand Breaks (DSBs)

3640:Cosentino C, Grieco D, Costanzo V (February 2011). 396:

Vision (ability to see objects in focus) is normal.

202:Many children are initially misdiagnosed as having 2301:Dar I, Biton S, Shiloh Y, Barzilai A (July 2006). 1593: 1591: 1192: 1190: 1188: 504:Delayed pubertal development (gonadal dysgenesis) 3971:"ATM and the epigenetics of the neuronal genome" 2648: 2646: 613:Histone hypermethylation and altered epigenetics 513:Immune system defects and immune-related cancers 224:), slower twisting movements of the upper body ( 6956:DNA replication and repair-deficiency disorders 4791:"Survival probability in ataxia telangiectasia" 4784: 4782: 4516:"Search Orphan Drug Designations and Approvals" 4492:"Search Orphan Drug Designations and Approvals" 4468:"Search Orphan Drug Designations and Approvals" 3393:Lee Y, Chong MJ, McKinnon PJ (September 2001). 2258: 2256: 1682:Lavin MF, Gueven N, Bottle S, Gatti RA (2007). 4252:"Molecular pathology of ataxia telangiectasia" 2296: 2294: 6678: 6253: 6071: 5141: 2397: 2395: 8: 2936:Bagley J, Singh G, Iacomini J (April 2007). 1321: 1319: 1150:: CS1 maint: DOI inactive as of July 2024 ( 820:are also targets for phosphorylation by the 180:Slowed rate of growth (weight and/or height) 4898:Yousefpour P, Chilkoti A (September 2014). 860:Symptoms: Feeding, Swallowing and Nutrition 354:Choking or coughing when eating or drinking 228:), adoption of stiff and twisted postures ( 6763: 6685: 6671: 6663: 6478:Purine nucleoside phosphorylase deficiency 6326:Transient hypogammaglobulinemia of infancy 6308: 6289: 6260: 6246: 6238: 6078: 6064: 6056: 5866: 5857: 5626: 5294: 5285: 5174: 5148: 5134: 5126: 4979: 2211:Derheimer FA, Kastan MB (September 2010). 965:the point of exhaustion should be avoided. 744:Ataxia–telangiectasia like disorder (ATLD) 252:Ocular telangiectasia in a person with A–T 6819:Hereditary nonpolyposis colorectal cancer 4923: 4874: 4864: 4822: 4640: 4630: 4589: 4418: 4369: 4359: 4275: 4155: 4145: 4092: 4043: 3994: 3945: 3896: 3847: 3798: 3749: 3665: 3616: 3606: 3557: 3516: 3467: 3418: 3326: 3242: 3153: 3112: 3054: 2953: 2912: 2828: 2772: 2762: 2670: 2583: 2483: 2427: 2375: 2326: 2236: 2063: 1931: 1890: 1806: 1788: 1744: 1695: 1615: 1571: 1552:Molecular Genetics & Genomic Medicine 1522: 1438: 1343: 4539:FRANCISCO, Estela Miranda (2018-12-20). 3276:European Journal of Paediatric Neurology 1920:Journal of the National Cancer Institute 1725:AJNR. American Journal of Neuroradiology 547:Increased alpha-fetoprotein (AFP) levels 76:, causing a predisposition to infection. 4120:, McKinnon P, Desai SD (January 2011). 1956:breast cancer susceptibility alleles". 1116: 6961:Syndromes affecting the nervous system 6642:Terminal complement pathway deficiency 5937:Distal hereditary motor neuronopathies 5610:Template:Demyelinating diseases of CNS 4975:Discusses importance of the ATM kinase 1143: 4968:GeneReviews for ataxia–telangiectasia 4116:Wood LM, Sankar S, Reed RE, Haas AL, 1766: 1764: 349:Warning signs of a swallowing problem 7: 6227:Encephalocraniocutaneous lipomatosis 5788:Idiopathic intracranial hypertension 4900:"Co-opting biology to deliver drugs" 3975:Mechanisms of Ageing and Development 2809:The Journal of Experimental Medicine 1464:American Journal of Medical Genetics 837:Ataxia and other neurologic problems 660:Immunodeficiency with low levels of 657:levels in serum after 2 years of age 210:Ataxia and other neurologic problems 189:(slurred, slow, or distorted speech) 6951:IUIS-PID table 3 immunodeficiencies 6647:Paroxysmal nocturnal hemoglobinuria 4301:The New England Journal of Medicine 4250:Taylor AM, Byrd PJ (October 2005). 3315:The Journal of Biological Chemistry 2566:Kanu N, Behrens A (November 2008). 1024:U.S. Food & Drug Administration 1012:U.S. Food & Drug Administration 446:The mode of inheritance for A–T is 406:) are common, but may be treatable. 6019:Infantile progressive bulbar palsy 3411:10.1523/JNEUROSCI.21-17-06687.2001 1419:American Journal of Human Genetics 1332:American Journal of Human Genetics 479:Characteristics of the ATM protein 439:A–T is caused by mutations in the 320:Feeding, swallowing, and nutrition 232:), occasional uncontrolled jerks ( 198:Premature changes in hair and skin 25: 6161:Bannayan–Riley–Ruvalcaba syndrome 5722:Template:Cerebrovascular diseases 5525:Frontotemporal lobar degeneration 4853:Orphanet Journal of Rare Diseases 4348:Orphanet Journal of Rare Diseases 4217:Molecular Genetics and Metabolism 2124:American Journal of Ophthalmology 1777:Orphanet Journal of Rare Diseases 1773:"Ataxia telangiectasia: a review" 903:Feeding, swallowing and nutrition 808:gene. This complex, known as the 119:A–T is caused by a defect in the 6931:Chromosome instability syndromes 6906:Severe combined immunodeficiency 6410:Common variable immunodeficiency 5742:For more detailed coverage, see 5720:For more detailed coverage, see 5691:For more detailed coverage, see 5657:For more detailed coverage, see 5608:For more detailed coverage, see 4904:Biotechnology and Bioengineering 4795:Archives of Disease in Childhood 2788: 773:Ataxia–oculomotor apraxia type 2 763:Ataxia–oculomotor apraxia type 1 739:Ataxia–oculomotor apraxia type 2 733:Ataxia–oculomotor apraxia type 1 607:Synaptic/vesicular dysregulation 57:refers to poor coordination and 6829:Mismatch repair cancer syndrome 6582:Idiopathic CD4+ lymphocytopenia 6207:Abdallat–Davis–Farrage syndrome 3822:Yang Y, Herrup K (March 2005). 1604:Seminars in Pediatric Neurology 653:Elevated and slowly increasing 288:, but other cancers can occur. 126:as low as 1 in 300,000 people. 6702:DNA repair-deficiency disorder 6652:Complement receptor deficiency 6522:Adenosine deaminase deficiency 3840:10.1523/JNEUROSCI.4946-04.2005 2319:10.1523/JNEUROSCI.2055-06.2006 796:The proteins expressed by the 673:Cerebellar atrophy on MRI scan 601:Defects in neuronal function: 43:ataxia–telangiectasia syndrome 27:Rare neurodegenerative disease 1: 6035:Amyotrophic lateral sclerosis 5920:Hereditary spastic paraplegia 5778:Normal pressure hydrocephalus 4256:Journal of Clinical Pathology 3372:10.1126/science.280.5366.1089 2672:10.1016/S0092-8674(00)80086-0 2229:10.1016/j.febslet.2010.05.031 2136:10.1016/s0002-9394(02)01796-8 2101:10.1016/s0022-3476(00)70106-5 2013:10.1016/s0022-3476(05)83043-4 1617:10.1016/s1071-9091(98)80007-7 1598:Crawford TO (December 1998). 1524:10.1136/jmedgenet-2018-105635 1268:10.1016/s0065-230x(01)83007-4 1061:Amyotrophic lateral sclerosis 6780:DeSanctis–Cacchione syndrome 6726:Aicardi–Goutières syndrome 4 6004:Progressive muscular atrophy 4147:10.1371/journal.pone.0016422 3791:10.1016/j.dnarep.2013.11.002 3703:10.1016/j.dnarep.2008.03.006 3199:10.1016/0014-4827(82)90169-0 2905:10.1016/j.molcel.2009.04.025 2866:10.1016/j.dnarep.2006.05.024 2764:10.1371/journal.pgen.1000076 2420:10.1182/blood-2011-08-373639 2368:10.1016/j.dnarep.2007.06.011 2277:10.1016/j.dnarep.2004.03.029 1246:Shiloh Y, Kastan MB (2001). 6946:Neurodegenerative disorders 6321:X-linked agammaglobulinemia 6146:Multiple hamartoma syndrome 5514:Primary progressive aphasia 4229:10.1016/j.ymgme.2003.09.008 3828:The Journal of Neuroscience 3399:The Journal of Neuroscience 3047:10.4049/jimmunol.181.4.2620 2955:10.4049/jimmunol.178.8.4757 2307:The Journal of Neuroscience 1844:10.1016/j.jpeds.2003.12.046 1511:Journal of Medical Genetics 1252:Advances in Cancer Research 1041:Niemann-Pick disease type C 930:Education and socialization 491:Cancer and radiosensitivity 375:Increase in lung infections 53:causing severe disability. 6987: 6852:Nijmegen breakage syndrome 6768:Nucleotide excision repair 5836:Hashimoto's encephalopathy 5542:Posterior cortical atrophy 5363:Striatonigral degeneration 5214:Cavernous sinus thrombosis 3288:10.1016/j.ejpn.2007.04.001 3235:10.1016/j.cell.2009.03.037 3187:Experimental Cell Research 3155:10.1016/j.cell.2007.06.016 922:Aspiration is problematic; 787:Nijmegen breakage syndrome 748:Nijmegen breakage syndrome 741:(AOA2 also known as SCAR1) 6885:Rothmund–Thomson syndrome 6108:Von Hippel–Lindau disease 5942:Spinal muscular atrophies 5910:Primary lateral sclerosis 5768:Intracranial hypertension 5548:Creutzfeldt–Jakob disease 4757:10.1007/s00415-018-9155-6 4632:10.1186/s40673-016-0046-2 4582:10.1007/s00415-013-7016-x 4545:European Medicines Agency 4411:10.1007/s12311-013-0531-6 4181:The Journal of Pediatrics 3987:10.1016/j.mad.2013.05.005 3969:Herrup K (October 2013). 3889:10.1016/j.cub.2009.10.039 2089:The Journal of Pediatrics 2001:The Journal of Pediatrics 1871:British Journal of Cancer 1832:The Journal of Pediatrics 1790:10.1186/s13023-016-0543-7 1028:European Medicines Agency 1016:European Medicines Agency 598:Mitochondrial dysfunction 583:Transcription stress and 569:and, to a lesser extent, 521:ATM and the immune system 51:neurodegenerative disease 6537:Bare lymphocyte syndrome 6389:Wiskott–Aldrich syndrome 6166:Lhermitte–Duclos disease 6009:Progressive bulbar palsy 5800:Intracranial hypotension 5783:Choroid plexus papilloma 5197:Herpesviral encephalitis 4951:About A–T from the NINDS 4619:Cerebellum & Ataxias 3546:Human Molecular Genetics 1688:British Medical Bulletin 800:(defective in ATLD) and 701:Cogan oculomotor apraxia 618:Altered protein turnover 331:If swallowing problems ( 6717:Separation/initiation: 6637:Complement 3 deficiency 6622:Complement 4 deficiency 6618:Complement 2 deficiency 6135:Pallister–Hall syndrome 5521:Frontotemporal dementia 5207:Encephalitis lethargica 4807:10.1136/adc.2006.094268 4268:10.1136/jcp.2005.026062 4193:10.1067/mpd.2002.123879 3608:10.1073/pnas.0913860107 2476:10.1126/science.1192912 1600:"Ataxia telangiectasia" 1304:Genetics Home Reference 1300:"Ataxia–telangiectasia" 1220:10.1126/science.7792600 1104:Phase II clinical trial 1020:Spinocerebellar Ataxias 946:General recommendations 431:A–T is inherited in an 195:in adolescence or later 41:), also referred to as 6747:Dyskeratosis congenita 6222:Peutz–Jeghers syndrome 6217:Incontinentia pigmenti 6131:Hypothalamic hamartoma 5826:Hepatic encephalopathy 4789:Crawford, T O (2005). 4699:Clinical trial number 4681:Clinical trial number 4663:Clinical trial number 4520:www.accessdata.fda.gov 4496:www.accessdata.fda.gov 4472:www.accessdata.fda.gov 4361:10.1186/1750-1172-6-23 3658:10.1038/emboj.2010.330 3509:10.1038/emboj.2009.302 3328:10.1074/jbc.M601895200 2609:Nature Reviews. Cancer 1167:Kroc Foundation Series 1140:(inactive 2024-07-15). 856:Symptoms: Lung Disease 759: 682:Differential diagnosis 585:abortive transcription 522: 480: 436: 253: 6966:Syndromes with tumors 6847:Ataxia–telangiectasia 6790:Xeroderma pigmentosum 6612:Hereditary angioedema 6468:Ataxia–telangiectasia 6313:Hypogammaglobulinemia 6212:Ataxia telangiectasia 6103:Sturge–Weber syndrome 5884:Ataxia–telangiectasia 5841:Static encephalopathy 5564:Mitochondrial disease 5402:Spasmodic torticollis 5312:Basal ganglia disease 5103:Ataxia-telangiectasia 4866:10.1186/1750-1172-9-5 4313:10.1056/NEJMra1006610 3460:10.1038/embor.2009.97 3035:Journal of Immunology 2942:Journal of Immunology 2044:Pediatric Pulmonology 1653:10.1212/wnl.54.7.1505 1384:10.1542/peds.102.1.98 1065:Restless Leg Syndrome 757: 520: 478: 430: 251: 151:Involuntary movements 31:Ataxia–telangiectasia 18:Ataxia telangiectasia 6901:Li–Fraumeni syndrome 6632:Properdin deficiency 6453:Di George's syndrome 6336:Dysgammaglobulinemia 5831:Toxic encephalopathy 5537:Lewy bodies dementia 4745:Journal of Neurology 4570:Journal of Neurology 4085:10.1093/brain/awv284 2821:10.1084/jem.20041074 2585:10.4161/cc.7.22.7044 1883:10.1038/bjc.2011.266 1476:10.1002/ajmg.a.20601 1126:Confinia Neurologica 385:Most people develop 6889:RAPADILINO syndrome 6824:Muir–Torre syndrome 6811:DNA mismatch repair 5879:Friedreich's ataxia 5262:Meningoencephalitis 5202:Limbic encephalitis 4138:2011PLoSO...616422W 4024:Nature Neuroscience 3742:10.1038/mt.2012.203 3599:2010PNAS..107.4153A 3364:1998Sci...280.1089H 3105:10.1038/nature07392 3097:2008Natur.456..819B 3000:10.1038/nature04866 2992:2006Natur.442..466B 2537:10.1038/nature01368 2529:2003Natur.421..499B 2468:2010Sci...330..517G 2171:1988Natur.336..577G 1933:10.1093/jnci/dji141 1212:1995Sci...268.1749S 1098:Research directions 697:Friedreich's ataxia 610:HDAC4 dysregulation 448:autosomal recessive 433:autosomal recessive 402:Eye misalignments ( 110:autosomal recessive 6484:Hyper IgM syndrome 6394:Hyper-IgE syndrome 6359:Hyper IgM syndrome 6275:disorders causing 6126:Tuberous sclerosis 5915:Pseudobulbar palsy 5653:Status epilepticus 5604:Multiple sclerosis 5441:Myoclonic epilepsy 5304:movement disorders 5250:Acute disseminated 5192:Viral encephalitis 5064:External resources 4956:2016-12-14 at the 4707:ClinicalTrials.gov 4689:ClinicalTrials.gov 4671:ClinicalTrials.gov 4079:(Pt 12): 3520–36. 3559:10.1093/hmg/ddp207 2716:10.1038/ng1297-457 2056:10.1002/ppul.21277 1737:10.3174/ajnr.A3646 1697:10.1093/bmb/ldm012 1378:(1 Pt 1): 98–100. 1069:Multiple Sclerosis 1057:Lewy Body Dementia 1045:GM2 Gangliosidosis 760: 627:Radiation exposure 523: 481: 452:Prenatal diagnosis 437: 360:Excessive drooling 254: 146:Oculomotor apraxia 130:Symptoms and signs 86:oculomotor apraxia 47:Louis–Bar syndrome 6918: 6917: 6914: 6913: 6776:Cockayne syndrome 6694:Metabolic disease 6660: 6659: 6545: 6544: 6444:thymic hypoplasia 6429:T cell deficiency 6423: 6422: 6235: 6234: 6178:Neurofibromatosis 6053: 6052: 6049: 6048: 6045: 6044: 5849: 5848: 5754: 5753: 5693:Template:Headache 5659:Template:Epilepsy 5580: 5579: 5554:Vascular dementia 5397:Status dystonicus 5270: 5269: 5245:Encephalomyelitis 5123: 5122: 4916:10.1002/bit.25307 3730:Molecular Therapy 3358:(5366): 1089–91. 2860:(9–10): 1030–41. 2523:(6922): 499–506. 1690:. 81–82: 129–47. 1564:10.1002/mgg3.1409 1206:(5218): 1749–53. 1138:10.1159/000106149 723:alpha fetoprotein 719:Friedreich ataxia 655:alpha-fetoprotein 643:alpha-fetoprotein 560:Neurodegeneration 16:(Redirected from 6978: 6764: 6687: 6680: 6673: 6664: 6532:ZAP70 deficiency 6463:Nezelof syndrome 6309: 6290: 6277:immunodeficiency 6262: 6255: 6248: 6239: 6151:Proteus syndrome 6080: 6073: 6066: 6057: 5867: 5858: 5816:Brain herniation 5627: 5467:Intention tremor 5462:Essential tremor 5327:Postencephalitic 5295: 5286: 5175: 5156:Diseases of the 5150: 5143: 5136: 5127: 4980: 4963:Orphanet for A–T 4938: 4937: 4927: 4895: 4889: 4888: 4878: 4868: 4843: 4837: 4836: 4826: 4786: 4777: 4776: 4740: 4734: 4733: 4731: 4730: 4721:. Archived from 4715: 4709: 4697: 4691: 4679: 4673: 4661: 4655: 4654: 4644: 4634: 4610: 4604: 4603: 4593: 4561: 4555: 4554: 4552: 4551: 4536: 4530: 4529: 4527: 4526: 4512: 4506: 4505: 4503: 4502: 4488: 4482: 4481: 4479: 4478: 4464: 4458: 4457: 4455: 4454: 4445:. Archived from 4439: 4433: 4432: 4422: 4390: 4384: 4383: 4373: 4363: 4339: 4333: 4332: 4296: 4290: 4289: 4279: 4247: 4241: 4240: 4211: 4205: 4204: 4176: 4170: 4169: 4159: 4149: 4113: 4107: 4106: 4096: 4064: 4058: 4057: 4047: 4015: 4009: 4008: 3998: 3966: 3960: 3959: 3949: 3917: 3911: 3910: 3900: 3868: 3862: 3861: 3851: 3819: 3813: 3812: 3802: 3770: 3764: 3763: 3753: 3721: 3715: 3714: 3686: 3680: 3679: 3669: 3646:The EMBO Journal 3637: 3631: 3630: 3620: 3610: 3578: 3572: 3571: 3561: 3537: 3531: 3530: 3520: 3497:The EMBO Journal 3488: 3482: 3481: 3471: 3439: 3433: 3432: 3422: 3390: 3384: 3383: 3347: 3341: 3340: 3330: 3321:(25): 17482–91. 3306: 3300: 3299: 3271: 3265: 3264: 3246: 3217: 3211: 3210: 3182: 3176: 3175: 3157: 3133: 3127: 3126: 3116: 3091:(7223): 819–23. 3075: 3069: 3068: 3058: 3026: 3020: 3019: 2986:(7101): 466–70. 2974: 2968: 2967: 2957: 2933: 2927: 2926: 2916: 2884: 2878: 2877: 2849: 2843: 2842: 2832: 2800: 2794: 2793: 2792: 2786: 2776: 2766: 2742: 2736: 2735: 2699: 2693: 2692: 2674: 2650: 2641: 2640: 2604: 2598: 2597: 2587: 2563: 2557: 2556: 2512: 2506: 2505: 2487: 2462:(6003): 517–21. 2451: 2442: 2441: 2431: 2399: 2390: 2389: 2379: 2362:(11): 1698–707. 2347: 2341: 2340: 2330: 2298: 2289: 2288: 2271:(8–9): 889–900. 2260: 2251: 2250: 2240: 2208: 2199: 2198: 2179:10.1038/336577a0 2165:(6199): 577–80. 2154: 2148: 2147: 2119: 2113: 2112: 2084: 2078: 2077: 2067: 2034: 2025: 2024: 1996: 1990: 1989: 1952: 1946: 1945: 1935: 1911: 1905: 1904: 1894: 1862: 1856: 1855: 1827: 1821: 1820: 1810: 1792: 1768: 1759: 1758: 1748: 1716: 1710: 1709: 1699: 1679: 1673: 1672: 1636: 1630: 1629: 1619: 1595: 1586: 1585: 1575: 1543: 1537: 1536: 1526: 1502: 1496: 1495: 1459: 1453: 1452: 1442: 1410: 1404: 1403: 1367: 1358: 1357: 1347: 1323: 1314: 1313: 1311: 1310: 1296: 1290: 1289: 1243: 1232: 1231: 1194: 1183: 1182: 1162: 1156: 1155: 1149: 1141: 1121: 1005:N-Acetyl-Leucine 1000:N-Acetyl-Leucine 910:food supplements 530:Progeric changes 369:Chewing problems 21: 6986: 6985: 6981: 6980: 6979: 6977: 6976: 6975: 6921: 6920: 6919: 6910: 6880:Werner syndrome 6856: 6833: 6801: 6753: 6710:DNA replication 6704: 6698:DNA replication 6691: 6661: 6656: 6593: 6586: 6574:Lymphocytopenia 6572: 6563: 6541: 6517: 6504: 6493: 6449:hypoparathyroid 6431: 6419: 6398: 6330: 6300: 6279: 6266: 6236: 6231: 6195: 6172: 6156:Cowden syndrome 6112: 6089: 6084: 6054: 6041: 5967:Congenital DSMA 5888: 5845: 5804: 5750: 5738:Sleep disorders 5726: 5703:Cerebrovascular 5697: 5663: 5620: 5614: 5576: 5558: 5483: 5429:Choreoathetosis 5302: 5279: 5266: 5230: 5164: 5154: 5124: 5119: 5118: 5059: 5058: 4991: 4958:Wayback Machine 4947: 4942: 4941: 4910:(9): 1699–716. 4897: 4896: 4892: 4845: 4844: 4840: 4788: 4787: 4780: 4742: 4741: 4737: 4728: 4726: 4717: 4716: 4712: 4698: 4694: 4680: 4676: 4662: 4658: 4612: 4611: 4607: 4576:(10): 2556–61. 4563: 4562: 4558: 4549: 4547: 4538: 4537: 4533: 4524: 4522: 4514: 4513: 4509: 4500: 4498: 4490: 4489: 4485: 4476: 4474: 4466: 4465: 4461: 4452: 4450: 4441: 4440: 4436: 4392: 4391: 4387: 4341: 4340: 4336: 4298: 4297: 4293: 4262:(10): 1009–15. 4249: 4248: 4244: 4213: 4212: 4208: 4178: 4177: 4173: 4115: 4114: 4110: 4066: 4065: 4061: 4036:10.1038/nn.3564 4030:(12): 1745–53. 4017: 4016: 4012: 3968: 3967: 3963: 3938:10.1038/nm.2709 3926:Nature Medicine 3919: 3918: 3914: 3877:Current Biology 3870: 3869: 3865: 3821: 3820: 3816: 3772: 3771: 3767: 3723: 3722: 3718: 3688: 3687: 3683: 3639: 3638: 3634: 3580: 3579: 3575: 3552:(14): 2656–69. 3539: 3538: 3534: 3503:(23): 3667–80. 3490: 3489: 3485: 3441: 3440: 3436: 3405:(17): 6687–93. 3392: 3391: 3387: 3349: 3348: 3344: 3308: 3307: 3303: 3273: 3272: 3268: 3219: 3218: 3214: 3184: 3183: 3179: 3135: 3134: 3130: 3077: 3076: 3072: 3028: 3027: 3023: 2976: 2975: 2971: 2935: 2934: 2930: 2886: 2885: 2881: 2851: 2850: 2846: 2802: 2801: 2797: 2787: 2757:(5): e1000076. 2744: 2743: 2739: 2704:Nature Genetics 2701: 2700: 2696: 2652: 2651: 2644: 2621:10.1038/nrc1011 2606: 2605: 2601: 2565: 2564: 2560: 2514: 2513: 2509: 2453: 2452: 2445: 2414:(6): 1490–500. 2401: 2400: 2393: 2349: 2348: 2344: 2313:(29): 7767–74. 2300: 2299: 2292: 2262: 2261: 2254: 2223:(17): 3675–81. 2210: 2209: 2202: 2156: 2155: 2151: 2121: 2120: 2116: 2086: 2085: 2081: 2036: 2035: 2028: 1998: 1997: 1993: 1958:Nature Genetics 1954: 1953: 1949: 1913: 1912: 1908: 1864: 1863: 1859: 1829: 1828: 1824: 1770: 1769: 1762: 1718: 1717: 1713: 1681: 1680: 1676: 1638: 1637: 1633: 1597: 1596: 1589: 1545: 1544: 1540: 1504: 1503: 1499: 1461: 1460: 1456: 1412: 1411: 1407: 1369: 1368: 1361: 1325: 1324: 1317: 1308: 1306: 1298: 1297: 1293: 1278: 1245: 1244: 1235: 1196: 1195: 1186: 1164: 1163: 1159: 1142: 1123: 1122: 1118: 1113: 1100: 1092: 1081: 1002: 994: 948: 932: 905: 884: 847: 845:Immune problems 839: 834: 767:Genetic testing 684: 662:immunoglobulins 638: 629: 562: 549: 541: 532: 515: 506: 493: 468: 466:Pathophysiology 425: 416: 382: 322: 310: 298: 278: 270:immunoglobulins 266: 264:Immune problems 246: 234:myoclonic jerks 212: 132: 106: 72:It weakens the 28: 23: 22: 15: 12: 11: 5: 6984: 6982: 6974: 6973: 6971:Rare syndromes 6968: 6963: 6958: 6953: 6948: 6943: 6938: 6936:Genodermatoses 6933: 6923: 6922: 6916: 6915: 6912: 6911: 6909: 6908: 6903: 6898: 6896:Fanconi anemia 6893: 6892: 6891: 6882: 6877: 6875:Bloom syndrome 6864: 6862: 6858: 6857: 6855: 6854: 6849: 6843: 6841: 6835: 6834: 6832: 6831: 6826: 6821: 6815: 6813: 6803: 6802: 6800: 6799: 6797:IBIDS syndrome 6794: 6793: 6792: 6782: 6772: 6770: 6761: 6755: 6754: 6752: 6751: 6750: 6749: 6731: 6730: 6729: 6728: 6714: 6712: 6706: 6705: 6692: 6690: 6689: 6682: 6675: 6667: 6658: 6657: 6655: 6654: 6649: 6644: 6639: 6634: 6629: 6627:MBL deficiency 6624: 6615: 6598: 6596: 6588: 6587: 6585: 6584: 6578: 6576: 6565: 6564: 6562: 6561: 6555: 6553: 6547: 6546: 6543: 6542: 6540: 6539: 6534: 6529: 6527:Omenn syndrome 6524: 6508: 6506: 6495: 6494: 6492: 6491: 6472: 6471: 6465: 6456: 6439: 6437: 6425: 6424: 6421: 6420: 6418: 6417: 6412: 6406: 6404: 6400: 6399: 6397: 6396: 6391: 6386: 6380: 6375: 6370: 6365: 6356: 6354:IgM deficiency 6351: 6349:IgG deficiency 6346: 6344:IgA deficiency 6340: 6338: 6332: 6331: 6329: 6328: 6323: 6317: 6315: 6306: 6287: 6281: 6280: 6267: 6265: 6264: 6257: 6250: 6242: 6233: 6232: 6230: 6229: 6224: 6219: 6214: 6209: 6203: 6201: 6197: 6196: 6194: 6193: 6188: 6182: 6180: 6174: 6173: 6171: 6170: 6169: 6168: 6163: 6158: 6153: 6143: 6141:Megalencephaly 6138: 6128: 6122: 6120: 6114: 6113: 6111: 6110: 6105: 6099: 6097: 6091: 6090: 6085: 6083: 6082: 6075: 6068: 6060: 6051: 6050: 6047: 6046: 6043: 6042: 6040: 6039: 6038: 6037: 6026: 6025: 6024: 6023: 6022: 6021: 6016: 6006: 6001: 6000: 5999: 5994: 5989: 5988: 5987: 5982: 5977: 5969: 5964: 5959: 5954: 5949: 5939: 5925: 5924: 5923: 5922: 5917: 5912: 5898: 5896: 5890: 5889: 5887: 5886: 5881: 5875: 5873: 5864: 5855: 5851: 5850: 5847: 5846: 5844: 5843: 5838: 5833: 5828: 5823: 5818: 5812: 5810: 5806: 5805: 5803: 5802: 5797: 5795:Cerebral edema 5792: 5791: 5790: 5785: 5780: 5775: 5764: 5762: 5756: 5755: 5752: 5751: 5749: 5748: 5747: 5746: 5744:Template:Sleep 5734: 5732: 5728: 5727: 5725: 5724: 5718: 5713: 5707: 5705: 5699: 5698: 5696: 5695: 5689: 5684: 5679: 5673: 5671: 5665: 5664: 5662: 5661: 5655: 5650: 5645: 5639: 5637: 5624: 5616: 5615: 5613: 5612: 5606: 5601: 5596: 5590: 5588: 5582: 5581: 5578: 5577: 5575: 5574: 5572:Leigh syndrome 5568: 5566: 5560: 5559: 5557: 5556: 5545: 5544: 5539: 5534: 5533: 5532: 5518: 5517: 5516: 5511: 5510: 5509: 5493: 5491: 5485: 5484: 5482: 5481: 5476: 5471: 5470: 5469: 5464: 5453: 5452: 5451: 5450: 5445: 5444: 5443: 5433: 5432: 5431: 5421: 5416: 5415: 5414: 5409: 5404: 5399: 5383: 5382: 5381: 5380: 5375: 5370: 5365: 5360: 5359: 5358: 5348: 5347: 5346: 5336: 5335: 5334: 5329: 5324: 5308: 5306: 5299:Extrapyramidal 5292: 5283: 5281:encephalopathy 5272: 5271: 5268: 5267: 5265: 5264: 5259: 5254: 5253: 5252: 5241: 5239: 5232: 5231: 5229: 5228: 5227: 5226: 5216: 5211: 5210: 5209: 5204: 5199: 5194: 5183: 5181: 5172: 5166: 5165: 5158:nervous system 5155: 5153: 5152: 5145: 5138: 5130: 5121: 5120: 5117: 5116: 5105: 5094: 5080: 5068: 5067: 5065: 5061: 5060: 5057: 5056: 5045: 5034: 5023: 5008: 4992: 4987: 4986: 4984: 4983:Classification 4977: 4976: 4970: 4965: 4960: 4946: 4945:External links 4943: 4940: 4939: 4890: 4838: 4801:(7): 610–611. 4778: 4751:(2): 525–529. 4735: 4710: 4692: 4674: 4656: 4605: 4556: 4541:"EU/3/18/2059" 4531: 4507: 4483: 4459: 4434: 4385: 4334: 4291: 4242: 4206: 4171: 4108: 4059: 4010: 3961: 3912: 3883:(24): 2091–6. 3863: 3834:(10): 2522–9. 3814: 3765: 3716: 3697:(7): 1028–38. 3681: 3632: 3573: 3532: 3483: 3434: 3385: 3342: 3301: 3266: 3229:(6): 1088–99. 3212: 3177: 3128: 3070: 3021: 2969: 2948:(8): 4757–63. 2928: 2893:Molecular Cell 2879: 2844: 2815:(9): 1111–21. 2795: 2737: 2694: 2642: 2599: 2578:(22): 3483–6. 2558: 2507: 2443: 2391: 2342: 2290: 2252: 2200: 2149: 2114: 2079: 2026: 1991: 1970:10.1038/ng1837 1947: 1926:(11): 813–22. 1906: 1857: 1822: 1760: 1711: 1674: 1631: 1587: 1538: 1517:(5): 308–316. 1497: 1470:(3): 272–277. 1454: 1431:10.1086/301706 1425:(2): 334–345. 1405: 1359: 1315: 1291: 1276: 1233: 1184: 1157: 1132:(1–2): 32–42. 1115: 1114: 1112: 1109: 1107:for the drug. 1102:An open-label 1099: 1096: 1091: 1088: 1080: 1077: 1026:(FDA) and the 1014:(FDA) and the 1001: 998: 993: 990: 989: 988: 984: 981: 978: 975: 972: 969: 966: 962: 959: 955: 952: 947: 944: 931: 928: 927: 926: 923: 920: 904: 901: 883: 880: 846: 843: 838: 835: 833: 830: 752: 751: 745: 742: 736: 709:Cerebral palsy 703: 702: 699: 694: 692:Cerebral palsy 683: 680: 675: 674: 671: 668: 665: 658: 637: 634: 628: 625: 620: 619: 616: 615: 614: 611: 608: 605: 599: 596: 593: 592: 591: 588: 581: 567:Purkinje cells 561: 558: 548: 545: 540: 539:Telangiectasia 537: 531: 528: 514: 511: 505: 502: 492: 489: 467: 464: 424: 421: 415: 412: 411: 410: 407: 400: 397: 394: 387:telangiectasia 381: 380:Eye and vision 378: 377: 376: 373: 370: 367: 364: 361: 358: 355: 351: 350: 321: 318: 309: 306: 297: 294: 277: 274: 265: 262: 245: 244:Telangiectasia 242: 211: 208: 204:cerebral palsy 200: 199: 196: 190: 184: 181: 178: 172: 161: 158: 155:Telangiectasia 152: 149: 143: 131: 128: 105: 102: 81: 80: 77: 70: 59:telangiectasia 26: 24: 14: 13: 10: 9: 6: 4: 3: 2: 6983: 6972: 6969: 6967: 6964: 6962: 6959: 6957: 6954: 6952: 6949: 6947: 6944: 6942: 6939: 6937: 6934: 6932: 6929: 6928: 6926: 6907: 6904: 6902: 6899: 6897: 6894: 6890: 6886: 6883: 6881: 6878: 6876: 6873: 6872: 6871: 6870: 6869:RecQ helicase 6866: 6865: 6863: 6859: 6853: 6850: 6848: 6845: 6844: 6842: 6840: 6836: 6830: 6827: 6825: 6822: 6820: 6817: 6816: 6814: 6812: 6808: 6804: 6798: 6795: 6791: 6788: 6787: 6786: 6785:Thymine dimer 6783: 6781: 6777: 6774: 6773: 6771: 6769: 6765: 6762: 6760: 6756: 6748: 6745: 6744: 6743: 6742: 6737: 6733: 6732: 6727: 6724: 6723: 6722: 6721: 6716: 6715: 6713: 6711: 6707: 6703: 6699: 6695: 6688: 6683: 6681: 6676: 6674: 6669: 6668: 6665: 6653: 6650: 6648: 6645: 6643: 6640: 6638: 6635: 6633: 6630: 6628: 6625: 6623: 6619: 6616: 6613: 6609: 6605: 6604: 6600: 6599: 6597: 6595: 6589: 6583: 6580: 6579: 6577: 6575: 6570: 6566: 6560: 6557: 6556: 6554: 6552: 6548: 6538: 6535: 6533: 6530: 6528: 6525: 6523: 6520: 6516: 6513: 6510: 6509: 6507: 6503: 6500: 6496: 6489: 6485: 6482: 6481: 6480: 6479: 6476: 6469: 6466: 6464: 6460: 6459:euparathyroid 6457: 6454: 6450: 6447: 6445: 6441: 6440: 6438: 6435: 6430: 6426: 6416: 6413: 6411: 6408: 6407: 6405: 6401: 6395: 6392: 6390: 6387: 6384: 6381: 6379: 6376: 6374: 6371: 6369: 6366: 6364: 6360: 6357: 6355: 6352: 6350: 6347: 6345: 6342: 6341: 6339: 6337: 6333: 6327: 6324: 6322: 6319: 6318: 6316: 6314: 6310: 6307: 6304: 6299: 6295: 6291: 6288: 6286: 6282: 6278: 6274: 6270: 6263: 6258: 6256: 6251: 6249: 6244: 6243: 6240: 6228: 6225: 6223: 6220: 6218: 6215: 6213: 6210: 6208: 6205: 6204: 6202: 6198: 6192: 6189: 6187: 6184: 6183: 6181: 6179: 6175: 6167: 6164: 6162: 6159: 6157: 6154: 6152: 6149: 6148: 6147: 6144: 6142: 6139: 6136: 6132: 6129: 6127: 6124: 6123: 6121: 6119: 6115: 6109: 6106: 6104: 6101: 6100: 6098: 6096: 6092: 6088: 6081: 6076: 6074: 6069: 6067: 6062: 6061: 6058: 6036: 6033: 6032: 6031: 6028: 6027: 6020: 6017: 6015: 6012: 6011: 6010: 6007: 6005: 6002: 5998: 5995: 5993: 5990: 5986: 5983: 5981: 5978: 5976: 5973: 5972: 5970: 5968: 5965: 5963: 5960: 5958: 5955: 5953: 5950: 5948: 5945: 5944: 5943: 5940: 5938: 5935: 5934: 5933: 5931: 5927: 5926: 5921: 5918: 5916: 5913: 5911: 5908: 5907: 5906: 5904: 5900: 5899: 5897: 5895: 5891: 5885: 5882: 5880: 5877: 5876: 5874: 5872: 5868: 5865: 5863: 5859: 5856: 5852: 5842: 5839: 5837: 5834: 5832: 5829: 5827: 5824: 5822: 5821:Reye syndrome 5819: 5817: 5814: 5813: 5811: 5807: 5801: 5798: 5796: 5793: 5789: 5786: 5784: 5781: 5779: 5776: 5774: 5773:Hydrocephalus 5771: 5770: 5769: 5766: 5765: 5763: 5761: 5757: 5745: 5741: 5740: 5739: 5736: 5735: 5733: 5729: 5723: 5719: 5717: 5714: 5712: 5709: 5708: 5706: 5704: 5700: 5694: 5690: 5688: 5685: 5683: 5680: 5678: 5675: 5674: 5672: 5670: 5666: 5660: 5656: 5654: 5651: 5649: 5646: 5644: 5641: 5640: 5638: 5636: 5632: 5628: 5625: 5623: 5617: 5611: 5607: 5605: 5602: 5600: 5597: 5595: 5592: 5591: 5589: 5587: 5586:Demyelinating 5583: 5573: 5570: 5569: 5567: 5565: 5561: 5555: 5552: 5551: 5550: 5549: 5543: 5540: 5538: 5535: 5531: 5528: 5527: 5526: 5522: 5519: 5515: 5512: 5508: 5505: 5504: 5503: 5500: 5499: 5498: 5495: 5494: 5492: 5490: 5486: 5480: 5477: 5475: 5474:Restless legs 5472: 5468: 5465: 5463: 5460: 5459: 5458: 5455: 5454: 5449: 5446: 5442: 5439: 5438: 5437: 5434: 5430: 5427: 5426: 5425: 5422: 5420: 5417: 5413: 5412:Blepharospasm 5410: 5408: 5405: 5403: 5400: 5398: 5395: 5394: 5393: 5390: 5389: 5388: 5385: 5384: 5379: 5376: 5374: 5371: 5369: 5368:Hemiballismus 5366: 5364: 5361: 5357: 5354: 5353: 5352: 5349: 5345: 5342: 5341: 5340: 5337: 5333: 5330: 5328: 5325: 5323: 5320: 5319: 5318: 5315: 5314: 5313: 5310: 5309: 5307: 5305: 5300: 5296: 5293: 5291: 5287: 5284: 5282: 5277: 5273: 5263: 5260: 5258: 5255: 5251: 5248: 5247: 5246: 5243: 5242: 5240: 5238: 5233: 5225: 5222: 5221: 5220: 5219:Brain abscess 5217: 5215: 5212: 5208: 5205: 5203: 5200: 5198: 5195: 5193: 5190: 5189: 5188: 5185: 5184: 5182: 5180: 5176: 5173: 5171: 5167: 5163: 5159: 5151: 5146: 5144: 5139: 5137: 5132: 5131: 5128: 5115: 5111: 5110: 5106: 5104: 5100: 5099: 5095: 5093: 5090: 5086: 5085: 5081: 5079: 5075: 5074: 5070: 5069: 5066: 5062: 5055: 5051: 5050: 5046: 5044: 5040: 5039: 5035: 5033: 5029: 5028: 5024: 5022: 5018: 5017: 5013: 5009: 5007: 5003: 5002: 4998: 4994: 4993: 4990: 4985: 4981: 4974: 4971: 4969: 4966: 4964: 4961: 4959: 4955: 4952: 4949: 4948: 4944: 4935: 4931: 4926: 4921: 4917: 4913: 4909: 4905: 4901: 4894: 4891: 4886: 4882: 4877: 4872: 4867: 4862: 4858: 4854: 4850: 4842: 4839: 4834: 4830: 4825: 4820: 4816: 4812: 4808: 4804: 4800: 4796: 4792: 4785: 4783: 4779: 4774: 4770: 4766: 4762: 4758: 4754: 4750: 4746: 4739: 4736: 4725:on 2019-08-01 4724: 4720: 4714: 4711: 4708: 4704: 4703: 4696: 4693: 4690: 4686: 4685: 4678: 4675: 4672: 4668: 4667: 4660: 4657: 4652: 4648: 4643: 4638: 4633: 4628: 4624: 4620: 4616: 4609: 4606: 4601: 4597: 4592: 4587: 4583: 4579: 4575: 4571: 4567: 4560: 4557: 4546: 4542: 4535: 4532: 4521: 4517: 4511: 4508: 4497: 4493: 4487: 4484: 4473: 4469: 4463: 4460: 4449:on 2019-08-01 4448: 4444: 4438: 4435: 4430: 4426: 4421: 4416: 4412: 4408: 4405:(2): 248–68. 4404: 4400: 4396: 4389: 4386: 4381: 4377: 4372: 4367: 4362: 4357: 4353: 4349: 4345: 4338: 4335: 4330: 4326: 4322: 4318: 4314: 4310: 4307:(7): 636–46. 4306: 4302: 4295: 4292: 4287: 4283: 4278: 4273: 4269: 4265: 4261: 4257: 4253: 4246: 4243: 4238: 4234: 4230: 4226: 4223:(4): 437–43. 4222: 4218: 4210: 4207: 4202: 4198: 4194: 4190: 4187:(6): 724–31. 4186: 4182: 4175: 4172: 4167: 4163: 4158: 4153: 4148: 4143: 4139: 4135: 4132:(1): e16422. 4131: 4127: 4123: 4119: 4112: 4109: 4104: 4100: 4095: 4090: 4086: 4082: 4078: 4074: 4070: 4063: 4060: 4055: 4051: 4046: 4041: 4037: 4033: 4029: 4025: 4021: 4014: 4011: 4006: 4002: 3997: 3992: 3988: 3984: 3981:(10): 434–9. 3980: 3976: 3972: 3965: 3962: 3957: 3953: 3948: 3943: 3939: 3935: 3932:(5): 783–90. 3931: 3927: 3923: 3916: 3913: 3908: 3904: 3899: 3894: 3890: 3886: 3882: 3878: 3874: 3867: 3864: 3859: 3855: 3850: 3845: 3841: 3837: 3833: 3829: 3825: 3818: 3815: 3810: 3806: 3801: 3796: 3792: 3788: 3784: 3780: 3776: 3769: 3766: 3761: 3757: 3752: 3747: 3743: 3739: 3735: 3731: 3727: 3720: 3717: 3712: 3708: 3704: 3700: 3696: 3692: 3685: 3682: 3677: 3673: 3668: 3663: 3659: 3655: 3652:(3): 546–55. 3651: 3647: 3643: 3636: 3633: 3628: 3624: 3619: 3614: 3609: 3604: 3600: 3596: 3593:(9): 4153–8. 3592: 3588: 3584: 3577: 3574: 3569: 3565: 3560: 3555: 3551: 3547: 3543: 3536: 3533: 3528: 3524: 3519: 3514: 3510: 3506: 3502: 3498: 3494: 3487: 3484: 3479: 3475: 3470: 3465: 3461: 3457: 3454:(8): 887–93. 3453: 3449: 3445: 3438: 3435: 3430: 3426: 3421: 3416: 3412: 3408: 3404: 3400: 3396: 3389: 3386: 3381: 3377: 3373: 3369: 3365: 3361: 3357: 3353: 3346: 3343: 3338: 3334: 3329: 3324: 3320: 3316: 3312: 3305: 3302: 3297: 3293: 3289: 3285: 3282:(6): 375–80. 3281: 3277: 3270: 3267: 3262: 3258: 3254: 3250: 3245: 3240: 3236: 3232: 3228: 3224: 3216: 3213: 3208: 3204: 3200: 3196: 3192: 3188: 3181: 3178: 3173: 3169: 3165: 3161: 3156: 3151: 3147: 3143: 3139: 3132: 3129: 3124: 3120: 3115: 3110: 3106: 3102: 3098: 3094: 3090: 3086: 3082: 3074: 3071: 3066: 3062: 3057: 3052: 3048: 3044: 3041:(4): 2620–5. 3040: 3036: 3032: 3025: 3022: 3017: 3013: 3009: 3005: 3001: 2997: 2993: 2989: 2985: 2981: 2973: 2970: 2965: 2961: 2956: 2951: 2947: 2943: 2939: 2932: 2929: 2924: 2920: 2915: 2910: 2906: 2902: 2899:(3): 285–97. 2898: 2894: 2890: 2883: 2880: 2875: 2871: 2867: 2863: 2859: 2855: 2848: 2845: 2840: 2836: 2831: 2826: 2822: 2818: 2814: 2810: 2806: 2799: 2796: 2791: 2784: 2780: 2775: 2770: 2765: 2760: 2756: 2752: 2751:PLOS Genetics 2748: 2741: 2738: 2733: 2729: 2725: 2721: 2717: 2713: 2710:(4): 457–61. 2709: 2705: 2698: 2695: 2690: 2686: 2682: 2678: 2673: 2668: 2665:(1): 159–71. 2664: 2660: 2656: 2649: 2647: 2643: 2638: 2634: 2630: 2626: 2622: 2618: 2615:(3): 155–68. 2614: 2610: 2603: 2600: 2595: 2591: 2586: 2581: 2577: 2573: 2569: 2562: 2559: 2554: 2550: 2546: 2542: 2538: 2534: 2530: 2526: 2522: 2518: 2511: 2508: 2503: 2499: 2495: 2491: 2486: 2481: 2477: 2473: 2469: 2465: 2461: 2457: 2450: 2448: 2444: 2439: 2435: 2430: 2425: 2421: 2417: 2413: 2409: 2405: 2398: 2396: 2392: 2387: 2383: 2378: 2373: 2369: 2365: 2361: 2357: 2353: 2346: 2343: 2338: 2334: 2329: 2324: 2320: 2316: 2312: 2308: 2304: 2297: 2295: 2291: 2286: 2282: 2278: 2274: 2270: 2266: 2259: 2257: 2253: 2248: 2244: 2239: 2234: 2230: 2226: 2222: 2218: 2214: 2207: 2205: 2201: 2196: 2192: 2188: 2184: 2180: 2176: 2172: 2168: 2164: 2160: 2153: 2150: 2145: 2141: 2137: 2133: 2129: 2125: 2118: 2115: 2110: 2106: 2102: 2098: 2095:(2): 225–31. 2094: 2090: 2083: 2080: 2075: 2071: 2066: 2061: 2057: 2053: 2050:(9): 847–59. 2049: 2045: 2041: 2033: 2031: 2027: 2022: 2018: 2014: 2010: 2007:(6): 917–22. 2006: 2002: 1995: 1992: 1987: 1983: 1979: 1975: 1971: 1967: 1963: 1959: 1951: 1948: 1943: 1939: 1934: 1929: 1925: 1921: 1917: 1910: 1907: 1902: 1898: 1893: 1888: 1884: 1880: 1877:(4): 586–91. 1876: 1872: 1868: 1861: 1858: 1853: 1849: 1845: 1841: 1838:(4): 505–11. 1837: 1833: 1826: 1823: 1818: 1814: 1809: 1804: 1800: 1796: 1791: 1786: 1782: 1778: 1774: 1767: 1765: 1761: 1756: 1752: 1747: 1742: 1738: 1734: 1731:(1): 119–23. 1730: 1726: 1722: 1715: 1712: 1707: 1703: 1698: 1693: 1689: 1685: 1678: 1675: 1670: 1666: 1662: 1658: 1654: 1650: 1647:(7): 1505–9. 1646: 1642: 1635: 1632: 1627: 1623: 1618: 1613: 1610:(4): 287–94. 1609: 1605: 1601: 1594: 1592: 1588: 1583: 1579: 1574: 1569: 1565: 1561: 1558:(10): e1409. 1557: 1553: 1549: 1542: 1539: 1534: 1530: 1525: 1520: 1516: 1512: 1508: 1501: 1498: 1493: 1489: 1485: 1481: 1477: 1473: 1469: 1465: 1458: 1455: 1450: 1446: 1441: 1436: 1432: 1428: 1424: 1420: 1416: 1409: 1406: 1401: 1397: 1393: 1389: 1385: 1381: 1377: 1373: 1366: 1364: 1360: 1355: 1351: 1346: 1341: 1338:(5): 573–83. 1337: 1333: 1329: 1322: 1320: 1316: 1305: 1301: 1295: 1292: 1287: 1283: 1279: 1277:9780120066834 1273: 1269: 1265: 1261: 1257: 1253: 1249: 1242: 1240: 1238: 1234: 1229: 1225: 1221: 1217: 1213: 1209: 1205: 1201: 1193: 1191: 1189: 1185: 1180: 1176: 1172: 1168: 1161: 1158: 1153: 1147: 1139: 1135: 1131: 1127: 1120: 1117: 1110: 1108: 1105: 1097: 1095: 1089: 1087: 1084: 1078: 1076: 1074: 1070: 1066: 1062: 1058: 1054: 1050: 1046: 1042: 1037: 1034: 1031: 1029: 1025: 1021: 1017: 1013: 1008: 1006: 999: 997: 991: 985: 982: 979: 976: 973: 970: 967: 963: 960: 956: 953: 950: 949: 945: 943: 939: 937: 929: 924: 921: 918: 917: 916: 913: 911: 902: 900: 896: 892: 891:antibiotics. 888: 881: 879: 875: 871: 867: 863: 861: 857: 851: 844: 842: 836: 831: 829: 825: 823: 819: 815: 811: 807: 803: 799: 794: 792: 788: 784: 781: 776: 774: 770: 768: 764: 756: 749: 746: 743: 740: 737: 734: 731: 730: 729: 726: 724: 720: 716: 712: 710: 706: 700: 698: 695: 693: 690: 689: 688: 681: 679: 672: 669: 666: 663: 659: 656: 652: 651: 650: 646: 644: 635: 633: 626: 624: 617: 612: 609: 606: 603: 602: 600: 597: 594: 589: 586: 582: 579: 578: 576: 575: 574: 572: 571:granule cells 568: 559: 557: 554: 546: 544: 538: 536: 529: 527: 519: 512: 510: 503: 501: 497: 490: 488: 486: 477: 473: 472: 465: 463: 459: 455: 453: 449: 444: 442: 434: 429: 422: 420: 413: 408: 405: 401: 398: 395: 393:) of the eye. 392: 388: 384: 383: 379: 374: 371: 368: 365: 362: 359: 356: 353: 352: 348: 347: 346: 343: 338: 334: 329: 325: 319: 317: 313: 307: 305: 303: 295: 293: 289: 287: 283: 275: 273: 271: 263: 261: 259: 250: 243: 241: 239: 235: 231: 227: 223: 218: 209: 207: 205: 197: 194: 191: 188: 185: 182: 179: 177: 173: 170: 166: 162: 159: 156: 153: 150: 147: 144: 141: 138: 137: 136: 129: 127: 124: 123: 117: 115: 111: 103: 101: 99: 95: 91: 87: 78: 75: 74:immune system 71: 68: 64: 63: 62: 60: 56: 52: 49:, is a rare, 48: 44: 40: 36: 32: 19: 6867: 6846: 6739: 6734:Termination/ 6718: 6603:C1-inhibitor 6601: 6518: 6511: 6474: 6473: 6467: 6458: 6448: 6442: 6415:ICF syndrome 6095:Angiomatosis 6087:Phakomatosis 6029: 5928: 5901: 5883: 5862:Degenerative 5599:Inflammatory 5546: 5479:Stiff-person 5317:Parkinsonism 5290:Degenerative 5187:Encephalitis 5170:Inflammation 5160:, primarily 5107: 5096: 5082: 5071: 5047: 5036: 5025: 5010: 4995: 4907: 4903: 4893: 4856: 4852: 4841: 4798: 4794: 4748: 4744: 4738: 4727:. Retrieved 4723:the original 4713: 4700: 4695: 4682: 4677: 4664: 4659: 4622: 4618: 4608: 4573: 4569: 4559: 4548:. Retrieved 4544: 4534: 4523:. Retrieved 4519: 4510: 4499:. Retrieved 4495: 4486: 4475:. Retrieved 4471: 4462: 4451:. Retrieved 4447:the original 4437: 4402: 4398: 4388: 4351: 4347: 4337: 4321:10068/785252 4304: 4300: 4294: 4259: 4255: 4245: 4220: 4216: 4209: 4184: 4180: 4174: 4129: 4125: 4111: 4076: 4072: 4062: 4027: 4023: 4013: 3978: 3974: 3964: 3929: 3925: 3915: 3880: 3876: 3866: 3831: 3827: 3817: 3782: 3778: 3768: 3733: 3729: 3719: 3694: 3690: 3684: 3649: 3645: 3635: 3590: 3586: 3576: 3549: 3545: 3535: 3500: 3496: 3486: 3451: 3448:EMBO Reports 3447: 3437: 3402: 3398: 3388: 3355: 3351: 3345: 3318: 3314: 3304: 3279: 3275: 3269: 3226: 3222: 3215: 3193:(1): 191–9. 3190: 3186: 3180: 3148:(1): 63–75. 3145: 3141: 3131: 3088: 3084: 3073: 3038: 3034: 3024: 2983: 2979: 2972: 2945: 2941: 2931: 2896: 2892: 2882: 2857: 2853: 2847: 2812: 2808: 2798: 2754: 2750: 2740: 2707: 2703: 2697: 2662: 2658: 2612: 2608: 2602: 2575: 2571: 2561: 2520: 2516: 2510: 2459: 2455: 2411: 2407: 2359: 2355: 2345: 2310: 2306: 2268: 2264: 2220: 2217:FEBS Letters 2216: 2162: 2158: 2152: 2130:(6): 891–6. 2127: 2123: 2117: 2092: 2088: 2082: 2047: 2043: 2004: 2000: 1994: 1964:(8): 873–5. 1961: 1957: 1950: 1923: 1919: 1909: 1874: 1870: 1860: 1835: 1831: 1825: 1780: 1776: 1728: 1724: 1714: 1687: 1677: 1644: 1640: 1634: 1607: 1603: 1555: 1551: 1541: 1514: 1510: 1500: 1467: 1463: 1457: 1422: 1418: 1408: 1375: 1371: 1335: 1331: 1307:. Retrieved 1303: 1294: 1255: 1251: 1203: 1199: 1170: 1166: 1160: 1146:cite journal 1129: 1125: 1119: 1101: 1093: 1090:Epidemiology 1085: 1082: 1038: 1035: 1032: 1009: 1003: 995: 940: 933: 914: 906: 897: 893: 889: 885: 882:Lung disease 876: 872: 868: 864: 859: 855: 852: 848: 840: 826: 795: 785: 777: 771: 761: 727: 717: 713: 707: 704: 685: 676: 647: 639: 630: 621: 563: 550: 542: 533: 524: 507: 498: 494: 484: 482: 470: 469: 460: 456: 445: 438: 417: 330: 326: 323: 314: 311: 308:Lung disease 299: 290: 279: 267: 255: 213: 201: 133: 121: 118: 107: 82: 46: 42: 38: 34: 30: 29: 6839:MRN complex 6475:peripheral: 6014:Fazio–Londe 5854:Both/either 5648:Generalised 5507:Early-onset 5502:Alzheimer's 5237:spinal cord 5098:GeneReviews 5073:MedlinePlus 4702:NCT03759665 4684:NCT03759639 4666:NCT03759678 3736:(1): 42–8. 414:Orthopedics 114:inheritance 112:pattern of 108:A–T has an 6925:Categories 6759:DNA repair 6736:telomerase 6608:Angioedema 6594:deficiency 6592:Complement 6569:Leukopenia 6519:autosomal: 6273:complement 5622:paroxysmal 5594:Autoimmune 5387:Dyskinesia 5257:Meningitis 5235:Brain and 5049:DiseasesDB 4729:2019-08-01 4719:"IntraBio" 4550:2019-08-01 4525:2019-08-01 4501:2019-08-01 4477:2019-08-01 4453:2019-08-01 4443:"IntraBio" 4399:Cerebellum 3779:DNA Repair 3691:DNA Repair 3244:2297/19337 2854:DNA Repair 2572:Cell Cycle 2356:DNA Repair 2265:DNA Repair 1783:(1): 159. 1372:Pediatrics 1309:2018-03-29 1111:References 936:dysarthria 832:Management 590:Aneuploidy 404:strabismus 217:wheelchair 187:Dysarthria 94:bronchitis 67:cerebellum 6512:x-linked: 6118:Hamartoma 5619:Episodic/ 5497:Tauopathy 5448:Akathisia 5436:Myoclonus 5419:Athetosis 5351:Tauopathy 5084:eMedicine 4815:0003-9888 3785:: 22–31. 2502:206527888 2485:2152/9689 1799:1750-1172 1641:Neurology 1079:Prognosis 1049:Tay-Sachs 992:Treatment 636:Diagnosis 342:dysphagia 337:Dysphagia 333:dysphagia 282:lymphomas 226:athetosis 176:menopause 169:leukemias 165:lymphomas 98:pneumonia 90:sinusitis 6720:RNASEH2A 6559:HIV/AIDS 6551:Acquired 6502:combined 6294:Antibody 6269:Lymphoid 5985:SMALED2B 5980:SMALED2A 5677:Migraine 5669:Headache 5635:epilepsy 5631:Seizures 5489:Dementia 5392:Dystonia 5109:Orphanet 5089:derm/691 4954:Archived 4934:24916780 4885:24405665 4859:(1): 5. 4833:16790721 4773:56148131 4765:30547273 4651:27073690 4600:23835634 4429:24222635 4380:21569628 4329:22335741 4286:16189143 4237:14654357 4201:12072877 4166:21298066 4126:PLOS ONE 4103:26510954 4054:24162653 4005:23707635 3956:22466704 3907:19962314 3858:15758161 3809:24342190 3760:23011031 3711:18456574 3676:21157431 3627:20160076 3568:19414482 3527:19851285 3478:19557000 3429:11517258 3337:16627474 3296:17540590 3261:16630060 3253:19524511 3172:17514413 3164:17599403 3123:18849970 3065:18684952 3008:16799570 2964:17404255 2923:19450527 2874:16934538 2839:15504820 2783:18497861 2689:11922073 2637:22770833 2629:12612651 2594:19001856 2545:12556884 2494:20966255 2438:22144182 2386:17706468 2337:16855104 2285:15279774 2247:20580718 2144:12470759 2109:10657830 2074:20583220 1978:16832357 1942:15928302 1901:21792198 1852:15069401 1817:27884168 1755:23886747 1706:17586848 1669:24908122 1661:10751267 1582:32748564 1533:30819809 1492:22090621 1484:15054841 1400:22538515 1286:11665719 1173:: 1–63. 1073:Migraine 1053:Sandhoff 987:helpful. 423:Genetics 302:vitiligo 286:leukemia 230:dystonia 193:Diabetes 6298:humoral 6285:Primary 6191:Type II 5997:SMA-PME 5992:SMA-PCH 5975:SMALED1 5687:Tension 5682:Cluster 5407:Meige's 5224:Amoebic 5092:oph/319 5043:D001260 4925:4251460 4876:3904207 4824:2082822 4642:4828858 4591:3824630 4420:4344126 4371:3116459 4277:1770730 4157:3027683 4134:Bibcode 4094:4668921 4045:3965909 3996:3791148 3947:3378917 3898:2805770 3849:6725172 3800:6211587 3751:3538311 3667:3034007 3618:2840158 3595:Bibcode 3518:2790489 3469:2726680 3420:6763074 3380:9582124 3360:Bibcode 3352:Science 3207:6213420 3114:2605662 3093:Bibcode 3056:3598579 3016:4320129 2988:Bibcode 2914:2709792 2830:2211853 2774:2374915 2724:9398850 2681:8689683 2553:4403303 2525:Bibcode 2464:Bibcode 2456:Science 2429:3286212 2377:2797317 2328:6674276 2238:2950315 2195:4255660 2187:3200306 2167:Bibcode 2065:4151879 2021:1960607 1986:2909283 1892:3170966 1808:5123280 1746:4106125 1626:9874856 1573:7549565 1449:9463314 1440:1376883 1392:9651420 1354:3788973 1345:1684065 1228:7792600 1208:Bibcode 1200:Science 1179:2415689 1030:(EMA). 435:fashion 238:tremors 6515:X-SCID 6499:Severe 6186:Type I 5716:Stroke 5530:Pick's 5457:Tremor 5424:Chorea 5078:001394 5032:208900 4932: 4922: 4883: 4873: 4831: 4821: 4813: 4771: 4763: 4649: 4639: 4598: 4588: 4427: 4417: 4378: 4368: 4354:: 23. 4327: 4284: 4274: 4235: 4199: 4164: 4154: 4118:Liu LF 4101: 4091: 4052: 4042: 4003: 3993: 3954: 3944: 3905: 3895: 3856: 3846: 3807: 3797: 3758: 3748: 3709: 3674: 3664: 3625: 3615: 3566: 3525: 3515: 3476: 3466: 3427: 3417: 3378: 3335: 3294: 3259: 3251: 3205: 3170: 3162: 3121: 3111: 3085:Nature 3063: 3053: 3014: 3006: 2980:Nature 2962: 2921: 2911: 2872: 2837: 2827: 2781: 2771: 2732:193465 2730: 2722: 2687: 2679: 2635: 2627: 2592: 2551: 2543: 2517:Nature 2500: 2492: 2436: 2426: 2384: 2374: 2335: 2325: 2283: 2245: 2235: 2193: 2185: 2159:Nature 2142: 2107: 2072: 2062: 2019: 1984: 1976: 1940: 1899: 1889: 1850: 1815: 1805: 1797: 1753: 1743: 1704: 1667: 1659: 1624: 1580: 1570: 1531: 1490: 1482: 1447: 1437: 1398: 1390: 1352: 1342: 1284: 1274: 1260:209–54 1226: 1177: 1071:, and 806:hRad50 798:hMre11 780:hMre11 735:(AOA1) 391:sclera 276:Cancer 258:sclera 222:chorea 140:Ataxia 104:Causes 96:, and 55:Ataxia 6861:Other 6505:(B+T) 6403:Other 6200:Other 6030:both: 5962:DSMA1 5957:SMAX2 5952:SMAX1 5932:only: 5905:only: 5809:Other 5731:Other 5643:Focal 5276:Brain 5179:Brain 5021:334.8 5006:G11.3 4769:S2CID 4625:: 8. 4073:Brain 3257:S2CID 3168:S2CID 3012:S2CID 2728:S2CID 2685:S2CID 2633:S2CID 2549:S2CID 2498:S2CID 2408:Blood 2191:S2CID 1982:S2CID 1665:S2CID 1488:S2CID 1396:S2CID 814:Mre11 750:(NBS) 6741:DKC1 6700:and 6271:and 5633:and 5344:PKAN 5339:NBIA 5054:1025 5038:MeSH 5027:OMIM 5016:9-CM 4930:PMID 4881:PMID 4829:PMID 4811:ISSN 4761:PMID 4647:PMID 4596:PMID 4425:PMID 4376:PMID 4325:PMID 4282:PMID 4233:PMID 4197:PMID 4162:PMID 4099:PMID 4050:PMID 4001:PMID 3952:PMID 3903:PMID 3854:PMID 3805:PMID 3756:PMID 3707:PMID 3672:PMID 3623:PMID 3564:PMID 3523:PMID 3474:PMID 3425:PMID 3376:PMID 3333:PMID 3292:PMID 3249:PMID 3223:Cell 3203:PMID 3160:PMID 3142:Cell 3119:PMID 3061:PMID 3004:PMID 2960:PMID 2919:PMID 2870:PMID 2835:PMID 2779:PMID 2720:PMID 2677:PMID 2659:Cell 2625:PMID 2590:PMID 2541:PMID 2490:PMID 2434:PMID 2382:PMID 2333:PMID 2281:PMID 2243:PMID 2183:PMID 2140:PMID 2105:PMID 2070:PMID 2017:PMID 1974:PMID 1938:PMID 1897:PMID 1848:PMID 1813:PMID 1795:ISSN 1751:PMID 1702:PMID 1657:PMID 1622:PMID 1578:PMID 1529:PMID 1480:PMID 1468:126A 1445:PMID 1388:PMID 1350:PMID 1282:PMID 1272:ISBN 1224:PMID 1175:PMID 1152:link 1051:and 1043:and 858:and 818:Nbs1 816:and 802:Nbs1 296:Skin 284:and 167:and 6807:MSI 5947:SMA 5930:LMN 5903:UMN 5894:MND 5760:CSF 5711:TIA 5356:PSP 5332:NMS 5301:and 5162:CNS 5114:100 5012:ICD 4997:ICD 4920:PMC 4912:doi 4908:111 4871:PMC 4861:doi 4819:PMC 4803:doi 4753:doi 4749:266 4637:PMC 4627:doi 4586:PMC 4578:doi 4574:260 4415:PMC 4407:doi 4366:PMC 4356:doi 4317:hdl 4309:doi 4305:366 4272:PMC 4264:doi 4225:doi 4189:doi 4185:140 4152:PMC 4142:doi 4089:PMC 4081:doi 4077:138 4040:PMC 4032:doi 3991:PMC 3983:doi 3979:134 3942:PMC 3934:doi 3893:PMC 3885:doi 3844:PMC 3836:doi 3795:PMC 3787:doi 3746:PMC 3738:doi 3699:doi 3662:PMC 3654:doi 3613:PMC 3603:doi 3591:107 3554:doi 3513:PMC 3505:doi 3464:PMC 3456:doi 3415:PMC 3407:doi 3368:doi 3356:280 3323:doi 3319:281 3284:doi 3239:hdl 3231:doi 3227:137 3195:doi 3191:140 3150:doi 3146:130 3109:PMC 3101:doi 3089:456 3051:PMC 3043:doi 3039:181 2996:doi 2984:442 2950:doi 2946:178 2909:PMC 2901:doi 2862:doi 2825:PMC 2817:doi 2813:200 2769:PMC 2759:doi 2712:doi 2667:doi 2617:doi 2580:doi 2533:doi 2521:421 2480:hdl 2472:doi 2460:330 2424:PMC 2416:doi 2412:119 2372:PMC 2364:doi 2323:PMC 2315:doi 2273:doi 2233:PMC 2225:doi 2221:584 2175:doi 2163:336 2132:doi 2128:134 2097:doi 2093:136 2060:PMC 2052:doi 2009:doi 2005:119 1966:doi 1928:doi 1887:PMC 1879:doi 1875:105 1840:doi 1836:144 1803:PMC 1785:doi 1741:PMC 1733:doi 1692:doi 1649:doi 1612:doi 1568:PMC 1560:doi 1519:doi 1472:doi 1435:PMC 1427:doi 1380:doi 1376:102 1340:PMC 1264:doi 1216:doi 1204:268 1134:doi 862:.) 822:ATM 810:MRN 791:AFP 553:AFP 485:ATM 441:ATM 240:). 122:ATM 45:or 39:A–T 37:or 6927:: 6738:: 6696:: 5871:SA 5378:OA 5373:HD 5322:PD 5112:: 5101:: 5087:: 5076:: 5052:: 5041:: 5030:: 5019:: 5004:: 5001:10 4928:. 4918:. 4906:. 4902:. 4879:. 4869:. 4855:. 4851:. 4827:. 4817:. 4809:. 4799:91 4797:. 4793:. 4781:^ 4767:. 4759:. 4747:. 4645:. 4635:. 4621:. 4617:. 4594:. 4584:. 4572:. 4568:. 4543:. 4518:. 4494:. 4470:. 4423:. 4413:. 4403:13 4401:. 4397:. 4374:. 4364:. 4350:. 4346:. 4323:. 4315:. 4303:. 4280:. 4270:. 4260:58 4258:. 4254:. 4231:. 4221:80 4219:. 4195:. 4183:. 4160:. 4150:. 4140:. 4128:. 4124:. 4097:. 4087:. 4075:. 4071:. 4048:. 4038:. 4028:16 4026:. 4022:. 3999:. 3989:. 3977:. 3973:. 3950:. 3940:. 3930:18 3928:. 3924:. 3901:. 3891:. 3881:19 3879:. 3875:. 3852:. 3842:. 3832:25 3830:. 3826:. 3803:. 3793:. 3783:13 3781:. 3777:. 3754:. 3744:. 3734:21 3732:. 3728:. 3705:. 3693:. 3670:. 3660:. 3650:30 3648:. 3644:. 3621:. 3611:. 3601:. 3589:. 3585:. 3562:. 3550:18 3548:. 3544:. 3521:. 3511:. 3501:28 3499:. 3495:. 3472:. 3462:. 3452:10 3450:. 3446:. 3423:. 3413:. 3403:21 3401:. 3397:. 3374:. 3366:. 3354:. 3331:. 3317:. 3313:. 3290:. 3280:11 3278:. 3255:. 3247:. 3237:. 3225:. 3201:. 3189:. 3166:. 3158:. 3144:. 3140:. 3117:. 3107:. 3099:. 3087:. 3083:. 3059:. 3049:. 3037:. 3033:. 3010:. 3002:. 2994:. 2982:. 2958:. 2944:. 2940:. 2917:. 2907:. 2897:34 2895:. 2891:. 2868:. 2856:. 2833:. 2823:. 2811:. 2807:. 2777:. 2767:. 2753:. 2749:. 2726:. 2718:. 2708:17 2706:. 2683:. 2675:. 2663:86 2661:. 2657:. 2645:^ 2631:. 2623:. 2611:. 2588:. 2574:. 2570:. 2547:. 2539:. 2531:. 2519:. 2496:. 2488:. 2478:. 2470:. 2458:. 2446:^ 2432:. 2422:. 2410:. 2406:. 2394:^ 2380:. 2370:. 2358:. 2354:. 2331:. 2321:. 2311:26 2309:. 2305:. 2293:^ 2279:. 2267:. 2255:^ 2241:. 2231:. 2219:. 2215:. 2203:^ 2189:. 2181:. 2173:. 2161:. 2138:. 2126:. 2103:. 2091:. 2068:. 2058:. 2048:45 2046:. 2042:. 2029:^ 2015:. 2003:. 1980:. 1972:. 1962:38 1960:. 1936:. 1924:97 1922:. 1918:. 1895:. 1885:. 1873:. 1869:. 1846:. 1834:. 1811:. 1801:. 1793:. 1781:11 1779:. 1775:. 1763:^ 1749:. 1739:. 1729:35 1727:. 1723:. 1700:. 1686:. 1663:. 1655:. 1645:54 1643:. 1620:. 1606:. 1602:. 1590:^ 1576:. 1566:. 1554:. 1550:. 1527:. 1515:56 1513:. 1509:. 1486:. 1478:. 1466:. 1443:. 1433:. 1423:62 1421:. 1417:. 1394:. 1386:. 1374:. 1362:^ 1348:. 1336:39 1334:. 1330:. 1318:^ 1302:. 1280:. 1270:. 1262:. 1258:: 1256:83 1254:. 1250:. 1236:^ 1222:. 1214:. 1202:. 1187:^ 1171:19 1169:. 1148:}} 1144:{{ 1128:. 1075:. 1067:, 1063:, 1059:, 1022:. 912:. 793:. 116:. 92:, 35:AT 6887:/ 6809:/ 6778:/ 6686:e 6679:t 6672:v 6620:/ 6614:) 6610:/ 6606:( 6571:: 6490:) 6488:1 6486:( 6470:) 6461:( 6455:) 6451:( 6446:: 6436:) 6434:T 6432:( 6385:) 6383:5 6378:4 6373:3 6368:2 6363:1 6361:( 6305:) 6303:B 6301:( 6296:/ 6261:e 6254:t 6247:v 6137:) 6133:( 6079:e 6072:t 6065:v 5523:/ 5278:/ 5149:e 5142:t 5135:v 5014:- 4999:- 4989:D 4936:. 4914:: 4887:. 4863:: 4857:9 4835:. 4805:: 4775:. 4755:: 4732:. 4653:. 4629:: 4623:3 4602:. 4580:: 4553:. 4528:. 4504:. 4480:. 4456:. 4431:. 4409:: 4382:. 4358:: 4352:6 4331:. 4319:: 4311:: 4288:. 4266:: 4239:. 4227:: 4203:. 4191:: 4168:. 4144:: 4136:: 4130:6 4105:. 4083:: 4056:. 4034:: 4007:. 3985:: 3958:. 3936:: 3909:. 3887:: 3860:. 3838:: 3811:. 3789:: 3762:. 3740:: 3713:. 3701:: 3695:7 3678:. 3656:: 3629:. 3605:: 3597:: 3570:. 3556:: 3529:. 3507:: 3480:. 3458:: 3431:. 3409:: 3382:. 3370:: 3362:: 3339:. 3325:: 3298:. 3286:: 3263:. 3241:: 3233:: 3209:. 3197:: 3174:. 3152:: 3125:. 3103:: 3095:: 3067:. 3045:: 3018:. 2998:: 2990:: 2966:. 2952:: 2925:. 2903:: 2876:. 2864:: 2858:5 2841:. 2819:: 2785:. 2761:: 2755:4 2734:. 2714:: 2691:. 2669:: 2639:. 2619:: 2613:3 2596:. 2582:: 2576:7 2555:. 2535:: 2527:: 2504:. 2482:: 2474:: 2466:: 2440:. 2418:: 2388:. 2366:: 2360:6 2339:. 2317:: 2287:. 2275:: 2269:3 2249:. 2227:: 2197:. 2177:: 2169:: 2146:. 2134:: 2111:. 2099:: 2076:. 2054:: 2023:. 2011:: 1988:. 1968:: 1944:. 1930:: 1903:. 1881:: 1854:. 1842:: 1819:. 1787:: 1757:. 1735:: 1708:. 1694:: 1671:. 1651:: 1628:. 1614:: 1608:5 1584:. 1562:: 1556:8 1535:. 1521:: 1494:. 1474:: 1451:. 1429:: 1402:. 1382:: 1356:. 1312:. 1288:. 1266:: 1230:. 1218:: 1210:: 1181:. 1154:) 1136:: 1130:4 1047:( 171:) 33:( 20:)

Text is available under the Creative Commons Attribution-ShareAlike License. Additional terms may apply.

Index