Ataxia-telangiectasia

Discussion

We describe an unusual AT phenotype, characterized by a clinical presentation mimicking the classic severe form with the typical biomarkers of this condition, such as absent ATM protein,⁷ 14 chromosome rearrangement, and increasing levels of AFP, with an unexpected favorable course of neurologic disorders during teenage years.

The ATM protein level and residual kinase activity seem to influence the severity of the clinical phenotype in patients with AT. Variant AT has been documented in patients presenting with a mild neurologic phenotype, often normal brain MRI, and less frequent extraneurologic involvement. In these cases, regulatory, missense, or leaky splicing ATM mutations and a residual ATM activity were detected.⁴ The genotype of our patient is characterized by an inframe deletion and a missense mutation without residual ATM activity. Accordingly, a classic presentation and outcome should have been expected. Recent reports showed that absent ATM activity and high AFP may be associated with a late-onset or atypical neurologic presentation (table e-3, links.lww.com/NXG/A45). Of interest, 3 patients belonging to the Canadian Mennonites with late dystonia/myoclonus-dystonia syndrome associated with 6200C>A mutation had transient ataxia in early childhood. The same genotype has been reported in a patient with early-onset myoclonus-dystonia, high blood AFP, and progressive cerebellar atrophy.⁴

In contrast to these cases, our patient experienced the classic presentation and course of the disease until the end of the first decade of life when progressively ataxia vanished, leaving a mild and stable choreic disorder. Nevertheless, AFP and some systemic manifestations of AT (such as ovarian polycystic syndrome, liver steatosis, and neoplasm) occurred. The assumption that the AFP level may mirror the progression of the disease remains debated.⁸ In our patient, the AFP level increased, despite the improvement in neurologic disorder.

The atypical favorable outcome reported in our patient suggests the possible effect of epigenetic modifying factors, which may confer resilience to the disease in some subjects. One modifying factor of the effect of ATM loss has been identified in the Rad50^s allele of the gene encoding the Rad50 component of the Mre11/Rad50/Nbs1 complex. In the murine model, Rad50^s has a role in alleviating senescence, radiosensitivity, and tumor formation, all hallmarks of ATM-deficient mice.⁹ Moreover, recent data suggested a pivotal role of the Rad50 hook domain in influencing the Mre11 complex-dependent DNA damage response. In our patient, peripheral Rad50 expression overlaps that detected in patients with AT with a typical phenotype. A further hypothesis concerns the variability in the maintaining of the cellular balance of reactive oxygen species, which cause, among the others, defects in hematopoietic stem cells¹⁰ and neurodegeneration.

In a recent article, we identified the transcriptome profile of patients with AT with respect to healthy controls.⁵ The present case exhibited transitional probe expression from that found in patients with classic AT and healthy controls. However interesting, this result requires caution because only known probes were screened while we were unable to determine whether unknown and unpredicted contributing events, such as splicing pattern alteration, could take place. In any case, the observed gene expression variation was part of the final outcome of the patient's biological individuality.

The 2 most important genes expressed were scrb1 and thoc3, which are involved in wound reparation and genome stability, respectively. Thoc3 is part of the THO complex, which plays a role in transcriptional elongations, nuclear RNA export, and genome stability.

The finding of a transitional transcriptome profile suggests the occurrence of modifying factors possibly influencing individual vulnerability and resilience to the altered ATM synthesis resulting in an unexpected mild outcome.