Background and aims Ataxia telangiectasia (A-T) is a rare progressive, multisystem genetic disease. Families of children with ultra-rare diseases often experience significant diagnostic delays. We reviewed the diagnostic process for A-T in order to identify causes of delay in an attempt to facilitate earlier identification of A-T in the future.
Methods A retrospective case note review of 79 children at the National Paediatric A-T clinic seen since May 2009. Data were collected on the nature and age of initial symptoms, the age at first presentation, measurement of alpha feto-protein (AFP) and age of genetic diagnostic confirmation.
Results At presentation, 71 children (90%) had ataxia. The median presentation delay (from first parental concern to presentation) was 8 months (range 0–118 months), and the median diagnostic delay (genetic confirmation of diagnosis) was 12 months (range 1–109 months).
Conclusions There are significant delays in presentation and diagnostic confirmation of A-T. A greater awareness of A-T and early measurement of AFP may help to improve this.
- Ataxia Telangiectasia
- Alpha Fetoprotein
- presentation delay
- diagnostic delay
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What is already known on this topic?
Families of children with ultra-rare diseases often experience significant diagnostic delays.
An important early step in the evaluation of young children presenting with ataxia should be measurement of alpha feto-protein (AFP), which is rarely normal in ataxia telangiectasia.
What this study adds?
There are significant delays in presentation and diagnostic confirmation of ataxia telangiectasia.
Early measurement of AFP may improve this.
Ataxia telangiectasia (A-T) is an autosomal-recessive, progressive, ultra-rare multisystem disease caused by mutations in the gene ATM (ataxia-telangiectasia mutated) (11q22.3) that codes ATM kinase protein. ATM kinase protein has important roles in cellular responses to damage, particularly of double-stranded DNA. The estimated UK prevalence of A-T is 3 per million,1 and hence individual clinicians are unlikely to have experience of the disease.
A-T has a large number of manifestations, including the immune system (variable degrees of immunodeficiency), increased risk of various cancers (especially lymphoid tumours), accelerated ageing and respiratory complications including, chronic sinopulmonary disease, bronchiectasis, interstitial lung disease/pulmonary fibrosis and aspiration syndromes due to the neuromuscular deficits resulting in bulbar and spinal system impairment. Ocular, cutaneous and mucosal telangiectasias form part of the clinical picture and give the condition its name. The severity of the neurological, immune system and pulmonary manifestations varies widely between patients. In the majority of cases, intelligence is normal: around 30% of patients have learning difficulties or moderate intellectual deficiency. Patients with A-T die prematurely, with the leading causes of death being cancer and diseases of the respiratory system. Elevated alpha feto-protein (AFP) levels are seen in A-T. This is of a hepatic origin as the AFP gene in the A-T liver may be under aberrant transcriptional control, perhaps secondary to a defect of DNA regulatory proteins that are necessary for hepatic maturation.2 Serum AFP concentrations vary considerably between A-T patients, increase with age and are lower in patients with variant (mild) A-T.
AFP levels are not specific to A-T and can be raised in some other neurodegenerative conditions characterised by the presence of cerebellar ataxia, abnormal ocular movements and neuropathy, but results are rarely normal in patients with A-T.3 Other neurodegenerative disorders that should be considered when encountering a child with ataxia and increased serum AFP include ataxia with oculomotor apraxia type 1 (AOA1) and ataxia with oculomotor apraxia type 2 (AOA2). In AOA1, the AFP levels are normal and telangiectasias and immunological problems do not tend to occur. In AOA2, the AFP levels are lower than in classic A-T and it has a much later onset (usually between 12 and 20 years of age) and is more common than A0A1.3 Milder variants of A-T that have some activity of ATM kinase are more common in the UK and in some cases diagnosis is significantly delayed, even until adulthood in milder forms.
An important early step in the evaluation of young children presenting with ataxia should be measurement of AFP. AFP is a cheap and simple blood test (£1.57 compared with £1.91 for a full blood count and £2.53 for urea and electrolytes).
The diagnosis of A-T should be confirmed by genetic testing. The typical form of A-T results from biallelic loss of ATM function that results in instability and total loss of the ATM protein and clinical presentation <2 years of age.4
A editorial in this journal5 discusses a Pan European proposal for a policy on rare diseases and states that, working together, “we will ensure the provision of sufficient services for expert diagnosis or confirmation of diagnosis”. In 2010, the UK's Chief Medical Officer pointed to the lack of awareness and effective services for rare diseases in the UK. He highlighted the fact that affected children are dying needlessly, after living for years with undiagnosed or misdiagnosed conditions, and called for urgent measures to improve understanding and, crucially, for more funding for services for >6000 rare diseases.6 Families and carers of children with rare diseases experience significant psychological stress due to social isolation, unemployment, diagnostic delays, uncertainty about the future, lack of information and difficulty accessing appropriate healthcare.7 Early diagnosis is important to help ensure affected children and their families receive appropriate support with proper multidisciplinary management and the opportunity to have genetic counselling support if they would like.8 Earlier diagnosis will ensure affected children can be offered tailored support from experienced professionals, via referral to the national centre, and also an opportunity to participate in research into potential therapeutic options.9 Finally, early diagnosis will lead to avoidance of radiation-based investigations, for example, high-resolution CT (HRCT) in a radiosensitive group with an increased risk of malignancy.
We hypothesised that there would be considerable delay between onset of symptoms and a confirmed diagnosis of A-T in children attending the National Paediatric A-T Clinic in Nottingham as this is an ultra-rare condition that many paediatricians have limited experience.
Data were collected via retrospective case note review (including photocopies of letters, notes and blood tests from referring hospitals and/or local information system) for children in the National A-T Clinic. Information was recorded on
The time of first documented concern from parents/carers and the nature of presenting symptoms. Where children had more than one symptom at presentation, for example, ataxia and infections, both were recorded.
The age at first presentation to any healthcare professional (primary or secondary care) with these symptoms.
The earliest time of AFP in measurement (either locally or in the national clinic) according to the available information.
The age at genetic confirmation of diagnosis.
This was used to calculate the length of presentation delay (time between first concern and first presentation to healthcare professionals) and diagnostic delay (time between presentation to healthcare professionals and genetic confirmation of the diagnosis).
Siblings of index cases were excluded from analysis of delayed diagnosis because it would be expected that a genetic disease would be considered sooner in a family with one affected child than in the general population, except for twins who presented simultaneously.
Data were collected from 79 children. There were nine sibling pairs, including one set of twins. At presentation, 71 (90%) (a set of twins were diagnosed at the same time and both were included in the analysis as two separate cases as they both presented as ‘new’ cases) children had ataxia, 13 (16%) had recurrent or persistent infections, 4 (5%) had ocular telangiectasia and 3 (4%) had malignancy. The median age at first symptoms was 18 (range 6–94) months, with a median age of first presentation of 29 (range 10–127) months. The median presentation delay was 8 (range 0–118) months (table 1).
The median age of first available AFP measurement was 60 (range 23–221) months, although we cannot exclude the possibility that some had an earlier measurement in the local clinic. All children had genetic confirmation of diagnosis and in some instances had their AFP measured at the national clinic at later date than their genetic confirmation. Genetic confirmation of the diagnosis was made at a median age of 51 (range 25–178) months. The median diagnostic delay was 12 (range 1–109) months. Thirty-nine per cent of the 79 children that data were collected from had a diagnosis at the age of 5 years or older.
We have found significant delays in presentation and diagnostic confirmation of A-T. The diagnostic delay may reflect a lack of awareness of this rare condition, the symptoms of this and the tests to do when the diagnosis is suspected. The overall delay in diagnosis is attributable to parents not seeking help for symptoms (presentation delay), which is likely to be due to a lack of public awareness of the condition and the symptoms being initially subtle (“Is the child just a bit clumsy toddler or developing ataxia?”). The diagnostic delay—the time it takes a medical professional on average to diagnose A-T–is likely to be due to the fact it is an ultra-rare disease10 that many health professionals do not consider when assessing a child. It is recognised that major efforts are also needed to train specialists with enough expertise to promptly recognise ultra-rare diseases, explore differential diagnoses and offer the most advanced treatment options.10 The article aims to increase awareness of A-T and help clinicians make the diagnosis by being more aware of the presenting symptoms and the use of AFP.
It appears that AFP testing is underused though we acknowledge that we do not have complete data on timing of the AFP tests at the ‘local clinics’, and this is a weakness of the study. However, we do believe that it is worth highlighting the use of this inexpensive quick blood test in children presenting with unsteadiness, especially when present in a child with occulocutaneous telangiectasia and/or recurrent sinopulmonary infections. Serum AFP is considered a baseline diagnostic test for children whose MRI brain scan shows cerebellar atrophy.11 If AFP is raised in an appropriate clinical setting, genetic testing for A-T should be performed.
A French national registry study has shown that the time to diagnosis of A-T decreased from 1954 to 2007, possibly because of increasing knowledge about A-T, the availability of karyotype analysis and ATM sequence analysis. The median age at diagnosis (years (IQR)) was 5.3 (2.9–8.0) and median time to diagnosis (years (IQR)) 2.8 (1.3–6.0) for their complete cohort of 240 patients. However, this has progressively improved when analysed by subgroups according to the dates of birth. The median age at diagnosis was 6.4 years and time to diagnosis 4.1 years for those born before 1980, and the median age at diagnosis was 3.3 years and time to diagnosis 2 years (at the time of analysis in 2005) for patients born since 2000.12
Our data showed diagnosis was a further year delayed compared with the most recent cohort in the French study. The proportion of patients with class A mutations (truncated or complete lack of ATM) was 73% and class B mutations (reduced expression or protein activity) was 27% in the French study, and the proportion did not change over time. Approximately 25% patients with A-T in the UK and Ireland have a milder phenotype,4 similar to the French cohort. Hence, the time to diagnosis and median age at diagnosis has progressively improved in the French study by increasing awareness of the disease rather than due to the difference in the severity of phenotypes.
The retrospective nature of the data collection is a weakness of the study, and delay times may have been overestimated or underestimated. However, it is clear that there is no room for complacency when a genetic disease takes >4 years to diagnose and takes a year longer than in France. It may be argued that, since there is no specific treatment for A-T, this does not matter, but parents spoke of their frustration at the delay in diagnosis, and this time represented a lost opportunity for the child to receive appropriate non-specific treatments such as aggressive use of antibiotics and airway clearance to prevent the development of bronchiectasis. Furthermore, the child may have had tests that are not merely unnecessary and expensive, but actually dangerous, such as chest HRCT in a child with known radiosensitivity. However, a weakness of the study is that we are unable to quantify how many unnecessary and potentially harmful investigations could have been avoided by an earlier diagnosis.
Furthermore, opportunities for genetic counselling and prenatal diagnosis in future pregnancies or the option of preimplantation genetic diagnosis to prevent the birth of another affected child may be lost. This is mirrored in our own experience, with nine sets of affected siblings attending the National Clinic.
This multidisciplinary clinic is held six times a year, over two days. Patients and their families attend either the morning or afternoon on both days. Consultations include the following paediatric specialties: neurology, clinical genetics, immunology, ophthalmology, respiratory, physiotherapy (neuromuscular and respiratory), speech and language therapy, dietetics, occupational therapy and psychology as well as a transition clinic.
The clinic is intended to be complimentary to local care arrangements and allows all the concerns of the family to be addressed at a ‘one-stop shop’ by interested and highly experienced staff. Referrals to the clinic are made through the A-T Society (http://www.atsociety.org.uk); as a direct result of a request by the families to their general practitioner or specialist; or on the initiative of a clinician to refer them directly.
In summary, there is a need for primary care clinicians and general and subspecialist paediatricians to be more aware of A-T. AFP is a cheap, simple and widely available test and should be considered early in the diagnostic work-up, in any child with otherwise unexplained ataxia especially so if there are associated frequent respiratory infections and/or occulocutaneous telangiectasia. A genetic confirmation of the diagnosis of A-T should be pursued if AFP levels are elevated.
Contributors JB, RD, MS, SP and AB made substantial contributions to the conception or design of the work, or the acquisition, analysis or interpretation of data. RD, MS, SP, AB and JB: Drafting the work or revising it critically for important intellectual content. JB and AB: Final approval of the version published.
Competing interests AB was supported by the NIHR Respiratory Disease Biomedical Research Unit at the Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.
Provenance and peer review Not commissioned; externally peer reviewed.
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