Ataxia-telangiectasia (AT) is a rare autosomal recessive multisystem disorder caused by mutations in the ataxia telangiectasia mutated (ATM) gene encoding a protein kinase with a key role in the cell cycle control and DNA repair (1, 2). Given the residual kinase activity and the type of ATM mutation, the clinical spectrum of AT varies from a severe (early-onset and rapidly progressing neurodegeneration classic) phenotype to a variant atypical form (a relatively mild neurological phenotype and a lower risk of systemic complications) (3).

Classical AT is characterized by early childhood-onset cerebellar ataxia, telangiectasia, immunodeficiency, increased serum alpha-fetoprotein (AFP) levels, autoimmune or other chronic inflammatory diseases, radiosensitivity, and increased susceptibility to malignancies. Most children are usually wheelchair-bound by age 10 years and die in the second decade of life due to malignancies or respiratory failure (4–6). In contrast to the classical AT group, variant AT patients with milder late-onset atypical phenotypes characterized by a predominance of extrapyramidal features (instead of cerebellar), late ataxia onset, slower neurologic progression with a mild phenotype, and an extended lifespan. Respiratory diseases and immunodeficiency are less severe in variant AT; however, the risk of malignancy is likely high, and such patients may also be radiosensitive (7–9). Overall, the classical form is caused by biallelic deleterious ATM mutations, which lead to a total loss of ATM protein, while majority of patients with milder phenotypes carry at least one missense or leaky splice site mutation (still producing the protein with residual function or kinase activity) (8). Moreover, some reports suggest that besides residual ATM kinase activity, other factors such as modifying genes and environmental factors might be involved in the presentation of milder phenotypes of AT (10).

Here, we describe three Iranian AT patients with variant atypical phenotypes who presented late-onset manifestations and developed autoimmunity in the course of the disease. For the first time, we reviewed systematically the literature of all previously reported AT atypical patients who had non-ataxia dominant signs or had late-onset ataxia presentation to illustrate a comprehensive picture of the milder AT phenotype.

Here we reported 3 variant atypical Iranian AT cases (1.2% of total 249 AT patients registered in the national database of primary immunodeficiency) with late-onset of ataxia despite the presence of homozygous deleterious ATM mutation. Surprisingly, all of these cases presented autoimmune disorders. Moreover, for the first time, we comprehensively reviewed 73 reported variant AT patients with atypical late-onset ataxia in terms of clinical, immunological and genetic findings. In contrast to currently reported cases, we found that biallelic mild mutations mainly lead to an atypical phenotype with an increased risk of cancer (47). Our study confirms that disease severity in variant AT is milder compared to the classical form. Similar to what was observed in our cases, more than 70% of reported patients were not wheelchair-bound at the last examination, indicating unexpected slow progression in variant AT patients. Wheelchair use as a result of progressive cerebellar ataxia, presenting in early childhood, is a characteristic feature of classical AT patients (4, 48). This is consistent with our findings that even atypical patients with the severe phenotype (wheelchair-bound) demonstrated a significantly lower age of presenting onset and ataxia onset than other groups.

Previous reports revealed that within variant atypical AT patients, extrapyramidal movement disorders are dominating presentation rather than cerebellar signs. Extrapyramidal symptoms are commonly observed in predate ataxia in these patients, and the later occurring ataxia is of mild to moderate degree (7, 8). However, our study showed that in long follow-up they can occur relative to the same extent. On the other hand, Verhagen et al. (7) revealed that variant atypical AT patients generally presents with extrapyramidal symptoms such as chorea and resting tremor, respectively. We observed that tremor and chorea after ataxia were the most frequent presenting manifestation. Dystonia generally appears as a late manifestation and rarely develops as a presenting feature in AT patients (49). Incompatible with a report by Méneret et al. (50), in which dystonia was the presenting feature in 14% of variant patients, only 5% of reported variant atypical AT patients in our literature review presented with dystonia. As observed in our 3 cases, the majority of reported patients showed neurological abnormalities. However, two patients (P2 and P7) reported by Trimis et al. (51) and Soresina et al. (52) did not present neurological involvements but both had a history of telangiectasia, frequent respiratory infections, elevated serum IgM, and mild mutations. The absence of neurological features makes many difficulties in the diagnosis of the disease, especially in this type of variant, as patients might lead to being misdiagnosed as hyper IgM syndrome (HIgM). It has been postulated that other genetic modifiers or environmental factors can affect the neurological and clinical features of AT (52) as classical AT were observed in the close relatvies of two of our newly reported patients, most likely with the same ATM mutations. Cerebellar ataxia and extrapyramidal symptoms, similar to our 3 cases, were seen in most of the reported atypical patients indicating that these patients are vulnerable to both pathophysiologic mechanisms.

Dysarthria, as a most frequent cerebellar symptom (after ataxia), has been reported in 80% of AT patients (53); however, our study revealed a lower frequency of dysarthria in variant AT patients (Cases 2 and 3 of the present study and 64% of previously reported patients). In accordance with previous reports, the most common extrapyramidal symptoms were dystonia and tremor in reported variant AT (50). Carrillo et al. (54) reported that patients presenting predominant dystonia tend to have a later onset and a milder disease course. However, some studies observed the rare existence of dystonia among adolescents and adult AT patients (55). Nonetheless, it remains unclear at this time if the dystonic presentation is related to a specific genotypic abnormality (54). Chorea presented in 28% reviewed variant AT atypical patients; in contrast, few studies reported chorea mostly in mild patients (7). Méneret et al. (50), did not find chorea in any of their variant atypical patients, suggested that myoclonic dystonia in patients who were only assessed clinically can easily be mistaken for chorea. On the other hand, as severe chorea may cover the presence of ataxia, it should be considered that not all neurological signs indicate the cerebellum as the central lesion (49). Apraxia, as a hallmark of atypical AT, was appeared only in 25% of reported variant patients (7, 56). However, there is no direct correlation between the severity of eye movements and the severity of other neurologic symptoms (53).

In imaging of variant atypical AT patients, cerebellar morphology is often normal (5), though our study shows that only 35% reported atypical patients did not have cerebellar atrophy. However, a hypothesis suggested that some defects in abnormal ATM function may lead to cerebellar atrophy (57). Although multiple studies revealed that AT almost universally affects the cerebellum, the integrity of other mechanisms such as the anterior horn cells, basal ganglia, peripheral nerves, and dorsal columns may be influenced heterogeneously by the disease process (58, 59). Moreover, a significant increase in the frequency of cerebellar atrophy in the severe group demonstrate the relationship between the cerebellar atrophy and its effect on the walking ability of the patient; however, a relatively minor role of cerebellar cortical volume in the immediate expression of the neurodegeneration of AT has been reported (60).

Immunodeficiency with great variability is a characteristic feature of 60%–80% of AT patients (49); however, it is rarely observed in mild AT forms (7). As observed in the currently reported 3 cases, about 38% of individuals had an immunoglobulin deficiency, although most of them did not present considerable clinical features suggesting immune system dysfunction. It has been recognized that patients with ATM protein expression have an ameliorated immunological phenotype regardless of the presence or absence of residual kinase activity (8). On the other hand, patients with no kinase activity present significantly more severe immunological phenotypes than those with low levels of ATM activity (61). Besides, Van Os et al. (9) reported no correlation between the immune defects and expression of the ATM protein in AT. One possible mechanism of immunodeficiency has been proposed to small thymuses with poorly developed Hassal’s corpuscles in AT patients (62). Moreover, it has been reported that defective DNA repair and high levels of ROS production following dysfunction of ATM leads to the induction of apoptosis and cell death in ATM-deficient T cells (4). In terms of immunodeficiency, approximately 10% of AT patients exhibit the HIgM phenotype in which respiratory infections manifest at a very young age (63). Since neurological symptoms in these patients could be mild or absent, this could lead to misdiagnosis of variant AT with HIgM syndrome (64). Similar to cases 1 and 2 in the present study 10% of variant patients presented HIgM phenotype, as all were homozygous for a truncating mutation predicting the absence of ATM protein. The HIgM phenotype of AT is also associated with autoimmunity and cutaneous granulomatous disease (65–68). Except for case 3 of the present study, all reported patients with autoimmunity and cutaneous granuloma presented with HIgM phenotype along with splenomegaly. The etiology of these complications is not well-defined, but it seems that reduced regulatory T cells and increased ratios of CD21^−/low B cells, as well as disturbed naïve T and B cells along with splenomegaly, could be attributed to these patients (64–66). However, in our 3 evaluated cases, despite a decrease in naïve and regulatory T cells, nobody had an increase in CD21^−/low B cells. Our findings confirm our previous observation in which AT patients with class switch recombination (CSR) defect had lower CD21^−/low B cells compared to remaining (CSR Normal) patients (13). On the other hand, it has been reported that an abundance of CD21^−/low B cells in AT patients is associated with an increase of naïve B cell proliferation (69). Increased CD21^−/low B cells and its association with autoimmunity and splenomegaly have been reported by in common variable immunodeficiency (CVID) (70, 71), however there are no other reports in AT patients to show an increase of this subset in autoimmune disease.

Rearrangements of chromosomes 7 and 14 presented in most reported variant AT patients in this study. Interestingly, the same was true for all reported variant AT patients in the literature (72). On the other hand, it has been postulated that chromosomal translocation between chromosomes 7 and 14 that are associated with Ig/TCR genes may be involved in Immunodeficiency in AT patients (73). This is confirming our data that the frequency of immunodeficiency and karyotype abnormalities are relatively associated among the groups. Also, by comparison, the frequency of karyotype abnormalities and immunodeficiency between our 3 groups, we demonstrated the inverse relationship between the frequency of them with the severity of neurological phenotypes, which indicates the severity of neurological phenotypes are not associated with the occurrence of karyotype abnormalities and immunodeficiency.

Among AT patients, the lifetime risk of malignancy is 10%–38% (74, 75). Furthermore, Verhagen et al. reported that cancer can occur later in the life of variant AT, which typically consists of solid malignancies rather than lymphoid cancer (7, 8). In line with the literature, 21% reported atypical patients who suffered from malignancies presented mostly in adulthood with predominately solid tumors. We found that about 85% of individuals with malignancy had a missense mutation, which can cause the production of a mutant ATM protein with retained kinase activity. Our findings correspond with the results of Schon et al. (47), indicating variant patients with a missense mutation are almost fivefold more at-risk to develop a malignancy. Moreover, previous reports revealed p.Ala2067Asp and p.Val2424Gly missense mutations as a high-risk cause of malignancy (76, 77). The nature of the underlying ATM mutation, which on the one hand does not protect against cancer development or radiation damage, but on the other, allows ATM expression with sufficient activity to protect against severe neurodegeneration, has not been fully understood. Maybe modifying genes/regulators affect these clinical and cellular responses (78). Infection and malignancy are the main causes of mortality in patients with AT (9). Our report revealed that malignancies, instead of respiratory failure, were the main cause of death in variant AT patients, which is similar to previous reports (8).

Consistent with the expected notion, we found that more than 80% of individuals had a missense mutation, possibly causing milder neurological features (7, 50). Although the correlation of neurodegenerative phenotype and defect of ATM is unclear, the hypothesis suggested that ATM protein expression may allow neurons to initiate apoptosis pathways or repair damaged DNA (79, 80). On the other hand, Verhang et al. (7) suggested that in AT variant, a better-conserved function of the mitochondrion due to less oxidative stress as a consequence of residual ATM kinase activity can describe the milder clinical symptoms. They also suggested that some splicing mutations with less ATM protein expression and kinase activity may result in a more severe phenotype rather than missense mutation. Besides, some cases (P26 and P27) showed no ATM kinase activity associated with the expressed protein despite ATM missense mutations and reduced ATM protein expression. A more sensitive assay would help detect low differential levels of ATM activity associated with different ATM proteins, while there may be some activity retained to cause milder features of the disease (47). Another possible explanation is that missense mutation in the kinase domain, may lead to a normal level of protein expression but not functional (kinase-dead) protein (81).

Here, we show that similar to our 3 cases, approximately 9% of variant AT patients with mild clinical phenotype can appear with the presence of null ATM mutations (frameshift and nonsense mutations causing truncation), leading to an absence of ATM protein and no kinase activity. These observations raise the possibility that the neuronal cells of these patients are affected by a modifying gene leading to a compensatory pathway that protects against the consequences of ATM loss (57). The rarity of such patients probably indicates that the highly influential alleles of such modifier genes are rare (60). Rarely, patients with mild or classical AT show a normal intensity of the ATM band on a Western blot (82, 83); as our study revealed that 9% of variant AT patients showed a normal ATM protein expression. One of the limitations of our study is that we did not have extra access to the material to check the level of ATM protein as well as its activity in our patients. Our previous report also showed that approximately 90% of AT patients with classical presentations had a homozygous mutation (84); however, we found that more than 60% of the reported variant AT patients had a compound heterozygous mutation. However, we did not find a significant genotype-phenotype association with regards to neurological groups in the study overall, indicating an additional influence of shared environmental factors or disease-modifying genes. Future examination of newly identified ATM functions may provide vital insights into the relationship between mutation and phenotype (10, 85–89).

There is no universally accepted definition of the variant AT phenotype. The clinical spectrum of these atypically affected AT patients may be similar, although the underlying causative ATM mutations may be different. Our results support previous results that AT is not only due to pure ataxia and may appear as only different extrapyramidal signs or even normal neurological symptoms. As they are likely to be under or misdiagnosed, early diagnosis using newborn screening or unbiased next-generation sequencing on suspected individuals is crucial considering the increased risk of malignancies, the related higher risk for side effects of radiation and certain chemotherapy regimens in cancer treatment, genetic counseling, carrier detection within the affected family, and prenatal diagnosis.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

Patients signed informed consent regarding publishing their data and photographs.

TM, AA, and RY designed and wrote the manuscript. SD, MH, SA, and MS-S collected clinical data and provided samples of patients for genetic and laboratory analyses. PA, NR, and HA performed and analyzed the results of next-generation sequencing and Sanger sequencing. TM performed and analyzed immunological tests of patients. All authors reviewed, contributed, and approved the final draft of the manuscript.

This work was supported by grants provided by the Jeffrey Modell Foundation, Åke Wibergs stiftelse and Crafoord Foundation.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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