(Louis-Bar Syndrome, AT Syndrome, Boder-Sedgwick Syndrome)

BASICS


DESCRIPTION


• Ataxia-telangiectasia (AT) is a multisystem neurodegenerative and immunodeficiency disorder characterized by cerebellar dysfunction, telangiectasias, immune dysfunction of both B- and T-lymphocytes, radiosensitivity, and lymphoproliferative cancer.


– Neurodegeneration/cerebellar atrophy results in profound loss of cerebellar function, oculomotor apraxia, progressive dysarthria, and choreoathetoid movements.


– Immune dysfunction results in recurrent sinopulmonary infections.


EPIDEMIOLOGY


Incidence


Varies by region, in the United States, the highest annual incidence was found to be 11.3 per million in Michigan. In England, the birth frequency has been estimated to be 1 in 300,000 live births.


Prevalence


• Varies by region, in the United States, the estimated prevalence of AT is from 1 in 40,000 to 100,000. In France, the prevalence of AT has been estimated to be 1 in 450,000.


• AT is the most common autosomal recessive ataxic disorder in children <5 years (1)[C].


RISK FACTORS


Genetics


• Autosomal recessive


• The ATM (ataxia-telangiectasia, mutated) gene is localized to 11q22–q23.


• Males and females are equally affected.


GENERAL PREVENTION


• Genetic counseling


• Early diagnosis and referral to appropriate specialists, including neurologists, ophthalmologists, infectious disease specialists, and physical therapists


PATHOPHYSIOLOGY


AT primarily involves severe degeneration of Purkinje fibers in the cerebellar and extrapyramidal areas of the central nervous system; however, the basket and granular cells of the cerebellar cortex may also be involved. Other pathophysiologic changes include diffuse fibrillary gliosis and the degeneration of the anterior horns of the spinal cord.


ETIOLOGY


• Over 400 mutations have been identified in the ATM gene in patients with AT.


– ATM encodes a protein kinase involved in the biochemical cascade that responds to DNA damage and is required for immune maturation and telomere maintenance.


COMMONLY ASSOCIATED CONDITIONS


• Recurrent sinopulmonary infections


• Lymphomas, leukemias


• Thymic dysplasia


DIAGNOSIS


HISTORY


• Abnormal eye movements (nearly 100%)


• Any episodes of recurrent sinopulmonary infections (48–81%)


• Growth retardation


• Difficulty walking, problems with balance (ataxia) (nearly 100%)


• Abnormal speech


• Choreoathetoid movements (30–90%)


• Abnormal blood vessels on the eyes or skin noticed by the parents


PHYSICAL EXAM


• Clinical diagnosis becomes most apparent after the age of 10 years when most children require a wheelchair, but can be detected in patients <5 years and as early as 3 months.


• Telangiectasias – the interpalpebral bulbar conjunctiva away from the limbus is the most common initial location of telangiectases, appearing at the age of 3–7. Eventually, the telangiectases can involve the entire conjunctiva, resembling conjunctivitis, and can spread to involve malar and orbital, auricular, antecubital and popliteal skin. Classically, these do not hemorrhage (2)[C].


• Positive oculomotor apraxia – slow, hypometric saccades with head-thrusting (1)


• Often abnormalities exist with the optokinetic nystagmus drum.


• Visual acuity (unless there is severe nystagmus), pupillary reflexes, and fundus appearance are usually normal.


• Ataxia can be observed in infancy, as soon as the child is able to walk.


• Stooped position


• Intention tremors that increase with age


• Romberg sign is classically negative because truncal movement is equally pronounced with eyes open or closed.


• Sensation is intact. This finding coupled with the negative Romberg differentiates it from Friedrich’s ataxia, which usually presents later in childhood.


• Other signs include premature gray hairs, mask-like faces, inelastic ears, a single café-au-lait spot, large freckles, vitiligo, seborrheic dermatitis, and common warts.


DIAGNOSTIC TESTS & INTERPRETATION


Lab


• More than 95% of AT children have an elevated blood alpha-fetoprotein (AFP) level. Although false positives are rare, in patients <2 years, AFP may be elevated because of the neonatal period (AFP is normally elevated in the pregnant mother) (1)[C].


• Karyotyping – translocations of chromosomes 7 and 14 are common (4)[C].


• Serum immunoglobulin testing reveals deficiencies of IgG2, IgE, and/or IgA.


• Less common – increased sensitivity of colony survival assays to ionizing radiation (5)[C], Western blots to confirm the presence of intracellular ATM protein, protein truncation testing of DNA complementary to the ATM gene is gaining popularity as a fast screening tool (1)[C].


Imaging


• MRI often shows cerebellar atrophy and enlargement of the fourth ventricle, which typically increases with age (3,4)[C].


• Chest radiographs will demonstrate minimal or absent thymic shadow, and changes that may be consistent with cystic fibrosis (1).


• In addition, absent or reduced adenoidal tissue in any area is so common on radiography that the presence of clinical lymphadenopathy is considered suggestive of lymphoma.


Pathological Findings


AT primarily involves severe degeneration of Purkinje fibers in the cerebellar and extrapyramidal areas of the central nervous system; however, the basket and granular cells of the cerebellar cortex may also be involved. Other pathophysiologic changes include diffuse fibrillary gliosis and the degeneration of the anterior horns of the spinal cord.


DIFFERENTIAL DIAGNOSIS


• Friedrich’s ataxia


• Cerebral palsy (cerebellar type)


• Familial spinocerebellar atrophies


• GM1 and GM2 gangliosidoses


• Metachromatic leukodystrophy


• Krabbe disease


• Maple syrup urine disease


• Progressive rubella panencephalitis


• Subacute sclerosing panencephalitis


• Postinfectious encephalomyelitis


• Encephalitis


• Other polyneuropathies


• Cerebellar tumor


TREATMENT


MEDICATION


• Appropriate antibiotic treatment for recurrent sinopulmonary infections; this treatment should be directed by the infectious disease specialist.


• Periodic administration of immunoglobulin replacement has been reported beneficial for patients with difficulty with vaccine responses. Refer to immunologist, infectious disease.


• No adequate treatment for the neurologic or ophthalmic manifestations has been found.


• Regular surveillance for leukemic or lymphoid malignancies must be observed.


ADDITIONAL TREATMENT


General Measures


• Children will eventually need full-time classroom aides for help with reading.


• Physical therapists and aides are also important for preventing muscle stiffness and position-related issues.


• Parents and guardians should be coached to recognize early signs of pulmonary or respiratory infection.


SURGERY/OTHER PROCEDURES


Muscle surgery if there is a strabismus or nystagmus causing problems with primary gaze or head tilt in primary gaze


ONGOING CARE


FOLLOW-UP RECOMMENDATIONS


• Neurologist to assess progression of ataxia, dysarthria, choreoathetoid movements


• Immunologist to monitor immune dysfunction


• Pulmonologist to monitor for infection


• Ophthalmologist to assess nystagmus and oculomotor apraxia, as well as to follow the conjunctival and palpebral telangiectasias


• Hematologist/oncologist for malignancy


DIET


No nutritional supplement has been shown to have a benefit.


PATIENT EDUCATION


• See “General Measures” and “Follow-up Recommendations


www.nlm.nih.gov/medlineplus/ency/article/001394.htm


www.nlm.nih.gov/medlineplus/ataxiatelangiectasia.html


PROGNOSIS


• Death is most commonly caused by a recurrent sinopulmonary infection, and most commonly occurs in adolescents, although the life expectancy is quite variable and some have survived to middle age.


• Other common causes of death include malignancy, or a combination of malignancy and infection.



REFERENCES


1. Perlman S, Becker-Catania S, Gatti R. Ataxia-telangiectasia: Diagnosis and treatment. Semin Pediatr Neurol 2003;10:173–182.


2. Morrell D, Cromartie E, Swift M. Mortality and cancer incidence in 263 patients with ataxia-telangiectasia. J Natl Cancer Inst 1986;77(1):89–92.


3. Tavani F, Zimmerman RA, Berry GT, et al. Ataxia-telangiectasia: The pattern of cerebellar atrophy on MRI. Neuroradiology 2003;45(5):315–319.


4. Lavin MF, Gueven N, Bottle S, et al. Current and potential therapeutic strategies for the treatment of ataxia-telangiectasia. Br Med Bull 2007;81–82:129–147.


5. Beamish H, Lavin MF. Radiosensitivity in ataxia-telangiectasia: Anomalies in radiation-induced cell cycle delay. Int J Radiat Biol 1994;65(2):175–184.

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Nov 9, 2016 | Posted by in OPHTHALMOLOGY | Comments Off on (Louis-Bar Syndrome, AT Syndrome, Boder-Sedgwick Syndrome)
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