Skip to main content
NCBI home page
Springer logoLink to Springer
. 2025 Jan 15;272(2):110. doi: 10.1007/s00415-024-12766-7

Biomarkers in Ataxia-Telangiectasia: a Systematic Review

M Y Tiet 1, B-I Guțu 1, P Springall-Jeggo 2, D Coman 3, M Willemsen 4, N Van Os 4, M Doria 5, H Donath 6, R Schubert 6, R A Dineen 7,8, S Biagiotti 9, A P Prayle 8,10, A T Biomarker Working Group, A E Hensiek 1, R Horvath 1,✉
PMCID: PMC11735505  PMID: 39812834

Abstract

Ataxia-Telangiectasia (A-T) is a very rare multisystem disease of DNA repair, associated with progressive disabling neurological symptoms, respiratory failure, immunodeficiency and cancer predisposition, leading to premature death. There are no curative treatments available for A-T but clinical trials have begun. A major limiting factor in effectively evaluating therapies for A-T is the lack of suitable outcome measures and biomarkers. We have performed a systematic review to collect the information currently available on biomarkers for A-T both in patients and preclinical studies. We have identified 56 reports discussing potential A-T biomarkers in both pre-clinical models and patients. These studies report on diagnostic biomarkers but prognostic biomarkers and responsive markers of clinical status are currently lacking. Some biomarkers of neurodegeneration in A-T show promise, including non-invasive neuroimaging biomarkers. Some biomarkers of oxidative stress and responsive markers to radiotherapy and steroid treatment have potential value in clinical trials. The formation of the A-T biomarker working group with international experts is an important step forward to facilitate the sharing of materials, data and expertise with the common goal of finding effective biomarkers for A-T.

Supplementary Information

The online version contains supplementary material available at 10.1007/s00415-024-12766-7.

Keywords: Ataxia-Telangiectasia, Biomarkers, Neurodegeneration, Clinical trials

Introduction

Ataxia-Telangiectasia (A-T) (OMIM 208900) is a rare autosomal recessive DNA repair disorder associated with neurodegeneration, elevated malignancy risk, respiratory disease, immunodeficiency and metabolic disruptions [1]. The ataxia telangiectasia-mutated (ATM) gene encodes the ATM protein, a serine-threonine kinase mainly involved in the response to DNA double-strand breaks and oxidative stress [2]. Patients with a complete lack of ATM kinase activity have “classic A-T” with characteristic disabling neurological symptoms of cerebellar ataxia, dysarthria, peripheral neuropathy, extrapyramidal features and oculomotor apraxia [3]. Most patients are wheelchair-dependent by the time they begin their second decade of life and have a markedly reduced average life expectancy to their mid-twenties due to malignancy, lung failure, or infection [4]. Diagnosis of A-T currently relies on clinical correlation by experienced clinicians and ordering the correct exome sequencing panels. Patients with residual ATM kinase activity have milder disease, the so-called “variant A-T”, generally without respiratory insufficiency or immunodeficiency. Variant A-T patients have a diverse neurological phenotype, often leading to delayed diagnosis of sometimes up to 20 years [5].

A-T causes significant morbidity and there is no known cure and only supportive, non-specific treatments are available to date. With an incidence rate between 1:40,000 to 1:100,000 [6], the scope for developing large-scale studies is challenging. In the era of widely available exome sequencing and newborn screening for immunodeficiencies, there is a need for reliable diagnostic biomarkers to prove or disapprove pathogenetic of ATM variants, and to predict the course of the disease. Previous clinical treatment studies have mainly focused on clinical severity scores such as the Scale for Assessing and Rating Ataxia (SARA), International Cooperative Ataxia Rating Scale (ICARS) [7] or the AT-NEST score [8]. Although severity scores are useful for rapid clinical correlation, suitably trained investigators are required to perform the clinical examination to ensure reproducibility. Mild improvements in clinical severity scores may reflect day-to-day symptom fluctuation. Disease progression biomarkers would serve as an unbiased objective measure to evaluate treatment effectiveness but they are currently lacking.

As treatment trials for A-T are underway, the employment of diagnostic and disease progression biomarkers is now imperative. To that end, as part of an international collaborative effort to find potential diagnostic and clinical trial-appropriate biomarkers for A-T, we have conducted a systematic review of the existing literature for biomarkers of neurodegeneration, immunological abnormalities and radiation sensitivity in A-T patients and in cell culture models.

Methods

Systematic review protocol

We aimed to identify specific diagnostic and prognostic biomarkers for A-T. The parameters for the systematic review were defined by the A-T International Working Group meeting and registered with the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42024536897). The systematic review is reported following the guidelines set out by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement. (https://doi.org/10.1371/journal.pmed.1000097).

Literature search strategy

To include all existing literature on biomarkers in A-T, we searched PubMed using a combination of free words and controlled vocabulary terms—(ataxia telangiectasia OR ATM OR AT OR Louis-Bar syndrome) AND (biomarker OR surrogate marker OR marker) on 25th August 2022. We restricted the time frame to 1995 to present, as the ATM mutation underlying A-T was first reported and described in 1995 (https://doi.org/10.1126/science.7792600).

Results

A total of 3,164 reports were found and uploaded onto the Rayyan QCRI platform. A full search strategy including search terms and filters can be found in Supplementary File 1. We excluded 47 articles including retracted articles, and articles not written in English or published before 1995 (Fig. 1, 2, 3, 4).

Fig. 1.

Fig. 1

Open in a new tab

PRISMA flow diagram of articles screened for biomarkers in Ataxia Telangiectasia

Fig. 2.

Fig. 2

Fig. 2

Fig. 2

Open in a new tab

CSF protein biomarkers in A-T, many associated with neurodegeneration and cancer. Key: AD Alzheimer’s disease, ALS amyotrophic lateral sclerosis, PD Parkinson’s disease

Fig. 3.

Fig. 3

Open in a new tab

A-T biomarkers from patient studies. NfL neurofilament light chain, 5mC 5-hydroxymethylcytosine, 18F-FDG 18F-fluorodeoxyglucose, AFP alpha fetoprotein, LDL low density lipoprotein, HDL high density lipoprotein, miR miRNA, mtDNA mitochondrial DNA, GSSG glutathione, Top1-css topoisomerase 1-DNA covalent complexes, GILZ glucocorticoid-induced leucine zipper, IL2 interleukin2, SPARC secreted protein acidic and rich in cysteine, CTSD cathepsin D, RELN reelin, CALB1 calbindin, CBLN cerebellin, FAT2 protocadherin fat 2, SEMA7A semaphorin 7A, ApoB Apolipoprotein B

Fig. 4.

Fig. 4

Fig. 4

Open in a new tab

Summary of the relevant A-T biomarker studies. NfL neurofilament light chain, 5mC 5-hydroxymethylcytosine, 18F-FDG 18F-fluorodeoxyglucose, AFP alpha fetoprotein, LDL low density lipoprotein, HDL high density lipoprotein, miR miRNA, mtDNA mitochondrial DNA, ERK extracellular signal-regulated protein kinase, HSP70 heat shock protein 70, GSSG glutathione, Top1-css topoisomerase 1-DNA covalent complexes, GILZ glucocorticoid-induced leucine zipper, EryDex intraerythrocyte dexamethasone, IL2 interleukin2, SPARC secreted protein acidic and rich in cysteine, CTSD cathepsin D, RELN reelin, CALB1 calbindin, CBLN cerebellin, FAT2 protocadherin fat 2, SEMA7A semaphorin 7A, ApoB Apolipoprotein B, CoQ10 coenzyme Q10, TEAC total antioxidant capacity, 8-OHdG 8-hydroxy-2-deoxyguanosine

Inclusion and exclusion criteria for screening

For the remaining reports, both the title & abstract and the full text were screened by two independent blinded reviewers (BG and MYT) and arbitrated by an expert reviewer (RH). We implemented the following inclusion and exclusion criteria (Text box 1).graphic file with name 415_2024_12766_Figa_HTML.jpg

Data extraction

A total of 56 reports met our inclusion criteria. The complete articles were grouped based on biomarker subtype, in vitro model, patient studies or interventional clinical trials. Full data extraction can be found in Supplementary File 2. Where possible, the demographic data and effect size have been included, such as fold change, mean, standard deviation, or range, if discussed in the original manuscript.

Evaluation of biomarkers.

Serum alpha fetoprotein (AFP)

Alpha Fetoprotein (AFP) is a foetal protein that is still present in serum in high concentrations at birth and slowly decreases to normal’’adult’’ levels around the age of two years [9]. In patients with A-T, serum AFP levels usually remain elevated [10, 11]. The precise mechanism for the failed decrease in serum AFP levels in patients with A-T is unknown. Although AFP is considered a reliable diagnostic biomarker for the disease, in a small proportion of variant A-T patients, AFP can be normal [12]. Furthermore, there is no clear association of AFP levels with disease severity [13], making this biomarker not suitable for therapeutic trials.

Lipoproteins

Altered lipid metabolism has been implicated in neurodegenerative disorders such as Parkinson’s disease, Alzheimer's disease and multiple sclerosis [14–16] but the mechanism is unclear. Impaired lipid homeostasis can potentially lead to impaired mitochondrial oxidative phosphorylation [17]. Metabolic syndromes are frequently associated with classic A-T. Commonly, triglyceride and low-density lipoprotein (LDL) levels are elevated with lower high-density lipoprotein (HDL) and lower vitamin E (per total lipid ratios) [18]. We also note associated fatty liver disease and type 2 diabetes which is progressive with age [19, 20]. Such findings are not specific to A-T, ataxia with oculomotor apraxia type 1 (AOA1) is also associated with elevated lipid levels [21]. The correlation between lipoprotein levels and clinical presentation of A-T has not been elucidated.

Biomarkers for neurodegeneration

Neurological symptoms in A-T are present in both classic and variant A-T and lead to considerable morbidity. The neurological phenotype has not been recapitulated in animal models with ATM mutations but biomarkers for neurodegeneration derived from patient samples and cell lines are emerging.

Neurofilament light chain (NfL) has gathered increasing interest in A-T and other neurodegenerative diseases such as Hereditary Motor and Sensory Neuropathy (Charcot-Marie-Tooth disease), multiple sclerosis and Parkinson’s disease, suggesting that elevated levels in the blood and cerebrospinal fluid (CSF) are associated with axonal damage [22–24]. Serum and plasma NfL are increased in A-T compared to age-matched controls and higher in classic than variant A-T, suggesting that NfL may serve as an indicator of disease severity [25, 26]. NfL reduces with age in A-T patients [27] and not specific to A-T, therefore, further longitudinal studies on the clinical relevance of NfL as a molecular biomarker in A-T are needed. NfL levels did not change in a 24-month longitudinal study of nicotinamide riboside (NR) therapy. During this study, NR was associated with improvement in disease severity scores (SARA, AT-NEST, ICARS) and oculomotor function [27]. NfL has been assessed as a longitudinal biomarker in a placebo-controlled randomized trial of triheptanoin (NCT04513002). The results of this study are awaited.

NfL has gathered increasing interest in other inherited ataxias, such as spinocerebellar ataxia type 3 (SCA3) [28, 29]. Similar to A-T [27], NfL levels are increased in SCA3, the difference is greater in younger patients [28]. NfL was elevated in pre-ataxic patients and early disease and correlated with SARA score [28, 29]. NfL levels are increased in Friedreich ataxia but does not correlate with disease severity [30]. In summary, whilst NfL levels are increased in A-T, similar to other neurodegenerative diseases, its usefulness as a marker of disease severity in interventional trials is as yet not established and further longitudinal studies are required.

CSF biomarkers

CSF is a filtrate from the choroid plexus in the brain. The proteins present in CSF, usually obtained by lumbar puncture (LP), contain important diagnostic information for many neurological disorders [31]. Albumin CSF/serum ratio (AR) is significantly increased with age in A-T, indicating the disruption of the blood–brain barrier. Inflammatory cytokines are not elevated, but IL-2 is decreased in the CSF and post-LP complications have been observed more commonly in A-T patients than in other diseases [32]. Although none of the aforementioned CSF proteins were validated in other tissues, such as fibroblasts [33].

Cytosine modification biomarkers

Cytosine modification is associated with tumorigenesis. Of the 5’-CpG-3’ dinucleosides, 5-hydroxymethylcytosine (5mC) is one of the most abundant epigenetic biomarkers [75]. 5-mC is found in high levels in neurons and is a potential cancer biomarker. In patient and Atm−/− mouse Purkinje cells, 5mC levels are reduced, leading to alteration of chromatin structure due to unknown mechanisms [76]. Cancer-specific 5-mC patterns are seen in the cell-free DNA of cancer patients (colorectal, gastric, pancreatic, liver, thyroid) [77]. Further studies distinguishing 5mC levels from other cancer patients without ATM defects are required.

Neuroimaging biomarkers

The most common brain MRI finding during diagnostic workup for A-T is cerebellar atrophy [12, 78, 79], but this may not be detectable in very young children at the time of first presentation. Quantitative studies have shown reduced volume of the cerebellar vermis and hemispheres compared to controls [80] which progresses through childhood [81]. Cerebellar atrophy is not specific for A-T, but a number of studies have reported the finding of cerebral hypointense foci on susceptibility-weighted imaging (SWI) in A-T [79, 82–85], and the combination of cerebellar atrophy and cerebral SWI hypointense foci in a child or young person with ataxia has potential as a specific diagnostic biomarker for A-T warranting further investigation.

Magnetic resonance spectroscopy (MRS) allows quantification of brain tissue metabolites. MRS studies in both children and adults with A-T have shown reductions in cerebellar N-acetyl aspartate (NAA) compared to healthy controls, expressed as normalized NAA, NAA to creatine ratio and NAA to choline ratio [79, 81, 86]. NAA is a marker of neuronal health, and the reduction in the cerebellum of people with A-T is likely to reflect neurodegeneration. Studies have also identified increased ratios of cerebellar choline to creatine [79, 81], which is likely to be a marker reflecting myelin turnover.

Diffusion MRI allows quantification of ultrastructural barriers to water motion and provides in-vivo measures of tissue cellularity and white matter integrity. Studies in A-T are limited, but Sahama et al. used diffusion tensor imaging (DTI) to quantify reduced tract integrity at multiple sites in the motor pathways of children and young adults with A-T compared to controls. The findings suggested alterations in the corticospinal and somatosensory tracts and in the cerebellar-thalamo-cortical pathway [87]. Diffusion MRI studies of intracerebellar white matter have shown loss of ultrastructural white matter integrity [80, 81].

18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) provides a marker of brain glucose metabolism. PET studies are limited in A-T, but Volkow and colleagues demonstrated reduced uptake in the cerebellum, fusiform gyrus and hippocampus and increased uptake in the globus pallidus of people with A-T compared to controls [88].

In a regression analysis of possible quantitative imaging predictors, fourth ventricular volume was the only variable that predicted neurological status as determined by the A-T Neurological Examination Toolkit (A-T-NEST) [81], Uptake of 18F-FDG in the globus pallidus of people with A-T has been shown to correlate negatively with motor performance [88]. While these imaging biomarkers have the potential to be clinically useful in A-T, they currently lack independent validation and require evaluation in longitudinal natural history studies with larger cohorts of patients.

Lung function parameters

Lung disease is a prominent characteristic and significant prognostic factor of A-T. Spirometry is an important diagnostic tool for the detection of lung disease. In many previous studies, lung function tests were performed on A-T patients. Repeatedly, A-T was shown to be associated with a progressive decrease in FVC and FEV1 [89–92]. A rapid increase in the FEF25-75/FVC ratio was associated with mortality within 2–3 years in a retrospective work [91]. However, forced spirometry results are influenced by a combination of lung volume, airway caliber, muscle power, neurological co-ordination of breathing, and the ability to make a seal around a mouthpiece. Low spirometry can be a result of any of these processes, and work is ongoing for biomarkers that more accurately assess individual components of lung function in A-T.

Oxidative stress

Reichenbach et al. demonstrated increased levels of lipid peroxidation products and oxidative stress-related DNA bases, such as 8-hydroxy-2-deoxyguanosine (8-OHdG) as well as decreased plasma total antioxidant capacity (TEAC), retinol, alpha-tocopherol and ubiquinol in A-T patients’ peripheral blood [93, 94]. Pietrucha et al. showed increased total oxidant status (TOS) and oxidative stress index (OSI) and reduced total antioxidant status (TAS), coenzyme Q10 (CoQ10) and vitamin E, respectively [95].

ATM is activated by increased production of reactive oxygen species from oxidative and metabolic stress [96] in conditions of glucose depletion, calcium transfer and when transfer between the endoplasmic reticulum and mitochondria is impaired [97, 98]. In A-T patients, blood glutathione levels (GSSG) were decreased suggesting adaptations to oxidative stress [99, 100].

Loss of ATM function leads to ROS accumulation and oxidative stress [101]. Nuclear factor erythroid 2-related factor (Nrf2) is a transcription factor that protects cells from oxidative stress and interacts with ATM- and Rad3-related protein (ATR) in response to double-stranded DNA breaks (DSBs) [102]. In Friedreich ataxia, the oxidative stress response is impaired due to the failure of NRF activation [103]. Treatment with Nrf2 activator, Omaveloxolone, restores complex I activity and protected from oxidative stress in mouse models and human primary fibroblasts. Omaveloxolone improves neurological symptoms in Friedreich ataxia patients [104]. In A-T, Nrf2 protein levels are not increased but nuclear translocation of NRF2 is promoted by Dexamethasone treatment in patient fibroblasts [105]. Further studies into the feasibility of Nrf2 as a progressive biomarker and therapeutic target in A-T are required.

Proinflammatory cytokines have been investigated in A-T patients, notably IL-6 and IL-8 are elevated in A-T patients, suggesting a chronic inflammatory state [100, 106–109]. In A-T fibroblasts, glutamine deprivation triggers the production of ROS and IL-8 [110] and is inhibited with anti-oxidant alpha lipoic acid [107]. Elevated IL-8 levels are associated with increased malignancy risk and mortality in a follow-up study and reanalysis by McGrath-Morrow et al. [109].

Biomarkers related to mitochondrial dysfunction

Mitochondrial DNA (mtDNA) accumulation or depletion can be an indicator of mitochondrial degeneration and neurodegenerative disorders. The accumulation of a common deletion (Δ-mtDNA4977) can be used as a surrogate marker for total mtDNA damage. Radiation exposure to immortalised radiosensitive A-T fibroblasts leads to the accumulation of Δ-mtDNA4977, raising the possibility that mtDNA abnormalities may contribute to the neurodegeneration in A-T [111]. The role of mitochondria and DNA repair in A-T is unclear, however, it is thought that the fusion of mitochondria from healthy cells is facilitated by ATM [112].

Radiosensitivity and cancer biomarkers

Cancer predisposition in A-T (irrespective of neurological disease severity) and heterozygous carriers highlight the importance of early diagnosis. A Delphi-based consensus survey of 35 panelists from 6 continents (Europe, Africa, Asia, Oceania, North and South America) support the need for evidence-based guidelines for cancer surveillance [113]. Currently, there are no universally agreed guidelines for cancer screening in A-T, although a recently completed feasibility trial (NCT05252819) of whole-body MRI cancer surveillance showed the approach is feasible and well-accepted by children and young people with A-T and their families [114].

Tumour suppressor gene p53 is vital in DNA repair responses. A-T fibroblasts showed lower induction of p53 and p21 and their phosphorylated substrates after irradiation compared to fibroblasts from breast cancer patients, A-T heterozygotes [115] and controls [116]. The clinical significance of this is unknown and does not explain why heterozygous carriers are also at increased risk of cancer [115]. The reduced level of phosphorylated p53 has also been reported in A-T-like disorder (ATLD) [128].

Radiosensitivity is a hallmark of DNA repair disorders such as A-T. Radiotherapy is a common treatment for cancers but can lead to severe reactions in A-T patients [117] but the degree of radiosensitivity is variable. Early detection of radiosensitivity can be an effective way to assist in diagnosis and avoid exposure to radiation from investigations and cancer treatment. Currently, radiosensitivity is determined using chromosomal breakage studies and chromosomal rearrangements after irradiation [118] in specialist diagnostic laboratories.

Histone H2A.X is phosphorylated by ATM during DSB repair, creating γ-H2A.X, and has previously created interest as a potential radiosensitivity biomarker for A-T. The results so far for γ-H2A.X have been mixed or have utilized a small number of A-T patient samples [116, 119–123]. Bryant et al. reported unchanged γ-H2A.X levels in all A-T cell lines but suggest that testing microRNA (miR-152-3p, miR-24-5p, miR-92-15p) associated with modulation of tumor suppressor phosphatase and tensin homolog (PTEN) and cyclin D1 (CCND1) may be of interest [124].

High levels of chromosomal abnormalities occur in about 10% of lymphocytes in A-T patients and can assist diagnosis. Most common is the t(7;14) translocation [125], estimated to be increased by 40-fold in A-T patients [126]. This is not a specific diagnostic biomarker as the translocation is also present in Nijmegen Breakage Syndrome (NBS) [127]. Elevated levels of complex aberrations and dicentric chromosomes have been detected after irradiation in A-T [128]. Colony survival assays (CSA) have previously been evaluated as an adjuvant biomarker for radiosensitivity but has a long turnaround time which would not be practical in the initiation of treatment of A-T patients with cancer [129]. Conversely, Bcl-2 apoptotic regulatory proteins, do not correlate with radiosensitivity in A-T cell lines [130].

Immunodeficiency

Most classic A-T patients show variable signs of immunodeficiency that, conversely, are uncommon in patients with variant A-T [5, 131]. Cases of A-T have been diagnosed using the T cell receptor excision circle (TREC)-base newborn screening [132, 133]. Reduced T- and B-cell counts, principally naïve CD4+ T, CD8+ T and B cell numbers, are found in almost all classic A-T patients [131, 134]. Of note, in an Italian cohort of 66 A-T patients, lymphopenia at diagnosis was associated with earlier age at disease onset and reduced life expectancy [135].

Deficiency of humoral immunity in A-T is more variable, including decreased or absent serum immunoglobulin A (IgA), IgG2, or IgE, increased serum IgM levels, and impairment of antibody responses to a variety of microbial antigens [131, 136]. In one retrospective study on 61 A-T patients, selective deficiency of IgG2 and the hyper IgM phenotype correlated with reduced survival [4]. Immunodeficiency in these patients may become clinically apparent over time due to progressive ageing of the immune system in the context of reduced ATM kinase activity [137].

Ineffective immune responses against viruses and cancer may contribute to A-T disease progression and reduced survival. Monitoring of immunoglobulin levels to characterize individual immunodeficiency profiles and prevent risk of infection is recommended [138].

Biomarkers used in clinical trials with Steroids in AT

The use of steroids in A-T for improvement in neurological symptoms is not universally accepted in A-T patients. Steroids lead to increased longevity and reduced microglial activation in a rat model of A-T with spinal cord atrophy [139]. Dexamethasone therapy improves nuclear translocation of NRF2 in A-T fibroblasts and lymphoblastoid cell lines [105, 140].

Transient improvements in patient SARA scores with short-term steroid use have been reported [141, 142] with deterioration during steroid washout periods [143]. Glucocorticoid-induced leucine zipper (GILZ) levels correlated with lower dose oral beclomethasone use and improved SARA scores. Following a second cycle of higher-dose beclomethasone, GILZ levels were not elevated in all patients [143].

In an attempt to ameliorate the long-term side effects of oral steroid use, autologous intra-erythrocyte dexamethasone (EryDex) allows for a slow delivery of encapsulated dexamethasone and has been explored with reported neurological symptomatic improvement measured by the ICARS score [144, 145]. The aim of the ATTeST study was to evaluate the efficacy and safety of intra-erythrocyte delivery of dexamethasone compared with placebo in children with ataxia telangiectasia [146]. Although there were no safety concerns, the primary efficacy endpoint was not met. Studies continue with EryDex in participants aged 6–9 years, on the basis of findings from subgroup analyses from this trial to define whether this treatment leads to the improvement in neurological symptoms (NCT02770807). ATMdexa1 transcript expression is higher in EryDex responders. As ATMdexa1 is undetectable in untreated A-T patients, the use of this biomarker would be reserved for the use of steroid therapy [147].

Discussion

This systematic review identified 56 reports discussing potential A-T biomarkers in both pre-clinical models and patients. Many of the manuscripts discuss biomarkers to explore disease mechanisms, while some biomarkers have been described only in single manuscripts in pre-clinical models. This can lead to potential selection and chronological bias, particularly from studies involving patient registries or studies with a lack of case controls. Where possible, we have evaluated the effect size of each potential biomarker (Supplementary file 2), however, this was mainly limited to clinical studies and is not standardised as we do not have the original data for the published studies. Pre-clinical studies describe increased or decreased expression of biomarkers, which do not allow quantitative evaluation of the effect size. We provide a comprehensive list of potential biomarkers to date and their value in A-T. A small number of validated biomarkers are not unique to A-T, such as AFP and triglycerides.

Some biomarkers of neurodegeneration in A-T show promise, including non-invasive neuroimaging biomarkers. Cerebellar atrophy is a universal feature of A-T but is non-specific. Fourth ventricular volume [81] and characteristic 13F-FDG signatures [88] are potential novel biomarkers, which require further clinical validation with longitudinal studies.

In recent years, large-scale omics have been employed for CSF studies in A-T, with reproducible results. Some of the CSF biomarkers described are not novel to A-T but have been previously described in other neurodegenerative disorders, malignancies, endocrine and dermatological disorders. Though lacking specificity, unique CSF biomarkers for A-T should be evaluated in longitudinal studies against established neurodegenerative biomarkers, such as NfL. In combination with mechanistic biomarkers, such as NrF2, these biomarkers provide further insight into the complex multiorgan involvement of A-T. Such biomarkers are not necessarily useful for diagnostic purposes but have a potential in treatment trials.

There are potential biomarkers emerging for immunodeficiency, chronic inflammation (CD4+, CD8+, T cells, B cells, IgA, IgG2, hyper IgM, IL-6 and IL-8) and steroid therapy use. GILZ and ATMdexa1 have been identified as useful responsive biomarkers for steroid therapy. However, to date, steroids are not routinely prescribed to A-T patients. More studies are required to assess the effectiveness of long-term steroid therapy. The advent of EryDex may circumvent the potential side effects of traditional oral steroid use.

In the era of first-line genomics ATM variants are frequently being identified and diagnostic biomarkers (AFP, NfL, cellular and humoral immunodeficiency, 5-mC) can assist in the validation of pathogenicity. However specific prognostic biomarkers, enabling quantitative monitoring of clinical progression are still lacking in A-T.

As new omics technologies are becoming more and more available and have been applied to other genetic ataxias such as ARSACS [152] and Friedreich ataxia [153,154], there is a hope that novel molecular biomarkers will be identified also in A-T. As A-T has a diverse clinical phenotype, samples from a diverse range of patients are required to validate the sensitivity and specificity of novel biomarkers in A-T, therefore, the use of better in vitro models is still vital in A-T biomarker discovery. International collaboration and data sharing can facilitate novel biomarker discoveries, as shown in previous studies with NfL [25, 26]. The formation of the A-T biomarker working group with international experts on board for this very rare disease is an important step forward to facilitate the sharing of materials, data and expertise with the common goal of finding effective biomarkers for A-T.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (XLSX 9 kb) (9.8KB, xlsx)
Supplementary file2 (XLSX 20 kb) (20.4KB, xlsx)

Acknowledgements

M.Y.T is supported by Action for A-T (TREAT-AT). M.D. is supported and by a grant of ‘Action for A-T’ and ‘BrAshAT’ (1145303) and by the Italian Ministry of Health with “Current Research funds”. R.H. is supported by the Wellcome Discovery Award (226653/Z/22/Z), the Medical Research Council (UK) (MR/V009346/1), the Addenbrookes Charitable Trust (G100142), the Hereditary Neuropathy Foundation, the Stoneygate Trust, the Lily Foundation, Ataxia UK, Action for AT, the Muscular Dystrophy UK, the LifeArc Centre to Treat Mitochondrial Diseases (LAC-TreatMito) and the UKRI/Horizon Europe Guarantee MSCA Doctoral Network Programme (Project 101120256: MMM). She is also supported by an MRC strategic award to establish an International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) MR/S005021/1. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.

Funding

The authors have no financial or non-financial interests that are directly or indirectly related to the work submitted for publication.

Data availability

All available data has been included in the supplementary files and have been stated within the manuscript.

Declarations

Conflict of interest

The authors have no conflict of interest.

References

  • 1.Tiet MY, Horvath R, Hensiek AE (2020) Ataxia telangiectasia: What the neurologist needs to know. Pract Neurol 20(5):404–414 [DOI] [PubMed] [Google Scholar]
  • 2.Ditch S, Paull TT (2012) The ATM protein kinase and cellular redox signaling: Beyond the DNA damage response. Trends Biochem Sci 37(1):15–22 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Rothblum-Oviatt C, Wright J, Lefton-Greif MA, McGrath-Morrow SA, Crawford TO, Lederman HM (2016) Ataxia telangiectasia: A review. Orphanet J Rare Dis 11(1):1–21 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.van Os NJH, Jansen AFM, van Deuren M, Haraldsson A, van Driel NTM, Etzioni A et al (2017) Ataxia-telangiectasia: Immunodeficiency and survival. Clin Immunol 178:45–55 [DOI] [PubMed] [Google Scholar]
  • 5.Schon K, van Os NJH, Oscroft N, Baxendale H, Scoffings D, Ray J et al (2019) Genotype, extrapyramidal features, and severity of variant ataxia-telangiectasia. Ann Neurol 85(2):170–180 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6.Riboldi G., Samanta D, Frucht S. Ataxia Telangiectasia. StatPearls. 2022;Jul. [PubMed]
  • 7.Trouillas P, Takayanagi T, Hallett M, Currier R, Subramony S, Wessel K et al (1997) International cooperative ataxia rating scale for pharmacological assessmentof the cerebellar syndrome. J Neurol Sci 145:205–211 [DOI] [PubMed] [Google Scholar]
  • 8.Schmitz-Hübsch T, Du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C et al (2006) Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 66(11):1717–1720 [DOI] [PubMed] [Google Scholar]
  • 9.Blohm MEG, Vesterling-Hörner D, Calaminus G, Göbel U (1998) Alpha1-fetoprotein (AFP) reference values in infants up to 2 years of age. Pediatr Hematol Oncol 15(2):135–142 [DOI] [PubMed] [Google Scholar]
  • 10.Dawson AJ, Marles S, Tomiuk M, Riordan D, Gatti RA (2015) Ataxia-telangiectasia with female fertility. Am J Med Genet Part A 167(8):1937–1939 [DOI] [PubMed] [Google Scholar]
  • 11.Navratil M, Đuranović V, Nogalo B, Švigir A, Dubravčić ID, Turkalj M (2015) Ataxia-telangiectasia presenting as cerebral palsy and recurrent wheezing: a case report. Am J Case Rep 16:631–636 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Méneret A, Ahmar-Beaugendre Y, Rieunier G, Mahlaoui N, Gaymard B, Apartis E et al (2014) The pleiotropic movement disorders phenotype of adult ataxia-telangiectasia. Neurology 83(12):1087–1095 [DOI] [PubMed] [Google Scholar]
  • 13.Stray-Pedersen A, Borresen-Dale AL, Paus E, Lindman CR, Burgers T, Abrahamsen TG (2007) Alpha fetoprotein is increasing with age in ataxia-telangiectasia. Eur J Paediatr Neurol 11(6):375–380 [DOI] [PubMed] [Google Scholar]
  • 14.Zalocusky KA, Najm R, Taubes AL, Hao Y, Yeon S, Koutsodendris N et al (2021) Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration neurodegeneration in alzheimer’s disease. Nat Neurosci 24(6):786–798 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Hallett PJ, Engelender S, Isacson O (2019) Lipid and immune abnormalities causing age-dependent neurodegeneration and Parkinson’s disease. J Neuroinflammation 16(1):1–15 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Shi Y, Andhey PS, Ising C, Wang K, Snipes LL, Boyer K et al (2021) Overexpressing low-density lipoprotein receptor reduces tau- associated neurodegeneration in relation to apoE-linked mechanisms. Neuron 109(15):2413–2426 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Jennings MJ, Hathazi D, Nguyen CDL, Munro B, Münchberg U, Ahrends R et al (2021) Intracellular lipid accumulation and mitochondrial dysfunction accompanies endoplasmic reticulum stress caused by loss of the co-chaperone DNAJC3. Front Cell Dev Biol 9:1–16 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Andrade IGA, Costa-Carvalho BT, Da Silva R, Hix S, Kochi C, Suano-Souza FI et al (2015) Risk of atherosclerosis in patients with ataxia telangiectasia. Ann Nutr Metab 66(4):196–201 [DOI] [PubMed] [Google Scholar]
  • 19.Donath H, Hess U, Kieslich M, Theis M, Ohlenschläger U, Schubert R et al (2020) Diabetes in patients with ataxia telangiectasia: a national cohort study. Front Pediatr 8:1–8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Donath H, Woelke S, Theis M, Heß U, Knop V, Herrmann E et al (2019) Progressive liver disease in patients with ataxia telangiectasia. Front Pediatr 7:1–8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Moreira M-C, Koenig M. Ataxia with Oculomotor Apraxia Type 1. GeneReviews. 2004;Nov 15.
  • 22.Aamodt WW, Waligorska T, Shen J, Tropea TF, Siderowf A, Weintraub D et al (2021) Neurofilament light chain as a biomarker for cognitive decline in parkinson disease. Mov Disord 36(12):2945–2950 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Benkert P, Meier S, Schaedelin S, Manouchehrinia A, Yaldizli Ö, Maceski A et al (2022) Serum neurofilament light chain for individual prognostication of disease activity in people with multiple sclerosis: a retrospective modelling and validation study. Lancet Neurol 21(3):246–257 [DOI] [PubMed] [Google Scholar]
  • 24.Jennings MJ, Kagiava A, Vendredy L, Spaulding EL, Stavrou M, Hathazi D et al (2022) NCAM1 and GDF15 are biomarkers of charcot-marie-tooth disease in patients and mice. Brain 145(11):3999–4015 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Veenhuis SJG, Gupta AS, de Gusmão CM, Thornton J, Margus B, Rothblum-Oviatt C et al (2021) Neurofilament light chain: a novel blood biomarker in patients with ataxia telangiectasia. Eur J Paediatr Neurol 32:93–97 [DOI] [PubMed] [Google Scholar]
  • 26.Donath H, Woelke S, Schubert R, Kieslich M, Theis M, Auburger G et al (2022) Correction to: neurofilament light chain is a biomarker of neurodegeneration in ataxia telangiectasia. The Cerebellum 21:39–47 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Presterud R, Deng WH, Wennerström AB, Burgers T, Gajera B, Mattsson K et al (2024) Long-term nicotinamide riboside use improves coordination and eye movements in ataxia telangiectasia. Mov Disord 39(2):360–369 [DOI] [PubMed] [Google Scholar]
  • 28.Garcia-Moreno H, Prudencio M, Thomas-Black G, Solanky N, Jansen-West KR, Hanna AL-Shaikh R, et al (2022) Tau and neurofilament light-chain as fluid biomarkers in spinocerebellar ataxia type 3. Eur J Neurol 29(8):2439–2452 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Wilke C, Haas E, Reetz K, Faber J, Garcia-Moreno H, Santana MM et al (2020) Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice. EMBO Mol Med 12(7):1–19 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Hayer SN, Liepelt I, Barro C, Wilke C, Kuhle J, Martus P et al (2020) NfL and pNfH are increased in Friedreich’s ataxia. J Neurol 267(5):1420–1430 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Wichmann TO, Damkier HH, Pedersen M (2022) A brief overview of the cerebrospinal fluid system and its implications for brain and spinal cord diseases. Front Hum Neurosci 15:1–7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Woelke S, Schrewe R, Donath H, Theis M, Kieslich M, Duecker R et al (2021) Altered cerebrospinal fluid (csf) in children with ataxia telangiectasia. Cerebellum 20(1):31–40 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 33.Cheema AK, Timofeeva O, Varghese R, Dimtchev A, Shiekh K, Shulaev V et al (2011) Integrated analysis of ATM mediated gene and protein expression impacting cellular metabolism. J Proteome Res 10(5):2651–2657 [DOI] [PubMed] [Google Scholar]
  • 34.Barschke P, Abu-Rumeileh S, Al Shweiki MHDR, Barba L, Paolini Paoletti F, Oeckl P et al (2022) Cerebrospinal fluid levels of proenkephalin and prodynorphin are differentially altered in Huntington’s and Parkinson’s disease. J Neurol 269(9):5136–5143 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.McGrath JA. Lipoid proteinosis. 1st ed. Vol. 132, Handbook of Clinical Neurology. Elsevier B.V.; 2015. 317–322 p. [DOI] [PubMed]
  • 36.Mattsson N, Rüetschi U, Podust VN, Stridsberg M, Li S, Andersen O et al (2007) Cerebrospinal fluid concentrations of peptides derived from chromogranin B and secretogranin II are decreased in multiple sclerosis. J Neurochem 103(5):1932–1939 [DOI] [PubMed] [Google Scholar]
  • 37.Whelan CD, Mattsson N, Nagle MW, Vijayaraghavan S, Hyde C, Janelidze S et al (2019) Multiplex proteomics identifies novel CSF and plasma biomarkers of early Alzheimer’s disease. Acta Neuropathol Commun 7(1):1–14 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.Alvarez-Saavedra M, De Repentigny Y, Yang D, O’Meara RW, Yan K, Hashem LE et al (2016) Voluntary running triggers vgf-mediated oligodendrogenesis to prolong the lifespan of snf2h-null ataxic mice. Cell Rep 17(3):862–875 [DOI] [PubMed] [Google Scholar]
  • 39.Brockmann K, Quadalti C, Lerche S, Rossi M, Wurster I, Baiardi S et al (2021) Association between CSF alpha-synuclein seeding activity and genetic status in Parkinson’s disease and dementia with Lewy bodies. Acta Neuropathol Commun 9(1):1–11 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Rotunno MS, Lane M, Zhang W, Wolf P, Oliva P, Viel C et al (2020) Cerebrospinal fluid proteomics implicates the granin family in Parkinson’s disease. Sci Rep 10(1):1–11 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Van Steenoven I, Koel-Simmelink MJA, Vergouw LJM, Tijms BM, Piersma SR, Pham TV et al (2020) Identification of novel cerebrospinal fluid biomarker candidates for dementia with Lewy bodies: a proteomic approach. Mol Neurodegener 15(1):1–15 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Waselle L, Quaglia X, Zurn AD (2009) Differential proteoglycan expression in two spinal cord regions after dorsal root injury. Mol Cell Neurosci 42(4):315–327 [DOI] [PubMed] [Google Scholar]
  • 43.Matsui F, Kawashima S, Shuo T, Yamauchi S, Tokita Y, Aono S et al (2002) Transient expression of juvenile-type neurocan by reactive astrocytes in adult rat brains injured by kainate-induced seizures as well as surgical incision. Neuroscience 112(4):773–781 [DOI] [PubMed] [Google Scholar]
  • 44.Okamoto M, Sakiyama J, Mori S, Kurazono S, Usui S (2003) Kainic acid-induced convulsions cause prolonged changes in the chondroitin sulfate proteoglycans neurocan and phosphacan in the limbic structures. Exp Neurol 184:179–195 [DOI] [PubMed] [Google Scholar]
  • 45.Tucker B, Klassen H, Yang L, Chen DF, Young MJ (2008) Permissive environment for retinal regeneration. Invest Ophthalmol Vis Sci 49(4):1686–1695 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Somnay Y, Lubner S, Gill H, Matsumura JB, Chen H (2017) The PARP inhibitor ABT-888 potentiates darbazine-induced cell death in carcinoids. Cancer Gene Ther 23(10):348–354 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Uhlig R, Dum D, Gorbokon N, Menz A, Büscheck F, Luebke AM et al (2022) Molecular and cellular endocrinology synaptophysin and chromogranin A expression analysis in human tumors. Mol Cell Endocrinol 555:111726 [DOI] [PubMed] [Google Scholar]
  • 48.Sathe G, Albert M, Darrow J, Saito A, Troncoso J, Pandey A et al (2021) Quantitative proteomic analysis of the frontal cortex in Alzheimer’s disease. J Neurochem 156(6):988–1002 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Podvin S, Jiang Z, Boyarko B, Rossitto L, Donoghue AO, Rissman RA et al (2022) Dysregulation of Neuropeptide and tau peptide signatures in human Alzheimer’s disease brain. ACS Chem Neurosci 13(13):1992–2005 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Lin L, Petralia RS, Holtzclaw L, Wang Y, Abebe D, Hoffman A (2022) Neurobiology of Disease Alzheimer’s disease / dementia-associated brain pathology in aging DPP6-KO mice. Neurobiol Dis 174:105887 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Kaiserova M, Grambalova Z, Otruba P, Stejskal D, Vranova HP, Mares J et al (2017) Cerebrospinal fluid levels of chromogranin A and phosphorylated neurofilament heavy chain are elevated in amyotrophic lateral sclerosis. Acta Neurol Scand 136(4):360–364 [DOI] [PubMed] [Google Scholar]
  • 52.Li M, Pan M, Wang J, You C, Zhao F, Zheng D et al (2020) miR-7 reduces breast cancer stem cell metastasis via inhibiting rela to decrease esam expression. Mol Ther Oncolytics 18:70–82 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Morgado-Palacin I, Day A, Murga M, Lafarga V, Elena M, Tubbs A et al (2017) Targeting the kinase activities of ATR and ATM exhibits therapeutic potential in a mouse model of MLL -rearranged AML. Sci Signal 9(445):24–27 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Zhao Q, Zhao R, Song C, Wang H, Rong J, Wang F et al (2021) Increased IGFBP7 expression correlates with poor prognosis and immune infiltration in gastric cancer. J Cancer 12(5):1343–1355 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Erin N, Ogan N, Yerlikaya A (2018) Secretomes reveal several novel proteins as well as TGF-β1 as the top upstream regulator of metastatic process in breast cancer. Breast Cancer Res Treat 170(2):235–250 [DOI] [PubMed] [Google Scholar]
  • 56.Nakamura K, Nakano SI, Miyoshi T, Yamanouchi K, Nishihara M (2013) Loss of sparc in mouse skeletal muscle causes myofiber atrophy. Muscle Nerve 48(5):791–799 [DOI] [PubMed] [Google Scholar]
  • 57.Brayman VL, Taetzsch T, Miko M, Dahal S, Risher WC, Valdez G (2021) Roles of the synaptic molecules Hevin and SPARC in mouse neuromuscular junction development and repair. Neurosci Lett 746:135663 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Sun Y, Almomani R, Breedveld GJ, Santen GWE, Aten E, Lefeber DJ et al (2013) Autosomal recessive spinocerebellar ataxia 7 (scar7) is caused by variants in tpp1, the gene involved in classic late-infantile neuronal ceroid lipofuscinosis 2 disease (cln2 disease). Hum Mutat 34(5):706–713 [DOI] [PubMed] [Google Scholar]
  • 59.Cheng A, Tse KH, Chow HM, Gan Y, Song X, Ma F et al (2021) ATM loss disrupts the autophagy-lysosomal pathway. Autophagy 17(8):1998–2010 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Chwastek J, Jantas D, Lasoń W (2016) The ATM kinase inhibitor KU-55933 provides neuroprotection against hydrogen peroxide-induced cell damage via a γH2AX/p-p53/caspase-3-independent mechanism: Inhibition of calpain and cathepsin D. Int J Biochem Cell Biol 2017(87):38–53 [DOI] [PubMed] [Google Scholar]
  • 61.Hersheson J, Jacques TS, Mills P, Wood NW, Gissen P, Clayton P (2014) Cathepsin D deficiency causes juvenile-onset ataxia and distinctive muscle pathology. Neurology 83:1873–1875 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Fritchie K, Siintola E, Armao D, Lehesjoki AE, Marino T, Powell C et al (2009) Novel mutation and the first prenatal screening of cathepsin D deficiency (CLN10). Acta Neuropathol 117(2):201–208 [DOI] [PubMed] [Google Scholar]
  • 63.Steinfeld R, Reinhardt K, Schreiber K, Hillebrand M, Kraetzner R, Brück W et al (2006) Cathepsin D deficiency is associated with a human neurodegenerative disorder. Am J Hum Genet 78(6):988–998 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Almaguer-Gotay D, Almaguer-Mederos LE, Aguilera-Rodríguez R, Rodríguez-Labrada R, Cuello-Almarales D, Estupiñán-Domínguez A et al (2017) Spinocerebellar ataxia type 2 is associated with the extracellular loss of superoxide dismutase but not catalase activity. Front Neurol 8:1–6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Wang J, Liu Y, Cheng X, Zhang X, Liu F, Liu G et al (2017) The effects of lw-afc on the hippocampal transcriptome in senescence-accelerated mouse prone 8 strain, a mouse model of alzheimer’s disease. J Alzheimer’s Dis 57(1):227–240 [DOI] [PubMed] [Google Scholar]
  • 66.Liu X, Chen H, Xu X, Ye M, Cao H, Xu L et al (2018) Insulin-like growth factor-1 receptor knockdown enhances radiosensitivity via the HIF-1α pathway and attenuates ATM/H2AX/53BP1 DNA repair activation in human lung squamous carcinoma cells. Oncol Lett 16(1):1332–1340 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Shen F, Gan X, Zhong R, Feng J, Chen Z, Guo M et al (2021) Identifying thyroid carcinoma-related genes by integrating GWAS and eQTL data. Front Cell Dev Biol [DOI] [PMC free article] [PubMed]
  • 68.Kumari S, Leishangthem B, Singh A, De A, Kalra N, Dutta P (2018) Growth hormone therapy in decompensated cirrhosis: a randomized pilot study. Hepatology 68:139A [Google Scholar]
  • 69.Chandra A, Senapati S, Roy S, Chatterjee G, Chatterjee R (2018) Epigenome-wide DNA methylation regulates cardinal pathological features of psoriasis. Clin Epigenetics 10(1):1–16 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Carino A, Graziosi L, Marchianò S, Biagioli M, Marino E, Sepe V et al (2021) Analysis of gastric cancer transcriptome allows the identification of histotype specific molecular signatures with prognostic potential. Front Oncol 11:1–17 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Puustinen P, Keldsbo A, Corcelle-Termeau E, Ngoei K, Sønder SL, Farkas T et al (2020) DNA-dependent protein kinase regulates lysosomal AMP-dependent protein kinase activation and autophagy. Autophagy 16(10):1871–1888 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Kondo D, Saegusa H, Tanabe T (2018) Involvement of phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin/peroxisome proliferator-activated receptor γ pathway for induction and maintenance of neuropathic pain. Biochem Biophys Res Commun 499(2):253–259 [DOI] [PubMed] [Google Scholar]
  • 73.Kaneda MM, Messer KS, Ralainirina N, Li H, Leem CJ, Gorjestani S et al (2016) PI3Kγ is a molecular switch that controls immune suppression. Nature 539(7629):437–442 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Scalise M, Pochini L, Console L, Losso MA, Indiveri C (2018) The Human SLC1A5 (ASCT2) amino acid transporter: from function to structure and role in cell biology. Front Cell Dev Biol. 6:1–17 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Vasanthakumar A, Godley LA (2015) 5-hydroxymethylcytosine in cancer: significance in diagnosis and therapy. Cancer Genet 208(5):167–177 [DOI] [PubMed] [Google Scholar]
  • 76.Jiang D, Zhang Y, Hart RP, Chen J, Herrup K, Li J (2015) Alteration in 5-hydroxymethylcytosine-mediated epigenetic regulation leads to Purkinje cell vulnerability in ATM deficiency. Brain 138(12):3520–3536 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 77.Li W, Zhang X, Lu X, You L, Song Y, Luo Z et al (2017) 5-Hydroxymethylcytosine signatures in circulating cell-free DNA as diagnostic biomarkers for human cancers. Cell Res 27(10):1243–1257 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 78.Cao J, Shen R, Zhang W, Mao B, Shi Q, Zhou R et al (2019) Clinical diagnosis and genetic counseling of atypical ataxia-telangiectasia in a Chinese family. Mol Med Rep 49(5):3441–3448 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Wallis LI, Griffiths PD, Ritchie SJ, Romanowski CAJ, Darwent G, Wilkinson ID (2007) Proton spectroscopy and imaging at 3T in ataxia-telangiectasia. Am J Neuroradiol 28(1):79–83 [PMC free article] [PubMed] [Google Scholar]
  • 80.Sahama I, Sinclair K, Fiori S, Pannek K, Lavin M, Rose SE (2014) Altered corticomotor-cerebellar integrity in young ataxia telangiectasia patients. Mov Disord 29(10):1289–1298 [DOI] [PubMed] [Google Scholar]
  • 81.Dineen RA, Raschke F, McGlashan HL, Pszczolkowski S, Hack L, Cooper AD et al (2019) Multiparametric cerebellar imaging and clinical phenotype in childhood ataxia telangiectasia. NeuroImage Clin 2020(25):102110 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 82.Lin DDM, Barker PB, Lederman HM, Crawford TO (2014) Cerebral abnormalities in adults with ataxia-telangiectasia. Am J Neuroradiol 35(1):119–123 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 83.Liu HS, Chen YC, Chen CY (2016) Cerebral microbleeds and iron depletion of dentate nuclei in ataxia-telangiectasia. Neurology 87(10):1062–1063 [DOI] [PubMed] [Google Scholar]
  • 84.Dineen RA, Blanchard C, Pszczolkowski S, Paine S, Prasad M, Chow G et al (2021) Accumulation of brain hypointense foci on susceptibility- weighted imaging in childhood ataxia telangiectasia. AJNR Am J Neuroradiol 42(6):1144–1150 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Tiet MY, Nannoni S, Scoffings D, Schon K, Horvath R, Markus HS et al (2021) White matter hyperintensities and cerebral microbleeds in ataxia-telangiectasia. Neurol Genet [DOI] [PMC free article] [PubMed]
  • 86.Lin DDM, Crawford TO, Lederman HM, Barker PB (2006) Proton MR spectroscopic imaging in ataxia-telangiectasia. Neuropediatrics 37(4):241–246 [DOI] [PubMed] [Google Scholar]
  • 87.Sahama I, Sinclair K, Fiori S, Doecke J, Pannek K, Reid L et al (2015) Motor pathway degeneration in young ataxia telangiectasia patients: a diffusion tractography study. NeuroImage Clin 9:206–215 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 88.Volkow ND, Tomasi D, Wang GJ, Studentsova Y, Margus B, Crawford TO (2014) Brain glucose metabolism in adults with ataxia-telangiectasia and their asymptomatic relatives. Brain 137(6):1753–1761 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 89.Mcgrath-morrow S, Lefton-greif M, Rosquist K, Crawford T, Kelly A, Zeitlin P et al (2008) Pulmonary function in adolescents with ataxia telangiectasia. Pediatr Pulmonol 43:59–66 [DOI] [PubMed] [Google Scholar]
  • 90.Mcgrath-morrow SA, Lederman HM, Aherrera AD, Lefton-greif MA, Crawford TO, Ryan T et al (2014) Pulmonary function in children and young adults with ataxia telangiectasia. Pediatr Pulmonol 49(1):84–90 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91.Vilozni D, Lavie M, Sarouk I, Dagan A, Ashkenazi M, Ofek M et al (2015) FVC deterioration, airway obstruction determination, and life span in Ataxia telangiectasia. Respir Med 109:890–896 [DOI] [PubMed] [Google Scholar]
  • 92.Berkun Y, Vilozni D, Levi Y, Borik S, Waldman D, Somech R et al (2010) Reversible airway obstruction in children with ataxia telangiectasia. Pediatr Pulmonol 45:230–235 [DOI] [PubMed] [Google Scholar]
  • 93.Reichenbach J, Schubert R, Schindler D, Müller K, Böhles H, Zielen S (2002) Elevated oxidative stress in patients with ataxia telangiectasia. Antioxid Redox Signal 4(3):465–469 [DOI] [PubMed] [Google Scholar]
  • 94.Reichenbach J, Schubert R, Schwan C, Muller K, Bohles H, Zielen S (1999) Anti-oxidative capacity in patients with ataxia telangiectasia. Clin Exp Immunol 117:535–539 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 95.Pietrucha B, Heropolitanska-Pliszka E, Maciejczyk M, Car H, Sawicka-Powierza J, Motkowski R, et al. Comparison of Selected Parameters of Redox Homeostasis in Patients with Ataxia-Telangiectasia and Nijmegen Breakage Syndrome. Oxid Med Cell Longev. 2017;2017. [DOI] [PMC free article] [PubMed]
  • 96.Subramanian GN, Yeo AJ, Gatei MH, Coman DJ, Lavin MF (2022) Metabolic stress and mitochondrial dysfunction in ataxia-telangiectasia. Antioxidants 11(4):653 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 97.Yeo AJ, Chong KL, Gatei M, Zou D, Stewart R, Withey S et al (2021) Impaired endoplasmic reticulum-mitochondrial signaling in ataxia-telangiectasia. iScience 24(1):101972 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 98.Yeo AJ, Subramanian GN, Chong KL, Gatei M, Parton RG, Coman D et al (2021) An anaplerotic approach to correct the mitochondrial dysfunction in ataxia-telangiectasia (A-T). Mol Metab 54:101354 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 99.Degan P, d’Ischia M, Pallardó FV, Zatterale A, Brusco A, Calzone R et al (2007) Glutathione levels in blood from ataxia telangiectasia patients suggest in vivo adaptive mechanisms to oxidative stress. Clin Biochem 40(9–10):666–670 [DOI] [PubMed] [Google Scholar]
  • 100.Andrade IGA, Suano-Souza FI, Fonseca FLA, Lago CSA, Sarni ROS (2021) Selenium levels and glutathione peroxidase activity in patients with ataxia - telangiectasia : association with oxidative stress and lipid status biomarkers. Orphanet J Rare Dis 16:83 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 101.Zhang Y, Lee J-H, Paull TT, Gehrke S, D’alessandro A, Dou Q et al (2019) Mitochondrial redox sensing by the kinase ATM maintains cellular antioxidant capacity. Sci Signal 11(538):1–24 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 102.Sun X, Wang Y, Ji K, Liu Y, Kong Y, Nie S et al (2020) NRF2 preserves genomic integrity by facilitating ATR activation and G2 cell cycle arrest. Nucleic Acids Res 48(16):9109–9123 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 103.Paupe V, Dassa EP, Goncalves S, Auchère F, Lönn M, Holmgren A et al (2009) Impaired nuclear Nrf2 translocation undermines the oxidative stress response in Friedreich ataxia. PLoS ONE 4(1):e4253 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 104.Lynch DR, Chin MP, Delatycki MB, Subramony SH, Corti M, Hoyle JC et al (2021) Safety and efficacy of omaveloxolone in friedreich ataxia (moxie study). Ann Neurol 89(2):212–225 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105.Biagiotti S, Bianchi M, Rossi L, Chessa L, Magnani M (2019) Activation of NRF2 by dexamethasone in ataxia telangiectasia cells involves KEAP1 inhibition but not the inhibition of p38. PLoS ONE 14(5):1–19 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 106.McGrath-Morrow SA, Collaco JM, Detrick B, Lederman HM (2016) Serum interleukin-6 levels and pulmonary function in ataxia-telangiectasia. J Pediatr 171:256–261 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 107.Yoon J, Lee H, Lim JW, Kim H (2020) Inhibitory effect of alpha-lipoic acid on mitochondrial dysfunction and interleukin-8 expression in interleukin-1beta-stimulated ataxia telangiectasia fibroblasts. Physiol Pharmacol 71(1):155–165 [DOI] [PubMed] [Google Scholar]
  • 108.Mcgrath-morrow SA, Collaco JM, Crawford TO, Carson KA, Lefton-greif MA, Zeitlin P et al (2010) Elevated serum il-8 levels in ataxia telangiectasia. J Pediatr 156:682–684 [DOI] [PubMed] [Google Scholar]
  • 109.McGrath-Morrow SA, Ndeh R, Collaco JM, Rothblum-Oviatt C, Wright J, O’Reilly MA et al (2018) Inflammation and transcriptional responses of peripheral blood mononuclear cells in classic ataxia telangiectasia. PLoS ONE 13(12):1–16 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 110.Kim M, Kim A, Yu JH, Lim JW, Kim H (2014) Glutamine deprivation induces interleukin-8 expression in ataxia telangiectasia fibroblasts. Inflamm Res 63:347–356 [DOI] [PubMed] [Google Scholar]
  • 111.Prithivirajsingh S, Story MD, Bergh SA, Geara FB, Kian Ang K, Ismail SM et al (2004) Accumulation of the common mitochondrial DNA deletion induced by ionizing radiation. FEBS Lett 571(1–3):227–232 [DOI] [PubMed] [Google Scholar]
  • 112.Jin S, Cordes N (2019) ATM controls DNA repair and mitochondria transfer between neighboring cells. Cell Commun Signal 17(1):1–11 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 113.Neves R, De Dios PB, Panek R, Jagani S, Wilne S, Bhatt JM et al (2023) Development of cancer surveillance guidelines in ataxia telangiectasia: a Delphi-based consensus survey of international experts. Cancer Med 12(13):14663–14673 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 114.Neves R, Panek R, Clarkson K, Panagioti O, Fernandez NS, Wilne S et al (2024) Feasibility of whole-body MRI for cancer screening in children and young people with ataxia telangiectasia: A mixed methods cross-sectional study. Cancer Med 13(14):1–16 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 115.Torres M, Al-Buhairi M, Alsbeih G (2004) Induction of p53 and p21 proteins by gamma radiation in skin fibroblasts derived from breast cancer patients. Int J Radiat Oncol Biol Phys 58(2):479–484 [DOI] [PubMed] [Google Scholar]
  • 116.Carlessi L, Poli EF, Bechi G, Mantegazza M, Pascucci B, Narciso L et al (2014) Functional and molecular defects of hiPSC-derived neurons from patients with ATM deficiency. Cell Death Dis 5(7):e1342–e1414 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 117.Byrd PJ, Srinivasan V, Last JI, Smith A, Biggs P, Carney EF et al (2012) Severe reaction to radiotherapy for breast cancer as the presenting feature of ataxia telangiectasia. Br J Cancer 106(2):262–268 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 118.Bitelo Ludwig L, Valiati VH, Palazzo RP, Jardim LB, Da Rosa DP, Bona S et al (2013) Chromosome instability and oxidative stress markers in patients with ataxia telangiectasia and their parents. Biomed Res Int [DOI] [PMC free article] [PubMed]
  • 119.Viktorisson A, Mathew ST, Hammarsten O, Johansson P (2018) A control for the day-to-day normalization of the flow cytometry γ-H2AX assay for clinical routine. Cytom Part B - Clin Cytom 94(6):946–949 [DOI] [PubMed] [Google Scholar]
  • 120.Johansson P, Fasth A, Ek T, Hammarsten O (2017) Validation of a flow cytometry-based detection of γ-H2AX, to measure DNA damage for clinical applications. Cytom Part B - Clin Cytom 92(6):534–540 [DOI] [PubMed] [Google Scholar]
  • 121.Mahrhofer H, Bürger S, Oppitz U, Flentje M, Djuzenova CS (2006) Radiation induced DNA damage and damage repair in human tumor and fibroblast cell lines assessed by histone H2AX phosphorylation. Int J Radiat Oncol Biol Phys 64(2):573–580 [DOI] [PubMed] [Google Scholar]
  • 122.Rübe CE, Fricke A, Schneider R, Simon K, Kühne M, Fleckenstein J et al (2010) DNA repair alterations in children with pediatric malignancies: novel opportunities to identify patients at risk for high-grade toxicities. Int J Radiat Oncol Biol Phys 78(2):359–369 [DOI] [PubMed] [Google Scholar]
  • 123.Zaharieva EK, Sasatani M, Kamiya K (2022) Kinetics of dna repair under chronic irradiation at low and medium dose rates in repair proficient and repair compromised normal fibroblasts. Radiat Res 197(4):332–349 [DOI] [PubMed] [Google Scholar]
  • 124.Bryant J, White L, Coen N, Shields L, McClean B, Meade AD et al (2020) MicroRNA analysis of atm-deficient cells indicate pten and ccdn1 as potential biomarkers of radiation response. Radiat Res 193(6):520–530 [DOI] [PubMed] [Google Scholar]
  • 125.Taylor AMR (1992) Ataxia telangiectasia genes and predisposition to leukaemia, lymphoma and breast cancer. Br J Cancer 66(1):5–9 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 126.Taylor AMR, Metcalfe JA, Thick J, Mak YF (1996) Leukemia and lymphoma in ataxia telangiectasia. Blood 87(2):423–438 [PubMed] [Google Scholar]
  • 127.Szeliga A, Zysnarska A, Szklarska Z, Truszkowska E, Podfigurna A, Czyzyk A et al (2019) A case of premature ovarian insufficiency in Nijmegen breakage syndrome patient and review of literature. From gene mutation to clinical management. Gynecol Endocrinol 35(11):999–1002 [DOI] [PubMed] [Google Scholar]
  • 128.Bucher M, Endesfelder D, Roessler U, Borkhardt A, Dückers G, Kirlum HJ et al (2021) Analysis of chromosomal aberrations and γH2A.X foci to identify radiation-sensitive ataxia-telangiectasia patients. Mutat Res 861–862:503301 [DOI] [PubMed] [Google Scholar]
  • 129.Sun X, Becker-Catania SG, Chun HH, Hwang MJ, Huo Y, Wang Z et al (2002) Early diagnosis of ataxia-telangiectasia using radiosensitivity testing. J Pediatr 140(6):724–731 [DOI] [PubMed] [Google Scholar]
  • 130.Jaworska A, Szumiel I, De Angelis P, Olsen G, Reitan J (2001) Evaluation of ionizing radiation sensitivity markers in a panel of lymphoid cell lines. Int J Radiat Biol 77(3):269–280 [DOI] [PubMed] [Google Scholar]
  • 131.Driessen GJ, Ijspeert H, Weemaes CMR, Haraldsson Á, Trip M, Warris A et al (2013) Antibody deficiency in patients with ataxia telangiectasia is caused by disturbed B- and T-cell homeostasis and reduced immune repertoire diversity. J Allergy Clin Immunol 131(5):1367–1375 [DOI] [PubMed] [Google Scholar]
  • 132.Thakar MS, Hintermeyer MK, Gries MG, Routes JM, Verbsky JW (2017) A practical approach to newborn screening for severe combined immunodeficiency using the T cell receptor excision circle assay. Front Immunol 8:1–6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 133.Mandola AB, Reid B, Sirror R, Brager R, Dent P, Chakroborty P et al (2019) Ataxia telangiectasia diagnosed on newborn screening-case cohort of 5 years’ experience. Front Immunol 10:1–7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 134.Moeini Shad T, Yousefi B, Amirifar P, Delavari S, Rae W, Kokhaei P et al (2021) Variable abnormalities in t and b cell subsets in ataxia telangiectasia. J Clin Immunol 41(1):76–88 [DOI] [PubMed] [Google Scholar]
  • 135.Cirillo E, Polizzi A, Soresina A, Prencipe R, Giardino G, Cancrini C et al (2022) Progressive depletion of b and t lymphocytes in patients with ataxia telangiectasia: results of the italian primary immunodeficiency network. J Clin Immunol 42(4):783–797 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 136.Zielen S, Duecker RP, Woelke S, Donath H, Bakhtiar S, Buecker A et al (2021) Simple measurement of iga predicts immunity and mortality in ataxia-telangiectasia. J Clin Immunol 41(8):1878–1892 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 137.Chopra C, Davies G, Taylor M, Anderson M, Bainbridge S, Tighe P et al (2014) Immune deficiency in Ataxia-Telangiectasia: a longitudinal study of 44 patients. Clin Exp Immunol 176(2):275–282 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 138.Lacorte E, Piscopo P, Bellomo G, Della GF, Vanacore N (2022) A guideline on the diagnosis and treatment of children with ataxias. Front Neurol 13:971781 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 139.Quek H, Luff J, Cheung KG, Kozlov S, Gatei M, Lee CS et al (2017) A rat model of ataxia-telangiectasia: evidence for a neurodegenerative phenotype. Hum Mol Genet 26(1):109–123 [DOI] [PubMed] [Google Scholar]
  • 140.Biagiotti S, Menotta M, Orazi S, Spapperi C, Brundu S, Fraternale A et al (2016) Dexamethasone improves redox state in ataxia telangiectasia cells by promoting an NRF2-mediated antioxidant response. FEBS J 283(21):3962–3978 [DOI] [PubMed] [Google Scholar]
  • 141.Quarantelli M, Giardino G, Prinster A, Aloj G, Carotenuto B, Cirillo E et al (2013) Steroid treatment in Ataxia-Telangiectasia induces alterations of functional magnetic resonance imaging during prono-supination task. Eur J Paediatr Neurol 17(2):135–140 [DOI] [PubMed] [Google Scholar]
  • 142.Cirillo E, Del Giudice E, Micheli R, Cappellari AM, Soresina A, Dellepiane RM et al (2018) Minimum effective betamethasone dosage on the neurological phenotype in patients with ataxia-telangiectasia: a multicenter observer-blind study. Eur J Neurol 25(6):833–840 [DOI] [PubMed] [Google Scholar]
  • 143.Broccoletti T, Del Giudice E, Cirillo E, Vigliano I, Giardino G, Ginocchio VM et al (2011) Efficacy of very-low-dose betamethasone on neurological symptoms in ataxia-telangiectasia. Eur J Neurol 18(4):564–570 [DOI] [PubMed] [Google Scholar]
  • 144.Leuzzi V, Micheli R, D’Agnano D, Molinaro A, Venturi T, Plebani A et al (2015) Positive effect of erythrocyte-delivered dexamethasone in ataxia-telangiectasia. Neurol Neuroimmunol NeuroInflammation 2(3):e98 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 145.Chessa L, Leuzzi V, Plebani A, Soresina A, Micheli R, Agnano DD et al (2014) Intra-erythrocyte infusion of dexamethasone reduces neurological symptoms in ataxia teleangiectasia patients: results of a phase 2 trial. Orphanet J Rare Dis [DOI] [PMC free article] [PubMed]
  • 146.Zielen S, Crawford T, Benatti L, Magnani M, Kieslich M, Ryan M et al (2024) Safety and efficacy of intra-erythrocyte dexamethasone sodium phosphate in children with ataxia telangiectasia (ATTeST): a multicentre, randomised, double-blind, placebo-controlled phase 3 trial. Lancet Neurol 23(9):871–882 [DOI] [PubMed] [Google Scholar]
  • 147.Menotta M, Biagiotti S, Spapperi C, Orazi S, Rossi L, Chessa L et al (2017) ATM splicing variants as biomarkers for low dose dexamethasone treatment of A-T. Orphanet J Rare Dis 12(1):1–7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 148.Donath H, Wölke S, Knop V, Heß U, Duecker RP, Trischler J, et al. Liver Assessment in Patients with Ataxia-Telangiectasia: Transient Elastography Detects Early Stages of Steatosis and Fibrosis. Can J Gastroenterol Hepatol. 2023;2023. [DOI] [PMC free article] [PubMed]
  • 149.Dzieciatkowska M, Qi G, You J, Bemis KG, Sahm H, Lederman HM et al (2011) Proteomic characterization of cerebrospinal fluid from ataxia-telangiectasia (a-t) patients using a lc/ms-based label-free protein quantification technology. Int J Proteomics 2011:1–13 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 150.Canet-Pons J, Schubert R, Duecker RP, Schrewe R, Wölke S, Kieslich M et al (2018) Ataxia telangiectasia alters the ApoB and reelin pathway. Neurogenetics 19(4):237–255 [DOI] [PubMed] [Google Scholar]
  • 151.McDonald CJ, Ostini L, Wallace DF, John AN, Watters DJ, Subramaniam VN (2011) Iron loading and oxidative stress in the Atm-/- mouse liver. Am J Physiol - Gastrointest Liver Physiol 300(4):554–560 [DOI] [PubMed] [Google Scholar]
  • 152.Liu N, Stoica G, Yan M, Scofield VL, Qiang W, Lynn WS et al (2005) ATM deficiency induces oxidative stress and endoplasmic reticulum stress in astrocytes. Lab Investig 85(12):1471–1480 [DOI] [PubMed] [Google Scholar]
  • 153.Morani F, Doccini S, Chiorino G, Fattori F, Galatolo D, Sciarrillo E et al (2021) Functional network profiles in arsacs disclosed by aptamer-based proteomic technology. Front Neurol 11:1–8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 154.Imbault V, Dionisi C, Naeije G, Communi D, Pandolfo M (2022) Cerebrospinal fluid proteomics in friedreich ataxia reveals markers of neurodegeneration and neuroinflammation. Front Neurosci 16:1–7 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary file1 (XLSX 9 kb) (9.8KB, xlsx)
Supplementary file2 (XLSX 20 kb) (20.4KB, xlsx)

Data Availability Statement

All available data has been included in the supplementary files and have been stated within the manuscript.

Articles from Journal of Neurology are provided here courtesy of Springer

RESOURCES