The natural history of ataxia-telangiectasia (A-T): A systematic review

Abstract

Background: Ataxia-telangiectasia is an autosomal recessive, multi-system, and life-shortening disease caused by mutations in the ataxia-telangiectasia mutated gene. Although widely reported, there are no studies that give a comprehensive picture of this intriguing condition.

Objectives: Understand the natural history of ataxia-telangiectasia (A-T), as reported in scientific literature.

Search methods: 107 search terms were identified and divided into 17 searches. Each search was performed in PubMed, Ovid SP (MEDLINE) 1946-present, OVID EMBASE 1980 -present, Web of Science core collection, Elsevier Scopus, and Cochrane Library.

Selection criteria: All human studies that report any aspect of A-T.

Data collection and analysis: Search results were de-duplicated, data extracted (including author, publication year, country of origin, study design, population, participant characteristics, and clinical features). Quality of case-control and cohort studies was assessed by the Newcastle-Ottawa tool. Findings are reported descriptively and where possible data collated to report median (interquartile range, range) of outcomes of interest.

Main results: 1314 cases reported 2134 presenting symptoms. The most common presenting symptom was abnormal gait (1160 cases; 188 studies) followed by recurrent infections in classical ataxia-telangiectasia and movement disorders in variant ataxia-telangiectasia. 687 cases reported 752 causes of death among which malignancy was the most frequently reported cause. Median (IQR, range) age of death (n = 294) was 14 years 0 months (10 years 0 months to 23 years 3 months, 1 year 3 months to 76 years 0 months).

Conclusions: This review demonstrates the multi-system involvement in A-T, confirms that neurological symptoms are the most frequent presenting features in classical A-T but variants have diverse manifestations. We found that most individuals with A-T have life limited to teenage or early adulthood. Predominance of case reports, and case series demonstrate the lack of robust evidence to determine the natural history of A-T. We recommend population-based studies to fill this evidence gap.

Fig 1. PRISMA diagram.

Fig 2. Number of cases per study.

Fig 3. Family history of other illness, and presenting symptoms and signs.

Fig 4. Ataxia, mobility, eye movements, oculomotor apraxia, and other neurological manifestations.

Fig 5. Tone and weakness, movement disorders, cerebellar signs, immunoglobulin levels, immunoglobulin replacement, and prophylactic antibiotics.

Fig 6. Age at start of prophylactic antibiotic and immunoglobulin replacement, non-infectious respiratory manifestations, and malignancy.

Fig 7. Alpha fetoprotein (AFP), endocrine, bulbar telangiectasia, skin, and orthopaedic manifestations.

Fig 8. Gastrointestinal, neuroimaging, cognitive and educational manifestations, and cause of death.