Ataxia-telangiectasia

Mendelian MONDO:0008840 Pathograph 26 Combined immunodeficiency Hereditary cerebellar ataxia DNA repair disorder

Ataxia-telangiectasia is a rare autosomal recessive multisystem disorder caused by biallelic pathogenic variants in ATM. Loss of ATM kinase function disrupts DNA double-strand break signaling, oxidative-stress responses, cell-cycle checkpoints, lymphocyte homeostasis, and tissue-specific stress responses in the cerebellum and respiratory tract. The clinical spectrum is dominated by progressive cerebellar ataxia, telangiectasia, combined immunodeficiency, recurrent sinopulmonary infection, elevated alpha-fetoprotein, marked radiosensitivity, and increased malignancy risk. Median age at symptom onset is approximately 1 year, with diagnosis typically delayed to age 5. Classical AT with absent ATM kinase activity causes severe childhood-onset disease, while variant AT with residual kinase activity follows a milder course.

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Inheritance

Autosomal recessive

Show evidence (1 reference)

PMID:30685876 SUPPORT Other

"Ataxia-telangiectasia (A-T) is an autosomal recessive primary immunodeficiency (PID) disease that is caused by mutations in ataxia-telangiectasia mutated (ATM) gene encoding a serine/threonine protein kinase."

Supports autosomal recessive inheritance and ATM as the causative gene.

◆

Subtypes

Classical ataxia-telangiectasia

Complete absence of ATM protein or kinase activity. Severe childhood-onset cerebellar ataxia with wheelchair dependence by late childhood, pronounced immunodeficiency, and high malignancy risk.

Show evidence (1 reference)

PMID:30888062 SUPPORT Human Clinical

"Classical A-T is caused by biallelic variants on ATM (ataxia telangiectasia mutated) gene, leading to a loss of function of the protein kinase ATM, involved in DNA damage repair."

Defines classical AT as arising from complete ATM loss of function.

Variant ataxia-telangiectasia

Limited residual ATM kinase activity. Later onset, slower neurologic progression, patients may remain ambulant for decades. May present with extrapyramidal features and dystonia rather than pure cerebellar ataxia. Variant AT is a recognized clinical subtype associated with hypomorphic ATM mutations that retain partial kinase activity.

Ataxia-Telangiectasia-Like Disorder 1 (MRE11) MONDO:0024557

MRE11 link autosomal recessive inheritance

A-T-like disorder caused by biallelic hypomorphic variants in MRE11, which encodes a core component of the MRE11-RAD50-NBN (MRN) complex that senses DNA double-strand breaks and activates ATM. ATLD1 phenocopies the neurodegenerative features of classical A-T with progressive cerebellar ataxia and oculomotor apraxia, typically with later onset and a more slowly progressive course. Unlike A-T, telangiectasia and elevated serum alpha-fetoprotein are generally absent, immunodeficiency is mild or absent, and malignancy risk is lower. Radiosensitivity is present because defective MRN impairs ATM activation and DSB repair.

Ataxia-Telangiectasia-Like Disorder 2 (PCNA) MONDO:0014399

PCNA link autosomal recessive inheritance

A-T-like disorder caused by a hypomorphic missense variant in PCNA, the sliding-clamp that coordinates DNA replication and multiple DNA repair pathways (translesion synthesis, nucleotide excision repair, mismatch repair). Clinical features include progressive ataxia, neurodegeneration, short stature, photosensitivity, and cellular hypersensitivity to UV and ionizing radiation. Unlike classical A-T, telangiectasia and alpha- fetoprotein elevation are not typical and immunodeficiency is mild. ATLD2 illustrates that genome-maintenance defects outside the canonical ATM-MRN axis can produce a convergent cerebellar-ataxia phenotype.

Ataxia with Oculomotor Apraxia Type 1 (APTX) MONDO:0008842

APTX link autosomal recessive inheritance

Early-onset autosomal recessive cerebellar ataxia caused by biallelic variants in APTX, encoding aprataxin, which resolves abortive DNA ligase intermediates (5'-adenylated DNA ends) during single-strand break repair. Defective single-strand break processing causes persistent DNA damage in post-mitotic neurons, with selective vulnerability of cerebellar neurons and peripheral nerves. Hallmark clinical features are childhood-onset ataxia, oculomotor apraxia, axonal sensorimotor neuropathy, and hypoalbuminemia with hypercholesterolemia. Serum alpha-fetoprotein is normal or only mildly elevated, and immunodeficiency, telangiectasia, and cancer predisposition are not features.

Ataxia with Oculomotor Apraxia Type 2 (SETX) MONDO:0018996

SETX link autosomal recessive inheritance

Adolescent-onset autosomal recessive cerebellar ataxia caused by biallelic loss-of-function variants in SETX, encoding senataxin, an RNA/DNA helicase that resolves R-loops and protects the genome from transcription-replication conflicts. Accumulated R-loops generate DNA damage that preferentially affects cerebellar and peripheral neurons. Clinical features include progressive cerebellar ataxia, axonal sensorimotor peripheral neuropathy, oculomotor apraxia (in a subset), and markedly elevated serum alpha- fetoprotein. Unlike A-T, immunodeficiency, telangiectasia, and cancer predisposition are absent.

Spinocerebellar Ataxia with Axonal Neuropathy 1 (TDP1) MONDO:0011801

TDP1 link autosomal recessive inheritance

Autosomal recessive cerebellar ataxia with axonal sensorimotor neuropathy caused by a homozygous TDP1 variant (H493R). TDP1 (tyrosyl-DNA phosphodiesterase 1) releases trapped topoisomerase 1 cleavage complexes from DNA and repairs 3'-blocked single-strand breaks. Loss of TDP1 activity causes accumulation of protein-linked DNA breaks in non-replicating neurons. Clinical features include late-childhood onset cerebellar ataxia, distal muscle wasting, pes cavus, and hypoalbuminemia with hypercholesterolemia, without telangiectasia, immunodeficiency, or cancer predisposition.

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Pathophysiology

ATM kinase deficiency and defective DNA damage signaling

ATM loss of function impairs the cellular response to DNA double-strand breaks and checkpoint signaling, creating genomic instability and broad tissue vulnerability. In classical disease, biallelic ATM variants abolish or markedly reduce ATM kinase activity. ATM normally coordinates DSB repair through the MRN complex (MRE11-RAD50-NBN) and downstream effectors including p53 and CHK2.

neuron link B cell link

ATM link

DNA damage response link double-strand break repair link cell cycle checkpoint signaling link

protein serine/threonine kinase activity link

Downstream

Oxidative stress and microglia-driven cerebellar neurodegeneration Loss of ATM redox and DSB-response functions drives oxidative stress and microglial activation in the cerebellum.

Combined immunodeficiency with lymphocyte depletion and dysfunction ATM is required for V(D)J recombination and class switch recombination, so its loss disrupts adaptive immunity.

Defective insulin-ATM signaling and metabolic inflexibility Loss of insulin-activated ATM disrupts the catabolic-anabolic glucose switch and produces intrinsic insulin resistance.

Genomic instability and cancer predisposition Defective DSB repair and checkpoint signaling produce chromosomal instability and malignant transformation.

Increased sensitivity to ionizing radiation Loss of ATM-dependent DSB repair confers cellular hypersensitivity to ionizing radiation and radiomimetic agents.

Elevated circulating alpha-fetoprotein concentration Persistent elevation of serum AFP is a recognized laboratory hallmark of ATM deficiency.

Show evidence (2 references)

PMID:30685876 SUPPORT Other

"The principal role of nuclear ATM is the coordination of cellular signaling pathways in response to DNA double-strand breaks, oxidative stress, and cell cycle checkpoint."

Review evidence linking ATM deficiency to defective DNA-damage and checkpoint signaling.

PMID:30888062 SUPPORT Human Clinical

"Classical A-T is caused by biallelic variants on ATM (ataxia telangiectasia mutated) gene, leading to a loss of function of the protein kinase ATM, involved in DNA damage repair."

Human genetic evidence that classical AT arises from biallelic ATM loss of function.

Oxidative stress and microglia-driven cerebellar neurodegeneration

Cerebellar degeneration in AT is linked to persistent oxidative stress and inflammatory signaling. ATM deficiency increases reactive oxygen species in the cerebellum and is associated with activated microglia that deliver neurotoxic cytokine signals to Purkinje and granule neurons. ATM expression is enriched in microglia throughout cerebellar development and adulthood, and pseudotime analysis shows microglial activation precedes neuronal apoptosis.

Purkinje cell link microglial cell link granule cell link

response to oxidative stress link cytokine production link neuron apoptotic process link

cerebellum link

Downstream

Cerebellar atrophy Progressive loss of Purkinje and granule neurons drives the macroscopic cerebellar atrophy seen on imaging.

Show evidence (7 references)

PMID:11280737 SUPPORT Model Organism

"Our findings support the hypothesis that the absence of functional ATM results in oxidative stress, which may be an important cause of the degeneration of cerebellar neurons in A-T."

Atm-deficient mouse brain data support oxidative stress as a driver of cerebellar neuron loss.

PMID:11280737 SUPPORT Model Organism

"We found alterations in the levels of thiol-containing compounds in Atm (-/-) brains, as well as significant changes in the activities of thioredoxin, catalase, and manganese superoxide dismutase in Atm (-/-) cerebella."

Direct biochemical evidence of altered antioxidant enzyme activity in Atm-deficient cerebella.

PMID:38159274 SUPPORT Human Clinical

"Here, we find evidence of microglial inflammation in the cerebellum of patients with A-T using single-nucleus RNA sequencing."

Patient cerebellar transcriptomics show microglial inflammation in AT.

+ 4 more references

Combined immunodeficiency with lymphocyte depletion and dysfunction

ATM deficiency disrupts adaptive immune homeostasis through impaired V(D)J recombination and class switch recombination. This leads to B-cell lymphopenia, defective immunoglobulin class switching (IgA deficiency in ~61%, IgG deficiency in ~29%), T-cell depletion, and NK-cell functional abnormalities. IgA deficiency is a strong prognostic indicator of worse survival.

B cell link T cell link natural killer cell link

isotype switching link V(D)J recombination link B cell differentiation link

Downstream

Combined immunodeficiency Defective V(D)J/class switch recombination yields the clinical combined immunodeficiency phenotype.

Decreased circulating IgA concentration Impaired class switch recombination in B cells produces selective IgA deficiency in the majority of patients.

Show evidence (4 references)

PMID:38834764 SUPPORT Human Clinical

"IgA deficiency was observed in 60.8% of patients and IgG deficiency in 28.6%. T- and B-lymphopenias were also present in most cases."

Multicenter cohort data show humoral deficiency and lymphopenia in AT.

PMID:39165363 SUPPORT Human Clinical

"We observed reduced levels of peripheral blood CD3+CD8+ cytotoxic T cells, CD3+CD4+ T helper cells, and CD19+ B cells, whereas the amount of CD3--CD56+ NK cells and CD3+CD56+ NKT-like cells was similar compared with age-matched controls."

Immune profiling demonstrates major T-cell and B-cell abnormalities in AT.

PMID:34477998 SUPPORT Human Clinical

"Overall survival of patients with IgA deficiency was significantly diminished."

Shows that more severe humoral immune deficiency is clinically relevant and associated with worse survival.

+ 1 more reference

Airway epithelial oxidative susceptibility and impaired innate immunity

AT respiratory disease is not explained solely by systemic immune defects. ATM-deficient airway epithelial cells show increased oxidative injury after pneumococcal challenge together with defective ASC-Caspase 1 inflammasome activation and altered cytokine output, providing a local epithelial mechanism for recurrent sinopulmonary disease.

airway epithelial cell link

response to oxidative stress link innate immune response link

lung link

Downstream

Recurrent respiratory infections Cell-intrinsic epithelial inflammasome and oxidative defects predispose the airway to recurrent pyogenic infection.

Bronchiectasis Repeated airway injury and infection drive airway remodeling and bronchiectasis.

Show evidence (2 references)

PMID:30796268 SUPPORT In Vitro

"These data suggest that the heightened susceptibility of these cells to S. pneumoniae infection is due to both increased oxidative damage and a defect in inflammasome activation, and has implications for lung disease in these patients."

Airway epithelial studies support a cell-intrinsic respiratory mechanism in AT.

PMID:30796268 SUPPORT In Vitro

"Further investigation revealed that the ASC-Caspase 1 signalling pathway was defective in A-T airway epithelial cells."

Identifies the specific inflammasome pathway defect in AT airway epithelium.

Defective insulin-ATM signaling and metabolic inflexibility

ATM is activated by insulin and acts as a critical regulator of metabolic flexibility, mediating the switch between catabolic and anabolic glucose fates by controlling PKM2 and HIF1alpha. In AT, loss of this insulin-ATM axis produces intrinsic insulin resistance and glucose intolerance, and cells become compensatorily dependent on glutamine for energy. Purkinje cells are unusually insulin-sensitive, providing a metabolic explanation for their disproportionate vulnerability in AT cerebellum and linking peripheral metabolic disease (insulin-resistant diabetes, hepatic metabolic injury) to neurodegenerative progression.

Purkinje cell link hepatocyte link

insulin receptor signaling pathway link ↓ DECREASED glucose metabolic process link L-glutamine metabolic process link ↑ INCREASED

Downstream

Insulin-resistant diabetes mellitus Loss of insulin-activated ATM produces intrinsic insulin resistance and glucose intolerance.

Hepatic fibrosis Metabolic inflexibility and chronic insulin resistance contribute to progressive liver injury and fibrosis in AT.

Show evidence (3 references)

PMID:41120320 SUPPORT Model Organism

"Here we show insulin-activated ATM is a critical mediator of this process, facilitating the swift transition between catabolic-and-anabolic fates of glucose by regulating the functional status of PKM2 and HIF1α."

Identifies the insulin-ATM axis as a regulator of metabolic flexibility through PKM2 and HIF1alpha.

PMID:41120320 SUPPORT Model Organism

"In Ataxia-Telangiectasia (A-T), these mechanisms are disrupted, resulting in intrinsic insulin resistance and glucose intolerance."

Establishes intrinsic insulin resistance and glucose intolerance as direct consequences of ATM deficiency.

PMID:41120320 SUPPORT Model Organism

"Cerebellar degeneration, a hallmark of A-T, is characterized by the pronounced vulnerability of Purkinje cells, attributed to their unexpected sensitivity to insulin."

Links peripheral insulin signaling defects to selective Purkinje cell vulnerability.

Genomic instability and cancer predisposition

ATM deficiency produces chromosomal instability, defective cell-cycle checkpoints, and impaired apoptotic responses, driving malignant transformation particularly in lymphoid tissues. The cumulative incidence of cancer reaches 29% by age 35, with hematologic malignancies (especially non-Hodgkin lymphoma) predominating in childhood and solid tumors becoming more frequent in adulthood.

B cell link

DNA damage response link cell cycle checkpoint signaling link apoptotic process link

Downstream

Lymphoma Chromosomal instability at lymphoid antigen-receptor loci drives non-Hodgkin lymphoma, the predominant childhood malignancy in AT.

Show evidence (3 references)

PMID:39521281 SUPPORT Human Clinical

"Eighty-four (16.5%) of 508 individuals were diagnosed with a primary cancer, of whom 62 (74%) were hematologic in origin and 22 (26%) were solid-organ cancers."

Large cohort data quantifying cancer incidence and types in AT.

PMID:39521281 SUPPORT Human Clinical

"Non-Hodgkin lymphoma occurred most frequently (n = 39), whereas solid cancers disproportionately affected those 18 years and older (n = 22)."

Identifies NHL as the most common malignancy and age-dependent shift to solid tumors.

PMID:30420857 SUPPORT Human Clinical

"Apart from a progressive neurodegenerative disorder, A-T leads to significantly increased susceptibility to malignancies."

Confirms increased cancer susceptibility as a core feature of AT.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

Blood 2

Decreased circulating IgA concentration VERY_FREQUENT Decreased circulating IgA concentration (HP:0002720)

Sequelae: Recurrent respiratory infections

Show evidence (2 references)

PMID:38834764 SUPPORT Human Clinical

"IgA deficiency was observed in 60.8% of patients and IgG deficiency in 28.6%. T- and B-lymphopenias were also present in most cases."

Multicenter cohort demonstrates IgA deficiency in 61% of AT patients.

PMID:34477998 SUPPORT Human Clinical

"IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients."

IgA deficiency serves as a prognostic biomarker in classical AT.

Lymphoma FREQUENT Lymphoma (HP:0002665)

Show evidence (1 reference)

PMID:39521281 SUPPORT Human Clinical

"Non-Hodgkin lymphoma occurred most frequently (n = 39), whereas solid cancers disproportionately affected those 18 years and older (n = 22)."

Non-Hodgkin lymphoma is the most common malignancy in AT.

Cardiovascular 1

Telangiectasia VERY_FREQUENT Telangiectasia (HP:0001009)

Conjunctival telangiectasias often appear by age 5-8 years, after neurologic onset.

Show evidence (1 reference)

PMID:30685876 SUPPORT Other

"A-T patients represent a broad range of clinical manifestations including progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, susceptibility to malignancies, and increased metabolic diseases."

Review evidence supporting telangiectasia as a defining clinical sign.

Digestive 1

Hepatic fibrosis OCCASIONAL Hepatic fibrosis (HP:0001395)

Hepatic fibrosis is increasingly recognized as a late multisystem complication, identified non-invasively in roughly one-fifth of patients and associated with metabolic alterations and ataxia severity.

Show evidence (2 references)

PMID:37147676 SUPPORT Human Clinical

"Significant hepatic fibrosis was observed in 5/25 (20%)."

Cross-sectional cohort quantifies hepatic fibrosis in 20% of AT patients.

PMID:37147676 SUPPORT Human Clinical

"A non-invasive diagnosis of significant hepatic fibrosis was observed in 20% of A-T patients associated with changes in liver enzymes, ferritin, increased HOMA-AD, and the severity of ataxia in comparison with patients without hepatic fibrosis."

Links hepatic fibrosis to metabolic alterations and ataxia severity.

Endocrine 1

Hypogonadism FREQUENT Hypogonadism (HP:0000135)

Both male and female sterility have been reported as part of the AT phenotype.

Show evidence (1 reference)

PMID:34854502 SUPPORT Model Organism

"Ataxia-telangiectasia (A-T) is a multisystem autosomal recessive disease caused by mutations in the ATM gene and characterized by cerebellar atrophy, progressive ataxia, immunodeficiency, male and female sterility, radiosensitivity, cancer predisposition, growth retardation, insulin-resistant..."

Review enumerates male and female sterility among defining features of AT.

Eye 1

Oculomotor apraxia VERY_FREQUENT Oculomotor apraxia (HP:0000657)

Show evidence (1 reference)

PMID:30888062 SUPPORT Human Clinical

"Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder characterized by progressive cerebellar ataxia, ocular apraxia, immunodeficiency, telangiectasia, elevated serum α-fetoprotein concentration, radiosensitivity and cancer predisposition."

Lists ocular apraxia as a defining characteristic of AT.

Immune 2

Combined immunodeficiency FREQUENT Combined immunodeficiency (HP:0005387)

Show evidence (1 reference)

PMID:39165363 SUPPORT Human Clinical

"Ataxia telangiectasia (AT) is a rare autosomal-recessive disorder characterized by profound neurodegeneration, combined immunodeficiency, and an increased risk for malignant diseases."

Supports combined immunodeficiency as part of the core AT phenotype.

Recurrent respiratory infections VERY_FREQUENT Recurrent respiratory infections (HP:0002205)

Sequelae: Bronchiectasis

Show evidence (1 reference)

PMID:38834764 SUPPORT Human Clinical

"Most patients presented recurrent airway infections, which was significantly associated with IgA deficiency."

Cohort evidence supports recurrent respiratory infection as a frequent clinical manifestation.

Integument 1

Premature aging FREQUENT Prematurely aged appearance (HP:0007495)

Show evidence (1 reference)

PMID:34854502 SUPPORT Model Organism

Review identifies premature aging as a defining AT feature.

Metabolism 1

Elevated circulating alpha-fetoprotein concentration VERY_FREQUENT Elevated circulating alpha-fetoprotein concentration (HP:0006254)

Show evidence (1 reference)

PMID:30888062 SUPPORT Human Clinical

Supports elevated alpha-fetoprotein as a characteristic laboratory abnormality in AT.

Nervous System 4

Progressive cerebellar ataxia VERY_FREQUENT Progressive cerebellar ataxia (HP:0002073)

Neurologic symptoms typically begin around age 1 year.

Sequelae: Dysarthria Cognitive impairment

Show evidence (2 references)

PMID:30888062 SUPPORT Human Clinical

Supports progressive cerebellar ataxia as a core neurologic manifestation.

PMID:38834764 SUPPORT Human Clinical

"Median (IQR) ages at symptom onset and diagnosis were 1.0 (1.0-2.0) and 5.0 (3.0-8.0) years, respectively."

Quantifies early onset of symptoms at median age 1 year.

Cerebellar atrophy VERY_FREQUENT Cerebellar atrophy (HP:0001272)

Sequelae: Progressive cerebellar ataxia Oculomotor apraxia

Show evidence (1 reference)

PMID:11280737 SUPPORT Model Organism

"A-T patients display a pleiotropic phenotype and suffer primarily from progressive ataxia caused by degeneration of cerebellar Purkinje and granule neurons."

Links cerebellar neuron degeneration to progressive atrophy.

Dysarthria FREQUENT Dysarthria (HP:0001260)

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:30137827 SUPPORT Other

"neurologically, dysarthria, oculomotor apraxia, extrapyramidal symptoms, axonal neuropathy, and cognitive impairment are common"

Reference text identifies dysarthria as a common neurologic feature of AT.

Cognitive impairment FREQUENT Cognitive impairment (HP:0100543)

Show evidence (1 reference)

PMID:30137827 SUPPORT Other

"neurologically, dysarthria, oculomotor apraxia, extrapyramidal symptoms, axonal neuropathy, and cognitive impairment are common"

Reference text identifies cognitive impairment as a common neurologic feature of AT.

Respiratory 1

Bronchiectasis FREQUENT Bronchiectasis (HP:0002110)

Show evidence (1 reference)

PMID:30796268 SUPPORT Human Clinical

"Respiratory disease is a major cause of morbidity and mortality in patients with ataxia-telangiectasia (A-T) who are prone to recurrent sinopulmonary infections, bronchiectasis, pulmonary fibrosis, and pulmonary failure."

Supports bronchiectasis as a clinically important respiratory complication in AT.

Cellular 1

Increased sensitivity to ionizing radiation VERY_FREQUENT Increased sensitivity to ionizing radiation (HP:0011133)

Show evidence (1 reference)

PMID:30685876 SUPPORT Other

Review evidence supporting radiosensitivity as a core AT feature.

Growth 1

Growth delay FREQUENT Growth delay (HP:0001510)

Show evidence (1 reference)

PMID:30420857 SUPPORT Human Clinical

"most of the A-T patients between 2–9 years and 10–16 years of age are usually below the 10th and 3rd percentile, respectively"

Growth data from AT cohort showing most patients fall below normal growth percentiles.

Other 3

Abnormal extrapyramidal motor function FREQUENT Abnormality of extrapyramidal motor function (HP:0002071)

Extrapyramidal features (including dystonia and chorea) are particularly prominent in variant AT and may dominate the phenotype as ataxia plateaus.

Show evidence (1 reference)

PMID:30137827 SUPPORT Other

"neurologically, dysarthria, oculomotor apraxia, extrapyramidal symptoms, axonal neuropathy, and cognitive impairment are common"

Reference text identifies extrapyramidal symptoms as a common neurologic feature of AT.

Peripheral axonal neuropathy FREQUENT Peripheral axonal neuropathy (HP:0003477)

Show evidence (1 reference)

PMID:30137827 SUPPORT Other

"neurologically, dysarthria, oculomotor apraxia, extrapyramidal symptoms, axonal neuropathy, and cognitive impairment are common"

Reference text identifies axonal neuropathy as a common neurologic feature of AT.

Insulin-resistant diabetes mellitus FREQUENT Insulin-resistant diabetes mellitus (HP:0000831)

Insulin-resistant diabetes is a recognized late metabolic complication of AT and is mechanistically linked to loss of insulin-activated ATM signaling.

Show evidence (2 references)

PMID:34854502 SUPPORT Model Organism

Review identifies insulin-resistant diabetes as a characteristic AT feature.

PMID:41120320 SUPPORT Model Organism

"In Ataxia-Telangiectasia (A-T), these mechanisms are disrupted, resulting in intrinsic insulin resistance and glucose intolerance."

Mouse-model evidence shows ATM deficiency directly produces insulin resistance and glucose intolerance.

🧬

Genetic Associations

ATM (Causative)

Show evidence (5 references)

PMID:30888062 SUPPORT Human Clinical

"Classical A-T is caused by biallelic variants on ATM (ataxia telangiectasia mutated) gene, leading to a loss of function of the protein kinase ATM, involved in DNA damage repair."

Supports ATM as the central disease gene in classical AT.

PMID:30420857 SUPPORT Human Clinical

"The incidence of cancer does not correlate with the type of ATM mutation, but rather with the extent of immunodeficiency, particularly profound IgA deficiency and a low number of B cells (1)."

Cancer risk in AT correlates with immunodeficiency severity, not mutation type.

PMID:38917355 SUPPORT Human Clinical

"Four-year EFS was 39.4% (95% CI, 29-53.3) vs 78.7% (95% CI, 63.7-97.2), (P < .001), and TRM rates were 37.6% (95% CI, 26.4-48.7) vs 4.0% (95% CI, 0-11.8), (P = .017), for those with absent and residual ATM kinase activity, respectively."

Cancer treatment outcomes in AT patients stratify sharply by residual ATM kinase activity, supporting kinase-activity-guided therapy.

+ 2 more references

💊

Treatments

Physical therapy

Action: physical therapy MAXO:0000011

Supportive rehabilitation focused on balance, strength, and functional mobility can improve participation and motor function in individual AT patients.

Target Phenotypes: Ataxia ↗

Show evidence (1 reference)

PMID:34107524 SUPPORT Human Clinical

"Positive changes were observed in the TCMS, PBBS, GMFM, and motor performance, participation, and quality of life."

Case-report evidence supports physical therapy for functional impairment in AT.

Intra-erythrocyte dexamethasone sodium phosphate

Action: Pharmacotherapy NCIT:C15986

Investigational corticosteroid delivery system (EryDex) evaluated for neurologic symptoms in AT. The ATTeST phase 3 trial (NCT02770807, n=176) showed acceptable safety but did not meet the primary efficacy endpoint overall, though prespecified subgroup analysis suggested possible benefit in children aged 6-9 years.

Target Phenotypes: Ataxia ↗

Show evidence (2 references)

PMID:39152028 PARTIAL Human Clinical

"Although there were no safety concerns, the primary efficacy endpoint was not met, possibly related to delays in treatment reducing the number of participants who received treatment as outlined in the protocol, and potentially different treatment effects according to age."

Supports this as a clinically tested therapy with acceptable safety but insufficient overall efficacy.

PMID:39152028 SUPPORT Human Clinical

"There were no reports of hyperglycaemia, hypertension, hirsutism, or Cushingoid appearance in any of the treatment groups, nor any treatment-related deaths."

Favorable safety profile without typical systemic steroid side effects.

Genetic counseling

Action: genetic counseling MAXO:0000079

Genetic counseling is essential for families affected by AT to inform about autosomal recessive inheritance, carrier risk, and reproductive options.

Show evidence (1 reference)

PMID:30685876 SUPPORT Other

Autosomal recessive inheritance necessitates genetic counseling for affected families.

Pioglitazone

Action: Pharmacotherapy NCIT:C15986

Agent: pioglitazone ↗

Investigational use of the thiazolidinedione PPAR-gamma agonist pioglitazone in AT, motivated by reported benefits on AT cell biology and on diabetic AT individuals. Targets the insulin resistance and metabolic inflexibility associated with ATM deficiency.

Target Phenotypes: Insulin-resistant diabetes mellitus ↗

Show evidence (1 reference)

PMID:39456197 PARTIAL Other

"Recently, pioglitazone, a thiazolidinedione class used to treat type 2 diabetes, has been demonstrated to exert beneficial effects on AT cells and on diabetic individuals with AT."

Review proposes pioglitazone as a candidate therapy targeting AT-specific cellular and metabolic defects.

Alpha-ketoglutarate supplementation

Action: dietary supplementation Ontology label: dietary intervention MAXO:0000088

Agent: 2-oxoglutaric acid ↗

Investigational metabolic therapy supplementing 2-oxoglutarate (the alpha-keto acid backbone of glutamine) to address the glutamine dependence seen in ATM-deficient cells. In an Atm-deficient mouse model, alpha- ketoglutarate alleviated glutamine dependence and attenuated Purkinje cell degeneration, supporting its preclinical rationale.

Target Phenotypes: Progressive cerebellar ataxia ↗

Show evidence (1 reference)

PMID:41120320 SUPPORT Model Organism

"Supplementation with α-ketoglutarate, the α-keto acid backbone of glutamine, has demonstrated potentials in alleviating glutamine dependence and attenuating Purkinje cell degeneration."

Mouse-model evidence that alpha-ketoglutarate mitigates the glutamine dependence and Purkinje cell loss caused by ATM deficiency.

Hematopoietic stem cell transplantation

Action: hematopoietic stem cell transplantation MAXO:0000747

Preemptive allogeneic HSCT can correct the immunodeficiency in AT and may prevent hematological malignancy in high-risk patients. Limited experience suggests acceptable transplant-related risk in selected patients with severe immunodeficiency.

Target Phenotypes: Combined immunodeficiency ↗

Show evidence (2 references)

PMID:30420857 SUPPORT Human Clinical

"pre-emptive alloHSCT can correct immunodeficiency in A-T with an acceptable risk of transplant-related mortality, and might be an early treatment of choice in some A-T patients at high risk of hematological malignancy."

Case series supports preemptive HSCT for immunodeficiency correction in selected AT patients.

PMID:30420857 SUPPORT Human Clinical

"Furthermore, this treatment provided complete immunological reconstitution and remission of the patient's granulomas without any need for immunosuppression or immunoglobulin replacement."

Demonstrates complete immune reconstitution following transplantation.

🔬

Clinical Trials

NCT06193200 PHASE_III RECRUITING

NEAT (Neurological Effects of EryDex on subjects with A-T): the Phase 3 follow-on to the ATTeST trial. International, multicenter, randomized, double-blind, placebo-controlled study of intra-erythrocyte dexamethasone sodium phosphate (EryDex) administered IV every 28 days, targeting neurological progression in AT.

Target Phenotypes: Progressive cerebellar ataxia ↗

Show evidence (1 reference)

clinicaltrials:NCT06193200 SUPPORT

"This is an international, multi-center, randomized, prospective, double-blind, placebo-controlled, Phase 3 study, designed to assess the effect of EryDex"

Confirms phase and design of the NEAT trial in AT.

NCT06673056 PHASE_III RECRUITING

Pivotal Phase 3 randomized, double-blind, placebo-controlled crossover trial of N-acetyl-L-leucine (IB1001) in patients aged 4 and older with confirmed AT, evaluating safety, tolerability, and efficacy versus standard of care.

Target Phenotypes: Progressive cerebellar ataxia ↗

Show evidence (1 reference)

clinicaltrials:NCT06673056 SUPPORT

"A pivotal, randomized, double-blind, placebo-controlled, multi-center therapeutic study for patients age 4 and older with a confirmed diagnosis of Ataxia-Telangiectasia (A-T). The objective of this study is to evaluate the safety, tolerability and efficacy of N-acetyl-L-leucine (IB1001) compared..."

Confirms pivotal Phase 3 N-acetyl-L-leucine trial design and AT enrollment criteria.

NCT04870866 PHASE_II ACTIVE_NOT_RECRUITING

Open-label proof-of-concept Phase 2 study of nicotinamide ribonucleoside (NR) supplementation in children with AT, evaluating effects on the NAD metabolome, neurological scales (SARA/ICARS/AT-NEST), and exploratory biomarkers.

Target Phenotypes: Progressive cerebellar ataxia ↗

Show evidence (1 reference)

clinicaltrials:NCT04870866 SUPPORT

"The study investigates the effect of dietary supplementation of nicotinamide ribonucleoside (NR) in children with ataxia telangiectasia (AT), with main focus on neurological symptoms."

Confirms NR supplementation study design and neurological focus in pediatric AT.

NCT07215416 PHASE_I NOT_RECRUITING

First-in-class precision-genetic-therapy trial (Phase 1/2) of intrathecal atipeksen, a mutation-targeted antisense oligonucleotide that restores ATM function in carriers of the recurrent ATM c.7865C>T splice variant.

Target Phenotypes: Progressive cerebellar ataxia ↗

Show evidence (1 reference)

clinicaltrials:NCT07215416 SUPPORT

"The investigators will conduct a clinical trial to study the safety and efficacy of intrathecal administration of atipeksen, a targeted genetic therapy that restores ATM gene function in A-T individuals bearing the recurrent ATM c.7865C\>T variant."

Confirms mutation-targeted ASO mechanism and ATM c.7865C>T variant population.

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Source YAML

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name: Ataxia-telangiectasia
creation_date: '2026-03-15T23:04:29Z'
updated_date: '2026-05-05T16:40:30Z'
category: Mendelian
synonyms:
- Louis-Bar syndrome
- AT
description: >-
  Ataxia-telangiectasia is a rare autosomal recessive multisystem disorder caused
  by biallelic pathogenic variants in ATM. Loss of ATM kinase function disrupts
  DNA double-strand break signaling, oxidative-stress responses, cell-cycle
  checkpoints, lymphocyte homeostasis, and tissue-specific stress responses in
  the cerebellum and respiratory tract. The clinical spectrum is dominated by
  progressive cerebellar ataxia, telangiectasia, combined immunodeficiency,
  recurrent sinopulmonary infection, elevated alpha-fetoprotein, marked
  radiosensitivity, and increased malignancy risk. Median age at symptom onset
  is approximately 1 year, with diagnosis typically delayed to age 5. Classical
  AT with absent ATM kinase activity causes severe childhood-onset disease,
  while variant AT with residual kinase activity follows a milder course.
disease_term:
  preferred_term: Ataxia-telangiectasia
  term:
    id: MONDO:0008840
    label: ataxia telangiectasia
parents:
- Combined immunodeficiency
- Hereditary cerebellar ataxia
- DNA repair disorder
has_subtypes:
- name: Classical ataxia-telangiectasia
  description: >-
    Complete absence of ATM protein or kinase activity. Severe childhood-onset
    cerebellar ataxia with wheelchair dependence by late childhood, pronounced
    immunodeficiency, and high malignancy risk.
  evidence:
  - reference: PMID:30888062
    reference_title: "Two novel variants in the ATM gene causing ataxia-telangiectasia, including a duplication of 90 kb: Utility of targeted next-generation sequencing in detection of copy number variation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Classical A-T is caused by biallelic variants on ATM (ataxia telangiectasia mutated) gene, leading to a loss of function of the protein kinase ATM, involved in DNA damage repair."
    explanation: Defines classical AT as arising from complete ATM loss of function.
- name: Variant ataxia-telangiectasia
  description: >-
    Limited residual ATM kinase activity. Later onset, slower neurologic
    progression, patients may remain ambulant for decades. May present with
    extrapyramidal features and dystonia rather than pure cerebellar ataxia.
    Variant AT is a recognized clinical subtype associated with hypomorphic
    ATM mutations that retain partial kinase activity.
- name: ATLD1
  display_name: Ataxia-Telangiectasia-Like Disorder 1 (MRE11)
  description: >-
    A-T-like disorder caused by biallelic hypomorphic variants in MRE11, which
    encodes a core component of the MRE11-RAD50-NBN (MRN) complex that senses
    DNA double-strand breaks and activates ATM. ATLD1 phenocopies the
    neurodegenerative features of classical A-T with progressive cerebellar
    ataxia and oculomotor apraxia, typically with later onset and a more
    slowly progressive course. Unlike A-T, telangiectasia and elevated serum
    alpha-fetoprotein are generally absent, immunodeficiency is mild or absent,
    and malignancy risk is lower. Radiosensitivity is present because defective
    MRN impairs ATM activation and DSB repair.
  subtype_term:
    preferred_term: ataxia-telangiectasia-like disorder 1
    term:
      id: MONDO:0024557
      label: ataxia-telangiectasia-like disorder 1
  genes:
  - preferred_term: MRE11
    term:
      id: hgnc:7230
      label: MRE11
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
- name: ATLD2
  display_name: Ataxia-Telangiectasia-Like Disorder 2 (PCNA)
  description: >-
    A-T-like disorder caused by a hypomorphic missense variant in PCNA, the
    sliding-clamp that coordinates DNA replication and multiple DNA repair
    pathways (translesion synthesis, nucleotide excision repair, mismatch
    repair). Clinical features include progressive ataxia, neurodegeneration,
    short stature, photosensitivity, and cellular hypersensitivity to UV and
    ionizing radiation. Unlike classical A-T, telangiectasia and alpha-
    fetoprotein elevation are not typical and immunodeficiency is mild.
    ATLD2 illustrates that genome-maintenance defects outside the canonical
    ATM-MRN axis can produce a convergent cerebellar-ataxia phenotype.
  subtype_term:
    preferred_term: ataxia-telangiectasia-like disorder 2
    term:
      id: MONDO:0014399
      label: ataxia-telangiectasia-like disorder 2
  genes:
  - preferred_term: PCNA
    term:
      id: hgnc:8729
      label: PCNA
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
- name: AOA1
  display_name: Ataxia with Oculomotor Apraxia Type 1 (APTX)
  description: >-
    Early-onset autosomal recessive cerebellar ataxia caused by biallelic
    variants in APTX, encoding aprataxin, which resolves abortive DNA ligase
    intermediates (5'-adenylated DNA ends) during single-strand break repair.
    Defective single-strand break processing causes persistent DNA damage in
    post-mitotic neurons, with selective vulnerability of cerebellar neurons
    and peripheral nerves. Hallmark clinical features are childhood-onset
    ataxia, oculomotor apraxia, axonal sensorimotor neuropathy, and
    hypoalbuminemia with hypercholesterolemia. Serum alpha-fetoprotein is
    normal or only mildly elevated, and immunodeficiency, telangiectasia, and
    cancer predisposition are not features.
  subtype_term:
    preferred_term: ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia
    term:
      id: MONDO:0008842
      label: ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia
  genes:
  - preferred_term: APTX
    term:
      id: hgnc:15984
      label: APTX
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
- name: AOA2
  display_name: Ataxia with Oculomotor Apraxia Type 2 (SETX)
  description: >-
    Adolescent-onset autosomal recessive cerebellar ataxia caused by biallelic
    loss-of-function variants in SETX, encoding senataxin, an RNA/DNA helicase
    that resolves R-loops and protects the genome from transcription-replication
    conflicts. Accumulated R-loops generate DNA damage that preferentially
    affects cerebellar and peripheral neurons. Clinical features include
    progressive cerebellar ataxia, axonal sensorimotor peripheral neuropathy,
    oculomotor apraxia (in a subset), and markedly elevated serum alpha-
    fetoprotein. Unlike A-T, immunodeficiency, telangiectasia, and cancer
    predisposition are absent.
  subtype_term:
    preferred_term: spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
    term:
      id: MONDO:0018996
      label: spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
  genes:
  - preferred_term: SETX
    term:
      id: hgnc:445
      label: SETX
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
- name: SCAN1
  display_name: Spinocerebellar Ataxia with Axonal Neuropathy 1 (TDP1)
  description: >-
    Autosomal recessive cerebellar ataxia with axonal sensorimotor neuropathy
    caused by a homozygous TDP1 variant (H493R). TDP1 (tyrosyl-DNA
    phosphodiesterase 1) releases trapped topoisomerase 1 cleavage complexes
    from DNA and repairs 3'-blocked single-strand breaks. Loss of TDP1
    activity causes accumulation of protein-linked DNA breaks in
    non-replicating neurons. Clinical features include late-childhood onset
    cerebellar ataxia, distal muscle wasting, pes cavus, and hypoalbuminemia
    with hypercholesterolemia, without telangiectasia, immunodeficiency, or
    cancer predisposition.
  subtype_term:
    preferred_term: spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1
    term:
      id: MONDO:0011801
      label: spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1
  genes:
  - preferred_term: TDP1
    term:
      id: hgnc:18884
      label: TDP1
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
inheritance:
- name: Autosomal recessive
  evidence:
  - reference: PMID:30685876
    reference_title: "Ataxia-telangiectasia: A review of clinical features and molecular pathology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ataxia-telangiectasia (A-T) is an autosomal recessive primary immunodeficiency (PID) disease that is caused by mutations in ataxia-telangiectasia mutated (ATM) gene encoding a serine/threonine protein kinase."
    explanation: Supports autosomal recessive inheritance and ATM as the causative gene.
prevalence:
- population: Global live births
  percentage: 1 in 40,000-100,000
  notes: >-
    Contemporary reviews estimate worldwide prevalence in the range of 1 in
    40,000 to 1 in 100,000 live births. Older U.S. ascertainment studies found
    a minimum observed incidence of 3.0 per million live births, highlighting
    likely under-ascertainment in historical cohorts.
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EPIDEMIOLOGY: The world-wide prevalence of A-T is estimated to be between 1 in 40,000 and 1 in 100,000 live births."
    explanation: A recent clinical review provides the standard global prevalence range for ataxia-telangiectasia.
  - reference: PMID:3788973
    reference_title: "The incidence and gene frequency of ataxia-telangiectasia in the United States."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "White patients identified in this study were born at the rate of 3.0 per million live births in the U.S. in the years 1965-69."
    explanation: Historical U.S. population ascertainment provides a concrete minimum incidence estimate and underscores how rarely cases were identified.
pathophysiology:
- name: ATM kinase deficiency and defective DNA damage signaling
  description: >-
    ATM loss of function impairs the cellular response to DNA double-strand
    breaks and checkpoint signaling, creating genomic instability and broad
    tissue vulnerability. In classical disease, biallelic ATM variants abolish
    or markedly reduce ATM kinase activity. ATM normally coordinates DSB repair
    through the MRN complex (MRE11-RAD50-NBN) and downstream effectors
    including p53 and CHK2.
  downstream:
  - target: Oxidative stress and microglia-driven cerebellar neurodegeneration
    description: Loss of ATM redox and DSB-response functions drives oxidative stress and microglial activation in the cerebellum.
  - target: Combined immunodeficiency with lymphocyte depletion and dysfunction
    description: ATM is required for V(D)J recombination and class switch recombination, so its loss disrupts adaptive immunity.
  - target: Defective insulin-ATM signaling and metabolic inflexibility
    description: Loss of insulin-activated ATM disrupts the catabolic-anabolic glucose switch and produces intrinsic insulin resistance.
  - target: Genomic instability and cancer predisposition
    description: Defective DSB repair and checkpoint signaling produce chromosomal instability and malignant transformation.
  - target: Increased sensitivity to ionizing radiation
    description: Loss of ATM-dependent DSB repair confers cellular hypersensitivity to ionizing radiation and radiomimetic agents.
  - target: Elevated circulating alpha-fetoprotein concentration
    description: Persistent elevation of serum AFP is a recognized laboratory hallmark of ATM deficiency.
  genes:
  - preferred_term: ATM
    term:
      id: hgnc:795
      label: ATM
  molecular_functions:
  - preferred_term: protein serine/threonine kinase activity
    term:
      id: GO:0004674
      label: protein serine/threonine kinase activity
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: DNA damage response
    term:
      id: GO:0006974
      label: DNA damage response
  - preferred_term: double-strand break repair
    term:
      id: GO:0006302
      label: double-strand break repair
  - preferred_term: cell cycle checkpoint signaling
    term:
      id: GO:0000075
      label: cell cycle checkpoint signaling
  evidence:
  - reference: PMID:30685876
    reference_title: "Ataxia-telangiectasia: A review of clinical features and molecular pathology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The principal role of nuclear ATM is the coordination of cellular signaling pathways in response to DNA double-strand breaks, oxidative stress, and cell cycle checkpoint."
    explanation: Review evidence linking ATM deficiency to defective DNA-damage and checkpoint signaling.
  - reference: PMID:30888062
    reference_title: "Two novel variants in the ATM gene causing ataxia-telangiectasia, including a duplication of 90 kb: Utility of targeted next-generation sequencing in detection of copy number variation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Classical A-T is caused by biallelic variants on ATM (ataxia telangiectasia mutated) gene, leading to a loss of function of the protein kinase ATM, involved in DNA damage repair."
    explanation: Human genetic evidence that classical AT arises from biallelic ATM loss of function.
- name: Oxidative stress and microglia-driven cerebellar neurodegeneration
  description: >-
    Cerebellar degeneration in AT is linked to persistent oxidative stress and
    inflammatory signaling. ATM deficiency increases reactive oxygen species in
    the cerebellum and is associated with activated microglia that deliver
    neurotoxic cytokine signals to Purkinje and granule neurons. ATM expression
    is enriched in microglia throughout cerebellar development and adulthood,
    and pseudotime analysis shows microglial activation precedes neuronal
    apoptosis.
  downstream:
  - target: Cerebellar atrophy
    description: Progressive loss of Purkinje and granule neurons drives the macroscopic cerebellar atrophy seen on imaging.
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  - preferred_term: granule cell
    term:
      id: CL:0000120
      label: granule cell
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  - preferred_term: cytokine production
    term:
      id: GO:0001816
      label: cytokine production
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
  evidence:
  - reference: PMID:11280737
    reference_title: "Increased oxidative stress in ataxia telangiectasia evidenced by alterations in redox state of brains from Atm-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our findings support the hypothesis that the absence of functional ATM results in oxidative stress, which may be an important cause of the degeneration of cerebellar neurons in A-T."
    explanation: Atm-deficient mouse brain data support oxidative stress as a driver of cerebellar neuron loss.
  - reference: PMID:11280737
    reference_title: "Increased oxidative stress in ataxia telangiectasia evidenced by alterations in redox state of brains from Atm-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found alterations in the levels of thiol-containing compounds in Atm (-/-) brains, as well as significant changes in the activities of thioredoxin, catalase, and manganese superoxide dismutase in Atm (-/-) cerebella."
    explanation: Direct biochemical evidence of altered antioxidant enzyme activity in Atm-deficient cerebella.
  - reference: PMID:38159274
    reference_title: "ATM-deficiency-induced microglial activation promotes neurodegeneration in ataxia-telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we find evidence of microglial inflammation in the cerebellum of patients with A-T using single-nucleus RNA sequencing."
    explanation: Patient cerebellar transcriptomics show microglial inflammation in AT.
  - reference: PMID:38159274
    reference_title: "ATM-deficiency-induced microglial activation promotes neurodegeneration in ataxia-telangiectasia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "A-T microglia co-culture with either control or A-T iPSC-derived neurons was sufficient to induce cytotoxicity."
    explanation: iPSC-derived microglia experiments support a direct pathogenic role for activated microglia.
  - reference: PMID:38159274
    reference_title: "ATM-deficiency-induced microglial activation promotes neurodegeneration in ataxia-telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pseudotime analysis revealed that activation of A-T microglia preceded upregulation of apoptosis-related genes in granule and Purkinje neurons and that microglia exhibited increased neurotoxic cytokine signaling to granule and Purkinje neurons in A-T."
    explanation: Temporal ordering shows microglial activation precedes neuronal death in AT cerebellum.
  - reference: PMID:34854502
    reference_title: "Dysfunction of cerebellar microglia in Ataxia-telangiectasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we demonstrate that microglia derived from Atm-/- mouse cerebellum display accelerated cell migration and are severely impaired in phagocytosis, secretion of neurotrophic factors, and mitochondrial activity, suggestive of apoptotic processes."
    explanation: Atm-deficient mouse cerebellar microglia show migration, phagocytic, neurotrophic, and mitochondrial defects.
  - reference: PMID:34854502
    reference_title: "Dysfunction of cerebellar microglia in Ataxia-telangiectasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Interestingly, no microglial impairment was detected in Atm-deficient cerebral cortex, and Atm deficiency had less impact on astroglia than microglia."
    explanation: Microglial dysfunction in AT is regionally restricted to cerebellum, supporting selective cerebellar vulnerability.
- name: Combined immunodeficiency with lymphocyte depletion and dysfunction
  description: >-
    ATM deficiency disrupts adaptive immune homeostasis through impaired V(D)J
    recombination and class switch recombination. This leads to B-cell
    lymphopenia, defective immunoglobulin class switching (IgA deficiency in
    ~61%, IgG deficiency in ~29%), T-cell depletion, and NK-cell functional
    abnormalities. IgA deficiency is a strong prognostic indicator of worse
    survival.
  downstream:
  - target: Combined immunodeficiency
    description: Defective V(D)J/class switch recombination yields the clinical combined immunodeficiency phenotype.
  - target: Decreased circulating IgA concentration
    description: Impaired class switch recombination in B cells produces selective IgA deficiency in the majority of patients.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  - preferred_term: natural killer cell
    term:
      id: CL:0000623
      label: natural killer cell
  biological_processes:
  - preferred_term: isotype switching
    term:
      id: GO:0045190
      label: isotype switching
  - preferred_term: V(D)J recombination
    term:
      id: GO:0033151
      label: V(D)J recombination
  - preferred_term: B cell differentiation
    term:
      id: GO:0030183
      label: B cell differentiation
  evidence:
  - reference: PMID:38834764
    reference_title: "Ataxia-telangiectasia in Latin America: clinical features, immunodeficiency, and mortality in a multicenter study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IgA deficiency was observed in 60.8% of patients and IgG deficiency in 28.6%. T- and B-lymphopenias were also present in most cases."
    explanation: Multicenter cohort data show humoral deficiency and lymphopenia in AT.
  - reference: PMID:39165363
    reference_title: "Immune profiling and functional analysis of NK and T cells in ataxia telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed reduced levels of peripheral blood CD3+CD8+ cytotoxic T cells, CD3+CD4+ T helper cells, and CD19+ B cells, whereas the amount of CD3--CD56+ NK cells and CD3+CD56+ NKT-like cells was similar compared with age-matched controls."
    explanation: Immune profiling demonstrates major T-cell and B-cell abnormalities in AT.
  - reference: PMID:34477998
    reference_title: "Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall survival of patients with IgA deficiency was significantly diminished."
    explanation: Shows that more severe humoral immune deficiency is clinically relevant and associated with worse survival.
  - reference: PMID:24568663
    reference_title: "Class switch recombination process in ataxia telangiectasia patients with elevated serum levels of IgM."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory evaluations revealed defective CSR while none of the three AT patients without HIgM presentation had a defect in the CSR process."
    explanation: Direct evidence of impaired class switch recombination in AT patients with hyper-IgM phenotype.
- name: Airway epithelial oxidative susceptibility and impaired innate immunity
  description: >-
    AT respiratory disease is not explained solely by systemic immune defects.
    ATM-deficient airway epithelial cells show increased oxidative injury after
    pneumococcal challenge together with defective ASC-Caspase 1 inflammasome
    activation and altered cytokine output, providing a local epithelial
    mechanism for recurrent sinopulmonary disease.
  downstream:
  - target: Recurrent respiratory infections
    description: Cell-intrinsic epithelial inflammasome and oxidative defects predispose the airway to recurrent pyogenic infection.
  - target: Bronchiectasis
    description: Repeated airway injury and infection drive airway remodeling and bronchiectasis.
  cell_types:
  - preferred_term: airway epithelial cell
    term:
      id: CL:0002368
      label: respiratory tract epithelial cell
  locations:
  - preferred_term: lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  - preferred_term: innate immune response
    term:
      id: GO:0045087
      label: innate immune response
  evidence:
  - reference: PMID:30796268
    reference_title: "Increased susceptibility of airway epithelial cells from ataxia-telangiectasia to S. pneumoniae infection due to oxidative damage and impaired innate immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These data suggest that the heightened susceptibility of these cells to S. pneumoniae infection is due to both increased oxidative damage and a defect in inflammasome activation, and has implications for lung disease in these patients."
    explanation: Airway epithelial studies support a cell-intrinsic respiratory mechanism in AT.
  - reference: PMID:30796268
    reference_title: "Increased susceptibility of airway epithelial cells from ataxia-telangiectasia to S. pneumoniae infection due to oxidative damage and impaired innate immunity."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Further investigation revealed that the ASC-Caspase 1 signalling pathway was defective in A-T airway epithelial cells."
    explanation: Identifies the specific inflammasome pathway defect in AT airway epithelium.
- name: Defective insulin-ATM signaling and metabolic inflexibility
  description: >-
    ATM is activated by insulin and acts as a critical regulator of metabolic
    flexibility, mediating the switch between catabolic and anabolic glucose
    fates by controlling PKM2 and HIF1alpha. In AT, loss of this insulin-ATM
    axis produces intrinsic insulin resistance and glucose intolerance, and
    cells become compensatorily dependent on glutamine for energy. Purkinje
    cells are unusually insulin-sensitive, providing a metabolic explanation
    for their disproportionate vulnerability in AT cerebellum and linking
    peripheral metabolic disease (insulin-resistant diabetes, hepatic
    metabolic injury) to neurodegenerative progression.
  downstream:
  - target: Insulin-resistant diabetes mellitus
    description: Loss of insulin-activated ATM produces intrinsic insulin resistance and glucose intolerance.
  - target: Hepatic fibrosis
    description: Metabolic inflexibility and chronic insulin resistance contribute to progressive liver injury and fibrosis in AT.
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: insulin receptor signaling pathway
    term:
      id: GO:0008286
      label: insulin receptor signaling pathway
    modifier: DECREASED
  - preferred_term: glucose metabolic process
    term:
      id: GO:0006006
      label: glucose metabolic process
  - preferred_term: L-glutamine metabolic process
    term:
      id: GO:0006541
      label: L-glutamine metabolic process
    modifier: INCREASED
  evidence:
  - reference: PMID:41120320
    reference_title: "Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here we show insulin-activated ATM is a critical mediator of this process, facilitating the swift transition between catabolic-and-anabolic fates of glucose by regulating the functional status of PKM2 and HIF1α."
    explanation: Identifies the insulin-ATM axis as a regulator of metabolic flexibility through PKM2 and HIF1alpha.
  - reference: PMID:41120320
    reference_title: "Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In Ataxia-Telangiectasia (A-T), these mechanisms are disrupted, resulting in intrinsic insulin resistance and glucose intolerance."
    explanation: Establishes intrinsic insulin resistance and glucose intolerance as direct consequences of ATM deficiency.
  - reference: PMID:41120320
    reference_title: "Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Cerebellar degeneration, a hallmark of A-T, is characterized by the pronounced vulnerability of Purkinje cells, attributed to their unexpected sensitivity to insulin."
    explanation: Links peripheral insulin signaling defects to selective Purkinje cell vulnerability.
- name: Genomic instability and cancer predisposition
  description: >-
    ATM deficiency produces chromosomal instability, defective cell-cycle
    checkpoints, and impaired apoptotic responses, driving malignant
    transformation particularly in lymphoid tissues. The cumulative incidence
    of cancer reaches 29% by age 35, with hematologic malignancies (especially
    non-Hodgkin lymphoma) predominating in childhood and solid tumors becoming
    more frequent in adulthood.
  downstream:
  - target: Lymphoma
    description: Chromosomal instability at lymphoid antigen-receptor loci drives non-Hodgkin lymphoma, the predominant childhood malignancy in AT.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  biological_processes:
  - preferred_term: DNA damage response
    term:
      id: GO:0006974
      label: DNA damage response
  - preferred_term: cell cycle checkpoint signaling
    term:
      id: GO:0000075
      label: cell cycle checkpoint signaling
  - preferred_term: apoptotic process
    term:
      id: GO:0006915
      label: apoptotic process
  evidence:
  - reference: PMID:39521281
    reference_title: "Prevalence and outcomes of cancer and treatment-associated toxicities for patients with ataxia telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eighty-four (16.5%) of 508 individuals were diagnosed with a primary cancer, of whom 62 (74%) were hematologic in origin and 22 (26%) were solid-organ cancers."
    explanation: Large cohort data quantifying cancer incidence and types in AT.
  - reference: PMID:39521281
    reference_title: "Prevalence and outcomes of cancer and treatment-associated toxicities for patients with ataxia telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Non-Hodgkin lymphoma occurred most frequently (n = 39), whereas solid cancers disproportionately affected those 18 years and older (n = 22)."
    explanation: Identifies NHL as the most common malignancy and age-dependent shift to solid tumors.
  - reference: PMID:30420857
    reference_title: "Pre-emptive Allogeneic Hematopoietic Stem Cell Transplantation in Ataxia Telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Apart from a progressive neurodegenerative disorder, A-T leads to significantly increased susceptibility to malignancies."
    explanation: Confirms increased cancer susceptibility as a core feature of AT.
phenotypes:
- name: Progressive cerebellar ataxia
  category: Neurologic
  frequency: VERY_FREQUENT
  notes: Neurologic symptoms typically begin around age 1 year.
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  sequelae:
  - target: Dysarthria
  - target: Cognitive impairment
  evidence:
  - reference: PMID:30888062
    reference_title: "Two novel variants in the ATM gene causing ataxia-telangiectasia, including a duplication of 90 kb: Utility of targeted next-generation sequencing in detection of copy number variation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder characterized by progressive cerebellar ataxia, ocular apraxia, immunodeficiency, telangiectasia, elevated serum α-fetoprotein concentration, radiosensitivity and cancer predisposition."
    explanation: Supports progressive cerebellar ataxia as a core neurologic manifestation.
  - reference: PMID:38834764
    reference_title: "Ataxia-telangiectasia in Latin America: clinical features, immunodeficiency, and mortality in a multicenter study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median (IQR) ages at symptom onset and diagnosis were 1.0 (1.0-2.0) and 5.0 (3.0-8.0) years, respectively."
    explanation: Quantifies early onset of symptoms at median age 1 year.
- name: Cerebellar atrophy
  category: Neurologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  sequelae:
  - target: Progressive cerebellar ataxia
  - target: Oculomotor apraxia
  evidence:
  - reference: PMID:11280737
    reference_title: "Increased oxidative stress in ataxia telangiectasia evidenced by alterations in redox state of brains from Atm-deficient mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A-T patients display a pleiotropic phenotype and suffer primarily from progressive ataxia caused by degeneration of cerebellar Purkinje and granule neurons."
    explanation: Links cerebellar neuron degeneration to progressive atrophy.
- name: Oculomotor apraxia
  category: Neurologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Oculomotor apraxia
    term:
      id: HP:0000657
      label: Oculomotor apraxia
  evidence:
  - reference: PMID:30888062
    reference_title: "Two novel variants in the ATM gene causing ataxia-telangiectasia, including a duplication of 90 kb: Utility of targeted next-generation sequencing in detection of copy number variation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder characterized by progressive cerebellar ataxia, ocular apraxia, immunodeficiency, telangiectasia, elevated serum α-fetoprotein concentration, radiosensitivity and cancer predisposition."
    explanation: Lists ocular apraxia as a defining characteristic of AT.
- name: Telangiectasia
  category: Vascular
  frequency: VERY_FREQUENT
  notes: Conjunctival telangiectasias often appear by age 5-8 years, after neurologic onset.
  phenotype_term:
    preferred_term: Telangiectasia
    term:
      id: HP:0001009
      label: Telangiectasia
  evidence:
  - reference: PMID:30685876
    reference_title: "Ataxia-telangiectasia: A review of clinical features and molecular pathology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A-T patients represent a broad range of clinical manifestations including progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, susceptibility to malignancies, and increased metabolic diseases."
    explanation: Review evidence supporting telangiectasia as a defining clinical sign.
- name: Combined immunodeficiency
  category: Immunologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  evidence:
  - reference: PMID:39165363
    reference_title: "Immune profiling and functional analysis of NK and T cells in ataxia telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ataxia telangiectasia (AT) is a rare autosomal-recessive disorder characterized by profound neurodegeneration, combined immunodeficiency, and an increased risk for malignant diseases."
    explanation: Supports combined immunodeficiency as part of the core AT phenotype.
- name: Decreased circulating IgA concentration
  category: Immunologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: IgA deficiency
    term:
      id: HP:0002720
      label: Decreased circulating IgA concentration
  sequelae:
  - target: Recurrent respiratory infections
  evidence:
  - reference: PMID:38834764
    reference_title: "Ataxia-telangiectasia in Latin America: clinical features, immunodeficiency, and mortality in a multicenter study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IgA deficiency was observed in 60.8% of patients and IgG deficiency in 28.6%. T- and B-lymphopenias were also present in most cases."
    explanation: Multicenter cohort demonstrates IgA deficiency in 61% of AT patients.
  - reference: PMID:34477998
    reference_title: "Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients."
    explanation: IgA deficiency serves as a prognostic biomarker in classical AT.
- name: Recurrent respiratory infections
  category: Respiratory
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  sequelae:
  - target: Bronchiectasis
  evidence:
  - reference: PMID:38834764
    reference_title: "Ataxia-telangiectasia in Latin America: clinical features, immunodeficiency, and mortality in a multicenter study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients presented recurrent airway infections, which was significantly associated with IgA deficiency."
    explanation: Cohort evidence supports recurrent respiratory infection as a frequent clinical manifestation.
- name: Bronchiectasis
  category: Respiratory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:30796268
    reference_title: "Increased susceptibility of airway epithelial cells from ataxia-telangiectasia to S. pneumoniae infection due to oxidative damage and impaired innate immunity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Respiratory disease is a major cause of morbidity and mortality in patients with ataxia-telangiectasia (A-T) who are prone to recurrent sinopulmonary infections, bronchiectasis, pulmonary fibrosis, and pulmonary failure."
    explanation: Supports bronchiectasis as a clinically important respiratory complication in AT.
- name: Elevated circulating alpha-fetoprotein concentration
  category: Laboratory
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Elevated circulating alpha-fetoprotein concentration
    term:
      id: HP:0006254
      label: Elevated circulating alpha-fetoprotein concentration
  evidence:
  - reference: PMID:30888062
    reference_title: "Two novel variants in the ATM gene causing ataxia-telangiectasia, including a duplication of 90 kb: Utility of targeted next-generation sequencing in detection of copy number variation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ataxia-telangiectasia (A-T) is a rare autosomal recessive neurodegenerative disorder characterized by progressive cerebellar ataxia, ocular apraxia, immunodeficiency, telangiectasia, elevated serum α-fetoprotein concentration, radiosensitivity and cancer predisposition."
    explanation: Supports elevated alpha-fetoprotein as a characteristic laboratory abnormality in AT.
- name: Increased sensitivity to ionizing radiation
  category: Cellular
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Radiosensitivity
    term:
      id: HP:0011133
      label: Increased sensitivity to ionizing radiation
  evidence:
  - reference: PMID:30685876
    reference_title: "Ataxia-telangiectasia: A review of clinical features and molecular pathology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A-T patients represent a broad range of clinical manifestations including progressive cerebellar ataxia, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, susceptibility to malignancies, and increased metabolic diseases."
    explanation: Review evidence supporting radiosensitivity as a core AT feature.
- name: Lymphoma
  category: Oncologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Lymphoma
    term:
      id: HP:0002665
      label: Lymphoma
  evidence:
  - reference: PMID:39521281
    reference_title: "Prevalence and outcomes of cancer and treatment-associated toxicities for patients with ataxia telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Non-Hodgkin lymphoma occurred most frequently (n = 39), whereas solid cancers disproportionately affected those 18 years and older (n = 22)."
    explanation: Non-Hodgkin lymphoma is the most common malignancy in AT.
- name: Growth delay
  category: Growth
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:30420857
    reference_title: "Pre-emptive Allogeneic Hematopoietic Stem Cell Transplantation in Ataxia Telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "most of the A-T patients between 2–9 years and 10–16 years of age are usually below the 10th and 3rd percentile, respectively"
    explanation: Growth data from AT cohort showing most patients fall below normal growth percentiles.
- name: Dysarthria
  category: Neurologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:30137827
    reference_title: "Ataxia-Telangiectasia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "neurologically, dysarthria, oculomotor apraxia, extrapyramidal symptoms, axonal neuropathy, and cognitive impairment are common"
    explanation: Reference text identifies dysarthria as a common neurologic feature of AT.
- name: Abnormal extrapyramidal motor function
  category: Neurologic
  frequency: FREQUENT
  notes: >-
    Extrapyramidal features (including dystonia and chorea) are particularly
    prominent in variant AT and may dominate the phenotype as ataxia plateaus.
  phenotype_term:
    preferred_term: Abnormality of extrapyramidal motor function
    term:
      id: HP:0002071
      label: Abnormality of extrapyramidal motor function
  evidence:
  - reference: PMID:30137827
    reference_title: "Ataxia-Telangiectasia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "neurologically, dysarthria, oculomotor apraxia, extrapyramidal symptoms, axonal neuropathy, and cognitive impairment are common"
    explanation: Reference text identifies extrapyramidal symptoms as a common neurologic feature of AT.
- name: Peripheral axonal neuropathy
  category: Neurologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Peripheral axonal neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: PMID:30137827
    reference_title: "Ataxia-Telangiectasia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "neurologically, dysarthria, oculomotor apraxia, extrapyramidal symptoms, axonal neuropathy, and cognitive impairment are common"
    explanation: Reference text identifies axonal neuropathy as a common neurologic feature of AT.
- name: Cognitive impairment
  category: Neurologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:30137827
    reference_title: "Ataxia-Telangiectasia."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "neurologically, dysarthria, oculomotor apraxia, extrapyramidal symptoms, axonal neuropathy, and cognitive impairment are common"
    explanation: Reference text identifies cognitive impairment as a common neurologic feature of AT.
- name: Insulin-resistant diabetes mellitus
  category: Metabolic
  frequency: FREQUENT
  notes: >-
    Insulin-resistant diabetes is a recognized late metabolic complication of AT
    and is mechanistically linked to loss of insulin-activated ATM signaling.
  phenotype_term:
    preferred_term: Insulin-resistant diabetes mellitus
    term:
      id: HP:0000831
      label: Insulin-resistant diabetes mellitus
  evidence:
  - reference: PMID:34854502
    reference_title: "Dysfunction of cerebellar microglia in Ataxia-telangiectasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ataxia-telangiectasia (A-T) is a multisystem autosomal recessive disease caused by mutations in the ATM gene and characterized by cerebellar atrophy, progressive ataxia, immunodeficiency, male and female sterility, radiosensitivity, cancer predisposition, growth retardation, insulin-resistant diabetes, and premature aging."
    explanation: Review identifies insulin-resistant diabetes as a characteristic AT feature.
  - reference: PMID:41120320
    reference_title: "Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In Ataxia-Telangiectasia (A-T), these mechanisms are disrupted, resulting in intrinsic insulin resistance and glucose intolerance."
    explanation: Mouse-model evidence shows ATM deficiency directly produces insulin resistance and glucose intolerance.
- name: Hepatic fibrosis
  category: Hepatic
  frequency: OCCASIONAL
  notes: >-
    Hepatic fibrosis is increasingly recognized as a late multisystem
    complication, identified non-invasively in roughly one-fifth of patients
    and associated with metabolic alterations and ataxia severity.
  phenotype_term:
    preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
  evidence:
  - reference: PMID:37147676
    reference_title: "Hepatic fibrosis: a manifestation of the liver disease evolution in patients with Ataxia-telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Significant hepatic fibrosis was observed in 5/25 (20%)."
    explanation: Cross-sectional cohort quantifies hepatic fibrosis in 20% of AT patients.
  - reference: PMID:37147676
    reference_title: "Hepatic fibrosis: a manifestation of the liver disease evolution in patients with Ataxia-telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A non-invasive diagnosis of significant hepatic fibrosis was observed in 20% of A-T patients associated with changes in liver enzymes, ferritin, increased HOMA-AD, and the severity of ataxia in comparison with patients without hepatic fibrosis."
    explanation: Links hepatic fibrosis to metabolic alterations and ataxia severity.
- name: Hypogonadism
  category: Endocrine
  frequency: FREQUENT
  notes: >-
    Both male and female sterility have been reported as part of the AT phenotype.
  phenotype_term:
    preferred_term: Hypogonadism
    term:
      id: HP:0000135
      label: Hypogonadism
  evidence:
  - reference: PMID:34854502
    reference_title: "Dysfunction of cerebellar microglia in Ataxia-telangiectasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ataxia-telangiectasia (A-T) is a multisystem autosomal recessive disease caused by mutations in the ATM gene and characterized by cerebellar atrophy, progressive ataxia, immunodeficiency, male and female sterility, radiosensitivity, cancer predisposition, growth retardation, insulin-resistant diabetes, and premature aging."
    explanation: Review enumerates male and female sterility among defining features of AT.
- name: Premature aging
  category: Constitutional
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Prematurely aged appearance
    term:
      id: HP:0007495
      label: Prematurely aged appearance
  evidence:
  - reference: PMID:34854502
    reference_title: "Dysfunction of cerebellar microglia in Ataxia-telangiectasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ataxia-telangiectasia (A-T) is a multisystem autosomal recessive disease caused by mutations in the ATM gene and characterized by cerebellar atrophy, progressive ataxia, immunodeficiency, male and female sterility, radiosensitivity, cancer predisposition, growth retardation, insulin-resistant diabetes, and premature aging."
    explanation: Review identifies premature aging as a defining AT feature.
genetic:
- name: ATM
  gene_term:
    preferred_term: ATM
    term:
      id: hgnc:795
      label: ATM
  association: Causative
  notes: >-
    Classical AT is caused by biallelic pathogenic ATM variants that reduce or
    abolish kinase function. Loss-of-function alleles are the predominant cause
    of the classic neurodegenerative and immunologic phenotype. Variant AT with
    residual ATM kinase activity follows a milder course. The incidence of
    cancer does not correlate with the type of ATM mutation but rather with the
    extent of immunodeficiency.
  evidence:
  - reference: PMID:30888062
    reference_title: "Two novel variants in the ATM gene causing ataxia-telangiectasia, including a duplication of 90 kb: Utility of targeted next-generation sequencing in detection of copy number variation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Classical A-T is caused by biallelic variants on ATM (ataxia telangiectasia mutated) gene, leading to a loss of function of the protein kinase ATM, involved in DNA damage repair."
    explanation: Supports ATM as the central disease gene in classical AT.
  - reference: PMID:30420857
    reference_title: "Pre-emptive Allogeneic Hematopoietic Stem Cell Transplantation in Ataxia Telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The incidence of cancer does not correlate with the type of ATM mutation, but rather with the extent of immunodeficiency, particularly profound IgA deficiency and a low number of B cells (1)."
    explanation: Cancer risk in AT correlates with immunodeficiency severity, not mutation type.
  - reference: PMID:38917355
    reference_title: "ATM germ line pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four-year EFS was 39.4% (95% CI, 29-53.3) vs 78.7% (95% CI, 63.7-97.2), (P < .001), and TRM rates were 37.6% (95% CI, 26.4-48.7) vs 4.0% (95% CI, 0-11.8), (P = .017), for those with absent and residual ATM kinase activity, respectively."
    explanation: Cancer treatment outcomes in AT patients stratify sharply by residual ATM kinase activity, supporting kinase-activity-guided therapy.
  - reference: PMID:38917355
    reference_title: "ATM germ line pathogenic variants affect outcomes in children with ataxia-telangiectasia and hematological malignancies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with A-T and leukemia/lymphoma may benefit from deescalated therapy for patients with absent ATM kinase activity and near-standard therapy regimens for those with residual kinase activity."
    explanation: Provides actionable kinase-activity-stratified treatment recommendation for hematological malignancies in AT.
  - reference: CGGV:assertion_02a69e27-77dc-41bd-83d2-dda9c224ee43-2021-07-27T205239.729Z
    reference_title: "ATM / ataxia telangiectasia (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "ATM | HGNC:795 | ataxia telangiectasia | MONDO:0008840 | AR | Definitive"
    explanation: ClinGen classifies the ATM-ataxia telangiectasia gene-disease relationship as definitive with autosomal recessive inheritance.
treatments:
- name: Physical therapy
  description: >-
    Supportive rehabilitation focused on balance, strength, and functional
    mobility can improve participation and motor function in individual AT
    patients.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: MAXO:0000011
      label: physical therapy
  target_phenotypes:
  - preferred_term: Ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:34107524
    reference_title: "Effectiveness of Physical Therapy on Ataxia-Telangiectasia: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Positive changes were observed in the TCMS, PBBS, GMFM, and motor performance, participation, and quality of life."
    explanation: Case-report evidence supports physical therapy for functional impairment in AT.
- name: Intra-erythrocyte dexamethasone sodium phosphate
  description: >-
    Investigational corticosteroid delivery system (EryDex) evaluated for
    neurologic symptoms in AT. The ATTeST phase 3 trial (NCT02770807, n=176)
    showed acceptable safety but did not meet the primary efficacy endpoint
    overall, though prespecified subgroup analysis suggested possible benefit
    in children aged 6-9 years.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:39152028
    reference_title: "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."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Although there were no safety concerns, the primary efficacy endpoint was not met, possibly related to delays in treatment reducing the number of participants who received treatment as outlined in the protocol, and potentially different treatment effects according to age."
    explanation: Supports this as a clinically tested therapy with acceptable safety but insufficient overall efficacy.
  - reference: PMID:39152028
    reference_title: "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."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There were no reports of hyperglycaemia, hypertension, hirsutism, or Cushingoid appearance in any of the treatment groups, nor any treatment-related deaths."
    explanation: Favorable safety profile without typical systemic steroid side effects.
- name: Genetic counseling
  description: >-
    Genetic counseling is essential for families affected by AT to inform
    about autosomal recessive inheritance, carrier risk, and reproductive
    options.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:30685876
    reference_title: "Ataxia-telangiectasia: A review of clinical features and molecular pathology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Ataxia-telangiectasia (A-T) is an autosomal recessive primary immunodeficiency (PID) disease that is caused by mutations in ataxia-telangiectasia mutated (ATM) gene encoding a serine/threonine protein kinase."
    explanation: Autosomal recessive inheritance necessitates genetic counseling for affected families.
- name: Pioglitazone
  description: >-
    Investigational use of the thiazolidinedione PPAR-gamma agonist pioglitazone
    in AT, motivated by reported benefits on AT cell biology and on diabetic AT
    individuals. Targets the insulin resistance and metabolic inflexibility
    associated with ATM deficiency.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pioglitazone
      term:
        id: CHEBI:8228
        label: pioglitazone
  target_phenotypes:
  - preferred_term: Insulin-resistant diabetes mellitus
    term:
      id: HP:0000831
      label: Insulin-resistant diabetes mellitus
  evidence:
  - reference: PMID:39456197
    reference_title: "Pioglitazone as a Possible Treatment for Ataxia-Telangiectasia."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: "Recently, pioglitazone, a thiazolidinedione class used to treat type 2 diabetes, has been demonstrated to exert beneficial effects on AT cells and on diabetic individuals with AT."
    explanation: Review proposes pioglitazone as a candidate therapy targeting AT-specific cellular and metabolic defects.
- name: Alpha-ketoglutarate supplementation
  description: >-
    Investigational metabolic therapy supplementing 2-oxoglutarate (the
    alpha-keto acid backbone of glutamine) to address the glutamine dependence
    seen in ATM-deficient cells. In an Atm-deficient mouse model, alpha-
    ketoglutarate alleviated glutamine dependence and attenuated Purkinje cell
    degeneration, supporting its preclinical rationale.
  treatment_term:
    preferred_term: dietary supplementation
    term:
      id: MAXO:0000088
      label: dietary intervention
    therapeutic_agent:
    - preferred_term: 2-oxoglutaric acid
      term:
        id: CHEBI:30915
        label: 2-oxoglutaric acid
  target_phenotypes:
  - preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:41120320
    reference_title: "Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Supplementation with α-ketoglutarate, the α-keto acid backbone of glutamine, has demonstrated potentials in alleviating glutamine dependence and attenuating Purkinje cell degeneration."
    explanation: Mouse-model evidence that alpha-ketoglutarate mitigates the glutamine dependence and Purkinje cell loss caused by ATM deficiency.
- name: Hematopoietic stem cell transplantation
  description: >-
    Preemptive allogeneic HSCT can correct the immunodeficiency in AT and
    may prevent hematological malignancy in high-risk patients. Limited
    experience suggests acceptable transplant-related risk in selected
    patients with severe immunodeficiency.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: MAXO:0000747
      label: hematopoietic stem cell transplantation
  target_phenotypes:
  - preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  evidence:
  - reference: PMID:30420857
    reference_title: "Pre-emptive Allogeneic Hematopoietic Stem Cell Transplantation in Ataxia Telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "pre-emptive alloHSCT can correct immunodeficiency in A-T with an acceptable risk of transplant-related mortality, and might be an early treatment of choice in some A-T patients at high risk of hematological malignancy."
    explanation: Case series supports preemptive HSCT for immunodeficiency correction in selected AT patients.
  - reference: PMID:30420857
    reference_title: "Pre-emptive Allogeneic Hematopoietic Stem Cell Transplantation in Ataxia Telangiectasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, this treatment provided complete immunological reconstitution and remission of the patient's granulomas without any need for immunosuppression or immunoglobulin replacement."
    explanation: Demonstrates complete immune reconstitution following transplantation.
clinical_trials:
- name: NCT06193200
  phase: PHASE_III
  status: RECRUITING
  description: >-
    NEAT (Neurological Effects of EryDex on subjects with A-T): the Phase 3
    follow-on to the ATTeST trial. International, multicenter, randomized,
    double-blind, placebo-controlled study of intra-erythrocyte
    dexamethasone sodium phosphate (EryDex) administered IV every 28 days,
    targeting neurological progression in AT.
  target_phenotypes:
  - preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: clinicaltrials:NCT06193200
    reference_title: "A Multi-center, Randomized, Double-blind, Placebo-controlled Trial to Evaluate the Neurological Effects of EryDex on Subjects With Ataxia Telangiectasia (NEAT)"
    supports: SUPPORT
    snippet: "This is an international, multi-center, randomized, prospective, double-blind, placebo-controlled, Phase 3 study, designed to assess the effect of EryDex"
    explanation: Confirms phase and design of the NEAT trial in AT.
- name: NCT06673056
  phase: PHASE_III
  status: RECRUITING
  description: >-
    Pivotal Phase 3 randomized, double-blind, placebo-controlled crossover
    trial of N-acetyl-L-leucine (IB1001) in patients aged 4 and older with
    confirmed AT, evaluating safety, tolerability, and efficacy versus
    standard of care.
  target_phenotypes:
  - preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: clinicaltrials:NCT06673056
    reference_title: "Effects of N-Acetyl-L-Leucine on Ataxia-Telangiectasia (A-T): A Phase III, Randomized, Placebo-controlled, Double-blind, Crossover Study"
    supports: SUPPORT
    snippet: "A pivotal, randomized, double-blind, placebo-controlled, multi-center therapeutic study for patients age 4 and older with a confirmed diagnosis of Ataxia-Telangiectasia (A-T). The objective of this study is to evaluate the safety, tolerability and efficacy of N-acetyl-L-leucine (IB1001) compared to standard of care."
    explanation: Confirms pivotal Phase 3 N-acetyl-L-leucine trial design and AT enrollment criteria.
- name: NCT04870866
  phase: PHASE_II
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Open-label proof-of-concept Phase 2 study of nicotinamide ribonucleoside
    (NR) supplementation in children with AT, evaluating effects on the NAD
    metabolome, neurological scales (SARA/ICARS/AT-NEST), and exploratory
    biomarkers.
  target_phenotypes:
  - preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: clinicaltrials:NCT04870866
    reference_title: "NAD Supplementation to Prevent Progressive Neurological Disease in Ataxia Telangiectasia"
    supports: SUPPORT
    snippet: "The study investigates the effect of dietary supplementation of nicotinamide ribonucleoside (NR) in children with ataxia telangiectasia (AT), with main focus on neurological symptoms."
    explanation: Confirms NR supplementation study design and neurological focus in pediatric AT.
- name: NCT07215416
  phase: PHASE_I
  status: NOT_RECRUITING
  description: >-
    First-in-class precision-genetic-therapy trial (Phase 1/2) of intrathecal
    atipeksen, a mutation-targeted antisense oligonucleotide that restores
    ATM function in carriers of the recurrent ATM c.7865C>T splice variant.
  target_phenotypes:
  - preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: clinicaltrials:NCT07215416
    reference_title: "A Phase 1/2 Study of Antisense Oligonucleotide Therapy for Treatment of Ataxia-Telangiectasia"
    supports: SUPPORT
    snippet: "The investigators will conduct a clinical trial to study the safety and efficacy of intrathecal administration of atipeksen, a targeted genetic therapy that restores ATM gene function in A-T individuals bearing the recurrent ATM c.7865C\\>T variant."
    explanation: Confirms mutation-targeted ASO mechanism and ATM c.7865C>T variant population.
notes: >-
  AT management also requires minimizing unnecessary exposure to ionizing
  radiation because of marked radiosensitivity. Chemotherapy regimens must be
  modified to avoid radiomimetic toxicity, as standard-dose chemotherapy is
  associated with significantly higher mortality (HR 2.2). Malignancy
  surveillance is clinically important given the elevated cancer risk.
  Mean survival in a Latin American cohort was 24.2 years with a 20-year
  survival rate of 52.6%; a 1314-case systematic review reported a median age
  at death of 14 years (PMID:35290391). For hematological malignancies,
  treatment outcomes stratify sharply by residual ATM kinase activity:
  4-year event-free survival is 39% with absent kinase activity versus 79%
  with residual activity, supporting kinase-activity-guided dose modification
  (PMID:38917355).
datasets: []
references:
- reference: DOI:10.1080/13543784.2023.2249399
  title: Ataxia-telangiectasia clinical trial landscape and the obstacles to overcome
  found_in:
  - Ataxia_Telangiectasia-deep-research-falcon.md
  findings:
  - statement: Ataxia-telangiectasia clinical trial landscape and the obstacles to overcome
    supporting_text: Ataxia-telangiectasia clinical trial landscape and the obstacles to overcome
- reference: DOI:10.1158/1078-0432.ccr-24-1098
  title: Update on Recommendations for Cancer Screening and Surveillance in Children with Genomic Instability Disorders
  found_in:
  - Ataxia_Telangiectasia-deep-research-falcon.md
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: Update on Recommendations for Cancer Screening and Surveillance in Children with Genomic Instability Disorders
    supporting_text: Genomic instability disorders are characterized by DNA or chromosomal instability, resulting in various clinical manifestations, including developmental anomalies, immunodeficiency, and increased risk of developing cancers beginning in childhood.
- reference: DOI:10.17863/cam.112012
  title: Exploring neurodegeneration in Ataxia-Telangiectasia
  found_in:
  - Ataxia_Telangiectasia-deep-research-falcon.md
  findings:
  - statement: Ataxia-Telangiectasia (A-T) is a very rare autosomal recessive DNA repair disorder.
    supporting_text: Ataxia-Telangiectasia (A-T) is a very rare autosomal recessive DNA repair disorder.
- reference: PMID:10449794
  title: Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '1999 Aug 17;96(17):9915-9. doi: 10.1073/pnas.96.17.9915.'
    supporting_text: '1999 Aug 17;96(17):9915-9. doi: 10.1073/pnas.96.17.9915.'
- reference: PMID:11285218
  title: Elevated Cu/Zn-SOD exacerbates radiation sensitivity and hematopoietic abnormalities of Atm-deficient mice.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2001 Apr 2;20(7):1538-46. doi: 10.1093/emboj/20.7.1538.'
    supporting_text: '2001 Apr 2;20(7):1538-46. doi: 10.1093/emboj/20.7.1538.'
- reference: PMID:15698568
  title: Three-dimensional structure and regulation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs).
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2005 Feb;13(2):243-55. doi: 10.1016/j.str.2004.12.006.'
    supporting_text: '2005 Feb;13(2):243-55. doi: 10.1016/j.str.2004.12.006.'
- reference: PMID:16603769
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2006 Jun 9;281(23):15741-6. doi: 10.1074/jbc.M513172200.'
    supporting_text: '2006 Jun 9;281(23):15741-6. doi: 10.1074/jbc.M513172200.'
- reference: PMID:16934683
  title: Dramatic extension of tumor latency and correction of neurobehavioral phenotype in Atm-mutant mice with a nitroxide antioxidant.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2006 Sep 15;41(6):992-1000. doi: 10.1016/j.freeradbiomed.2006.06.018.'
    supporting_text: '2006 Sep 15;41(6):992-1000. doi: 10.1016/j.freeradbiomed.2006.06.018.'
- reference: PMID:17524020
  title: Lung disease in ataxia-telangiectasia.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2007 Jul;96(7):1021-4. doi: 10.1111/j.1651-2227.2007.00338.x.'
    supporting_text: '2007 Jul;96(7):1021-4. doi: 10.1111/j.1651-2227.2007.00338.x.'
- reference: PMID:21665257
  title: Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM expression or activity.
    supporting_text: Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM expression or activity.
- reference: PMID:22213089
  title: 'Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study.'
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2012 Mar;33(3):561-71. doi: 10.1002/humu.22016.'
    supporting_text: '2012 Mar;33(3):561-71. doi: 10.1002/humu.22016.'
- reference: PMID:22575700
  title: Disease severity in a mouse model of ataxia telangiectasia is modulated by the DNA damage checkpoint gene Hus1.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2012 Aug 1;21(15):3408-20. doi: 10.1093/hmg/dds173.'
    supporting_text: '2012 Aug 1;21(15):3408-20. doi: 10.1093/hmg/dds173.'
- reference: PMID:23598976
  title: Brain and induced pluripotent stem cell-derived neural stem cells as an in vitro model of neurodegeneration in ataxia-telangiectasia.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2013 Mar;238(3):301-7. doi: 10.1177/1535370213480703.'
    supporting_text: '2013 Mar;238(3):301-7. doi: 10.1177/1535370213480703.'
- reference: PMID:23761391
  title: Infections of the respiratory system in patients with ataxia-telangiectasia.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2014 Apr;49(4):389-99. doi: 10.1002/ppul.22817.'
    supporting_text: '2014 Apr;49(4):389-99. doi: 10.1002/ppul.22817.'
- reference: PMID:25032865
  title: Functional and molecular defects of hiPSC-derived neurons from patients with ATM deficiency.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2014 Jul 17;5(7):e1342. doi: 10.1038/cddis.2014.310.'
    supporting_text: '2014 Jul 17;5(7):e1342. doi: 10.1038/cddis.2014.310.'
- reference: PMID:26033643
  title: FVC deterioration, airway obstruction determination, and life span in Ataxia telangiectasia.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2015 Jul;109(7):890-6. doi: 10.1016/j.rmed.2015.05.013.'
    supporting_text: '2015 Jul;109(7):890-6. doi: 10.1016/j.rmed.2015.05.013.'
- reference: PMID:27573920
  title: Growth and nutrition in children with ataxia telangiectasia.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: Ataxia telangiectasia (A-T) is a rare multisystem disease with high early mortality from lung disease and cancer.
    supporting_text: Ataxia telangiectasia (A-T) is a rare multisystem disease with high early mortality from lung disease and cancer.
- reference: PMID:28007901
  title: 'A rat model of ataxia-telangiectasia: evidence for a neurodegenerative phenotype.'
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2017 Jan 1;26(1):109-123. doi: 10.1093/hmg/ddw371.'
    supporting_text: '2017 Jan 1;26(1):109-123. doi: 10.1093/hmg/ddw371.'
- reference: PMID:28063379
  title: Oxidative stress, mitochondrial abnormalities and antioxidant defense in Ataxia-telangiectasia, Bloom syndrome and Nijmegen breakage syndrome.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2017 Apr;11:375-383. doi: 10.1016/j.redox.2016.12.030.'
    supporting_text: '2017 Apr;11:375-383. doi: 10.1016/j.redox.2016.12.030.'
- reference: PMID:28126470
  title: 'Ataxia-telangiectasia: Immunodeficiency and survival.'
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2017 May;178:45-55. doi: 10.1016/j.clim.2017.01.009.'
    supporting_text: '2017 May;178:45-55. doi: 10.1016/j.clim.2017.01.009.'
- reference: PMID:32114444
  title: 'Structural and strategic landscape of PIKK protein family and their inhibitors: an overview.'
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2020 Mar 1;25(8):1538-1567. doi: 10.2741/4867.'
    supporting_text: '2020 Mar 1;25(8):1538-1567. doi: 10.2741/4867.'
- reference: PMID:32119081
  title: Radiation Treatment, ATM, BRCA1/2, and CHEK2*1100delC Pathogenic Variants and Risk of Contralateral Breast Cancer.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2020 Dec 14;112(12):1275-1279. doi: 10.1093/jnci/djaa031.'
    supporting_text: '2020 Dec 14;112(12):1275-1279. doi: 10.1093/jnci/djaa031.'
- reference: PMID:32531978
  title: Tracking of Infused Mesenchymal Stem Cells in Injured Pulmonary Tissue in Atm-Deficient Mice.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2020 Jun 10;9(6):1444. doi: 10.3390/cells9061444.'
    supporting_text: '2020 Jun 10;9(6):1444. doi: 10.3390/cells9061444.'
- reference: PMID:32871349
  title: 'The cerebellar degeneration in ataxia-telangiectasia: A case for genome instability.'
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2020 Nov;95:102950. doi: 10.1016/j.dnarep.2020.102950.'
    supporting_text: '2020 Nov;95:102950. doi: 10.1016/j.dnarep.2020.102950.'
- reference: PMID:33052516
  title: Variable Abnormalities in T and B Cell Subsets in Ataxia Telangiectasia.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: Ataxia-telangiectasia (AT) is a rare genetic condition, caused by biallelic deleterious variants in the ATM gene, and has variable immunological abnormalities.
    supporting_text: Ataxia-telangiectasia (AT) is a rare genetic condition, caused by biallelic deleterious variants in the ATM gene, and has variable immunological abnormalities.
- reference: PMID:33734555
  title: NAD(+) supplementation prevents STING-induced senescence in ataxia telangiectasia by improving mitophagy.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2021 Apr;20(4):e13329. doi: 10.1111/acel.13329.'
    supporting_text: '2021 Apr;20(4):e13329. doi: 10.1111/acel.13329.'
- reference: PMID:34133717
  title: Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP-HIPK2 axis.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2021 Jul 9;49(12):6788-6803. doi: 10.1093/nar/gkab489.'
    supporting_text: '2021 Jul 9;49(12):6788-6803. doi: 10.1093/nar/gkab489.'
- reference: PMID:34440406
  title: Mechanisms Underlying the Suppression of Chromosome Rearrangements by Ataxia-Telangiectasia Mutated.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2021 Aug 10;12(8):1232. doi: 10.3390/genes12081232.'
    supporting_text: '2021 Aug 10;12(8):1232. doi: 10.3390/genes12081232.'
- reference: PMID:34493284
  title: 'The prevalence of ataxia telangiectasia mutated (ATM) variants in patients with breast cancer patients: a systematic review and meta-analysis.'
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2021 Sep 8;21(1):474. doi: 10.1186/s12935-021-02172-8.'
    supporting_text: '2021 Sep 8;21(1):474. doi: 10.1186/s12935-021-02172-8.'
- reference: PMID:34573351
  title: ATM's Role in the Repair of DNA Double-Strand Breaks.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2021 Aug 31;12(9):1370. doi: 10.3390/genes12091370.'
    supporting_text: '2021 Aug 31;12(9):1370. doi: 10.3390/genes12091370.'
- reference: PMID:34597127
  title: Cancer in Children With Fanconi Anemia and Ataxia-Telangiectasia-A Nationwide Register-Based Cohort Study in Germany.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2022 Jan 1;40(1):32-39. doi: 10.1200/JCO.21.01495.'
    supporting_text: '2022 Jan 1;40(1):32-39. doi: 10.1200/JCO.21.01495.'
- reference: PMID:36186632
  title: Imaging in children with ataxia-telangiectasia-The radiologist's approach.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2022 Sep 16;10:988645. doi: 10.3389/fped.2022.988645. eCollection 2022.'
    supporting_text: '2022 Sep 16;10:988645. doi: 10.3389/fped.2022.988645. eCollection 2022.'
- reference: PMID:36340711
  title: 'Infections and immune dysregulation in ataxia-telangiectasia children with hyper-IgM and non-hyper-IgM phenotypes: A single-center experience.'
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2022 Oct 20;10:972952. doi: 10.3389/fped.2022.972952. eCollection 2022.'
    supporting_text: '2022 Oct 20;10:972952. doi: 10.3389/fped.2022.972952. eCollection 2022.'
- reference: PMID:37009283
  title: Two novel heterozygote mutations of ATM in a Chinese family with dystonia-dominant ataxia telangiectasia and literature review.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: Ataxia-telangiectasia (A-T) is an autosomal recessive disorder with high clinical heterogeneity.
    supporting_text: Ataxia-telangiectasia (A-T) is an autosomal recessive disorder with high clinical heterogeneity.
- reference: PMID:37851290
  title: Ethnicity-specific BRCA1, BRCA2, PALB2, and ATM pathogenic alleles in breast and ovarian cancer patients from the North Caucasus.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: Mountain areas of the North Caucasus host several large ethnic communities that have preserved their national identity over the centuries.
    supporting_text: Mountain areas of the North Caucasus host several large ethnic communities that have preserved their national identity over the centuries.
- reference: PMID:38280573
  title: Causative mechanisms and clinical impact of immunoglobulin deficiencies in ataxia telangiectasia.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: Ataxia telangiectasia (AT) is characterized by cerebellar ataxia, telangiectasia, immunodeficiency, and increased cancer susceptibility and is caused by mutations in the ataxia telangiectasia mutated (ATM) gene.
    supporting_text: Ataxia telangiectasia (AT) is characterized by cerebellar ataxia, telangiectasia, immunodeficiency, and increased cancer susceptibility and is caused by mutations in the ataxia telangiectasia mutated (ATM) gene.
- reference: PMID:38807759
  title: PARP inhibitor synthetic lethality in ATM biallelic mutant cancer cell lines is associated with BRCA1/2 and RAD51 downregulation.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: PARP inhibitor synthetic lethality in ATM biallelic mutant cancer cell lines is associated with BRCA1/2 and RAD51 downregulation
    supporting_text: Ataxia telangiectasia-mutated (ATM) kinase is a central regulator of the DNA damage response (DDR) signaling pathway, and its function is critical for the maintenance of genomic stability in cells that coordinate a network of cellular processes, including DNA replication, DNA repair, and cell cycle progression.
- reference: PMID:39636577
  title: 'Management of individuals with heterozygous germline pathogenic variants in ATM: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).'
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2025 Jan;27(1):101243. doi: 10.1016/j.gim.2024.101243.'
    supporting_text: '2025 Jan;27(1):101243. doi: 10.1016/j.gim.2024.101243.'
- reference: PMID:39826692
  title: Profiling Tel1 signaling reveals a non-canonical motif targeting DNA repair and telomere control machineries.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2025 Mar;301(3):108194. doi: 10.1016/j.jbc.2025.108194.'
    supporting_text: '2025 Mar;301(3):108194. doi: 10.1016/j.jbc.2025.108194.'
- reference: PMID:40270454
  title: 'Endocrinopathies in children with inborn errors of immunity: a single-center experience.'
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '2025 Apr 25;38(7):735-742. doi: 10.1515/jpem-2024-0593.'
    supporting_text: '2025 Apr 25;38(7):735-742. doi: 10.1515/jpem-2024-0593.'
- reference: PMID:40616902
  title: 'Phase 2a/b randomised placebo-controlled dose-escalation trial of triheptanoin for ataxia-telangiectasia: treating mitochondrial dysfunction with anaplerosis.'
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: Ataxia-telangiectasia (A-T) is a rare multisystem disease characterised by neurodegenerative cerebellar ataxia, lung disease, immune deficiency, high cancer risk, and mitochondrial dysfunction.
    supporting_text: Ataxia-telangiectasia (A-T) is a rare multisystem disease characterised by neurodegenerative cerebellar ataxia, lung disease, immune deficiency, high cancer risk, and mitochondrial dysfunction.
- reference: PMID:41044616
  title: 'Expanding the clinical spectrum of pediatric ataxia-telangiectasia: a case series of novel genetic variants, lupus vulgaris, and hyper-IgM phenotypes.'
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by pathogenic ATM gene variants, characterised by progressive cerebellar ataxia, telangiectasia, immunodeficiency, and cancer predisposition.
    supporting_text: Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by pathogenic ATM gene variants, characterised by progressive cerebellar ataxia, telangiectasia, immunodeficiency, and cancer predisposition.
- reference: PMID:41451872
  title: 'Genetic and Epidemiological Aspects of Louis-Bar Syndrome Transmission: The Impact of Consanguineous Marriages on the Incidence of Hereditary Disorders.'
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: The aim of this study was to investigate the genetic and epidemiological aspects of Louis-Bar syndrome transmission in the population of Kyrgyzstan, with a particular focus on the impact of consanguineous marriages.
    supporting_text: The aim of this study was to investigate the genetic and epidemiological aspects of Louis-Bar syndrome transmission in the population of Kyrgyzstan, with a particular focus on the impact of consanguineous marriages.
- reference: PMID:9083516
  title: Bronchiolitis obliterans in ataxia-telangiectasia.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '1997 Feb;430(2):131-7. doi: 10.1007/BF01008034.'
    supporting_text: '1997 Feb;430(2):131-7. doi: 10.1007/BF01008034.'
- reference: PMID:9735376
  title: 'ATM: from gene to function.'
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings:
  - statement: '1998;7(10):1555-63. doi: 10.1093/hmg/7.10.1555.'
    supporting_text: '1998;7(10):1555-63. doi: 10.1093/hmg/7.10.1555.'
- reference: DOI:10.1007/s12026-024-09494-5
  title: 'Ataxia-telangiectasia in Latin America: clinical features, immunodeficiency, and mortality in a multicenter study'
  found_in:
  - Ataxia_Telangiectasia-deep-research-falcon.md
  findings: []
- reference: DOI:10.1016/j.celrep.2023.113622
  title: ATM-deficiency-induced microglial activation promotes neurodegeneration in ataxia-telangiectasia
  found_in:
  - Ataxia_Telangiectasia-deep-research-falcon.md
  findings: []
- reference: DOI:10.1016/j.spen.2024.101169
  title: Ataxia telangiectasia
  found_in:
  - Ataxia_Telangiectasia-deep-research-falcon.md
  findings: []
- reference: DOI:10.1111/pai.13020
  title: 'Ataxia‐telangiectasia: A review of clinical features and molecular pathology'
  found_in:
  - Ataxia_Telangiectasia-deep-research-falcon.md
  findings: []
- reference: DOI:10.1186/s13023-023-02720-7
  title: 'Hepatic fibrosis: a manifestation of the liver disease evolution in patients with Ataxia-telangiectasia'
  found_in:
  - Ataxia_Telangiectasia-deep-research-falcon.md
  findings: []
- reference: PMID:30685876
  title: 'Ataxia-telangiectasia: A review of clinical features and molecular pathology.'
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings: []
- reference: PMID:30888062
  title: 'Two novel variants in the ATM gene causing ataxia-telangiectasia, including a duplication of 90 kb: Utility of targeted next-generation sequencing in detection of copy number variation.'
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings: []
- reference: PMID:39152028
  title: '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.'
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings: []
- reference: PMID:39264246
  title: Update on Recommendations for Cancer Screening and Surveillance in Children with Genomic Instability Disorders.
  found_in:
  - Ataxia_Telangiectasia-deep-research-openscientist.md
  findings: []

📚

References & Deep Research

References

DOI:10.1080/13543784.2023.2249399

Ataxia-telangiectasia clinical trial landscape and the obstacles to overcome

1 finding

Ataxia-telangiectasia clinical trial landscape and the obstacles to overcome

"Ataxia-telangiectasia clinical trial landscape and the obstacles to overcome"

DOI:10.1158/1078-0432.ccr-24-1098

Update on Recommendations for Cancer Screening and Surveillance in Children with Genomic Instability Disorders

1 finding

Update on Recommendations for Cancer Screening and Surveillance in Children with Genomic Instability Disorders

"Genomic instability disorders are characterized by DNA or chromosomal instability, resulting in various clinical manifestations, including developmental anomalies, immunodeficiency, and increased risk of developing cancers beginning in childhood."

DOI:10.17863/cam.112012

Exploring neurodegeneration in Ataxia-Telangiectasia

1 finding

Ataxia-Telangiectasia (A-T) is a very rare autosomal recessive DNA repair disorder.

"Ataxia-Telangiectasia (A-T) is a very rare autosomal recessive DNA repair disorder."

PMID:10449794

Loss of the ataxia-telangiectasia gene product causes oxidative damage in target organs.

1 finding

1999 Aug 17;96(17):9915-9. doi: 10.1073/pnas.96.17.9915.

"1999 Aug 17;96(17):9915-9. doi: 10.1073/pnas.96.17.9915."

PMID:11285218

Elevated Cu/Zn-SOD exacerbates radiation sensitivity and hematopoietic abnormalities of Atm-deficient mice.

1 finding

2001 Apr 2;20(7):1538-46. doi: 10.1093/emboj/20.7.1538.

"2001 Apr 2;20(7):1538-46. doi: 10.1093/emboj/20.7.1538."

PMID:15698568

Three-dimensional structure and regulation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs).

1 finding

2005 Feb;13(2):243-55. doi: 10.1016/j.str.2004.12.006.

"2005 Feb;13(2):243-55. doi: 10.1016/j.str.2004.12.006."

PMID:16603769

1 finding

2006 Jun 9;281(23):15741-6. doi: 10.1074/jbc.M513172200.

"2006 Jun 9;281(23):15741-6. doi: 10.1074/jbc.M513172200."

PMID:16934683

Dramatic extension of tumor latency and correction of neurobehavioral phenotype in Atm-mutant mice with a nitroxide antioxidant.

1 finding

2006 Sep 15;41(6):992-1000. doi: 10.1016/j.freeradbiomed.2006.06.018.

"2006 Sep 15;41(6):992-1000. doi: 10.1016/j.freeradbiomed.2006.06.018."

PMID:17524020

Lung disease in ataxia-telangiectasia.

1 finding

2007 Jul;96(7):1021-4. doi: 10.1111/j.1651-2227.2007.00338.x.

"2007 Jul;96(7):1021-4. doi: 10.1111/j.1651-2227.2007.00338.x."

PMID:21665257

Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype.

1 finding

Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM expression or activity.

"Ataxia-telangiectasia (A-T) is a rare genetic disease caused by germline biallelic mutations in the ataxia-telangiectasia mutated gene (ATM) that result in partial or complete loss of ATM expression or activity."

PMID:22213089

Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study.

1 finding

2012 Mar;33(3):561-71. doi: 10.1002/humu.22016.

"2012 Mar;33(3):561-71. doi: 10.1002/humu.22016."

PMID:22575700

Disease severity in a mouse model of ataxia telangiectasia is modulated by the DNA damage checkpoint gene Hus1.

1 finding

2012 Aug 1;21(15):3408-20. doi: 10.1093/hmg/dds173.

"2012 Aug 1;21(15):3408-20. doi: 10.1093/hmg/dds173."

PMID:23598976

Brain and induced pluripotent stem cell-derived neural stem cells as an in vitro model of neurodegeneration in ataxia-telangiectasia.

1 finding

2013 Mar;238(3):301-7. doi: 10.1177/1535370213480703.

"2013 Mar;238(3):301-7. doi: 10.1177/1535370213480703."

PMID:23761391

Infections of the respiratory system in patients with ataxia-telangiectasia.

1 finding

2014 Apr;49(4):389-99. doi: 10.1002/ppul.22817.

"2014 Apr;49(4):389-99. doi: 10.1002/ppul.22817."

PMID:25032865

Functional and molecular defects of hiPSC-derived neurons from patients with ATM deficiency.

1 finding

2014 Jul 17;5(7):e1342. doi: 10.1038/cddis.2014.310.

"2014 Jul 17;5(7):e1342. doi: 10.1038/cddis.2014.310."

PMID:26033643

FVC deterioration, airway obstruction determination, and life span in Ataxia telangiectasia.

1 finding

2015 Jul;109(7):890-6. doi: 10.1016/j.rmed.2015.05.013.

"2015 Jul;109(7):890-6. doi: 10.1016/j.rmed.2015.05.013."

PMID:27573920

Growth and nutrition in children with ataxia telangiectasia.

1 finding

Ataxia telangiectasia (A-T) is a rare multisystem disease with high early mortality from lung disease and cancer.

"Ataxia telangiectasia (A-T) is a rare multisystem disease with high early mortality from lung disease and cancer."

PMID:28007901

A rat model of ataxia-telangiectasia: evidence for a neurodegenerative phenotype.

1 finding

2017 Jan 1;26(1):109-123. doi: 10.1093/hmg/ddw371.

"2017 Jan 1;26(1):109-123. doi: 10.1093/hmg/ddw371."

PMID:28063379

Oxidative stress, mitochondrial abnormalities and antioxidant defense in Ataxia-telangiectasia, Bloom syndrome and Nijmegen breakage syndrome.

1 finding

2017 Apr;11:375-383. doi: 10.1016/j.redox.2016.12.030.

"2017 Apr;11:375-383. doi: 10.1016/j.redox.2016.12.030."

PMID:28126470

Ataxia-telangiectasia: Immunodeficiency and survival.

1 finding

2017 May;178:45-55. doi: 10.1016/j.clim.2017.01.009.

"2017 May;178:45-55. doi: 10.1016/j.clim.2017.01.009."

PMID:32114444

Structural and strategic landscape of PIKK protein family and their inhibitors: an overview.

1 finding

2020 Mar 1;25(8):1538-1567. doi: 10.2741/4867.

"2020 Mar 1;25(8):1538-1567. doi: 10.2741/4867."

PMID:32119081

Radiation Treatment, ATM, BRCA1/2, and CHEK2*1100delC Pathogenic Variants and Risk of Contralateral Breast Cancer.

1 finding

2020 Dec 14;112(12):1275-1279. doi: 10.1093/jnci/djaa031.

"2020 Dec 14;112(12):1275-1279. doi: 10.1093/jnci/djaa031."

PMID:32531978

Tracking of Infused Mesenchymal Stem Cells in Injured Pulmonary Tissue in Atm-Deficient Mice.

1 finding

2020 Jun 10;9(6):1444. doi: 10.3390/cells9061444.

"2020 Jun 10;9(6):1444. doi: 10.3390/cells9061444."

PMID:32871349

The cerebellar degeneration in ataxia-telangiectasia: A case for genome instability.

1 finding

2020 Nov;95:102950. doi: 10.1016/j.dnarep.2020.102950.

"2020 Nov;95:102950. doi: 10.1016/j.dnarep.2020.102950."

PMID:33052516

Variable Abnormalities in T and B Cell Subsets in Ataxia Telangiectasia.

1 finding

Ataxia-telangiectasia (AT) is a rare genetic condition, caused by biallelic deleterious variants in the ATM gene, and has variable immunological abnormalities.

"Ataxia-telangiectasia (AT) is a rare genetic condition, caused by biallelic deleterious variants in the ATM gene, and has variable immunological abnormalities."

PMID:33734555

NAD(+) supplementation prevents STING-induced senescence in ataxia telangiectasia by improving mitophagy.

1 finding

2021 Apr;20(4):e13329. doi: 10.1111/acel.13329.

"2021 Apr;20(4):e13329. doi: 10.1111/acel.13329."

PMID:34133717

Prostate cancer-associated SPOP mutations lead to genomic instability through disruption of the SPOP-HIPK2 axis.

1 finding

2021 Jul 9;49(12):6788-6803. doi: 10.1093/nar/gkab489.

"2021 Jul 9;49(12):6788-6803. doi: 10.1093/nar/gkab489."

PMID:34440406

Mechanisms Underlying the Suppression of Chromosome Rearrangements by Ataxia-Telangiectasia Mutated.

1 finding

2021 Aug 10;12(8):1232. doi: 10.3390/genes12081232.

"2021 Aug 10;12(8):1232. doi: 10.3390/genes12081232."

PMID:34493284

The prevalence of ataxia telangiectasia mutated (ATM) variants in patients with breast cancer patients: a systematic review and meta-analysis.

1 finding

2021 Sep 8;21(1):474. doi: 10.1186/s12935-021-02172-8.

"2021 Sep 8;21(1):474. doi: 10.1186/s12935-021-02172-8."

PMID:34573351

ATM's Role in the Repair of DNA Double-Strand Breaks.

1 finding

2021 Aug 31;12(9):1370. doi: 10.3390/genes12091370.

"2021 Aug 31;12(9):1370. doi: 10.3390/genes12091370."

PMID:34597127

Cancer in Children With Fanconi Anemia and Ataxia-Telangiectasia-A Nationwide Register-Based Cohort Study in Germany.

1 finding

2022 Jan 1;40(1):32-39. doi: 10.1200/JCO.21.01495.

"2022 Jan 1;40(1):32-39. doi: 10.1200/JCO.21.01495."

PMID:36186632

Imaging in children with ataxia-telangiectasia-The radiologist's approach.

1 finding

2022 Sep 16;10:988645. doi: 10.3389/fped.2022.988645. eCollection 2022.

"2022 Sep 16;10:988645. doi: 10.3389/fped.2022.988645. eCollection 2022."

PMID:36340711

Infections and immune dysregulation in ataxia-telangiectasia children with hyper-IgM and non-hyper-IgM phenotypes: A single-center experience.

1 finding

2022 Oct 20;10:972952. doi: 10.3389/fped.2022.972952. eCollection 2022.

"2022 Oct 20;10:972952. doi: 10.3389/fped.2022.972952. eCollection 2022."

PMID:37009283

Two novel heterozygote mutations of ATM in a Chinese family with dystonia-dominant ataxia telangiectasia and literature review.

1 finding

Ataxia-telangiectasia (A-T) is an autosomal recessive disorder with high clinical heterogeneity.

"Ataxia-telangiectasia (A-T) is an autosomal recessive disorder with high clinical heterogeneity."

PMID:37851290

Ethnicity-specific BRCA1, BRCA2, PALB2, and ATM pathogenic alleles in breast and ovarian cancer patients from the North Caucasus.

1 finding

Mountain areas of the North Caucasus host several large ethnic communities that have preserved their national identity over the centuries.

"Mountain areas of the North Caucasus host several large ethnic communities that have preserved their national identity over the centuries."

PMID:38280573

Causative mechanisms and clinical impact of immunoglobulin deficiencies in ataxia telangiectasia.

1 finding

Ataxia telangiectasia (AT) is characterized by cerebellar ataxia, telangiectasia, immunodeficiency, and increased cancer susceptibility and is caused by mutations in the ataxia telangiectasia mutated (ATM) gene.

"Ataxia telangiectasia (AT) is characterized by cerebellar ataxia, telangiectasia, immunodeficiency, and increased cancer susceptibility and is caused by mutations in the ataxia telangiectasia mutated (ATM) gene."

PMID:38807759

PARP inhibitor synthetic lethality in ATM biallelic mutant cancer cell lines is associated with BRCA1/2 and RAD51 downregulation.

1 finding

PARP inhibitor synthetic lethality in ATM biallelic mutant cancer cell lines is associated with BRCA1/2 and RAD51 downregulation

"Ataxia telangiectasia-mutated (ATM) kinase is a central regulator of the DNA damage response (DDR) signaling pathway, and its function is critical for the maintenance of genomic stability in cells that coordinate a network of cellular processes, including DNA replication, DNA repair, and cell..."

PMID:39636577

Management of individuals with heterozygous germline pathogenic variants in ATM: A clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).

1 finding

2025 Jan;27(1):101243. doi: 10.1016/j.gim.2024.101243.

"2025 Jan;27(1):101243. doi: 10.1016/j.gim.2024.101243."

PMID:39826692

Profiling Tel1 signaling reveals a non-canonical motif targeting DNA repair and telomere control machineries.

1 finding

2025 Mar;301(3):108194. doi: 10.1016/j.jbc.2025.108194.

"2025 Mar;301(3):108194. doi: 10.1016/j.jbc.2025.108194."

PMID:40270454

Endocrinopathies in children with inborn errors of immunity: a single-center experience.

1 finding

2025 Apr 25;38(7):735-742. doi: 10.1515/jpem-2024-0593.

"2025 Apr 25;38(7):735-742. doi: 10.1515/jpem-2024-0593."

PMID:40616902

Phase 2a/b randomised placebo-controlled dose-escalation trial of triheptanoin for ataxia-telangiectasia: treating mitochondrial dysfunction with anaplerosis.

1 finding

Ataxia-telangiectasia (A-T) is a rare multisystem disease characterised by neurodegenerative cerebellar ataxia, lung disease, immune deficiency, high cancer risk, and mitochondrial dysfunction.

"Ataxia-telangiectasia (A-T) is a rare multisystem disease characterised by neurodegenerative cerebellar ataxia, lung disease, immune deficiency, high cancer risk, and mitochondrial dysfunction."

PMID:41044616

Expanding the clinical spectrum of pediatric ataxia-telangiectasia: a case series of novel genetic variants, lupus vulgaris, and hyper-IgM phenotypes.

1 finding

Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by pathogenic ATM gene variants, characterised by progressive cerebellar ataxia, telangiectasia, immunodeficiency, and cancer predisposition.

"Ataxia-telangiectasia (A-T) is a rare autosomal recessive disorder caused by pathogenic ATM gene variants, characterised by progressive cerebellar ataxia, telangiectasia, immunodeficiency, and cancer predisposition."

PMID:41451872

Genetic and Epidemiological Aspects of Louis-Bar Syndrome Transmission: The Impact of Consanguineous Marriages on the Incidence of Hereditary Disorders.

1 finding

The aim of this study was to investigate the genetic and epidemiological aspects of Louis-Bar syndrome transmission in the population of Kyrgyzstan, with a particular focus on the impact of consanguineous marriages.

"The aim of this study was to investigate the genetic and epidemiological aspects of Louis-Bar syndrome transmission in the population of Kyrgyzstan, with a particular focus on the impact of consanguineous marriages."

PMID:9083516

Bronchiolitis obliterans in ataxia-telangiectasia.

1 finding

1997 Feb;430(2):131-7. doi: 10.1007/BF01008034.

"1997 Feb;430(2):131-7. doi: 10.1007/BF01008034."

PMID:9735376

ATM: from gene to function.

1 finding

1998;7(10):1555-63. doi: 10.1093/hmg/7.10.1555.

"1998;7(10):1555-63. doi: 10.1093/hmg/7.10.1555."

DOI:10.1007/s12026-024-09494-5

Ataxia-telangiectasia in Latin America: clinical features, immunodeficiency, and mortality in a multicenter study