Ataxia with Telangiectasia

Synonym: Louis-Bar's syndrome

Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder.^[1]The gene responsible has been localised to 11q22.3-23.1.^[2] A-T is characterised by:^{[3, 4, 5]}

• Progressive neurodegeneration.
• High risk of malignancy, especially breast cancer in women.
• Immunodeficiency.
• Hypersensitivity to ionising radiation.
• Chromosomal breakage (t(7;14) translocations typically).

There is significant phenotypic heterogeneity, both in clinical presentation (particularly in susceptibility to pulmonary infection, presence and degree of cognitive impairment and predisposition to leukaemia) and rate of progression, reflecting allelic diversity.^[6]

Epidemiology

A-T is a rare disease:

• The disease is inherited as an autosomal recessive trait with full penetrance. It has been reported throughout the world.
• It is sometimes associated with high rates of consanguinity.^[7]

Carriers (heterozygotes) of A-T locus mutations have a significantly reduced life expectancy compared with non-carriers, with an increased risk of death from cancer and ischaemic heart disease. Female heterozygotes have a particular risk of breast cancer.^{[5, 8]} Other studies have questioned these findings and although they also have confirmed a moderate risk of breast cancer in A-T heterozygotes, did not find large mutation-specific differences in overall risk.^[9]

Genetics

The molecular pathology of A-T has been well described in recent times:

• The classical form of A-T results from the presence of two A-T mutated (ATM) genes on chromosome 11, leading to total loss of the ATM protein (a protein kinase). ATM protein normally recognises DNA damage, and activates the DNA repair machinery and the cell cycle checkpoints to repair and minimise the risk of genetic damage.
• Understanding ATM's function through the effect of its loss in A-T has provided broader insights into cancer predisposition and some aspects of neurodegeneration.^[10]
• Milder forms of A-T with later-onset or slower-progressing neurological degeneration seem to reflect some retained ATM protein kinase activity due to the impact of different mutations.^[11]

Presentation^[12]

• A-T usually presents by the age of 2 years with a progressive cerebellar ataxia.
• Other symptoms which may be present include:
  • Lack of facial expression.
  • Tendency to drool.
  • Slow slurred speech.
  • Recurrent infections, particularly sinus and respiratory - due to decreased immunoglobulin A (IgA).
• Telangiectasias develop from about the age of 3 years and may not be present until the age of 10 years, but will be present in all cases. The telangiectasias may be present anywhere on the body - most usually involving the conjunctivae, pinnae, face, sternum and flexures.
• Other signs include:
  • Truncal ataxia
  • Oculomotor apraxia
  • Decreased tendon reflexes
  • Pulmonary infections
  • Sinus infections
  • Bulbar dysfunction
  • Recurrent aspiration
  • Gonadal atrophy
  • Dystonia
  • Chorea
  • Sensory neuropathy
  • Growth restriction

Differential diagnosis

There is a need to differentiate from other autosomal recessive ataxias:^[13] Friedreich's ataxia (most common in European countries) and much rarer conditions such as ataxia with vitamin E deficiency, abetalipoproteinaemia, Refsum's disease, spastic ataxia, infantile-onset spinocerebellar ataxia and ataxia with oculomotor apraxia.

A-T is usually distinguished by an earlier age of onset, the presence of telangiectasias and the later development of dystonia and chorea and by specific investigations.

Investigations^[14]

• Serum alpha-fetoprotein level (raised in 90%).
• Genetic testing for ATM genes and absence of ATM protein in nuclear extracts.
• In vitro radiosensitivity testing (colony survival assay).

Associated diseases

Increased cancer risk

• On autopsy, almost a half of individuals have a malignancy.
• Lymphoreticular malignancies (lymphomas and acute lymphoblastic leukaemia (ALL)) dominate in the first two decades followed by solid tumours thereafter.

Immunodeficiency^[15]

• A-T is associated with a high prevalence of laboratory immunological abnormalities - most commonly, IgA, IgG and IgE deficiencies and lymphopenia with reduced B lymphocytes, and reduced CD4 and CD8 T cells.
• Recurrent upper and lower respiratory tract infections are common. Severe systemic bacterial or viral and opportunistic infections are uncommon in A-T. The immune defect does not appear progressive.

Management

Currently there is no cure and there is no treatment for slowing the progression of the ataxia. A-T is a multisystem disorder requiring multiple therapeutic interventions to slow or halt the neurodegeneration, to prevent or treat the tumours and to correct the associated immunodeficiency. Despite an increased molecular understanding of the disease, we have no effective answer to these challenges. In the future, embryonic stem cell transfer, use of antioxidants and targeted gene therapy may offer some hope.^[6]

Pragmatic treatment of the condition consists of the following:

• Neurological symptoms are difficult to treat. Treatment of basal ganglia dysfunction can be attempted with L-DOPA derivatives, dopamine antagonists and anticholinergics. Loss of balance, and speech and co-ordination problems may be improved by the use of amantadine, fluoxetine and buspirone. Tremors can be treated with gabapentin, clonazepam and propranolol.^[6]
• Prompt treatment of infections and, in some cases, use of prophylactic antibiotics. Regular injection of immunoglobulins has been used in some centres. Fetal thymus implants have not been shown to be beneficial.
• Screening for swallow-related problems and aspiration. Consider the use of thickeners and enteral feeding.^[6]
• Some advocate regular screening for malignancies with FBC and serum tumour markers.
• Multidisciplinary team involvement - input of physiotherapy, speech and occupational therapists is particularly important.
• High-dose vitamin regimes, folic acid and alpha lipoic acid have all been advocated due to their claimed anti-cancer properties. However, multivitamins do not correct the ataxia of A-T.^[6]
• Avoid X-rays wherever possible, unless treatment is dependent on them and an alternative (such as MRI or ultrasound) is not possible.

Prognosis

• A-T is an incurable and unremitting disease.
• Most A-T children are wheelchair-dependent by their teens although milder variants do exist.
• Communication becomes progressively difficult as handwriting, speech and eye movement control deteriorates.
• Median survival is 19-25 years (wide range) with death due to cancer and respiratory failure.^[16]

Prevention

Prenatal testing is available for families considered at risk, but is not carried out routinely. The ATM gene is too large to allow practical mutational analysis for clinical screening.^[10]