History

Fact Explanation
Introduction to the disease Ataxia telangiectasia (A-T) is autosomal recessively inherited progressive neurological disorder resulted due to cerebellar degeneration. It is usually found by the age of 2 years.[2].There are classic form of A-T as well as non classic forms of Ataxia-Telangiectasia.[1]. Diagnosis criteria of A-T include ataxia or significant motor incoordination with raised alpha fetoprotein (AFP) (>2x) and at least 3 of the following four characteristic clinical features.They are Incoordination of head and eyes in lateral gaze deflection,gait ataxia associated with an inappropriately narrow-base,ocular telangiectasia and Immunoglobulin deficiencies [3].
Progressive gait and truncal ataxia It is the primary manifestation of classic A-T and the age of onset between 1 to 4 years. It occurs due to cerebellar degeneration. Children with A-T begin to stagger, shortly after they learnt to walk. The ataxia initialy begins as purely truncal but later on, within several years peripheral coordination also get involved. Due to progressive nature children will confined to a wheelchair by the age of 10 years.[1] Affected children have a peculiar gait like “little clowns” which is highly suggestive of A-T.[3].
Oculocutaneous telangiectasia Telangiectasia is a second major clinical manifestation of the disease and it has a later onset than ataxia.[4].These are dilated vessels usually found at corners of eyes as well as on the surface of the ears and cheeks which usually exposed to sunlight. The underline mechanism of telangiectasia is not clear. However they are found after the age of 3-6 years and sometimes not notice until adolescence .[3]. Telangiectasia can seen in different parts of the body, but most noticeable in bulbar conjunctiva. [2].
Slurred speech Slurred speech is also found in early stage of the disease.[1]. Occurs due to involvement of cerebellum.[5].
Poor head control Poor control of head and torso is identified By the end of first decade.[4]. Head tilt occurs due to defect in the vermal zone of the cerebellum.[5]
Difficulty in swallowing Swallowing is not well coordinated in affected individuals. They need others help for eating. Aspiration of food can be occur.[1].
Learning difficulties Intelligence is found to be normal but learning difficulties are common. Individuals may face difficulty in completing timed IQ tests due to low motor and verbal responses.[1].
Frequent infections The spectrum of infection in classic A-T doesn't include opportunistic infections. The frequency as well as severity of infections are found to be correlates with patients general nutritional status than with the immune status. Chronic bronchiectasis seen in patients with classic A-T.[1]. There is an increase risk for lower respiratory tract infections with age mostly due to aspiration of food as a result of impaired swallowing as well as deficient cough reflex.[2].
Growth retardation It is frequently detected in affected individuals. [2]. Premature aging can also detect in some patients.[1].
Immunodeficiency Serum and cellular immunodeficiencies can be seen. It seen among 60% to 80% of individuals. Serum concentration of immunoglobulins including IgA, IgE, and IgG2 may be reduced. T-cell deficiencies found in 30% of affected patients with classic AT. Immunodeficiency is non progressive.[1].
Thymic dysplasia Absence or dysplasia of thymus gland is found in some patients.[3].
Risk of malignancy The risk of developing cancer in a classic AT patient is approximately 38%. Leukemia and lymphoma are found to be responsible for about 85% of malignancies. Acute lymphocytic leukemia (ALL) of T-cell origin seen among young children and aggressive T-cell leukemia can occur in older children. Lymphomas are usually B-cell types. Ovarian c, breast , and gastric cancers, as well as melanoma, leiomyomas, and sarcomas are also reported in affected individuals.[1].
Drooling Drooling of saliva is commonly found in A-T patients.[1].
Endocrine abnormality Endocrine abnormalities seen in some patients, such as insulin resistant diabetes mellitus.[1].
Early death They have decreased life span.But somehow recently their life expectancy have been increased. Most affected individuals may live beyond 25 years and some have survived up to 50 years. Pulmonary failure, and infections are found to be major causative factors for death where some may develop life threatening lymphocytic infiltration of the lung.[1].
References
  1. GATTI R, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Ataxia-Telangiectasia [online] 1993 [viewed 22 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301790
  2. TAYLOR AM, BYRD PJ. Molecular pathology of ataxia telangiectasia J Clin Pathol [online] 2005 Oct, 58(10):1009-1015 [viewed 22 September 2014] Available from: doi:10.1136/jcp.2005.026062
  3. SESHACHALAM A, CYRIAC S, REDDY N, GNANA ST. Ataxia telangiectasia: Family management Indian J Hum Genet [online] 2010, 16(1):39-42 [viewed 22 September 2014] Available from: doi:10.4103/0971-6866.64940
  4. LAVIN M. F., GUEVEN N., BOTTLE S., GATTI R. A.. Current and potential therapeutic strategies for the treatment of ataxia-telangiectasia. British Medical Bulletin [online] 2007 February, 81-82(1):129-147 [viewed 22 September 2014] Available from: doi:10.1093/bmb/ldm012
  5. MARMOLINO D, MANTO M. Past, Present and Future Therapeutics for Cerebellar Ataxias Curr Neuropharmacol [online] 2010 Mar, 8(1):41-61 [viewed 22 September 2014] Available from: doi:10.2174/157015910790909476

Examination

Fact Explanation
Oculomotor apraxia It means inability to follow an object across visual fields. Also identified in early stage of the disease. Here the both horizontal and vertical saccadic eye movements are get affected.[1].
Absent or decreased tendon reflexes Deep tendon reflexes are found to be decreased or absent in older individuals. Up going or absent plantar reflexes can be identified. [1].
Myoclonic jerking and intention tremors About 25% of individuals may reported to have myoclonic jerking and intention tremors.[1]. kinetic tremor occurs due to defect in the lateral zone of the cerebellum.[3].
Contractures Even though the muscle strength is normal at first, it wanes with disuse, specially in the legs. This will cause formation of contractures commonly in the fingers and toes in older individuals.[1].
Dystonia Dystonia also found in affected individuals.[2]. It is a manifestation of extra pyramidal deficits.[3].
Choreoathetosis They are writhing movements that found in almost all patients with A-T.[1].Choreiform movements commonly seen in hands and feet.[4].
References
  1. GATTI R, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Ataxia-Telangiectasia [online] 1993 [viewed 22 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301790
  2. SESHACHALAM A, CYRIAC S, REDDY N, GNANA ST. Ataxia telangiectasia: Family management Indian J Hum Genet [online] 2010, 16(1):39-42 [viewed 22 September 2014] Available from: doi:10.4103/0971-6866.64940
  3. MARMOLINO D, MANTO M. Past, Present and Future Therapeutics for Cerebellar Ataxias Curr Neuropharmacol [online] 2010 Mar, 8(1):41-61 [viewed 22 September 2014] Available from: doi:10.2174/157015910790909476
  4. LAVIN M. F., GUEVEN N., BOTTLE S., GATTI R. A.. Current and potential therapeutic strategies for the treatment of ataxia-telangiectasia. British Medical Bulletin [online] 2007 February, 81-82(1):129-147 [viewed 23 September 2014] Available from: doi:10.1093/bmb/ldm012

Differential Diagnoses

Fact Explanation
Cerebral palsy (CP) It is difficult to diagnose A-T in young children because all characteristic features are not found in that age. So it is commonly misdiagnose with cerebral palsy.[2]. CP is a neurodevelopmental disorder of movement and posture. It is a non progressive disorder which occurs in early life. It is characterized by the presence of pyramidal as well as extra pyramidal signs and symptoms.There are several types of CP depending on motor symptoms such as diplegia, tetraplegia, hemiplegia, dyskinesia, and ataxia.Even there is profound hypotonia detected in CP there is no apparent muscle weakness. Splasticity can be seen. Dystonia and involuntary movements can be seen but not common. Ataxia is difficult to recognise in the early life life. It may initially present with profound truncal hypotonia and delay in achieving fine and gross motor milestones.Bulbar symptoms and oromotor dysfunction, features such as speech and feeding difficulties may also associated with CP.[7].
Nijmegen breakage syndrome (NBS) It is caused by mutation of the NBS1 gene. Both NBS and A-T show similar features at the cellular level. Both of them show increased sensitivity to radiation. However Clinical overlap, between A-T and NBS is only partial including immunodeficiency and increased risk of lymphoid malignancies. B cell tumours predominantly found in patients with NBS. Patients with NBS develop microcephaly and borderline mental retardation.Cerebellar degeneration or telangiectasia are not seen in these patients.[1].
Ataxia oculomotor apraxia 1 It is characterized by childhood onset of slowly progressive cerebellar ataxia, severe primary motor peripheral axonal motor neuropathy and oculomotor apraxia. Dysarthria, upper-limb dysmetria and mild intention tremor also can be seen.[3].Neurologically, patients with Ataxia oculomotor apraxia 1 are almost identical to patients with A-T. But these patients do not develop immunodeficiency, abnormal chromosome translocations in the peripheral blood,raised concentrations of serum AFP, or cancer predisposition like non neurological features.[1].
Ataxia oculomotor apraxia 2 The mean age of onset of the cerebellar ataxia is about 15 years. [1].Elevated serum concentration of alpha-fetoprotein (AFP),cerebellar atrophy, axonal sensorimotor neuropathy and oculomotor apraxia, can be seen.[4].
Spinocerebellar ataxia with axonal neuropathy Extremely rare disorder. It is caused by mutation of the DNA repair protein tyrosyl DNA phosphodiesterase 1. Onset usually begins at teenage and associated with moderate ataxia and mild dysarthria but they do not develop abnormal eye movements.[1].
X-Linked Sideroblastic Anemia and Ataxia It is characterized by moderate anemia and early onset spinocerebellar syndrome in males. In early childhood they may develop delayed walking and ataxia. Dysmetria, and dysdiadochokinesis can also be found. They may also develop dysarthria and mild intention tremors.Brisk deep tendon reflexes, equivocal or extensor plantar responses and unsustained ankle clonus like UMN signs present in some affected individuals. Strabismus and nystagmus are two other features that can be seen in affected individuals.[5].
Friedreich’s ataxia (FRDA) It is a severe neurodegenerative disorder that occurs due to pathological GAA triplet expansion within the first intron of the FXN gene. Gait and limb ataxia, dysarthria, proprioceptive loss, areflexia, ,and Babinski sign are the commonly found clinical signs and symptoms. They may prone to develop cardiomyopathy and diabetes mellitus.[6].
References
  1. TAYLOR AM, BYRD PJ. Molecular pathology of ataxia telangiectasia J Clin Pathol [online] 2005 Oct, 58(10):1009-1015 [viewed 22 September 2014] Available from: doi:10.1136/jcp.2005.026062
  2. GATTI R, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Ataxia-Telangiectasia [online] 1993 [viewed 22 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301790
  3. COUTINHO P, BARBOT C, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Ataxia with Oculomotor Apraxia Type 1 [online] 1993 [viewed 22 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301629
  4. MOREIRA MC, KOENIG M, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Ataxia with Oculomotor Apraxia Type 2 [online] 1993 [viewed 22 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301333
  5. BEKRI S, D’HOOGHE M, VERMEERSCH P, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. X-Linked Sideroblastic Anemia and Ataxia [online] 1993 [viewed 22 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301496
  6. MARMOLINO D, MANTO M. Past, Present and Future Therapeutics for Cerebellar Ataxias Curr Neuropharmacol [online] 2010 Mar, 8(1):41-61 [viewed 22 September 2014] Available from: doi:10.2174/157015910790909476
  7. GUPTA R, APPLETON R. Cerebral palsy: not always what it seems Arch Dis Child [online] 2001 Nov, 85(5):356-360 [viewed 23 September 2014] Available from: doi:10.1136/adc.85.5.356

Investigations - for Diagnosis

Fact Explanation
Serum concentration of alpha-fetoprotein (AFP). Diagnosis is established with the help of characteristic clinical symptoms as well as laboratory investigation findings.Serum AFP concentration is found to be elevated above 10 ng/mL in more than 95% of individuals with A-T. However serum AFP levels may remain above normal in unaffected children up to the age of 2 years.[1].
Immunoblotting for ATM protein This test is the most sensitive and specific clinical test to establish the diagnosis of A-T. Intracellular ATM protein level is found to be severely depleted in affected individuals. But this needs further validation.[1].
Radiosensitivity assay The colony survival assay (CSA) is an in vitro assay. It is carried out to determine the survival of patient derived lymphoblastoid cells following irradiation with 1.0 Gy. Increased sensitivity of cells to radiation exposure can be seen in affected individuals.[1].
ATM serine/threonine kinase activity. Immunoblotting of cell lysates and commercial antibodies to many phosphorylated ATM target substrates such as p53-serine15 are the procedures that performed to assess ATM serine/threonine kinase activity. Cells are first irradiated and evaluated after 30 minutes. ATM serine/threonine kinase activity is found to be undetectable in all cases where ATM protein levels are undetectable.[1].
Serum immunoglobulin assay Impaired immunological status is a feature of almost all AT patients.Serum IgA and IgE levels may be decreased or absent. 50-80% of affected individuals show selective IgA deficiency.IgG4 subclass levels reduced in some individuals.[2].
MRI brain It will show a small cerebellum,/ cerebellar atrophy.However it is not usually apparent in young children.[1],[3].
Chromosome analysis. 5%-15% of peripheral blood cells in A-T patients show chromosome translocation. The break points are commonly at 14q11 and 14q32.[1].
Molecular Genetic Testing ATM gene is the only gene known to be associated with ataxia-telangiectasia. Molecular genetic testing reveals mutations in ATM gene, greater than 99% of individuals with classic A-T.[1].
References
  1. GATTI R, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Ataxia-Telangiectasia [online] 1993 [viewed 23 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301790
  2. SHARMA A, BUXI G, YADAV R, KOHLI A. Ataxia telangiectasia: A report of two cousins and review of literature Indian J Med Paediatr Oncol [online] 2011, 32(4):217-222 [viewed 23 September 2014] Available from: doi:10.4103/0971-5851.95145
  3. SESHACHALAM A, CYRIAC S, REDDY N, GNANA ST. Ataxia telangiectasia: Family management Indian J Hum Genet [online] 2010, 16(1):39-42 [viewed 23 September 2014] Available from: doi:10.4103/0971-6866.64940

Investigations - Fitness for Management

Fact Explanation
Full blood count FBC with differential count is performed as a baseline investigation for screening for leukemia.[1].
Chest x-ray and pulmonary function Since A-T patients prone to develop recurrent lower respiratory tract infections baseline Chest x-ray and pulmonary function test should be performed.[1].
Fasting blood glucose concentration and Hgb A1C Urinalysis, fasting blood glucose concentration and Hgb A1C levels used as diabetes screening tests since A-T patients may develop endocrine abnormalities such as insulin resistant diabetes mellitus.[1].
References
  1. GATTI R, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Ataxia-Telangiectasia [online] 1993 [viewed 23 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301790

Investigations - Followup

Fact Explanation
CEA and AFP levels A-T patients tend to develop variety of cancers. They tend to have elevated AFP and CEA, which are tumor markers. Changes in these tumor markers levels can be used to early cancer detection during follow-up.[1].
Serum immunoglobulin levels Has to assess during follow up because affected individuals prone to get immunodeficiency as well as recurrent infections.[2].
References
  1. SESHACHALAM A, CYRIAC S, REDDY N, GNANA ST. Ataxia telangiectasia: Family management Indian J Hum Genet [online] 2010, 16(1):39-42 [viewed 23 September 2014] Available from: doi:10.4103/0971-6866.64940
  2. GATTI R, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Ataxia-Telangiectasia [online] 1993 [viewed 23 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301790

Investigations - Screening/Staging

Fact Explanation
Amniocentesis or chorionic villus sampling Performed in prenatal diagnosis in pregnancies.Analysis of DNA extracted from fetal cells is carried out Those DNA is extracted either by amniocentesis performed around ~15-18 weeks’ gestation or chorionic villus sampling performed around ~10-12 weeks’ gestation.[1].
References
  1. GATTI R, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Ataxia-Telangiectasia [online] 1993 [viewed 23 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301790

Management - General Measures

Fact Explanation
Physiotheraphy Carried out to minimize contractures. Early and continued physical therapy is useful in minimizing development of contractures thereby improving quality of life. And also prolonged time in a wheelchair may leads to serious complications such as scoliosis. It can prevent by aggressive physical therapy.[1].
Aggressive pulmonary hygiene Useful in patients with chronic bronchiectasis .[1]. Pulmonary infections well respond to antibiotics.[2].
Treatment for dysfunctional swallowing and aspiration Thickeners to thin liquids and in case of severe malnutrition,the placement of a gastroscopy tube can use to facilitate feeding.[2].
Reduce the intensity of radiotherapy and dosage of radiomimetic chemotherapy A-T patients are hypersensitive to ionizing radiation. These measures are carried out to minimize tissue damage in patients while retaining effectiveness of treatment of the tumor. Some chemotherapeutic agents are better to be avoid. Cyclophosphamide may cause haemorrhagic cystitis and gastrointestinal toxicity may caused by methotrexate.[2].
Genetic councelling It is "the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions." Since this is a autosomal recessively inherited disease genetic counselling is a must. Family members and patient should educate about the carrier detection methods as well as the family planing methods.[1].
Proper counselling, patient and family education. Once diagnosis is established proper counselling should be carried out by the doctor with the explanation of nature of the disease, life expectancy and complications. Educate them well regarding the malignancy and infection risk and there by importance of proper follow up. Tell the family members that patient can not do their day today works alone and they may need family members helping hand. Tell them that patient may need a wheelchair probably at the age of 10 years.[1].
References
  1. GATTI R, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Ataxia-Telangiectasia [online] 1993 [viewed 23 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301790
  2. LAVIN M. F., GUEVEN N., BOTTLE S., GATTI R. A.. Current and potential therapeutic strategies for the treatment of ataxia-telangiectasia. British Medical Bulletin [online] 2007 February, 81-82(1):129-147 [viewed 23 September 2014] Available from: doi:10.1093/bmb/ldm012

Management - Specific Treatments

Fact Explanation
IV immunoglobulin replacement therapy It should be carried out in patients with frequent and severe infections and also who have a very low IgG levels.[2].
L-DOPA derivatives, dopamine agonists and, anticholinergics Slight improvement of neurological symptoms and basal ganglia dysfunction in respond to these treatments can be seen. Anticholinergics may useful in reducing drooling.[1].
Amantadine and fluoxetine The loss of balance may respond to amantadine, buspiron or fluoxetine like antidepressant agents. These drugs may also found to improve speech and coordination.[1].
Beta blockers Propanalol like beta blockers useful to control tremors.[1].
Steroids Recent studies have showed short-term improvement in ataxia can be seen after treat with steroids but tends to reappear within days of their discontinuation. However its side effect profile overcomes this short term benefit.[1],[2].
References
  1. LAVIN M. F., GUEVEN N., BOTTLE S., GATTI R. A.. Current and potential therapeutic strategies for the treatment of ataxia-telangiectasia. British Medical Bulletin [online] 2007 February, 81-82(1):129-147 [viewed 23 September 2014] Available from: doi:10.1093/bmb/ldm012
  2. GATTI R, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Ataxia-Telangiectasia [online] 1993 [viewed 23 September 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301790