Ataxia telangiectasia

Author(s): Vikki A. Stefans, MD

Originally published:04/12/2013

Last updated:08/22/2016

1. DISEASE/DISORDER:

Definition

Ataxia telangiectasia (AT) is an autosomal recessive, multisystem disorder caused by homozygous or compound heterozygous mutations of the ATM (ataxia telangiectasia mutated) gene which codes for a phosphatidylinositol 3-kinase that responds to cellular DNA damage. It is characterized by progressive neurodegeneration particularly in the cerebellum, with ataxia, oculomotor apraxia, dysarthria, dysphagia, dystonia, movement disorder, immunodeficiency, predisposition to various cancers, recurrent sinopulmonary infections, and progeroid symptoms, typically but not always including telangiectasias.

Etiology

The ATM gene maps to chromosome region 11q22.3 and its protein product is normally expressed in all tissues in the body. Its functions include:

  1. Response to deoxyribonucleic acid (DNA) damage and coordination of DNA repair, particularly double strand breaks due to ionizing radiation.
  2. Regulation of cell cycle and apoptosis and telomere maintenance.
  3. Response to oxidative stress.
  4. Mitochondrial homeostasis.
  5. Regulation of cellular protein turnover.1

Epidemiology including risk factors and primary prevention

The incidence is 1 in 100,000 with a carrier frequency of 1.4% to 2.0% with no predilection for any racial, sexual, economic, geographic, or educational group.2 The prevalence in the United States is about 1 in 40,000.3

Lifetime risk of cancer is 38%. In children, 85% of neoplasms are lymphomas and acute leukemias. In adults, solid tumors are more frequent. Immunodeficiency occurs in 70%. Choreoathetosis occurs in almost all patients.3 Sinopulmonary infections occur in more than 80% of patients.4Average lifespan was under 25 years but has been improving, and some individuals with later onset of disease and slower progression survive into their 50s.3

Primary prevention via genetic counseling and prenatal diagnosis is possible. Avoiding consanguinity reduces but does not eliminate risks of autosomal recessive diseases. There is a 25% recurrence risk for each child when both parents are carriers.3

Patho-anatomy/physiology

Patients with truncating or inactivating mutations (deletions, insertions, nonsense) in the ATM gene who have no functioning kinase cannot repair DNA damage and are severely radiosensitive. Mitochondrial DNA dysfunction is prominent and affects cerebellar, basal gangliar, and peripheral nerve function. Missense mutations tend to lead to a milder disease with later, even adult onset and more solid tumor than hematologic malignancy risk. The severity and progression rate vary even within affected families. 4

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

The first symptom is usually ataxic gait, seen soon after independent walking is achieved. In rare cases, dystonia may be the presenting symptom. From 0 to 5 years, recurrent sinopulmonary infections in those with immune deficiencies are common. Cerebellar atrophy on MRI may not be seen at this stage and telangiectasia may be minimal or absent.

By 5 to 15 years, increased falling and overt dysmetria are usually present, and oropharyngeal dysphagia, dysarthria, and oculocutaneous telangiectasias first notable in the bulbar conjunctivae usually develop. These can be seen on the face, neck, and other sun-exposed areas starting at 8-10 years. Oculomotor apraxia (irregular saccades with extraocular movement testing) is usually present by 10 years of age. Walker and wheelchair use, supplemental tube feedings, and academic modifications start to become necessary.

During the adolescent years, ataxia worsens and is accompanied by extrapyramidal symptoms including choreoathetosis, dystonia, tremor, reduced facial expression, bradykinesis and hyperkinesis, and sometimes spasticity. Acquired strabismus may be seen. Aspiration is increasingly common. Some, but not all, individuals experience progressive cognitive dysfunction and academic impairments. Lymphoblastic leukemia and lymphoma are the most common malignancies at this stage.

Beyond 15 years of age and into the third decade, there are also progressive central nervous system vascular abnormalities and the risks of solid tumors increase. Insulin-resistant pre-diabetes or diabetes may occur. Pulmonary restrictive disease with intersitial fibrosis may develop in addition to recurrent infections and bronchiectasis.

Specific secondary or associated conditions and complications

  1. Combined immunodeficiency with thymic dysplasia, decreased immunoglobulins, and reduction of T-lymphocytes is common but not universal.
  2. Recurrent sinopulmonary infections and bronchiectasis alone can lead to chronic pulmonary compromise, further complicated by progressive injury due to aspiration, and restrictive lung disease with interstitial fibrosis may develop.
  3. Cancer risks include acute lymphocytic leukemia, lymphoma, and solid tumors, with extreme sensitivity to chemotherapy and radiation therapies; these are not untreatable, but selection of agents used and dosages must be adjusted.
  4. Diabetes mellitus type 2 due to insulin resistance tends to develop in the third decade.

Somatic growth is slowed and limited with adult heights below the third percentile, and pubertal growth spurt and fertility may not occur due to hypogonadism. Both undernutrition and cellular protein turnover deficiencies may contribute. Hypopituitarism and/or hypothyroidism are not usually part of this condition.

2. ESSENTIALS OF ASSESSMENT

History

  1. Birth and early developmental history (usually normal)
  2. Frequent falls, clumsiness, gait abnormalities
  3. Frequently dropping things
  4. Inability to sit or stand still
  5. Uncontrolled eye or limb movements
  6. Frequent infections
  7. Family history will usually be negative; ask sensitively about consanguinity, other members with neurologic disorders that could be AT mimics, and cancer occurrence particularly in young adults.

Physical examination

  1. General: Small size, low weight .
  2. HEENT: Possible microcephaly, conjunctival telangiectasias (not before 3-5 years), small tonsils.
  3. Chest: abnormal breath sounds, congestion.
  4. Neurologic: Initially intact sensation and negative Romberg, but may later develop proprioceptive and vibratory loss. Look for truncal ataxia followed by dysmetria, dystonia especially in the hands and fingers, bradykinesia, facial and proximal hypotonia, choreoathetosis and myoclonic jerks on intention. After age 7-8 decreased or absent muscle stretch reflexes may be noted. Babinskis may eventually become upgoing, or mute.
  5. Ophthalmologic exam findings include oculomotor apraxia, slow hypometric saccades, head tilt, turn, or thrust, forced blinking, and absent optokinetic nystagmus. Strabismus may develop. Seborrheic blepharitis may be noted later.
  6. Orthopedic effects include equinovarus positioning with tight heel cords and postural kyphosis. Scoliosis is uncommon. Gait may show initial contact with whole foot, stomping, and leaning forward in running. Patients commonly cannot stay still when sitting or standing.
  7. Look for skin and hair progeric changes, such as gray hair and atrophic and inelastic skin, plus cutaneous telangiectasias, and sometimes hirsutism in women.

Functional assessment

Findings Seen in: First Decade Second Decade
Mobility Ambulates with walker

Ankle-foot orthoses: solid or articulated

Frequent falls

Wheelchair use more often; may need power chair depending on progression.
Self-care Uses utensils

Progressive oral and pharyngeal dysphagia

Assistance for dressing/toileting

May lose self-feeding and swallowing abilities; gastrostomy placement may be needed

Drooling

Dependent for most activities of daily living

Communication Speaks softly in sentences

Slow, with monotone, “scanning” dysarthria

Hypomimia (limited facial expression)

Fatigues with writing

Can communicate verbally but with severe fatigue

Poor respiratory control

May lose abilities to read and write

Social interaction Friendly, shy

Responsive, appreciative, undemanding

Good sense of humor

May be limited by severe fatigue

Cognition Slow information processing

Learns well auditorily

Measured IQ may decline

Short-term memory loss may

develop

 

Laboratory studies

Consider this diagnosis in cases of progressive ataxia or “ataxic cerebral palsy” that worsen or develop additional neurologic findings.

  1. Elevated serum alpha-fetoprotein >2 standard deviations above normal is a fairly specific screen for this condition. It is also seen in some of the other autosomal recessive ataxias such as ataxia with oculomotor apraxia.
  2. Molecular genetic testing for the specific trinucleotide expansion of Friedreich ataxia, serum albumin, cholesterol, very long chain fatty acids, ceruloplasmin and copper studies, lactate/pyruvate and coenzyme Q10 levels may be determined to look for other entities which may be in the differential diagnosis depending on presentation and neuroimaging.
  3. Definitive diagnosis is usually made by ATM gene sequencing.
  4. Immunoblotting for ATM protein, cell culture radiosensitivity, chromosomal studies for breakage and translocations often involving chromosomes 7 and 14 may be available in some centers.
  5. White blood cell analysis shows lymphopenia with prominent reduction in T-cells.
  6. Immunoglobulin analysis shows deficiencies of immunoglobulin E, immunoglobulin G subclass 2, and immunoglobulin A with some increases in IgM.

Imaging

Avoid x-rays whenever possible due to radiosensitivity.

Magnetic resonance imaging

  1. Early: normal.
  2. Later: progressive cerebellar atrophy; small scattered hypointensities suggestive of capillary telangiectasia and basal gangliar lesions may appear.15
  3. Second and third decades: marked extracerebellar hyperintense lesions in the cerebral white matter, pontine, and spinal atrophy.
  4. Increased choline signal intensity (magnetic resonance spectroscopy) in 12 adults.6

Early predictions of outcomes

Early diagnosis of AT is important for initiation of surveillance for cancer and prevention of ionizing radiation damage. There are over 600 variant mutations, and phenotype severity seems to vary with ATM protein levels; protein assays may become available to help predict prognosis;1,7 however analysis of the type of mutation and the predicted effect on the protein may suffice.

Environmental

Identify barriers to participation including stairs, door width, uneven terrain, loose rugs, counter height, bath and toilet equipment, and hand rails. Ask about environmental exposures that could increase the risk of various cancers.

Social role and social support system

Parents should be asked about the emotional and psychologic stresses of parenting a child with a degenerative disease and offered any assistance and support available in the community, as well as encouragement to connect with other families affected by this condition via online support groups.

Professional Issues

Heterozygotes with disease-causing mutations in ATM have a cancer risk 4 times that of the general population3 and are at risk for transmitting the mutation to their children.8 Do not overestimate cognitive decline based on facial expression and speech production.

3. REHABILITATION MANAGEMENT AND TREATMENTS

Available or current treatment guidelines

Genetic therapy for ATM is not available, no therapies significantly alter the course of the disease, and no specific treatment exists for the ataxic syndrome or the progressive neurodegeneration. However, cancer surveillance, nutritional support, and management of immunodeficiency may greatly improve health and well-being; rehabilitation therapies and management of other movement disorders and abnormal tome may promote better functional abilities.

Management includes:

  1. Preventing unnecessary deterioration, including promoting activity to preserve strength and endurance, and stretching to delay or reverse progressive deformities of the feet.
  2. Teaching compensatory strategies to decrease effects of ataxia, tremor, dysphagia, and dysarthria.
  3. Enabling academic participation and success.
  4. Monitoring for and managing cancer, pulmonary disease, and immune deficiencies.
  5. Minimizing use of x-rays and environmental exposure to ionizing radiation.

At home

  1. Bathroom: shower chair, toilet rails, tub bar, modified sinks for wheelchair access, mirror at eye level, bath mitt, liquid soap, urinal built-up handles, wider door frames, tiled floors, and wheelchair use at table and computer.
  2. Eating: weighted, large-handled utensils, bent-angled spoons, bowl with suction cup, sticky-type place mat to stabilize plates, and decrease hand to mouth distance with plate platform.
  3. Mobility: walker, gait trainer, manual chair with solid or slightly contoured seat and back, lateral trunk supports, headrest and forearm supports, and power chair when unable to propel.

At different disease stages

Preschool

  1. Permit whole-handed grasp of spoon.
  2. Finger foods and textures easy to self-feed.
  3. Electric toothbrush.
  4. Modify clothing to simplify dressing and toileting.
  5. Encourage truncal stabilization: arms close to body and elbows on table.
  6. Discourage unhelpful compensatory strategies.

School age

  1. Special education (Individual education program, IEP) and/or Section 504 evaluation should address cognitive, fine, gross motor, activities of daily living, speech and language, and modifications for academic testing to extend time limits and avoid fine motor function becoming the main determinant of grades or results.
  2. Serial neuropsychological evaluations.
  3. Teach child to recognize and communicate the need for increased time and fatigue.
  4. Less course work, shortened days, personal aide for safety, scribing notes, increased time for assignments, and computer use.
  5. Cultivate critical listening, auditory learning strategies, and oral testing.
  6. Communicate and give directions to follow with short key word phrases.
  7. Oral motor strengthening for eating, speech, and control of secretions.
  8. Breathing exercises to improve voice production.
  9. Continued exposure to vocabulary and semantic or phonemic cues to assist word finding.
  10. People with AT are able to communicate effectively throughout life and rarely need augmentative communication devices.

School

  1. Wrap-around desk that supports forearms.
  2. Slant board at 45° degrees for upper-extremity stability.
  3. Computer access with appropriate keyboard and mouse.
  4. Auditory feedback software such as IntelliTalk and Write:Outloud talking word processing
  5. Optical character recognition or screen reading software
  6. Resources:
  7. wordq.com or 800-726-7784
  8. Don Johnston, Inc. (800-999-4660) donjohnston.com
  9. texthelp.com
  10. Educational Resources (800-624-2926 or edresources.com)
  11. Fastrack (800-927-3936 or fastrack.com)
  12. Edmark (800-362-2890 or edmark.com)
  13. Recording for the Blind (800-221-4792)
  14. kurzweiledu.com.
  15. texthelp.com
  16. Other assistive technology (closingthegap.com)http://www.closingthegap.com)

Oropharyngeal dysphagia

  1. Modified barium swallow.
  2. Advance enteral feeds slowly after gastrostomy when needed for nutritional suport, and permit any oral intake still safely possible.

Preterminal or end of life care

  1. Noninvasive ventilation.
  2. Home-bound instruction.

Coordination of care

When possible, children are best served by interdisciplinary cooperation. The ideal team would include the following:

  1. Geneticist and genetic counselors aid in making the diagnosis and help with family planning issues.
  2. Physiatrists and neurologists to recommend and prescribe therapies, orthotics, assistive devices, durable medical equipment, and environmental modifications, therapeutic trials of medications to manage abnormal tone and movement.
  3. Developmental pediatrician and/or neuropsychologist to assess and recommend specific academic and/or behavioral school accommodations
  4. Physical therapist and occupational therapist: safety, energy efficiency, and appropriate physical independence.
  5. Speech language therapist: eating, drinking, and communication.
  6. Nutritionist
  7. Immunologist: gamma globulin infusions, pneumococcal, flu, and other vaccines.
  8. Oncologist: CBC q 3 months.
  9. Pulmonologist: pulmonary function tests, antibiotics prophylaxis, chest clearance, and cough assist.
  10. Effective social work and/or case management to help connect with local resources including respite care and advocacy, and assess eligibility for state funding and insurance coverage options.
  11. Referral to information resources, parent and sibling support groups.
  12. Ataxia-Telangiectasia Children’s Project (http://www.communityatcp.org/, http://www.atcp.org)
  13. National Ataxia Foundation (http://www.ataxia.org/)
  14. Ataxia-Telangiectasia Clinical Center at Johns Hopkins (http://www.hopkinschildrens.org/Ataxia-Telangiectasia.aspx)

Patient & family education

  1. Promote respect for the child’s need for extra processing time.
  2. Understand organic nature of fatigue.
  3. Encourage child to communicate need for extra time.
  4. Develop signs and key words to communicate.
  5. Avoidance of x-rays and unprotected sun or other environmental exposures.
  6. Benefits of maintaining activity as tolerated for preserving strength, and other compensation for ataxia; distinction between ataxia and weakness.
  7. Whole family vaccination.

Emerging/unique Interventions

  • Scale for Assessment and Rating of Ataxia (SARA).
  • International Cooperative Ataxia Rating Scale.
  • Semi-quantitative measures, such as timing of:
    • Gait
    • Single-leg stance.
    • Hand and foot tapping.
    • Maze or pegboard.
    • Paragraph reading.
  • Self-report: aid for gait, number of falls, success at keyboard, video game, cup carrying, activities of daily living assistance, and intelligibility.10
  • Cerebellar spectroscopy: choline signal intensity may monitor treatment efficacy.11

Translation into practice: practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

AT should be considered in children who present with progressive ataxia, even if telangiectasia is not obvious. Alpha fetoprotein should be ordered as part of an ataxia workup. Not only ataxia but the other movement disorders which emerge need to be addressed. Referrals for immunologic and oncologic care and surveillance are critical.

4. CUTTING EDGE/EMERGING AND UNIQUE CONCEPTS AND PRACTICE

Cutting edge concepts and practice

Pharmacologic trials

  • Amantadine: well-tolerated and effective treatment for motor symptoms (ataxia, involuntary movements, dysarthria).10
  • Betamethasone: 0.03 mg/kg/day for 10 days significantly improved SARA scores and demonstrated increased cortical activation on functional magnetic resonance imaging.12
  • Dopamine agonists or anticholinergics: extrapyramidal movements.1,5,12
  • Baclofen: eye movements and tremor.1,5
  • Gabapentin, clonazepam, and propranolol: tremors.1,5
  • Fluoxetine or buspirone: speech and balance.12
  • Trihexyphenidyl may be helpful for dystonia even if levodopa-carbidopa is not. 14
  • Oxidative stress clinical trial: nicotinamide and the antioxidant alpha-lipoic acid improved 2 laboratory markers of oxidative stress and increased lymphocytes.11
  • Therapy: there is class III evidence that coordinative training improves motor performance and reduces ataxia symptoms.13

5. GAPS IN THE EVIDENCE-BASED KNOWLEDGE

Gaps in the evidence-based knowledge

Drug therapies are actually based on very small therapeutic trials. In the absence of curative or strong evidence-based treatment, recommendations at present are based on expert consensus and use for similar signs and symptoms in other neurological disorders.1 Individual tolerance and response to any of these agents may vary.  Metabolic derangements in brain tissue are being explored as possible therapeutic targets. Gene therapy for AT remains theoretical and stem cell therapies are controversial at this time.15,16

References

  1. Hoche F, Seidel K, Theis M, et al. Neurodegeneration in ataxia telangiectasia: what is new? What is evident? Neuropediatrics. 2012;43:119-129.
  2. Swift M, Morrell D, Cromartie E, Chamberlain AR, Skolnick MH, Bishop DT. The incidence and gene frequency of ataxia-telangiectasia in the United States. Am J Hum Genet. 1986;39:573-583.
  3. Gatti R. Ataxia telangiectasia. In NCBI bookshelf: Gene Reviews, Pagon RA, Adam MP, Ardinger HH, et al., editors. Last update March 20, 2010. http://www.ncbi.nlm.nih.gov/books/NBK26468/.
  4. Verhagen, M. M. M et al., Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: A genotype–phenotype study. Hum. Mutat. 2012;33: 561–571.
  5. Wallis LI, Griffiths PD, Ritchie SJ, Romanoski CA, Darwent G, Wilkinson ID. Proton spectroscopy and imaging at 3T in ataxia-telangiectasia. AJNR Am J Neuroradiol. 2007;28:79-83.
  6. Verhagen MM, Last JI, Hogervorst FB, et al. Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study. Hum Mutat. 2012;33:561-571.
  7. Fanos JH, Mackintosh MA. Never again joy without sorrow: the effect on parents of a child with ataxia- telangiectasia. Am J Med Genet. 1999;87:413-419.
  8. A-T Children’s Project. A-T caregiver handbook. Available at: http://www.communityatcp.org/page.aspx?pid=3509. Accessed August 14, 2012.
  9. Nissenkorn A, Hassin-Baer S, Lerman SF, Banet Levi Y, Tzadok M, Ben-Zeev B. Movement disorder in ataxia-telangiectasia: treatment with amantadine sulfate. J Child Neurol. 2013;28:155-160.
  10. Kieslich M, Hoche F, Reichenbach J, et al. Extracerebellar MRI – lesions in ataxia telangiectasia go along with deficiency of the GH/IGF-1 axis, markedly reduced body weight, high ataxia scores and advanced age. Cerebellum. 2010;9:190-197.
  11. Perlman SL. Cerebellar ataxia. Curr Treat Options Neurol. 2000;2:215-224.
  12. Broccoletti T, Del Giudice E, Cirillo E, et al. Efficacy of very-low-dose betamethasone on neurological symptoms in ataxia-telangiectasia. Eur J Neurol. 2011;18:564-570.
  13. Quaranrelli M, Giardino G, Prinster A, et al. Steroid treatment in ataxia-telangiectasia induces alterations of functional magnetic resonance during prono-supination task. Eur J Paediatr Neurol. 2013;17:135-140.
  14. Koepp M. Schelosky L, Cordes I, Cordes M, Poewe W, Dystonia in ataxia telangiectasia: report of a case with putaminal lesions and decreased striatal 123I-iodobenzamide binding, Mov. Disord. 1994 Jul;9(4):455-9.
  15. Amariglio N, Hirshberg A, Scheithauer BW, et al. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med. 2009;6:e1000029.
  16. Ghosh S, Schuster FR, Binder V, et al. Fatal outcome despite full lympho-hematopoietic reconstitution after allogeneic stem cell transplantation in atypical ataxia telangiectasia. J Clin Immunol. 2012;32:438-440.

Bibliography

Ilg W, Synofzik M, Bratz D, Burkard S, Giese MA, Schols L. Intensive coordinative training improves motor performance in degenerative cerebellar disease. Neurology. 2009;73:1823-1830

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

Mancebo E, Bernardo I, Castro MJ, et al. Rapid molecular prenatal diagnosis of ataxia-telangiectasia by direct mutational analysis. Prenat Diagn. 2007;27:861-864.

McKinnon P. ATM and the molecular pathogenesis of ataxia telangiectasia. Annu Rev Pathol. 2012;7:303-321.

Nissenkorn A, Levi YB, Vilozni D, et al. Neurologic presentation in children with ataxia-telangiectasia: is small head circumferance a hallmark of the disease? J Pediatr. 2011;159:466-471.

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Original Version of the Topic:

Barbara Wechsler, MD, Monika Y. Patel, MD, Adiaha Spinks-Franklin, MD, MPH. Ataxia telangiectasia. Publication Date: 2013/04/12.

Author Disclosure

Vikki A. Stefans, MD
Sarepta: Honorarium and expenses – Clinical expert panel for Duchenne gene therapy held in Dallas, TX

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