Ataxia-Telangiectasia

Clinical characteristics.

Classic ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between ages one and four years, oculomotor apraxia, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, frequent infections, and an increased risk for malignancy, particularly leukemia and lymphoma. Individuals with A-T are unusually sensitive to ionizing radiation. Non-classic forms of A-T have included adult-onset A-T and A-T with early-onset dystonia.

Diagnosis/testing.

The diagnosis of A-T is suspected based on suggestive clinical and preliminary laboratory findings and – in some instances – neuroimaging and family history. The diagnosis is established in a proband either by molecular genetic testing to document the presence of biallelic (homozygous or compound heterozygous) ATM pathogenic variants or (when available) by immunoblotting to test for absent or reduced ATM protein.

Management.

Treatment of manifestations:

• Neurologic: supportive therapy and medications (when possible) as well as early and continued physical therapy to reduce the risk for contractures and scoliosis.
• Immunodeficiency: IVIG replacement therapy as needed for (a) frequent and severe infections and (b) low IgG levels.
• Pulmonary: multidisciplinary management that emphasizes monitoring of recurrent infection, pulmonary function, swallowing, nutrition, scoliosis, and immune function.
• Cancer: because of the increased sensitivity of A-T cells, use of ionizing radiation and some chemotherapeutic agents requires careful monitoring.

Prevention of secondary complications: Gastrostomy tube feedings are occasionally needed to prevent pulmonary and nutritional complications of dysphagia. Attention to potential risks of anesthesia including impaired swallowing, increased risk of aspiration, reduced pulmonary function, and infection.

Surveillance: In those with severe recurrent infections or undergoing immunomodulatory therapy: monitoring of pulmonary function and other signs of pulmonary disease and early signs of malignancy (e.g., weight loss, bruising, localized pain or swelling).

Genetic counseling.

A-T is inherited in an autosomal recessive manner. At conception, the sibs of an affected individual have a 25% chance of being affected, a 50% chance of being asymptomatic carriers, and a 25% chance of being unaffected and not carriers. ATM heterozygotes (carriers) are at increased risk of developing cancer. Once the ATM pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

Ataxia-telangiectasia (A-T) should be suspected in children who have the following clinical, MRI, and preliminary laboratory findings.

Clinical findings. Progressive cerebellar dysfunction between ages one and four years manifests as:

• Gait and truncal ataxia;
• Head tilting;
• Slurred speech;
• Oculomotor apraxia and abnormal ocular saccades.
  "If oculomotor apraxia cannot be clearly documented in a cooperative patient, the diagnosis of A-T should be viewed with suspicion" [E Boder, pediatric neurologist and A-T pioneer (1909-1995)].

Note: The diagnosis of A-T is most difficult in very young children: they do not yet exhibit all the characteristic features of A-T and are typically unable to cooperate during neurologic examination.

MRI. The classic cerebellar findings are atrophy of the frontal and posterior vermis and both hemispheres. Note: Although a small cerebellum is not always apparent on MRI in young children, diffusion-weighted MRI allowed quantitation of cerebellar corticomotor pathway pathology in children as young as age three years, suggesting that this imaging may be useful in early confirmation of the diagnosis of A-T when the necessary equipment and expertise are available [Tavani et al 2003, Al-Maawali et al 2012, Sahama et al 2014a, Sahama et al 2014b].

Preliminary laboratory findings

• Newborn screening (NBS) for severe combined immunodeficiency identifies reduced T-cell receptor excision circle (TREC) levels. This method of NBS most likely identifies the estimated 50% of children with A-T who have lymphopenia; however, it may be less sensitive in older children with A-T (in whom T cell lymphopenias are less severe) [Mallott et al 2013].
• Serum concentration of alpha-fetoprotein (AFP) is elevated above10 ng/mL in about 95% of individuals with A-T.
  Note: (1) Serum AFP concentration may remain above normal in unaffected children until age 24 months. (2) Persistent elevation of AFP does not necessarily indicate ongoing cerebellar damage or correlate with prognosis.
• Chromosome analysis. A 7;14 chromosome translocation is identified in 5%-15% of cells in routine chromosome studies of peripheral blood of individuals with A-T. The break points are commonly at 14q11 (the T-cell receptor-alpha locus) and at 14q32 (the B- cell immunoglobulin heavy chain receptor [IGH] locus).

Establishing the Diagnosis

The diagnosis of A-T is established in a proband either by molecular genetic testing to document the presence of biallelic (homozygous or compound heterozygous) ATM pathogenic variants or (when available) by immunoblotting to test for absent or reduced ATM protein.

Molecular genetic testing approaches can include single-gene testing or use of a multigene panel.

Single-gene testing. Sequence analysis of ATM is performed first, followed by gene-targeted deletion/duplication analysis if only one or no pathogenic variant is found.

Targeted analysis for the following ATM pathogenic variants in specific populations can be performed first when appropriate:

• Amish: c.1564_1565delAG
• North African Jewish: c.103C>T (p.Arg35Ter)
• Sardinian: c.3894dupT

A multigene panel that includes ATM and other genes of interest, such as PP2A (see Differential Diagnosis), may also be considered. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.

For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.

Immunoblotting for ATM protein in a lymphoblastoid cell line (LCL) is more than 95% sensitive and more than 98% specific for diagnosing A-T [Chun et al 2003]. This testing may be performed to help interpret sequence variants of uncertain significance or confirm a diagnosis when only one ATM pathogenic variant is identified.

Of individuals with A-T:

• About 90% have no detectable ATM protein (i.e., <15% of control levels);
• About 10% have trace amounts to 15% of control levels of ATM protein;
• About 1% have a near-normal amount of ATM protein that lacks ATM serine/threonine kinase activity (so-called "kinase-dead" protein) [Stewart et al 2001].

Note: The presence of more than 15% ATM protein suggests one of the following:

• Another diagnosis
• An ATM pathogenic missense variant
• A leaky splicing ATM variant
• An ATM pathogenic variant resulting in "kinase-dead" protein
• Possibly, a pathogenic variant in a gene encoding an ancillary ATM-activating phosphatase like PP2A. However, to the authors' knowledge, PP2A deficiency results mainly from somatic pathogenic PP2A variants in tumor cells or PP2A inhibitors. To date, a person with PP2A deficiency has not been described.

For more detailed information on the interpretation of the results of ATM protein testing and research testing for ATM, click here (pdf).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ataxia-telangiectasia (A-T), the following evaluations are recommended:

• Neurologic consultation with attention to ataxia, including assessment of extraocular movement
• Assessment of speech re communication and swallowing re risk of aspiration
• Nutrition and feeding assessment
• Immune status of specific parameters that were previously aberrant (e.g., immunoglobulin levels, B/T cell levels, T cell function)
• Chest x-ray and pulmonary function for baseline
• CBC with differential
• Diabetes screen (urinalysis, fasting blood glucose concentration, Hgb A1C)
• Consultation with a clinical geneticist and/or genetic counselor

Treatment of Manifestations

Neurologic. Supportive therapy can minimize drooling, choreoathetosis, myoclonus/tremor, and ataxia. However, individual responses to specific medications (e.g., amantadine and 4-aminopyridine) and to treatments used for myoclonus vary [Perlman et al 2012, Nissenkorn et al 2013, Shaikh et al 2013, van Egmond et al 2015]. Thus, it is recommended that treatment options be discussed with an experienced neurologist.

Early and continued physical therapy can minimize the risk for contractures (which appear in almost all individuals with time and often lead to other problems such as pressure sores and pain) and scoliosis (which can, for example, be the consequence of prolonged sitting in a wheelchair – particularly the tendency to lean on the same elbow).

Although steroids are reported to temporarily improve the neurologic symptoms of A-T in children, the symptoms reappear within days of their discontinuation [Gatti 1985, Buoni et al 2006, Broccoletti et al 2008, Gatti & Perlman 2009]. (See also Therapies Under Investigation.)

Immunodeficiency. IVIG replacement therapy should be considered for individuals with frequent and severe infections and very low IgG levels [Nowak-Wegrzyn et al 2004].

Pulmonary. The European Respiratory Society (ERS) has prepared extensive guidelines for the multidisciplinary respiratory management of A-T, emphasizing the need for monitoring of immune function, recurrent infection, pulmonary function, swallowing, nutrition, and scoliosis, all of which can contribute to increased respiratory morbidity and mortality in persons with A-T [Bhatt et al 2015] (full text).

Cancer. Because cells from individuals with A-T are 30% more sensitive to ionizing radiation than cells from controls, conventional doses of ionizing radiation are potentially lethal in individuals with A-T. Thus, the use of radiotherapy and some radiomimetic chemotherapeutic agents should be administered carefully and monitored closely [Schütte et al 2016].

Doses of some chemotherapeutic agents are often reduced by 25%-50% and longer recovery periods between treatments are considered to allow for the slower DNA repair that occurs in A-T [Schütte et al 2016].

Prevention of Secondary Complications

Pulmonary and nutritional complications of dysphagia are common. Often, gastrostomy tube feedings are recommended to manage these comorbidities. Children with disorders with predictable progression (like A-T) and impaired swallowing may benefit from early rather than late placement of a feeding tube [Lefton-Greif et al 2000].

Anesthesia carries unique potential risks in persons with A-T because of impaired coordination of swallowing, increased risk of aspiration, reduced respiratory capacity, and propensity to infections [McGrath-Morrow et al 2008]. In a recent review, 24% of patients required supplemental oxygen (maximum duration 24 hours) post anesthesia; mild postoperative hypothermia was also relatively common [Lockman et al 2012].

Surveillance

The European Respiratory Society (ERS) has prepared extensive guidelines for the multidisciplinary respiratory management of A-T, emphasizing the need for monitoring of immune function, recurrent infection, pulmonary function, swallowing, nutrition, and scoliosis, all of which could contribute to increased respiratory morbidity and mortality in A-T [Bhatt et al 2015] (full text).

Parents should be counseled to monitor for – and report to a physician – the early warning signs of malignancy (which can occur at any age) including weight loss, bruising, and localized pain or swelling. Periodic CBCs are warranted.

Immune status needs to be monitored if severe recurrent infections occur or immunomodulatory therapy is in progress.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Research suggests the following:

• Antioxidants (e.g., vitamin E or alpha-lipoic acid) are recommended, although no formal testing for efficacy has been conducted in individuals with A-T. Alpha-lipoic acid has the theoretic advantage of crossing the blood-brain barrier and improving mitochondrial function in A-T cells [Ambrose et al 2007].
• In culture, certain aminoglycoside antibiotics can induce small amounts of full-length ATM protein and return ATM functions to A-T cells with primary nonsense pathogenic variants [Lai et al 2004, Gatti 2012]. Non-aminoglycoside read-through chemicals, identified by a high-throughput screen of 70,000 compounds, induce ATM protein in A-T cells [Du & Gatti 2009]; and chemical derivatives of those compounds – such as RTC13, RTC14, RTC216, RTC202, RTC204, and RTC219 – have produced encouraging results in other diseases besides A-T (e.g., a mouse model of Duchenne muscular dystrophy [Kayali et al 2012], epidermolysis bullosa keratinocytes, xeroderma pigmentosum [Kuschal et al 2013], and retinal cells from amaurotic congenital blindness [Pillers et al 2015].
  Thus, it is anticipated that in future patients will be candidates for mutation-targeted therapeutic trials, which will be based on the class of pathogenic variants present and not on the specific gene itself. These drugs will be grouped according to the class of pathogenic variants for which they can address/correct the underlying molecular pathogenicity. – rendering them potentially useful for treating a molecular spectrum of genetic diseases based on the class of pathogenic variant rather than the disease itself [Du et al 2007, Hu & Gatti 2008, Du & Gatti 2009, Jung et al 2011, Gatti 2012, Du et al 2013, Lavin 2013].
• Antisense morpholino oligonucleotides (AMOs) induce substantial corrections of ATM protein in cell lines with certain types of ATM splicing variants [Du et al 2007, Du et al 2009]. AMOs remain active in A-T cells for more than 14 days. In animal studies, they are well tolerated when a cell-penetrating protein moiety is added to the AMO. Groundbreaking clinical trials using AMO to treat spinal muscular atrophy – and a particular splicing variant that causes Duchenne muscular dystrophy – are in progress.
• Amlexanox (Aphthasol^®) is another non-aminoglycoside (similar to ataluren [PTC124]) read-through compound for nonsense pathogenic variants that is being tested. To date, it is approved as an ointment for mouth ulcers and is prescribed primarily by dentists [Loudon 2013].
• Dexamethasone and betamethasone, but not methylprednisolone, have been reported to decrease neurologic manifestations in A-T [Buoni et al 2006, Broccoletti et al 2008, Gatti & Perlman 2009]. However, the neurologic improvement, which is also accompanied by signs of steroid toxicity, disappears within days of discontinuation of the steroids. Additional studies are in progress. Delivery of the steroids by loading them into erythrocytes affords much better dose control and delivery at 0.001% of previous steroid doses [Leuzzi et al 2015].
  In a formal clinical trial in progress, betamethasone is being delivered within autologous red cells that have been infused with doses 100-1000 times lower than what was previously manageable, thereby mitigating most side effects of chronic steroid therapy.
• Use of insulin-like growth factor 1(IGF-1) treatment for A-T has been suggested [Fernandez et al 2005]. More recently, Voss et al [2014] showed that the GH/IGF-1 axis was perturbed in 58.3% of individuals with A-T (age range 2 to 9 years). A clinical trial is presently underway.
• Manganese-containing superoxide dismutase (SOD) mimics have a radioprotective effect on A-T cells [Pollard et al 2009]. A recent report provides compelling evidence that treatment of a transgenic mouse model of amyotrophic lateral sclerosis (ALS) with a copper-chaperone for SOD extends by 500 days the life expectancy of mice that normally die within three months [Williams et al 2016]. This potential advance in treating motor degeneration may be applicable to A-T as well.
• Mutation-targeted therapy for other rare genetic diseases has been encouraging [Wilschanski et al 2003, Welch et al 2007, Du et al 2009]. The number of potential disease targets for read-through therapy exceeds 8000 [Keeling & Bedwell 2011]. It is also estimated that 10%-15% of human pathogenic variants are nonsense variants [Mort et al 2008], predicting investigation of many millions of potential drug candidates.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Other

Any child younger than age five years with malignancy should be evaluated for A-T before starting chemotherapy and/or radiotherapy since conventional doses of either can be fatal in A-T.