An atypical presentation of ataxia telangiectasia in a school-aged boy secondary to an intronic mutation

Ataxia telangiectasia (AT) is a DNA breakage syndrome caused by mutations in ATM, a large gene comprising of 66 exons as well as pseudo-exons (Platzer et al. 1997). The ATM gene product, the serine/threonine kinase ATM, is essential in induction of cell-cycle arrest and activation of repair mechanisms following detection of double-stranded DNA breaks. Given the ubiquitous nature of ATM activity, AT is marked by a multi-systemic presentation. A hallmark feature of AT is early-onset progressive ataxia, usually occurring between ages 2 and 5 years, with patients often becoming wheelchair-bound by age 10. Other typical manifestations include oculocutaneous telangiectasias, sinopulmonary infections, radiosensitivity and malignant predisposition (Teive et al. 2015). Surrogate markers in patients with AT include an elevated alpha fetoprotein (AFP), and abnormal chromosomal breakage studies. However, a definitive diagnosis requires the detection of biallelic mutations in ATM (Platzer et al. 1997; Yanofsky et al. 2009; Teive et al. 2015).

In recent years, cases of atypical AT have been increasingly reported. Such patients may present with unusual features such as dyskynesia, dysarthria, hypotonia, parkinsonism, or early malignancy, with few or no telangiectasias. While elevated AFP is seen in most cases, biallelic exonic mutation in ATM are not always detected (Platzer et al. 1997; Yanofsky et al. 2009; Teive et al. 2015). We hereby present a school-aged boy, who presented with late-onset progressive neurological decline and sinopulmonary infections. He was found to have a novel homozygous intronic mutation in the ATM gene, establishing a novel cause of atypical AT.

We report a case of a boy with late-onset AT and unusual disease manifestations, found to have a homozygous splice-site mutation in ATM. This may result in a “leaky” splicing or regulatory mutation, allowing for some gene product to be formed, possibly explaining the delayed presentation and unusual features. Our patient had 2 possibly affected cousins who had passed away at ages 6 and 22. Although the cause of death was never determined for those family members, it is likely that they had shared the same mutation as our patient, in particular given reported issues with ambulation in both cases. This suggests that prognosis may be similar for our patient, despite the relatively delayed onset of symptoms in this case.

The phenomenon of atypical or late-onset AT has been a topic of interest in recent years. In a study, Verhagen et al. (2012) demonstrated that the presence of residual ATM may result in a less severe phenotype. Cases correlating with residual kinase activity may manifest with less pronounced neurological symptoms, little or no telangiectasias, normal immunoglobulins levels, and later onset of malignancy (Verhagen et al. 2012). From a genetic standpoint, atypical or “leaky” presentations may be explained by regulatory or splicing mutations, allowing for some production of ATM kinase. Indeed, in a study, Teraoka et al. (1999) found that 30 out of 62 patients with ataxia telangiectasia had mutations resulting in defective splicing. Such mutations may result in exon skipping, intron retention, or activation of cryptic splice sites. Importantly, testing for ATM mutations in current clinical practice typically involves sequencing of the exonic portion of the gene only, which will not detect deep intronic mutations (Coutinho et al. 2005).

The notion of intronic splicing mutation in ataxia telangiectasia has other important implications which will need to be considered. From the prognostic perspective, data regarding long-term outcome in cases of atypical or leaky AT is scarce. A second point relates to family member counselling. It is known that heterozygous carriers of ATM gene mutations are at increased risk of breast cancer; however, it is unclear whether this is the case for intronic splicing mutations as well. In this regard, a recent study has identified intronic mutations resulting in micro-satellite instability in a subset of patients with gastric cancer, suggesting that such mutations may in fact be related to malignant predisposition (Kim et al. 2013). Finally, the presence of intronic mutations may have implications on developing therapies which target rescue of splicing defects, as has already been demonstrated both in vitro and in vivo for other conditions, such as Duchenne muscular dystrophy (Cavalieri et al. 2013).

We conclude that AT may present with unusual neurologic features, and with a late-onset. We caution clinicians to suspect a diagnosis of AT in patients with progressive cerebellar abnormalities and signs of immunodeficiency, even in the absence of telangiectasias and other classical features of AT. In such cases, screening with alpha fetoprotein is a simple, fast and reliable initial test, which should be elevated even in patients with atypical presentations. For definitive diagnosis, we recommend sequencing of the full ATM gene to detect deep intronic mutations. Further longitudinal data and research is required to counsel patients with atypical AT, as well as family members who are carriers of intronic mutations in the ATM gene.