Clinical characteristics.

The phenotypic spectrum of ataxia-telangiectasia (A-T), a multisystem disorder, is a continuum ranging from classic A-T at the severe end and variant A-T at the milder end. Nonetheless, distinguishing between classic A-T and variant A-T on this spectrum helps understand differences in disease course, rate of progression, and life expectancy.

Classic A-T is characterized by childhood onset of progressive neurologic manifestations (initially cerebellar ataxia, followed typically by extrapyramidal involvement and peripheral sensorimotor neuropathy), immunodeficiency (variably associated with abnormalities of humoral immunity, cellular immunity, or combined immune deficiency), pulmonary disease (resulting from recurrent infections, immune deficiency, aspiration, interstitial lung disease, and neurologic abnormalities), and increased risk of malignancy. Although it is generally accepted that intellectual disability is not common in A-T, disturbances in cerebellar as well as non-cerebellar brain areas and networks may result in cognitive deficits. Increased sensitivity to ionizing radiation (x-ray and gamma ray) can result in severe side effects from such treatments. Life expectancy is significantly reduced due to cancer, pulmonary disease, and infections.

Variant A-T has a significantly milder disease course. While cerebellar ataxia can be absent, extrapyramidal movement disorders are common (typically dystonia and dystonic tremor) and most individuals have manifestations of axonal sensorimotor polyneuropathy. In contrast to classic A-T, immune function is generally normal, respiratory infections are not increased, and pulmonary disease is not a major feature. However, risk of developing malignancies is increased, particularly in premenopausal females who have an increased risk of developing breast cancer and hematologic malignancies.

Diagnosis/testing.

The diagnosis of A-T is established in a proband with suggestive findings and biallelic pathogenic variants in ATM identified by molecular genetic testing. Of note, newborn screening (NBS) for severe combined immunodeficiency (SCID) that relies on the identification of reduced T-cell receptor excision circle (TREC) levels in blood spots most likely identifies about 50% of children with classic A-T, who require immediate subspecialty evaluation at a center with expertise in the diagnosis of SCID, its causes, and its treatment.

Management.

Treatment of manifestations: Supportive care to improve quality of life, maximize function, and reduce complications ideally involves multidisciplinary care by specialists in (pediatric) neurology, pulmonology, immunology, pediatrics (for children) and internal medicine (for adults), rehabilitation medicine, and professionals in physical therapy, speech-language therapy, occupational therapy, and nutrition. For specific issues care may be provided by specialists in oncology, medical genetics, endocrinology, orthopedics, dermatology, mental health, and social work.

Surveillance: Routine evaluations by treating clinicians is necessary to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations. Recommended surveillance is the same for individuals with classic A-T and variant A-T, with the exception that individuals who do not have evidence of lung disease at the time of initial diagnosis do not require annual screening for pulmonary disease.

Agents/circumstances to avoid: Rubella vaccination should be avoided in individuals with severe immunodeficiency as it can possibly increase the risk for granulomas; ionizing radiation (x-ray and gamma ray) is contraindicated, due to increased sensitivity; and radiation therapy is contraindicated because increased radiosensitivity may lead to very severe complications.

Evaluation of relatives at risk: It is appropriate to offer molecular genetic testing for the familial ATM pathogenic variants to apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible sibs with biallelic ATM pathogenic variants who would benefit from prompt initiation of treatment of manifestations of A-T, surveillance for malignancy, and awareness of agents/circumstances to avoid; and family members who are heterozygous for an ATM pathogenic variant and who would benefit from age-appropriate intensified surveillance for breast cancer.

Therapies under investigation: Use of intra-erythrocyte dexamethasone; the effects of nicotinamide riboside (a form of vitamin B₃) on ataxia scores and immunoglobulin levels; gene therapy with antisense oligonucleotides in a single case study; effect of allogenic hematopoietic stem cell transplantation on neurologic functioning.

Genetic counseling.

A-T is caused by biallelic pathogenic variants in ATM and inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an ATM pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and having A-T, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial ATM pathogenic variants. Although individuals heterozygous for an ATM pathogenic variant are not at risk for A-T, their risk of developing cancer is increased compared to that of the general population (in particular, heterozygous females have an increased risk of developing breast cancer). Once the ATM pathogenic variants have been identified in an affected family member, heterozygote testing for at-risk relatives and prenatal and preimplantation genetic testing for A-T are possible.

Scenario 1: Abnormal Newborn Screening for Severe Combined Immunodeficiency

Newborn screening (NBS) for severe combined immunodeficiency (SCID), a severe but treatable immunologic disorder, relies on the identification of reduced T-cell receptor excision circle (TREC) levels in blood spots.

Classic A-T. Newborns with classic A-T (who are still asymptomatic and undiagnosed) may have low TREC levels comparable to the TREC levels of newborns with SCID and, thus, may have a positive NBS. NBS for SCID most likely identifies about 50% of children with classic A-T [Mallott et al 2013]. Note: Infants with classic A-T who have an abnormal NBS result also demonstrate the laboratory findings suggestive of classic A-T.

Variant A-T. Since variant A-T is not associated with immunodeficiencies, NBS for SCID does not detect variant A-T.

Note: This chapter specifically focuses on A-T; for potential causes of decreased TREC levels in NBS other than classic A-T and SCID, see Puck [2019].

Newborns with an abnormal NBS for SCID require immediate subspecialty immunology evaluation at a center with expertise in the diagnosis of SCID, its genetic causes, and its treatment protocols, including hematopoietic stem cell transplantation (HSCT). (See Management, Evaluations Following Initial Diagnosis.)

Scenario 2: Symptomatic Proband with Findings Suggestive of A-T

Establishing the Diagnosis

The diagnosis of A-T is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in ATM identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) Identification of biallelic ATM variants of uncertain significance (or of one known ATM pathogenic variant and one ATM variant of uncertain significance) itself does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Ataxia-telangiectasia (A-T) is often described has having a "classic A-T" phenotype and a "variant A-T" phenotype; however, these phenotypes are more of a continuum ranging from classic A-T at the severe end to variant A-T at the milder end. Nonetheless, distinguishing between classic A-T and variant- A-T on this phenotypic spectrum helps understand differences in disease course, rate of progression, and life expectancy (see Table 2) [van Os et al 2017b, Levy & Lang 2018, Amirifar et al 2019, Schon et al 2019, van Os et al 2020b, Veenhuis et al 2021b].

Genotype-Phenotype Correlations

In general, nonsense and/or frameshift variants lead to the classic A-T phenotype, whereas missense and splice site variants are more typically associated with variant A-T. Within families, phenotypes of affected individuals are generally similar [Verhagen et al 2012, Taylor et al 2015].

Specific ATM variants with genotype-phenotype correlations include the following (see Table 6):

• c.3576G>A. Individuals who are either homozygous or compound heterozygous for this splice site variant have milder classic A-T with prolonged survival and lower susceptibility to immunodeficiency, respiratory disease, and cancer [van Os et al 2019a].
• c.5763-1050A>G. This splice site variant, associated with the A-T variant phenotype, is a founder variant in the United Kingdom [McConville et al 1996, Stewart et al 2001].
• Compound heterozygosity for c.6154G>A (a missense variant) and c.7886_7890delTATTA (a frameshift variant) result in the variant A-T phenotype with dopa-responsive dystonia [Charlesworth et al 2013].
• c.6200C>A. This missense variant in Canadian Mennonites is associated with a dystonia-predominant variant A-T phenotype [Saunders-Pullman et al 2012].
• c.7271T>G. Four of six individuals homozygous for this missense variant had variant A-T and normal serum alpha-fetoprotein levels [Schon et al 2019]. This variant is associated with a high risk of breast cancer [Stankovic et al 1998].
• c.8147T>C. All individuals who are compound heterozygous for this missense variant have variant A-T [van Os et al 2020b].

Nomenclature

Ataxia-telangiectasia was previously referred to as Louis-Bar syndrome.

Prevalence

The reported incidence of A-T, a rare disorder, varies between 1:300,000 and 1:40,000. The estimated prevalence is 1-9:100,000 [Swift et al 1986, Rothblum-Oviatt et al 2016].

In the United States approximately 350 children with A-T are known to the patient organization A-T Children's Project (see www.atcp.org).

Based on the incidence of A-T in the United States, the heterozygote frequency is estimated to be one in 200 persons [Swift et al 1986].

Increased heterozygote frequencies have been reported in the following populations due to founder variants (see Table 6):

• One in three to one in 15 in the Druze population in northern Israel [Fares et al 2004]
• One in 81 in the Moroccan and Tunisian Jewish population [Gilad et al 1996]
• One in 36 in the Romani population in Spain [Mancebo et al 2007, Carranza et al 2017]

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with ataxia-telangiectasia (A-T), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

There is no cure for ataxia-telangiectasia.

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in (pediatric) neurology, pulmonology, immunology, pediatrics (for children) and internal medicine (for adults), rehabilitation medicine, and professionals in physical therapy, speech-language therapy, occupational therapy, and nutrition. For specific issues care may be provided by specialists in oncology, medical genetics, endocrinology, orthopedics, dermatology, mental health, and social work [van Os et al 2017a] (full text).

The following discussion takes into consideration that distinctions between the findings in classic A-T and variant A-T are not always possible; thus, clinicians need to focus on the issues that are most relevant to each affected individual.

Ataxia. Nicotinamide riboside, a form of vitamin B₃, at 25 mg/kg/day (maximum dose of 900 mg/day), has significantly reduced ataxia scores (i.e., improved the motor disorder) in a single trial with 24 individuals with both classic and variant A-T [Veenhuis et al 2021a].

Extrapyramidal movement disorders. The effectiveness of pharmacotherapy in movement disorders in A-T is low to moderate. Only a few non-randomized studies have investigated the treatment of movement disorders in individuals with A-T specifically [Zannolli et al 2012, Nissenkorn et al 2013, Shaikh et al 2013, Leuzzi et al 2015, Veenhuis et al 2021a].

Dystonia, the most troublesome movement disorder in A-T, can vary in distribution and severity and varies among affected individuals.

• Focal dystonia. As in individuals with torticollis, botulinum toxin A is the treatment of first choice.
• Generalized dystonia. Anticholinergic drugs and GABA mimetics can be helpful.
• Generalized, dopa-responsive dystonia. A trial with levodopa may be useful in some individuals [Charlesworth et al 2013].
• Deep brain stimulation (DBS) of the globus pallidus pars interna, described to date in two individuals with A-T and dystonia, had conflicting results [Georgiev et al 2016].

For recommendations on the treatment of ataxia, chorea, myoclonus, and tremor, see van Os et al [2017b].

Rehabilitation / activities of daily living. The main goal of supportive treatment by a rehabilitation specialist (physiatrist), physical therapists, occupational therapists, and allied health care workers is the maintenance of physical function and condition and prevention of complications such as contractures. A multidisciplinary approach is the cornerstone of the treatment of motor disability.

Physical therapists can provide exercises to maintain muscle strength, overall condition, and activity and to prevent joint contractures. Necessary aids can include:

• Foot orthoses;
• A (wheel)chair to provide a good upright sitting position to reduce scoliosis and prevent choking;
• Standing frames.

Occupational therapists can provide aids and devices for activities of daily living.

Dysarthria. A speech-language therapist can help address dysarthria and provide practical advice to improve speech intelligibility and support families [Veenhuis et al 2021b]. In most individuals with A-T, oral communication is possible. When dysarthria is severe, a speech-language therapist can suggest use of communication aids (e.g., augmentative and alternative communication [AAC]) and equipment.

Dysphagia/feeding/nutrition. Management of dysphagia may involve feeding teams that include speech-language therapists, nutritionists (regarding thickened liquids and caloric intake), and gastroenterologists (who recommend gastrostomy feeding when appropriate).

Good nutritional status is required for optimal effectiveness of all other treatments in A-T. Individuals with A-T are often malnourished, as a result of the combination of physical difficulties with eating (i.e., oral-motor problems affecting chewing and swallowing), easy fatigability, and endocrine abnormalities that affect growth [Lefton-Greif et al 2000, Lefton-Greif et al 2011, Ehlayel et al 2014, Ross et al 2015, Nissenkorn et al 2016, Natale et al 2021]. In addition to these secondary factors, the underlying molecular defect itself seems to make affected individuals prone to have poor linear growth.

Practical tips such as attention to a good sitting position, use of a straw, thickening of thin liquids, and giving children easily chewable foods may help [Ross et al 2015, van Os et al 2017a].

Gastrostomy placement early in the disease course can improve clinical outcomes [Lefton-Greif et al 2011, Ross et al 2015].

Oculomotor problems. Ophthalmologists can advise regarding visual aids that may be helpful (e.g., for reading) in the context of eye movement abnormalities.

Nystagmus and oculomotor apraxia generally do not require drug treatment.

• 4-aminopyridine did improve oculomotor and vestibular function in a small case series [Shaikh et al 2013].
• Acetyl-DL-leucine was shown to have an effect on downbeat nystagmus in a small study [Brueggemann et al 2022].

Malignancy. To date, there are no specific consensus treatment protocols for malignancies in A-T [Machida et al 2013, Pérez-Villena et al 2013, Schoenaker et al 2016, van Os et al 2017a].

Treatment protocols for an individual with A-T with a malignancy should be individualized based on patient-related factors (such as mobility, lung function) and malignancy-related factors (such as type of malignancy and alternative treatment options).

Chemotherapy in general can be initiated with dose-adjusted protocols; doses can be increased when chemotherapy is tolerated.

Radiation therapy is contraindicated in individuals with classic A-T and variant A-T because increased radiosensitivity may lead to very severe complications.

Allogenic stem cell transplantation, described in several individuals with A-T and a malignancy, has had differing outcomes. There seems to be a serious risk of adverse events when this therapy is given without an adjusted conditioning regime [Ghosh et al 2012, Ussowicz et al 2013, Beier et al 2016, Bakhtiar et al 2018, Slack et al 2018].

Cognition. When there are concerns about cognition, the following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country.

• Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.
• Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.
• All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:
  • An IEP provides specially designed instruction and related services to children who qualify.
  • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.

Behavior. Over time individuals with A-T are prone to develop cerebellar cognitive affective syndrome [Hoche et al 2014, Hoche et al 2019], for which monitoring is warranted (see Surveillance).

As individuals with A-T have a severe disorder, attention should be paid to their emotional well-being [van Os et al 2020b].

Prophylactic antibiotic treatment should be considered early in the disease course in individuals with recurrent or severe infections and in those with immunoglobulin G deficiency or specific polysaccharide antibody deficiency [van Os et al 2017a].

Immunoglobulin replacement therapy is indicated in individuals with severe IgG deficiency and in those with the hyper IgM phenotype. It may be considered in individuals with recurrent infections, mild humoral immune defects, or low antibody responses despite booster immunizations [Davies 2009].

Immunizations. Most children have had their immunizations before the diagnosis of A-T is established; generally, this goes without any complications. Inactivated vaccines are safe in all persons with A-T. Flu vaccines, 13-valent pneumococcal conjugate, and 23-valent pneumococcal polysaccharide vaccines should be given to all individuals with A-T.

Of note, in individuals with severe immunodeficiency, rubella vaccination should be avoided, as it can possibly increase the risk for granulomas [Bodemer et al 2014, Buchbinder et al 2019].

Respiratory. 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).

Anesthetic and perioperative risk. Due to pulmonary problems and often poor nutritional status, individuals with A-T are at increased risk of developing complications during and shortly after anesthesia [McGrath‐Morrow et al 2008, Verhagen et al 2009b, McGrath‐Morrow et al 2010, Lockman et al 2012]. Therefore, individuals with A-T should be operated on in a hospital with specialists with expertise in A-T. Forced weaning and early extubation can improve outcomes, specifically in individuals with severe restrictive pulmonary dysfunction [Verhagen et al 2009b].

Endocrinology. Young adults with A-T may develop insulin-resistant diabetes mellitus and hypercholesterolemia [Andrade et al 2015, Donath et al 2020], which can be treated following protocols for the general population. However, the shortened life expectancy of individuals with classic A-T can result in the decision not to treat high cholesterol levels, since treatment will not have any expected clinical consequences.

In females with gonadal failure (in case of primary or secondary amenorrhea), estrogen supplementation can prevent osteoporosis [Ehlayel et al 2014].

Growth hormone treatment may be an option for children with severe growth failure [Woelke et al 2017].

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

Note the recommended surveillance is the same for individuals with classic A-T and variant A-T, with the exception that individuals who do not have evidence of lung disease at the time of the initial diagnosis do not require annual screening for pulmonary disease.

Agents/Circumstances to Avoid

Affected individuals

• Rubella vaccination should be avoided in individuals with severe immunodeficiency as it can possibly increase the risk for granulomas [Bodemer et al 2014, Buchbinder et al 2019].
• Ionizing radiation (x-ray and gamma ray) is contraindicated, due to increased sensitivity [Lavin & Khanna 1999].
• Radiation therapy is contraindicated because increased radiosensitivity may lead to very severe complications [Perlman et al 2003].

Heterozygotes. There are no agents/circumstances to avoid.

Evaluation of Relatives at Risk

It is appropriate to offer molecular genetic testing for the ATM pathogenic variants identified in the proband to apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible:

• Sibs with biallelic ATM pathogenic variants who would benefit from prompt initiation of treatment of manifestations of A-T, surveillance for malignancy, and awareness of agents/circumstances to avoid;
• Family members who are heterozygous for an ATM pathogenic variant and who would benefit from age-appropriate intensified surveillance for breast cancer (see Clinical Description, Heterozygotes and Surveillance, Heterozygotes).

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

Therapies Under Investigation

Currently, a multicenter randomized controlled trial with intra-erythrocyte dexamethasone in patients with A-T is being conducted (see NCT03563053).

Nicotinamide riboside (a form of vitamin B₃) was shown to have a positive effect on ataxia scores and immunoglobulin levels in a proof-of-concept study [Veenhuis et al 2021a]. A second study on the same topic is being conducted (see NCT04870866).

Gene therapy with antisense oligonucleotides in A-T is currently being studied in a single case study in the United States (see www.atcp.org). To date, no toxic side effects have been reported, but the clinical effects are not available yet.

Allogenic hematopoietic stem cell transplantation in A-T has been conducted in single cases and small case series, with divergent results regarding effect on neurologic functioning [Broccoletti et al 2008, Ghosh et al 2012, Ussowicz et al 2013, Beier et al 2016, Bakhtiar et al 2018, Slack et al 2018, Duecker et al 2019].

Treatment studies with steroids in individuals with A-T. Although such studies have shown promising results for neurologic manifestations [Buoni et al 2006, Broccoletti et al 2008, Zannolli et al 2012, Hasegawa et al 2019], long-term use of steroids may potentially cause severe side effects.

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.

Mode of Inheritance

Ataxia-telangiectasia (A-T) is caused by biallelic pathogenic variants in ATM and inherited an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for an ATM pathogenic variant.
• Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an ATM pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Although individuals heterozygous for an ATM pathogenic variant are not at risk for A-T, their risk of developing cancer is increased compared to that of the general population. In particular, heterozygous females younger than age 50 years have an increased risk of developing breast cancer (see Clinical Description, Heterozygotes); intensified breast cancer screening is recommended for heterozygous females (see Surveillance, Heterozygotes).

Sibs of a proband

• If both parents are known to be heterozygous for an ATM pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and having A-T, a 50% chance of inheriting one pathogenic variant and being heterozygous, and a 25% chance of inheriting neither of the familial ATM pathogenic variants.
• Sibs with biallelic ATM pathogenic variants may show some differences in clinical presentation and laboratory findings (including immunologic abnormalities); however, the phenotype within families tends to be similar [Taylor et al 2015].
• Although individuals heterozygous for an ATM pathogenic variant are not at risk for A-T, their risk of developing cancer is increased compared to that of the general population. In particular, heterozygous females younger than age 50 years have an increased risk of developing breast cancer (see Clinical Description, Heterozygotes); intensified breast cancer screening is recommended for heterozygous females (see Surveillance, Heterozygotes).

Offspring of a proband

• Although most individuals with A-T do not reproduce, exceptions have been reported [Stankovic et al 1998; Byrd et al 2012; Dawson et al 2015; Blancato et al, unpublished data]. Reproduction has been reported in several women with variant A-T [Schon et al 2019].
• The offspring of an individual with A-T are obligate heterozygotes for a pathogenic variant in ATM and are at increased risk for cancer (see Surveillance, Heterozygotes).

Other family members. Each sib of the proband's parents is at a 50% risk of being heterozygous for an ATM pathogenic variant and at increased risk for cancer (see Surveillance, Heterozygotes).

Heterozygote Detection

Heterozygote testing for at-risk relatives requires prior identification of the ATM pathogenic variants in the family.

Although individuals with a heterozygous ATM pathogenic variant are not at risk for A-T, their risk of developing cancer is increased compared to that of the general population (see Clinical Description, Heterozygotes). In particular, heterozygous females have an increased risk of developing breast cancer, and intensified breast cancer screening is recommended [van Os et al 2016] (see Surveillance, Heterozygotes).

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous.
• ATM genetic testing should be considered for the reproductive partners of individuals known to be heterozygous for an ATM pathogenic variant, particularly if both partners are of the same ancestral background. Increased heterozygote frequencies have been reported in the following populations due to founder variants: the Druze population in northern Israel, the Moroccan and Tunisian Jewish population, and the Romani population in Spain (see Table 6).

Prenatal Testing and Preimplantation Genetic Testing

Once the ATM pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

ATM encodes a serine/threonine kinase, serine-protein kinase ATM, that is a member of the family of phosphoinositide 3-kinases. Some of these kinases, including ATM, are involved in DNA damage response and repair. Double-strand DNA breaks activate ATM, which in turn phosphorylates many substrates involved in DNA repair, cell cycle checkpoints, and apoptosis. ATM is also involved in RNA metabolism and transcription regulation that affect redox and calcium homeostasis. As such, the absence of ATM leads to disruption of multiple pathways in the cell’s nucleus, cytoplasm, as well as other cellular compartments such as the mitochondria and peroxisomes, resulting in widespread consequences. In the nervous system of individuals with ataxia-telangiectasia (A-T), abnormalities are most prominent in the cerebellum. However, many other cell types and organs are affected. Knowledge of the underlying disease mechanisms in each of these organs is still evolving [Lee & Paull 2021].

Individuals with classic A-T have no ATM kinase activity, whereas individuals with variant A-T have residual ATM kinase activity, and – compared to classic A-T – have a less severe disease course [Verhagen et al 2012].

Mechanism of disease causation. Loss of function

• Classic A-T. Many ATM variants associated with classic A-T (i.e., out-of-frame deletions or start codon, nonsense, frameshift, or splice site variants) cause loss of function, and most will lead to nonsense-mediated mRNA decay and absence of the ATM protein. Other variants (i.e., missense or in-frame deletions) may encode stable but inactive proteins.
• Variant A-T often involves variants with residual protein function. These are mainly missense variants or variants where a part of the transcript is spliced normally, despite the presence of a splice site variant.

ATM-specific laboratory technical considerations. Multiple deep intronic ATM pathogenic variants have been identified that would not be detected by standard exome sequencing [McConville et al 1996, Castellví-Bel et al 1999, Fiévet et al 2019, Schon et al 2019, Cremin et al 2020, Klee et al 2021].

If a variant of uncertain significance (VUS) is identified, additional testing such as immunoblotting for ATM and/or functional analysis of ATM kinase activity is recommended.

Acknowledgments

We want to thank all our colleagues from the multidisciplinary ataxia-telangiectasia (A-T) team at the Radboud University Medical Center for their cooperation. We also want to thank the Twan Foundation (Veenendaal, the Netherlands) for their financial support of A-T research and their social support of affected individuals and their families.

Author History

Richard Gatti, MD; David Geffen School of Medicine at UCLA (1999-2023)

Erik-Jan Kamsteeg, MD, PhD (2023-present)

Susan Perlman, MD; David Geffen School of Medicine at UCLA (2016-2023)

Nienke van Os, MD, PhD (2023-present)

Stefanie Veenhuis, MD (2023-present)

Corry Weemaes, MD, PhD (2023-present)

Michèl Willemsen, MD, PhD (2023-present)

Revision History

• 5 October 2023 (bp) Comprehensive update posted live
• 27 October 2016 (bp) Comprehensive update posted live
• 11 March 2010 (me) Comprehensive update posted live
• 15 February 2005 (me) Comprehensive update posted live
• 8 October 2002 (me) Comprehensive update posted live
• 19 March 1999 (pb) Review posted live
• 13 April 1998 (rg) Original submission

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