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Ataxia telangiectasia: what the neurologist needs to know
  1. May Yung Tiet1,
  2. Rita Horvath1,
  3. Anke E Hensiek1,2
  1. 1Department of Clinical Neurosciences, Addenbrookes Hospital, Cambridge, UK
  2. 2National Adult Clinic for Ataxia Telangiectasia, Papworth Hospital NHS Foundation Trust, Cambridge, UK
  1. Correspondence to Anke E Hensiek, Clinical Neurosciences, Addenbrookes Hospital, Cambridge CB2 2QQ, UK; Ahensiek{at}


Ataxia telangiectasia is an autosomal recessive DNA repair disorder characterised by complex neurological symptoms, with an elevated risk of malignancy, immunodeficiency and other systemic complications. Patients with variant ataxia telangiectasia—with some preserved ataxia telangiectasia-mutated (ATM) kinase activity—have a milder and often atypical phenotype, which can lead to long delays in diagnosis. Clinicians need to be aware of the spectrum of clinical presentations of ataxia telangiectasia, especially given the implications for malignancy surveillance and management. Here, we review the phenotypes of ataxia telangiectasia, illustrated with case reports and videos, and discuss its pathological mechanisms, diagnosis and management.


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Ataxia telangiectasia is a very rare DNA repair disorder caused by mutations in the ataxia telangiectasia-mutated gene (ATM). Affected patients have a complex neurological phenotype associated with a predisposition to malignancy, immunodeficiency and respiratory complications. With fewer than 200 confirmed cases in the UK, most neurologists will have seen very few cases. The ataxia telangiectasia phenotype varies widely; those with a mild or atypical presentation usually have an adult onset. Patients with variant ataxia telangiectasia are a diagnostic challenge and are probably often underdiagnosed or misdiagnosed.1 2 However, it is important not to miss this diagnosis, given its significant implications on management, including surveillance for immunodeficiency and malignancy, not only for patients but also their relatives.1

DNA repair disorders and neurological disease

Our DNA is under constant risk of damage; continuous DNA repair is vital to maintaining cell function.3 People with DNA repair disorders often have an increased risk of malignancy and immunodeficiency. Some DNA repair disorders, such as ataxia telangiectasia, xeroderma pigmentosum, Bloom syndrome and Cockayne syndrome, lead to sensitivity to ionising radiation. There are commonly neurological sequelae: the cerebellum seems particularly vulnerable, possibly related to the high-energy demand of Purkinje cells.4 Patients may also develop neuropathies, extrapyramidal features, cognitive impairment and seizures. However, some DNA repair disorders have no neurological involvement, such as Rothmund–Thomson syndrome, which predominantly involves skin and bone, or Fanconi anaemia. Ataxia telangiectasia manifests most aspects of the spectrum of DNA repair disorders, being associated with neurodegeneration, immunodeficiency and an increased risk of malignancy (please see supplementary figure 1).5

Clinical features

Classic ataxia telangiectasia

The classic form of ataxia telangiectasia is due to mutations that result in the complete absence of ATM kinase activity. Patients typically present in early childhood and develop a progressive neurodegenerative disorder. An elevated serum alpha-fetoprotein is a useful biomarker. The neurological presentation includes cerebellar ataxia, dysarthria, peripheral neuropathy and extrapyramidal features, including dystonia, dystonic tremor and chorea. Patients have a characteristic eye movement disorder comprising oculomotor apraxia, slow saccades and nystagmus. Ocular telangiectasiae appear by the age of 10 (figure 1) and may also occur on the skin and pharyngeal wall.6 7 Cognitive decline is uncommon, but few studies have formally evaluated this. Most patients are wheelchair dependent by the time they finish primary school.

Figure 1

Ocular telangiectasia.

The absence of ATM kinase in classic ataxia telangiectasia predisposes patients to malignancy (10–30% risk),5 and particularly lymphoid and brain tumours.8 Most people with classic ataxia telangiectasia have an immunodeficiency,9 presenting as recurrent infections, particularly respiratory tract infections, leading to bronchiectasis.7 All patients with classic ataxia telangiectasia have cerebellar atrophy on MRI, but occasionally also white matter hyperintensities (assumed to be related to white matter oedema, possibly from leaky blood vessels) or microhaemorrhages10 (figure 2). Patients usually die in their mid-20s from malignancy or infection.6 11 However, there are rare reports of people with absent ATM kinase activity who present late with mild symptoms,12 and we have one patient in her 50s who is still mobile with assistance. These unusual phenotypes most likely relate to unidentified disease-modifying genes.

Figure 2

Cerebellar atrophy (A) and white matter changes (B) in patients with classic ataxia telangiectasia. Originally published in Hensiek and Taylor ACNR 2015. (C) Microhaemorrhages in variant ataxia telangiectasia. Originally published in Schon et al Ann Neurol 2019.

Variant ataxia telangiectasia

People with variant ataxia telangiectasia have a detectable but reduced level of ATM kinase activity which leads to a milder phenotype and longer life expectancy (table 1). In particular, patients with some missense ATM mutations (giving mutant ATM) have milder symptoms.2 Patients may have minimal symptoms in childhood and only come to medical attention as adults, some being still ambulant decades after disease onset. Some people with variant ataxia telangiectasia may have normal eye movements and ocular telangiectasiae may be absent.6

Table 1

Molecular characteristics of LGI1, CASPR2, and associated proteins

In the largest published cohort of variant ataxia telangiectasia to date, including our patients in Papworth, we have observed three main clinical presentations:

  • Cerebellar ataxia ± peripheral neuropathy with minimal/no extrapyramidal features.

  • Cerebellar ataxia ± peripheral neuropathy + extrapyramidal features.

  • Extrapyramidal features without significant ataxia ± peripheral neuropathy.

About one-third of patients have predominant ataxia with or without a peripheral neuropathy (usually sensorimotor). About 10%–20% of patients have pure extrapyramidal presentations without significant ataxia or neuropathy. Most patients have a mixture of ataxia and extrapyramidal features.2

Extrapyramidal features in ataxia telangiectasia are highly variable and include cervical dystonia, dystonic tremors, orofacial dystonia, truncal dystonic spasms, chorea-athetosis, hemichorea and resting tremors1 2 13 17; these may respond to botulinum toxin, levodopa or deep-brain stimulation. Patients with pure extrapyramidal symptoms have a milder disease course1 2 6 and often first present to adult neurologists. Long diagnostic delays are common in the group, and sometimes it is not until patients develop malignancies that a more systemic genetic disorder is suspected.

In addition to the three main clinical phenotypes, there are reports of people with variant ataxia telangiectasia presenting with anterior horn cell disease or muscle weakness2 6 We have not seen this phenotype among the cohort at Papworth Hospital, although distal weakness can occur in association with axonal sensorimotor neuropathies with spinal muscular atrophy phenotypes in neurophysiology studies (see supplementary figure 2).2

Most people with variant ataxia telangiectasia have a pure neurological disorder where respiratory or immunological features are rare. Their serum alpha-fetoprotein concentration ranges from normal to markedly elevated.2 6 Although variant ataxia telangiectasia presents with a milder disease course and better overall survival the risk of malignancy is still significantly increased and a significant cause of mortality.1 2 Cancers present later than in classic ataxia telangiectasia and may precede the diagnosis of variant ataxia telangiectasia.2 13 Women with variant ataxia telangiectasia have an increased risk of breast cancer, particularly those with certain missense mutations, such as the c.7271T>G (p.Val2424Gly) variant. Most malignancies in variant ataxia telangiectasia are non-lymphoid tumours (neuroendocrine, astrocytomas, ganglioma, hepatocellular carcinoma, medulloblastoma, thyroid, pancreatic, testicular, prostate and breast), but haematological malignancies also occur.2 8 Patients are sensitive to ionising radiation and may have severe reactions to radiotherapy and chemotherapeutic agents. Heterozygous carriers also have an increased risk of malignancy, and there are specific cancer surveillance guidelines for both patients and their relatives.14

People with variant ataxia telangiectasia usually have cerebellar atrophy on MRI (as in the classic form), but white matter changes and microbleeds are rare (figure 2).

Ataxia telangiectasia-like disease

Individuals with ataxia telangiectasia-like disease, caused by mutations in MRE11, have similar neurological features to those with the variant form, including a milder phenotype and slower disease progression. There is no immunodeficiency or risk of increased malignancy. This condition is rare, with fewer than 10 currently known cases in the UK. MRE11 forms part of the MRE11-RAD50-NBS1 complex, binding broken ends of DNA and activating ATM.3 RNF168 mediates histone H2A ubiquitination in double-strand break repair. Mutations in RNF168 also lead to an ataxia telangiectasia-like disorder with a much milder phenotype.3

Potential pathological mechanisms

Ataxia telangiectasia is a DNA repair disorder, but the exact mechanism of neurodegeneration in the condition remains unknown. Various hypotheses include defective neuronal functioning from failed cell cycle regulation, defective oxidative stress and altered epigenetics.13 Purkinje cells and extrapyramidal neurones are particularly vulnerable. The atypical and very mild presentations that occasionally occur probably relate to disease-modifying genes that are currently not identified. There is increasing evidence to support the role of mitochondrial dysfunction in ataxia telangiectasia. ATM is present in the mitochondrial membrane,15 and ATP depletion leads to the generation of reactive oxygen species and ATM activation in Purkinje cells.4 Mitochondrial disorders can resemble DNA repair disorders clinically with ataxia, abnormal eye movements and peripheral nerve involvement. Novel treatments for ataxia telangiectasia have reached the clinical trial stage, with four active clinical trials currently, including one extension study (

Diagnosing ataxia Telangiectasia

Individuals with extrapyramidal disorders or cerebellar ataxia of unknown cause should be considered for testing for ATM mutations. This is particularly so in those with a raised serum alpha-fetoprotein concentration (although normal values do not exclude the diagnosis) or where there is a history or family history of malignancy. Mutations may be identified by whole-genome screening or by dedicated sequencing of the ATM gene through specialist ataxia telangiectasia services. In areas with no national specialist centre, there may still be facilities for DNA sequencing. Larger centres or commercial companies can usually offer next-generation sequencing, usually whole-exome sequencing, as well as sequencing of panels of ‘ataxia’ genes, ‘DNA repair’ or ‘immunodeficiency’ genes. Whenever possible, lithium heparin and EDTA bottle samples should be sent for ATM sequencing and functional studies including measurement of radiosensitivity, protein level and ATM kinase activity are carried out (figure 3) (see Appendix 1 for UK-based diagnostic services).5

Figure 3

How to approach a potential diagnosis of ataxia telangiectasia. ATM, ataxia -telangiectasia- mutated gene.

The most important test for confirming the diagnosis is to identify ATM mutations, and sequencing is widely available. The measurement of ATM protein and its activity may be difficult to access outside of specialist services; national ataxia telangiectasia services can arrange to receive bloods for the required tests.

Case presentations

The wide phenotypic spectrum of ataxia telangiectasia (in particular the variant and adult-onset forms) makes it a diagnostic challenge, particularly in patients with atypical or mild presentations without telangiectasiae, eye movement abnormalities or ataxia and normal serum alpha-fetoprotein. The examples below (including supplementary videos 1–5 online) highlight the phenotypic heterogeneity of variant ataxia telangiectasia.

Case 1 (and supplementary video 1)

A 44-year-old woman developed right-sided oestrogen receptor-positive breast cancer with lymph node involvement. Following lumpectomy, chemotherapy and radiotherapy, she developed a severe reaction to radiotherapy with shrinkage of the affected breast (figure 4). She walked unaided but reported mild, slowly progressive unsteadiness, thought to be chemotherapy-induced neuropathy. During the investigations of her severe radiosensitivity, she was eventually found to have biallelic mutations in the ATM gene. She had reduced ATM kinase activity, and skin fibroblasts showed increased radiosensitivity, confirming a diagnosis of variant ataxia telangiectasia.14 18 When first seen in our clinic, there were normal eye movements without ocular telangiectasia and no oculomotor apraxia or nystagmus. She had an ataxic gait, dysmetria and reduction of vibration sense up to the knees (supplementary video 1). Her electromyography confirmed a mild axonal polyneuropathy.

Figure 4

Severe reaction to radiotherapy in a patient with variant ataxia telangiectasia.

Table 2

Differential diagnoses of classic ataxia telangiectasia.3 5 AD, autosomal dominant; AR, autosomal recessive

Key message

This patient initially presented with breast cancer and a severe reaction to radiation that raised the possibility of a DNA repair disorder. The subsequent findings of a neurological disorder (ataxia and neuropathy) pointed towards a diagnosis of ataxia telangiectasia. The fact that she had only very mild neurological involvement in her fifth decade emphasises the wide phenotypic spectrum of variant ataxia telangiectasia.

Case 2

A 15-year-old boy gave a 1-year history of progressive right-sided torticollis, postural hand tremor, laryngeal dystonia, clawing of the fingers and chorea. He had ocular telangiectasia but no ataxia and normal eye movements. He was one of five children. His older brother and a younger sister were also affected. He and his siblings all had elevated serum alpha-fetoprotein concentrations, and all improved with levodopa treatment. His parents were unaffected. Discovered using exome sequencing, this patient carried compound heterozygous in pathogenic mutations (frameshift and missense) in ATM, leading to skipping of exon 44, known to cause variant ataxia telangiectasia. One unaffected male sibling, who carried a single copy of the frameshift mutation, had two affected daughters who were homozygous for the frameshift mutation (the sibling and his partner were probably consanguineous).16

Key message

This boy presented with a dopa-responsive extrapyramidal syndrome, but no other neurological abnormalities. In particular, there were no ataxia and normal eye movements. His case highlights that variant ataxia telangiectasia can present with pure extrapyramidal symptoms, and it is important to consider this diagnosis in people with dystonia and to check serum alpha-fetoprotein as a matter of routine.

Case 3 (and supplementary video 2)

A 59-year-old woman gave a 20-year history of slowly progressive ataxia (supplementary video 2). She had a dysplastic colonic polyp removed in her 40s, but there was no family history of neurological disease or malignancy. On examination, she had dysarthria and mild upper limb ataxia. She had slow saccades but no nystagmus or oculomotor dyspraxia, and no ocular telangiectasiae. She could walk with a stick and had an ataxic gait, impaired heel–shin coordination and dystonic hand and foot posturing. Her reflexes were preserved and power was normal. Her serum alpha-fetoprotein level was 11 ng/mL (normal 0–10). She had been diagnosed with variant ataxia telangiectasia at the age of 56 after a genome screen.

Key message

This patient presented with late-onset very slowly progressive ataxia. Her serum alpha-fetoprotein was only just outside the normal range, and she had none of the classic clinical features or family history to suggest ataxia telangiectasia. This case highlights the wide phenotypic spectrum and the need for clinicians to have a low threshold to consider this diagnosis in anyone with an undiagnosed cerebellar or extrapyramidal syndrome, even if there are none of the usual pointers towards the diagnosis.

Case 4

A 19-year-old woman had been noticed to be slightly clumsy when in primary school, with intermittent involuntary movements; a paediatric neurologist had assessed her but with no diagnosis. At the age of 9 years, she developed acute lymphocytic leukaemia, now in remission. Her neurological symptoms had never significantly progressed, and she was currently not limited in her activities and could still run and participate in sports. She had three healthy sisters. On examination, she had slow saccades and broken smooth pursuit eye movements with very occasional myoclonic limb and truncal jerks. There were no ocular telangiectasiae, and neurological examination was otherwise normal, with a Scale for the Assessment and Rating of Ataxia score of 3/40, indicating mild disease. Her serum alpha-fetoprotein was 2 ng/mL (normal 0–10). She has two pathogenic mutations in the ATM gene with a greatly reduced ATM protein concentration, but some detectable kinase activity.

Key message

This patient had only minimal neurological symptoms and a normal serum alpha-fetoprotein. However, she had a history of leukaemia, and this, together with some neurological symptoms, should raise the possibility of ataxia telangiectasia, even with a normal serum alpha-fetoprotein.

Differential diagnosis and mimics of ataxia telangiectasia

We have illustrated chameleons of ataxia telangiectasia that resemble dopamine-responsive dystonia (case 2) and adult-onset ataxia (case 3). The very wide phenotypic spectrum of ataxia telangiectasia, particularly its variant types, makes it a diagnostic challenge (see table. Case 5 is an example of an ataxia telangiectasia mimic. Tables 2 and 3 list the important differential diagnoses of classic and variant ataxia telangiectasia and their clinical features.

Table 3

Differential diagnoses for variant Ataxia-Telangiectasia17 AD = autosomal dominant, AR = autosomal recessive, XL = X-linked

Case 5

A 43-year-old-man presented with ataxia and neuropathy. His neurological phenotype was compatible with ataxia telangiectasia, although there were atypical features including reported bladder dysfunction and a demyelinating rather than axonal neuropathy. He had a single pathogenic ATM mutation only, together with a single-nucleotide variant of unknown significance c.4424A>G (p.Tyr1475Cys) in ATM. His ATM protein levels were reduced but he had normal ATM kinase activity, which would be unusual in variant ataxia telangiectasia. Eventually, he underwent an ataxia panel, which identified that he had autosomal recessive ataxia of Charlevoix-Saguenay.

Key message

Although this patient had ataxia and neuropathy, he had some features that were atypical of ataxia telangiectasia (bladder dysfunction and demyelinating neuropathy). The single pathogenic mutation led to a reduction of ATM protein levels, but the normal ATM kinase level made ataxia telangiectasia unlikely (it is typically absent or reduced in people with ataxia telangiectasia). This case highlights how variants of unknown significance should be interpreted with caution.

Classic ataxia telangiectasia

This condition usually has a uniform presentation, invariably with young onset, and with oculomotor apraxia, ataxia, neuropathy, ocular telangiectasia, extrapyramidal signs, myoclonus and systemic complications with reduced life expectancy. Table 2 shows mimics of classic ataxia telangiectasia.

Variant ataxia telangiectasia

Variant ataxia telangiectasia is often pnly evident inadulthood and can progresses only slowly. Serum alpha-fetoprotein can be normal, and the classical eye movement disorder and ocular telangiectasia may be absent. Patients often have an exclusively neurological presentation with no systemic involvement. The neurological features may vary widely, including pure extrapyramidal presentations without ataxia, leading to many mimics (Table 2).


Ataxia telangiectasia is a complex and life-limiting disease that requires multidisciplinary management (figure 5). People with classic ataxia telangiectasia typically have immunodeficiencies; their management should be supervised by an immunologist and includes immunoglobulin replacement, vaccination and prophylactic antibiotics. Patients are prone to aspiration, and early gastrostomy or jejunostomy may improve their prognosis. Active respiratory surveillance and management are important to prevent recurrent pulmonary infections, bronchiectasis or neuromuscular breathing problems. Neurological management is mainly symptomatic, including botulinum toxin or deep-brain stimulation for dystonia. Genetic counselling should be considered not only for patients but also first-degree relatives who may require specific malignancy surveillance.

Figure 5

Management of ataxia telangiectasia patients and their families.

People with ataxia telangiectasia are sensitive to therapeutic doses of ionising radiation and need to avoid repeated irradiating scans. Where possible, consider alternative imaging modalities such as MRI.5 Ataxia telangiectasia patients are also vulnerable to chemotherapy-related toxicity. We advise liaising with national specialist ataxia telangiectasia clinics and charities for further guidance.5

Malignancy surveillance includes annual breast MRI for female patients from the age of 25 years; female carriers require mammograms every 18 months between ages 40 and 50 years, as part of the national breast screening programme.5

National ataxia telangiectasia clinics

We recommend that all patients diagnosed with ataxia telangiectasia are referred to specialist ataxia telangiectasia centres, if possible. Many European countries have a de facto specialist clinic for ataxia telangiectasia, by virtue of the particular interest of one or more clinicians (neurologist, paediatrician, geneticist or immunologist). All the larger European countries, therefore, have effective centres. Also, there are major recognised specialist centres in North America and internationally, where there is access to genetic services and who can help.

The UK has two National specialist clinics for ataxia telangiectasia (for adults at Papworth Hospital, Cambridge, and for children at Nottingham City Hospital). The national specialist clinics also actively recruit patients into clinical trials and natural history studies. Patient organisations such as the Ataxia-Telangiectasia Society (, Action for Ataxia-Telangiectasia ( and the Ataxia-Telangiectasia Children’s Project ( provide excellent support for patients and families.


Ataxia telangiectasia is a very rare but life-limiting disease. When ATM kinase is absent, it has a classical presentation; when there is residual ATM kinase function, the disorder is heterogeneous (variant ataxia telangiectasia) with milder phenotypes and a late presentation. This can lead to a long diagnostic delay of even decades. It is worth considering ataxia telangiectasia in people with pure ataxias and pure extrapyramidal phenotypes, with or without systemic complications. A family history of malignancy and immunodeficiency may suggest the diagnosis. It is important to avoid diagnostic delay as even mildly affected patients and heterozygote carriers require malignancy surveillance.

Key points

  • Ataxia-telangiectasia is an autosomal recessive DNA repair disorder, leading to neurodegeneration, malignancies and immunosuppression.

  • The phenotype of variant ataxia-telangiectasia is widely variable and may present as a pure extrapyramidal disorder or with only mild neurological symptoms.

  • Clinicians should have a high index of suspicion in patients with a neurodegenerative disorder and consider the diagnosis even if eye movements or serum alpha-fetoprotein is normal.

  • Both classic and variant ataxia-telangiectasia are associated with an increased malignancy risk for patients as well as heterozygous carriers.

  • Families with the condition require multidisciplinary management including malignancy surveillance.


  1. Schon K, van Os NJH, Oscroft N, et al. Genotype, extrapyramidal features, and severity of variant at axia-telangiectasia. Ann Neurol 2019;85:170–80.

  2. Taylor M, Bhatt J, Brown A, et al. Ataxia-telangiectasia in children guidance on diagnosis and clinical care. Ataxia-Telangiectasia Soc 2014;1–31.

  3. Rothblum-Oviatt C, Wright J, Lefton-Greif MA, et al. Ataxia telangiectasia: a review. Orphanet J Rare Dis [Internet] 2016;11:1–21.


We thank Professor Malcolm Taylor, Institute of Cancer and Genomic Sciences, University of Birmingham, for his advice during the preparation of this manuscript. The study was supported by the Medical Research Council (UK) (MR/N025431/1 to RH) and the Wellcome Investigator fund (109915/Z/15/Z to RH). MT is funded by Addenbrooke’s Charitable Trust (900214). The study was supported by the Medical Research Council (UK) (MR/N025431/1 to RH) and the Wellcome Investigator fund (109915/Z/15/Z to RH).



  • Correction notice This article erroneously published with an open access licence in print. This article has been published under a standard licence.

  • Contributors MT, RH and AH contributed to the drafting of the text and preparation of figures. MT edited the supplementary videos.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Consent obtained directly from patient(s).

  • Provenance and peer review Commissioned. Externally peer reviewed by Rajith de Silva, London, UK.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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