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Inheritance

1

Autosomal recessive inheritance HP:0000007

A-T results from biallelic pathogenic ATM variants. When both parents are heterozygous, each pregnancy has a 25% probability of an affected child, a 50% probability of a heterozygous child, and a 25% probability of a child who inherited neither familial variant.

autosomal recessive inheritance

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. Classical A-T is caused..."

The human case report's background directly states both autosomal recessive inheritance and the biallelic ATM requirement.

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Subtypes

2

Classic ataxia-telangiectasia

ATM hgnc:795

The severe end of the ATM-related spectrum. Progressive cerebellar ataxia begins in early childhood and is followed by extrapyramidal involvement, sensorimotor neuropathy, variable combined immunodeficiency, pulmonary disease, and early malignancy risk. ATM kinase activity is usually absent or extremely low, but clinical severity should not be inferred from variant class alone.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/books/NBK26468/ SUPPORT Other

"childhood onset of progressive neurologic manifestations (initially cerebellar ataxia, followed typically by extrapyramidal involvement and peripheral sensorimotor neuropathy), immunodeficiency (variably associated with abnormalities of humoral immunity, cellular immunity, or combined immune..."

The current GeneReviews revision defines the principal manifestations of classic A-T without treating every feature as universal.

PMID:22213089 SUPPORT Human Clinical

"Patients without ATM kinase activity showed the classical phenotype."

A human genotype-phenotype cohort links absent kinase activity to classic disease while leaving room for individual variability.

Variant ataxia-telangiectasia

ATM hgnc:795

The milder end of the ATM-related spectrum, commonly associated with residual ATM kinase activity. Onset and neurologic progression are later or slower; dystonia, tremor, or axonal neuropathy may dominate and cerebellar ataxia can be absent. Immune and pulmonary manifestations are generally less prominent, but malignancy risk remains increased and may present in adulthood.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/books/NBK26468/ SUPPORT Other

"While cerebellar ataxia can be absent, extrapyramidal movement disorders are common (typically dystonia and dystonic tremor) and most individuals have manifestations of axonal sensorimotor polyneuropathy."

GeneReviews defines variant A-T as part of the same ATM-related continuum and describes its distinguishing neurologic pattern.

PMID:22213089 SUPPORT Human Clinical

"Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan."

Human data associate residual kinase activity with a milder phenotype; this is a correlation rather than an absolute genotype rule.

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Discussions and Knowledge Gaps

3

Which ATM-dependent failure is necessary and sufficient for selective Purkinje and granule neuron degeneration in human A-T, and how much is driven by neuronal DNA-damage responses versus oxidative, mitochondrial, epigenetic, or microglial pathways?

KNOWLEDGE GAP OPEN gap_at_selective_neurodegeneration

Attached to

pathophysiology#ATM kinase deficiency and defective DNA-damage signaling pathophysiology#Oxidative stress and microglial neuroinflammation pathophysiology#Progressive cerebellar and peripheral neurodegeneration

Human cerebellar single-nucleus data and patient-derived co-cultures support microglial involvement, but the ATM-to-selective-neuron causal chain remains unresolved and multiple hypotheses may coexist. The graph therefore marks the microglial branch provisional and the root-to-neurodegeneration edge as indirect with unknown intermediates.

Show evidence (1 reference)

PMID:38159274 SUPPORT Human Clinical

"While ATM loss of function has long been identified as the genetic cause of ataxia-telangiectasia (A-T), how it leads to selective and progressive degeneration of cerebellar Purkinje and granule neurons remains unclear."

The recent human study explicitly states the unresolved causal problem.

Which intervention can produce durable, clinically meaningful slowing of neurologic decline across age and ATM-function strata rather than a short-term scale or biomarker change?

KNOWLEDGE GAP OPEN gap_at_neurologic_disease_modification

Attached to

treatments#Intra-erythrocyte dexamethasone sodium phosphate (EryDex) treatments#Triheptanoin treatments#Atipeksen for ATM c.7865C>T

ATTeST missed its overall primary endpoint, the triheptanoin study was small and dose-limited, and atipeksen is mutation-specific and just entering first-in-human evaluation. No therapy is yet established to arrest the neurodegenerative course.

Show evidence (2 references)

PMID:39152028 SUPPORT Human Clinical

"Although there were no safety concerns, the primary efficacy endpoint was not met"

The largest published phase 3 neurologic study did not establish overall efficacy.

clinicaltrials:NCT07215416 SUPPORT Human Clinical

"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."

The registry shows both the early trial stage and narrow genotype eligibility.

Which individuals, if any, obtain a net survival benefit from pre-emptive allogeneic HSCT once immune reconstitution, malignancy risk, conditioning toxicity, and continued neurodegeneration are considered together?

CONTROVERSY OPEN gap_at_hsct_net_benefit

Attached to

treatments#Hematopoietic stem cell transplantation pathophysiology#Adaptive immune-development and antibody-production defects pathophysiology#Progressive cerebellar and peripheral neurodegeneration

Small reports show immune reconstitution, but they cannot establish prevention of malignancy or neurologic benefit and conditioning is especially consequential in a DNA-repair disorder. HSCT is therefore retained as investigational, not standard preventive care.

Show evidence (1 reference)

PMID:30420857 SUPPORT Human Clinical

"It is a matter of discussion whether pre-emptive allogeneic hematopoietic stem cell transplantation (alloHSCT) using a reduced intensity conditioning regimen would be an option to restore immune-competence and prevent malignancy"

The proof-of-concept report itself frames the indication as unsettled.

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Pathophysiology

6

ATM kinase deficiency and defective DNA-damage signaling

Biallelic pathogenic ATM variants reduce or abolish ATM kinase function. ATM normally coordinates signaling after DNA double-strand breaks and oxidative or genotoxic stress, including checkpoint activation and repair. Its deficiency is the established proximal lesion; downstream tissue selectivity is not explained by the DNA-damage response alone.

ATM hgnc:795

DNA damage response GO:0006974 ↓ DECREASED double-strand break repair GO:0006302 ↓ DECREASED cell cycle checkpoint signaling GO:0000075 ↓ DECREASED

protein serine/threonine kinase activity GO:0004674 ↓ DECREASED

Downstream

Genomic instability, radiosensitivity, and cancer predisposition Failure of ATM-dependent double-strand-break signaling impairs repair and checkpoints, permitting chromosomal instability and hypersensitivity to DNA-break-inducing radiation.

Adaptive immune-development and antibody-production defects ATM-dependent repair is required when lymphocyte antigen-receptor and class-switch recombination create programmed DNA breaks.

Progressive cerebellar and peripheral neurodegeneration ATM deficiency ultimately causes selective progressive neurologic injury, but the necessary molecular intermediates are not established.

Oxidative stress and microglial neuroinflammation ATM loss is associated with oxidative stress and an inflammatory microglial state, a plausible contributor to neuronal injury rather than an established sole cause.

Telangiectasia Telangiectasia belongs to the ATM-deficiency phenotype, but the causal tissue pathway is unknown.

Elevated circulating alpha-fetoprotein concentration Persistent AFP elevation is strongly associated with A-T after early childhood, although its mechanistic link to ATM loss is unknown.

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."

The review defines the central DNA-damage and stress-signaling role of ATM.

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 molecular diagnoses link biallelic ATM loss of function to classic A-T.

Genomic instability, radiosensitivity, and cancer predisposition

Defective double-strand-break repair and checkpoint signaling permit spontaneous and induced chromosome breaks and rearrangements. Ionizing radiation and radiomimetic agents therefore cause disproportionate cytotoxicity. Genomic instability also promotes malignancy, especially lymphoid cancers in children; solid tumors comprise a larger share in adults and in variant A-T.

double-strand break repair GO:0006302 ↓ DECREASED cell cycle checkpoint signaling GO:0000075 ↓ DECREASED chromosome organization GO:0051276 ⚠ ABNORMAL

Downstream

Increased sensitivity to ionizing radiation Ionizing radiation produces DNA lesions whose repair is severely impaired without ATM.

Neoplasm Accumulated genomic instability permits malignant transformation across hematologic and solid tissues.

Lymphoma Aberrant repair during lymphocyte antigen-receptor rearrangement can generate oncogenic translocations, contributing to the characteristic lymphoma risk.

Show evidence (2 references)

PMID:27884168 SUPPORT Other

"The result is genomic instability which can lead to the development of cancers [6]."

This directly links the defective ATM stress response to genomic instability and cancer.

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."

A large contemporary cohort quantifies the cancer burden and spectrum.

Oxidative stress and microglial neuroinflammation

Patient cerebellar single-nucleus data show inflammatory microglial states, while patient-derived co-cultures show microglia-associated neuronal cytotoxicity. Oxidative stress and microglial signaling are therefore represented as a provisional contributing pathway, not as the unique or sufficient explanation for A-T neurodegeneration.

microglial cell CL:0000129 Purkinje cell CL:0000121 cerebellar granule cell CL:0001031

response to oxidative stress GO:0006979 cytokine production GO:0001816

cerebellum UBERON:0002037

Downstream

Progressive cerebellar and peripheral neurodegeneration Neurotoxic microglial signaling may contribute to Purkinje and granule neuron injury within the broader, multifactorial neurologic mechanism.

Show evidence (2 references)

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 identify microglial inflammation.

PMID:38159274 SUPPORT In Vitro

"A-T microglia co-culture with either control or A-T iPSC-derived neurons was sufficient to induce cytotoxicity."

Patient-derived co-culture provides functional evidence while remaining an in-vitro model.

Progressive cerebellar and peripheral neurodegeneration

Progressive loss and dysfunction of cerebellar Purkinje and granule neurons produce cerebellar atrophy and ataxia. Eye-movement, speech, swallowing, extrapyramidal, and peripheral nerve abnormalities broaden with age. The clinical neurodegenerative process is established, but no single upstream molecular hypothesis fully explains its selectivity.

Purkinje cell CL:0000121 cerebellar granule cell CL:0001031

neuron apoptotic process GO:0051402

cerebellum UBERON:0002037

Downstream

Progressive cerebellar ataxia Cerebellar neuronal dysfunction and loss produce progressive ataxia.

Cerebellar atrophy Progressive loss of cerebellar neurons produces macroscopic atrophy.

Oculomotor apraxia Progressive neurologic dysfunction impairs voluntary saccadic initiation and coordination.

Dysarthria Progressive motor-system dysfunction impairs speech production.

Abnormal extrapyramidal motor function Basal-ganglia and connected motor-system involvement produces dystonia, tremor, chorea, or parkinsonism.

Peripheral axonal neuropathy Progressive peripheral nerve involvement produces an axonal sensorimotor neuropathy.

Dysphagia Progressive bulbar incoordination compromises safe swallowing.

Multifactorial chronic pulmonary injury Bulbar weakness and dysphagia contribute to aspiration and impaired airway clearance.

Show evidence (1 reference)

PMID:27884168 SUPPORT Other

"guably some of the most devastating symptoms of A-T are a result of progressive cerebellar degeneration, char- acterized by the gradual loss and/or aberrant location of PCs and, to a lesser extent, the gradual loss of granule cells [122, 123]."

The review establishes the anatomic substrate while separately acknowledging uncertainty about its cause.

Adaptive immune-development and antibody-production defects

Impaired repair of programmed DNA breaks during lymphocyte development reduces lymphocyte number and repertoire diversity and can disrupt immunoglobulin class switching. Immune findings vary from selective antibody deficiency to combined immunodeficiency; variant A-T often has normal immune function.

B cell CL:0000236 T cell CL:0000084

V(D)J recombination GO:0033151 ↓ DECREASED immunoglobulin isotype switching GO:0045190 ↓ DECREASED

Downstream

Combined immunodeficiency Variable B- and T-cell abnormalities can produce combined immune deficiency.

Decreased circulating IgA concentration Defective B-cell maturation and class switching commonly reduce serum IgA.

Recurrent respiratory infections Antibody deficiency and lymphopenia increase susceptibility to recurrent airway infection.

Multifactorial chronic pulmonary injury Recurrent infection and impaired immune clearance contribute to cumulative lung injury.

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."

A multicenter human cohort demonstrates both humoral deficiency and lymphopenia.

PMID:24568663 SUPPORT Human Clinical

"Laboratory evaluations revealed defective CSR while none of the three AT patients without HIgM presentation had a defect in the CSR process."

Functional testing identifies defective class-switch recombination in the hyper-IgM subset and also demonstrates that it is not universal.

Multifactorial chronic pulmonary injury

Pulmonary disease reflects interacting recurrent infection, immunodeficiency, aspiration and weak cough from neurologic disease, interstitial injury, and tissue stress. Patient-derived airway epithelial cells also show oxidative and inflammasome abnormalities, but that cell-intrinsic pathway is not assumed to explain all clinical lung disease.

respiratory tract epithelial cell CL:0002368

innate immune response GO:0045087 response to oxidative stress GO:0006979

lung UBERON:0002048

Downstream

Recurrent respiratory infections Impaired immune defense and airway integrity permit repeated sinopulmonary infection.

Bronchiectasis Repeated airway infection and injury can produce permanent bronchial dilation.

Show evidence (1 reference)

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."

Patient-derived epithelial experiments support one local contributor; PARTIAL prevents generalizing the cell model to the entire pulmonary phenotype.

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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

18

Blood 2

Decreased circulating IgA concentration FREQUENT HP:0002720

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."

The multicenter cohort reports IgA deficiency in 60.8% of patients.

PMID:34477998 SUPPORT Human Clinical

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

IgA deficiency also stratifies prognosis in classic A-T cohorts.

Lymphoma OCCASIONAL HP:0002665

Non-Hodgkin lymphoma was the most common individual cancer in a 508-person cohort; OCCASIONAL reflects its patient-level frequency, not its share among cancers.

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)."

The cohort identifies non-Hodgkin lymphoma as the most frequent cancer type.

Cardiovascular 1

Telangiectasia FREQUENT HP:0001009

Ocular and cutaneous telangiectasias often appear after neurologic onset; they may be absent in variant A-T.

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."

The review supports oculocutaneous telangiectasia as a characteristic feature.

Digestive 1

Dysphagia FREQUENT HP:0002015

Often emerges during the second decade in classic A-T and contributes to aspiration, prolonged meals, and inadequate nutrition.

Show evidence (1 reference)

PMID:27884168 SUPPORT Other

"Dysphagia is common in A-T and typically appears during the second decade of life because of the neuro- logical changes which interfere with the coordination of mouth and pharynx movements necessary for safe and efficient swallowing [64]."

The review describes the timing and neurologic basis of dysphagia.

Eye 1

Oculomotor apraxia VERY_FREQUENT HP:0000657

Common and progressive in classic A-T, but it can appear later or remain absent in variant A-T.

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."

The human genetic report lists ocular apraxia as a characteristic feature.

Immune 2

Combined immunodeficiency FREQUENT HP:0005387

Immune abnormalities are heterogeneous and can involve humoral, cellular, or combined immunity; immune function is often normal in variant A-T.

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."

Human immune profiling supports combined immunodeficiency in A-T.

Recurrent respiratory infections FREQUENT HP:0002205

Show evidence (1 reference)

PMID:38834764 SUPPORT Human Clinical

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

The cohort supports recurrent airway infection and its association with IgA deficiency.

Metabolism 1

Elevated circulating alpha-fetoprotein concentration VERY_FREQUENT HP:0006254

Serum AFP is usually elevated and slowly rises after age two in classic A-T; normal AFP does not exclude variant A-T.

Show evidence (1 reference)

PMID:27884168 SUPPORT Other

"mately 95% of people with A-T have elevated serum AFP levels after the age of two, and measured levels of AFP appear to increase slowly over time [137]."

The review provides the approximate frequency and age qualification.

Nervous System 3

Progressive cerebellar ataxia VERY_FREQUENT HP:0002073

Usually the presenting manifestation of classic A-T in early childhood; ataxia can be mild, delayed, or absent in variant A-T.

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."

Progressive cerebellar ataxia is a defining classic A-T manifestation.

Cerebellar atrophy VERY_FREQUENT HP:0001272

Show evidence (1 reference)

PMID:27884168 SUPPORT Other

"Cerebellar atrophy detected by MRI"

The review lists MRI-detected cerebellar atrophy among characteristic abnormalities.

Dysarthria FREQUENT 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"

The clinical review identifies dysarthria as a common neurologic feature.

Respiratory 1

Bronchiectasis FREQUENT 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."

The clinical background identifies bronchiectasis as an important complication.

Cellular 1

Increased sensitivity to ionizing radiation VERY_FREQUENT HP:0011133

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."

The review supports radiosensitivity as a core A-T feature.

Neoplasm 1

Neoplasm OCCASIONAL HP:0002664

A contemporary cohort found primary cancer in 16.5% of 508 individuals. Hematologic malignancies predominate in childhood; solid tumors become more prominent in adults and in variant A-T. This frequency is cohort- and age-dependent rather than lifetime penetrance.

Show evidence (1 reference)

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."

The contemporary cohort quantifies cancer prevalence and spectrum.

Other 4

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

Dystonia, dystonic tremor, chorea, myoclonus, or parkinsonism can occur; extrapyramidal disease may dominate variant A-T.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK26468/ SUPPORT Other

"While cerebellar ataxia can be absent, extrapyramidal movement disorders are common (typically dystonia and dystonic tremor)"

GeneReviews emphasizes extrapyramidal manifestations in variant A-T.

Peripheral axonal neuropathy FREQUENT HP:0003477

Show evidence (1 reference)

PMID:30137827 SUPPORT Other

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

The clinical review identifies axonal neuropathy as a common neurologic feature.

Insulin-resistant diabetes mellitus OCCASIONAL HP:0000831

Insulin-resistant diabetes affects a minority of people with A-T and typically appears late in disease progression.

Show evidence (1 reference)

PMID:27884168 SUPPORT Other

"A minority of patients with A-T suffer from insulin resistant diabetes which typically appears as a late event during disease progression."

The review directly supports an OCCASIONAL frequency band and late onset.

Chromosome breakage HP:0040012

Spontaneous and radiation-induced chromosome breaks and rearrangements in cultured lymphocytes and fibroblasts are a diagnostic laboratory finding in A-T. The source does not quantify frequency or specify 7;14 translocations, so those stronger claims are intentionally omitted.

Show evidence (1 reference)

PMID:27884168 SUPPORT Other

"Spontaneous and X-ray induced chromosomal breaks and rearrangements in cultured lymphocytes and fibroblasts"

The finding appears in the review's table of laboratory abnormalities in A-T.

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Genetic Associations

1

ATM (Causative)

Gene: ATM hgnc:795 relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal recessive inheritance

Show evidence (3 references)

CGGV:assertion_02a69e27-77dc-41bd-83d2-dda9c224ee43-2021-07-27T205239.729Z SUPPORT Other

ClinGen classifies the autosomal-recessive ATM-A-T relationship as definitive.

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 molecular diagnosis supports biallelic ATM loss of function.

PMID:22213089 SUPPORT Human Clinical

"The genotypes of severely affected patients generally included truncating mutations resulting in total absence of ATM kinase activity, while patients with milder phenotypes harbored at least one missense or splice site mutation resulting in expression of ATM with some kinase activity."

The genotype-phenotype cohort supports, but does not make absolute, the relationship between residual kinase activity and milder disease.

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Medical Actions

12

Multidisciplinary rehabilitation

Category: Therapeutic Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Physical, occupational, and speech-language therapy, together with rehabilitation medicine, are supportive care. They aim to preserve safe mobility, communication, participation, and independence but have not been shown to stop neurodegeneration.

Target Phenotypes: Progressive cerebellar ataxia HP:0002073 Dysarthria HP:0001260 Dysphagia HP:0002015

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/books/NBK26468/ SUPPORT Other

"Supportive care to improve quality of life, maximize function, and reduce complications ideally involves multidisciplinary care"

Current GeneReviews recommends multidisciplinary supportive care rather than claiming a disease-modifying rehabilitation effect.

PMID:34107524 SUPPORT Human Clinical

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

A single-child case report provides low-certainty evidence of functional benefit and is therefore marked PARTIAL.

Immunology-guided infection prevention and immunoglobulin replacement

Category: Therapeutic Action: immunoglobulin infusion therapy Ontology label: Immunoglobulin Therapy NCIT:C62710

Vaccination, antimicrobial prophylaxis, and intravenous or subcutaneous immunoglobulin are individualized according to immunoglobulin levels, vaccine responses, lymphocyte status, and infection history. Live rubella vaccine should be avoided in severe immunodeficiency; management should be directed by an immunodeficiency specialist.

Mechanism Target:

BYPASSES Adaptive immune-development and antibody-production defects — Replacement immunoglobulin supplies antibody function without correcting the underlying ATM-dependent lymphocyte-development defect.

Target Phenotypes: Combined immunodeficiency HP:0005387 Recurrent respiratory infections HP:0002205

Show evidence (1 reference)

PMID:27884168 SUPPORT Other

"The need for additional im- munizations (especially with pneumococcal and influenza vaccines), antibiotics to provide prophylaxis from infec- tions, and/or gamma globulin therapy should be deter- mined by an expert in the field of immunodeficiency or infectious diseases."

The review recommends individualized specialist-directed preventive and replacement therapy.

Airway clearance and pulmonary care

Category: Therapeutic Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Pulmonary follow-up addresses secretion retention, infection, weak cough, aspiration, and restrictive or interstitial disease. Manual chest therapy, oscillating devices, or a chest physiotherapy vest can be used when secretions are increased, with cough-assist support when needed.

Mechanism Target:

MODULATES Multifactorial chronic pulmonary injury — Airway-clearance techniques reduce retained secretions and secondary airway injury.

Target Phenotypes: Bronchiectasis HP:0002110 Recurrent respiratory infections HP:0002205

Show evidence (1 reference)

PMID:27884168 SUPPORT Other

"Children and adults with increased bronchial secre- tions may benefit from routine chest therapy using the manual method, and a cappella device or a chest physio- therapy vest."

The review supports airway-clearance therapy when secretions are increased.

Swallowing and nutritional support

Category: Therapeutic Action: nutritional support Ontology label: Nutritional Support NCIT:C15433

Speech-language and nutrition teams adapt food texture, meal support, and caloric intake. Gastrostomy is considered when oral intake cannot sustain growth or weight, aspiration is problematic, or meals are excessively long and stressful.

Target Phenotypes: Dysphagia HP:0002015

Show evidence (1 reference)

PMID:27884168 SUPPORT Other

"A gastrostomy tube (G-tube or feeding tube) is recom- mended when any of the following occur: a child cannot eat enough to grow or a person of any age cannot eat enough to maintain weight; aspiration is problematic; mealtimes are stressful or too long, interfering with other activities [161]."

The review states clinical thresholds for escalation to gastrostomy rather than recommending it universally.

Malignancy surveillance

Category: Screening Action: surveillance for malignancies Ontology label: Cancer Screening NCIT:C15406

Lifelong clinical and laboratory surveillance is required because cancer can occur in childhood or adulthood. Evaluation is symptom- and age-directed, and imaging choices should minimize ionizing radiation.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK26468/ SUPPORT Other

"Eval for clinical manifestations of malignancy (e.g., lymphadenopathy)"

GeneReviews includes malignancy assessment in recommended evaluation and surveillance; the record does not imply a validated universal imaging protocol.

Avoidance of ionizing radiation and radiotherapy

Action: therapeutic procedure Ontology label: Therapeutic Procedure NCIT:C49236

Diagnostic x-rays and CT should be limited to medically necessary situations and non-ionizing alternatives used when suitable. Therapeutic radiation is contraindicated in affected individuals because severe radiosensitivity can cause major complications. This restriction does not automatically apply to heterozygous relatives.

Target Phenotypes: Increased sensitivity to ionizing radiation HP:0011133

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/books/NBK26468/ SUPPORT Other

"Ionizing radiation (x-ray and gamma ray) is contraindicated, due to increased sensitivity"

Current GeneReviews explicitly advises avoidance in affected individuals.

url:https://www.ncbi.nlm.nih.gov/books/NBK26468/ SUPPORT Other

"Radiation therapy is contraindicated because increased radiosensitivity may lead to very severe complications"

GeneReviews separately identifies therapeutic radiation as contraindicated.

ATM-activity-adapted treatment of hematologic malignancy

Category: Therapeutic Action: therapeutic procedure Ontology label: Therapeutic Procedure NCIT:C49236

Cancer therapy requires an A-T-experienced oncology team and avoidance of standard radiotherapy. A 2024 international cohort suggests de-escalated leukemia or lymphoma therapy when ATM kinase activity is absent and near-standard regimens when residual activity is present; this is risk-adapted evidence, not a universal protocol.

Target Phenotypes: Neoplasm HP:0002664 Lymphoma HP:0002665

Show evidence (1 reference)

PMID:38917355 SUPPORT Human Clinical

"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."

The authors propose kinase-activity-stratified therapy; PARTIAL preserves the observational and non-protocol nature of the recommendation.

Genetic counseling

Category: Counseling / Informational Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counseling covers autosomal recessive recurrence risk, testing of relatives for familial ATM variants, reproductive options, and the distinct cancer implications of heterozygosity.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/books/NBK26468/ SUPPORT Other

"including discussion of potential risks to offspring and reproductive options"

GeneReviews explicitly includes offspring risk and reproductive options in counseling.

PMID:27884168 SUPPORT Other

"Genetic counseling: Genetic counseling can help family members of a patient with A-T understand when genetic testing for A-T is feasible, and how the test results should be interpreted."

The clinical review supports family counseling about the availability and interpretation of testing.

Intra-erythrocyte dexamethasone sodium phosphate (EryDex)

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

EryDex is an investigational erythrocyte-delivered corticosteroid for neurologic symptoms. The published ATTeST phase 3 trial did not meet its primary efficacy endpoint overall, although safety was acceptable and an age-defined subgroup signal was explored. The separate NEAT phase 3 trial (NCT06193200) is completed; no disease-modifying efficacy should be inferred until results are available.

Mechanism Target:

MODULATES Progressive cerebellar and peripheral neurodegeneration — The clinical program tests symptomatic neurologic modulation rather than proven ATM restoration.

Target Phenotypes: Progressive cerebellar ataxia HP:0002073

Show evidence (1 reference)

PMID:39152028 SUPPORT 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."

The phase 3 result supports continued investigation but not established efficacy.

Triheptanoin

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Triheptanoin is investigational anaplerotic therapy studied in a 31-person phase 2a/b dose-escalation trial. Respiratory epithelial-cell death and selected neurologic, speech, and swallowing measures improved, but 38% of participants had gastrointestinal adverse events and dosing was capped. These early outcomes do not establish routine use.

Target Phenotypes: Progressive cerebellar ataxia HP:0002073 Dysphagia HP:0002015

Show evidence (1 reference)

PMID:40616902 SUPPORT Human Clinical

"Adverse events including abdominal pain, nausea, vomiting, and diarrhoea, requiring dose capping at 20%, were observed in 12 (38%) participants."

The phase 2 trial documents tolerability limitations; efficacy remains preliminary.

Hematopoietic stem cell transplantation

Category: Therapeutic Action: hematopoietic stem cell transplantation Ontology label: Hematopoietic Cell Transplantation NCIT:C15431

Allogeneic HSCT can reconstitute hematopoietic immunity in selected individuals, but experience is limited to single cases and small series, neurologic outcomes are divergent, and transplant conditioning is hazardous in a radiosensitive DNA-repair disorder. It remains investigational rather than standard preventive therapy.

Mechanism Target:

RESTORES Adaptive immune-development and antibody-production defects — Donor hematopoiesis can restore lymphocyte and antibody function but not ATM in neural tissue.

Target Phenotypes: Combined immunodeficiency HP:0005387

Show evidence (2 references)

PMID:30420857 SUPPORT Human Clinical

"Our manuscript provides a proof-of-concept of alloHSCT as an individual pre-emptive treatment strategy from which some A-T patients might benefit."

The publication itself frames the evidence as individual proof of concept, so routine use is not supported.

url:https://www.ncbi.nlm.nih.gov/books/NBK26468/ SUPPORT Other

"in A-T has been conducted in single cases and small case series, with divergent results regarding effect on neurologic functioning"

Current GeneReviews emphasizes the small evidence base and divergent neurologic outcomes.

Atipeksen for ATM c.7865C>T

Category: Therapeutic Action: Pharmacotherapy NCIT:C15986

Atipeksen is an investigational intrathecal antisense oligonucleotide designed for individuals carrying the recurrent ATM c.7865C>T variant. The first phase 1/2 study is recruiting with an estimated August 2026 start; the intervention is mutation-specific and has no established clinical efficacy.

Mechanism Target:

RESTORES ATM kinase deficiency and defective DNA-damage signaling — The mutation-targeted program is intended to restore ATM function in the eligible genotype.

Target Phenotypes: Progressive cerebellar ataxia HP:0002073

Show evidence (2 references)

PMID:37438524 SUPPORT In Vitro

"Several of these ASOs were effective in restoring normal splicing on allele-specific RT–PCR in patient fibroblasts (Supplementary Table 14), with two designs (AT007 and AT008) showing the most promise."

Patient-fibroblast experiments directly support atipeksen/AT008 as a splice-restoring ASO for this ATM variant.

clinicaltrials:NCT07215416 SUPPORT Human Clinical

"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."

The registry documents the intended mutation-specific mechanism and trial plan, not demonstrated clinical benefit.

🔬

Diagnosis

4

Molecular confirmation of biallelic ATM pathogenic variants

Diagnosis is established in a person with suggestive findings by identifying biallelic pathogenic variants in ATM. Sequence analysis should be complemented by deletion/duplication analysis when needed.

molecular genetic testing NCIT:C19770

Results: Biallelic pathogenic or likely pathogenic ATM variants establish the molecular diagnosis.

Show evidence (2 references)

PMID:27884168 SUPPORT Other

"A diagnosis of A-T can be confirmed by the finding of an absence or deficiency of the ATM protein or its kinase activity in cultured cell lines, and/or identification of the pathological mutations in the ATM gene."

The clinical review identifies ATM mutation detection as a confirmatory diagnostic route.

PMID:30888062 SUPPORT Human Clinical

"radiosensitivity and cancer predisposition. 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."

The human genetic report supports the biallelic ATM requirement.

Clinical and laboratory evaluation for suspected A-T

Progressive ataxia and abnormal eye movements raise suspicion. Supporting clues include telangiectasia, recurrent sinopulmonary infection, elevated AFP after age two, immunoglobulin deficiency, and lymphopenia. No single supporting clue substitutes for molecular confirmation.

Results: A convergent neurologic, immunologic, and laboratory pattern supports targeted ATM testing.

Show evidence (1 reference)

PMID:27884168 SUPPORT Other

"The diagnosis of A-T is usually suspected by the combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability) with one or more of the following which may vary in their appearance: telangiectasia, frequent sinopulmonary infections and specific..."

The review defines the clinical and laboratory suspicion pattern.

ATM protein and kinase functional testing

When molecular findings are incomplete or phenotype classification matters, specialized laboratories can assess ATM protein abundance and kinase activity in cultured cells. Cellular radiosensitivity and chromosome-break assays can support the diagnosis but are not substitutes for variant interpretation.

Results: Absent or deficient ATM protein or kinase activity supports A-T and helps distinguish classic from variant disease.

Show evidence (1 reference)

PMID:27884168 SUPPORT Other

"A diagnosis of A-T can be confirmed by the finding of an absence or deficiency of the ATM protein or its kinase activity in cultured cell lines, and/or identification of the pathological mutations in the ATM gene."

The review identifies specialized protein and kinase assays as confirmatory tests.

SCID newborn-screen signal

TREC-based newborn screening for severe combined immunodeficiency can detect lymphopenic classic A-T before neurologic manifestations, but sensitivity is incomplete and a positive screen requires specialist evaluation and molecular diagnosis.

Results: Reduced T-cell receptor excision circles can trigger evaluation for A-T among causes of neonatal lymphopenia.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK26468/ SUPPORT Other

"newborn screening (NBS) for severe combined immunodeficiency (SCID) that relies on the identification of reduced T-cell receptor excision circle (TREC) levels in blood spots most likely identifies about 50% of children with classic A-T"

GeneReviews quantifies the incomplete sensitivity of TREC screening for classic A-T.

📈

Progression

4

Classic A-T - early childhood onset

Classic ataxia-telangiectasia Age: Infancy to early childhood

Postural instability and progressive ataxia usually become apparent when a child begins sitting or walking; telangiectasia can emerge later, so its absence early does not exclude A-T.

Show evidence (1 reference)

PMID:27884168 SUPPORT Other

"Neurological symptoms most often first appear in early childhood when children begin to sit or walk."

The review places typical neurologic onset in early childhood.

Classic A-T - progressive neurologic disability

Classic ataxia-telangiectasia Age: School age through adolescence

Gait, eye-movement, speech, extrapyramidal, and peripheral nerve abnormalities progress. Many affected children require a wheelchair around the beginning of the second decade; dysphagia commonly emerges during that decade.

Show evidence (2 references)

PMID:27884168 SUPPORT Other

"Around the beginning of their second decade children with classic A-T start using a wheelchair in the community setting [4]."

This gives a representative functional milestone for classic A-T, not an invariant deadline.

PMID:27884168 SUPPORT Other

"Dysphagia is common in A-T and typically appears during the second decade of life because of the neuro-"

The clinical review describes dysphagia as a later neurologic complication.

Classic A-T - later multisystem morbidity

Classic ataxia-telangiectasia Age: Childhood through adulthood

Cancer, chronic lung disease, and infection drive premature mortality. Improved supportive care has extended survival, so adult pulmonary, metabolic, hepatic, and solid-tumor complications are increasingly encountered.

Show evidence (1 reference)

PMID:21665257 SUPPORT Human Clinical

"Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality."

A 240-patient cohort identifies cancer and respiratory infection as major mortality determinants.

Variant A-T - slower and later course

Variant ataxia-telangiectasia Age: Childhood to adulthood

Neurologic decline is generally slower and life expectancy longer than in classic A-T. Immunodeficiency and pulmonary disease may be absent, whereas cancer risk persists and malignancy can precede recognition of A-T.

Show evidence (1 reference)

PMID:22213089 SUPPORT Human Clinical

"Overall, the phenotypic manifestations in A-T show a continuous spectrum from severe classical childhood-onset A-T to a relatively mild adult-onset disorder, depending on the presence of ATM protein and kinase activity."

This cohort supports a continuum rather than sharply separated diseases.

📊

Prevalence

1

Global live births

Birth Prevalence 1.0–2.5 per 100,000 1–9 per 100,000

The frequently cited worldwide birth-prevalence estimate is one in 40,000 to one in 100,000, equivalent to 1.0-2.5 per 100,000 live births. Founder populations can have higher local frequencies, and ascertainment is incomplete.

Show evidence (1 reference)

PMID:27884168 SUPPORT Other

"EPIDEMIOLOGY: The world-wide prevalence of A-T is estimated to be between 1 in 40,000 and 1 in 100,000 live births."

The clinical review supplies the standard worldwide range, normalized here to cases per 100,000 live births.

⚖️

Clinical Burden

High

Classic A-T causes progressive loss of motor independence together with recurrent infection, chronic pulmonary morbidity, feeding impairment, marked treatment-related radiosensitivity, and early cancer risk. Variant A-T can be substantially milder, but no part of the spectrum is free of malignancy risk or the need for lifelong multidisciplinary surveillance.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK26468/ SUPPORT Other

"Life expectancy is significantly reduced due to cancer, pulmonary disease, and infections."

GeneReviews directly identifies the major life-limiting complications of classic A-T.

🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from Ataxia-telangiectasia:

Ataxia-telangiectasia-like disorder 1 Not Yet Curated MONDO:0024557

Overlapping Features Biallelic MRE11 deficiency can produce progressive ataxia, oculomotor abnormalities, cerebellar atrophy, and cellular radiosensitivity that resemble A-T.

Distinguishing Features

Telangiectasia, immunodeficiency, elevated AFP, and cancer predisposition are absent or less prominent than in classic A-T.
Molecular testing identifies biallelic MRE11 rather than ATM variants.

Show evidence (1 reference)

PMID:30888062 SUPPORT Other

"Atypical presentations can be found in A-T-like disease or in Nijmegen breakage syndrome, caused by deficiency of mre11 or nibrin proteins, respectively."

The review identifies MRE11-deficient A-T-like disease as a phenocopy.

Nijmegen breakage syndrome MONDO:0009623

Overlapping Features Biallelic NBN deficiency overlaps through immunodeficiency, radiosensitivity, chromosome instability, growth failure, and cancer risk.

Distinguishing Features

Progressive microcephaly and characteristic facies are typical, whereas progressive cerebellar neurodegeneration is not.
Molecular testing identifies biallelic NBN rather than ATM variants.

Show evidence (1 reference)

PMID:30888062 SUPPORT Other

"Atypical presentations can be found in A-T-like disease or in Nijmegen breakage syndrome, caused by deficiency of mre11 or nibrin proteins, respectively."

The review identifies nibrin deficiency as the basis of this overlapping disorder.

Ataxia with oculomotor apraxia type 1 MONDO:0008842

Overlapping Features Biallelic APTX disease overlaps through childhood-onset ataxia, oculomotor apraxia, and axonal neuropathy.

Distinguishing Features

Hypoalbuminemia and hypercholesterolemia favor AOA1.
AFP is generally normal, and telangiectasia, immunodeficiency, radiosensitivity, and cancer predisposition are not typical.

Show evidence (1 reference)

PMID:27884168 SUPPORT Other

"These include: ataxia oculomotor apraxia type 1 (AOA1), ataxia oculomotor apraxia type 2 (AOA2, also known as SCAR1), ataxia telangiectasia like disorder (ATLD) and Nijmegen breakage syndrome (NBS)."

The clinical review explicitly includes AOA1 in the A-T differential.

Ataxia with oculomotor apraxia type 2 Not Yet Curated MONDO:0018996

Overlapping Features Biallelic SETX disease overlaps through progressive ataxia, axonal sensorimotor neuropathy, occasional oculomotor apraxia, and elevated AFP.

Distinguishing Features

Onset is usually later than classic A-T and immunodeficiency, telangiectasia, radiosensitivity, and cancer predisposition are not typical.
Molecular testing identifies biallelic SETX rather than ATM variants.

Show evidence (1 reference)

PMID:27884168 SUPPORT Other

"These include: ataxia oculomotor apraxia type 1 (AOA1), ataxia oculomotor apraxia type 2 (AOA2, also known as SCAR1), ataxia telangiectasia like disorder (ATLD) and Nijmegen breakage syndrome (NBS)."

The clinical review explicitly includes AOA2 in the A-T differential.

Friedreich ataxia MONDO:0100339

Overlapping Features Biallelic FXN disease is a common recessive childhood or adolescent ataxia and can overlap through progressive gait and peripheral nerve dysfunction.

Distinguishing Features

Telangiectasia and oculomotor apraxia are absent; AFP is normal.
Early areflexia, sensory proprioceptive loss, scoliosis, and cardiomyopathy favor Friedreich ataxia.

Show evidence (1 reference)

PMID:27884168 SUPPORT Other

"In FRDA, ataxia typically appears between 10 and 15 years of age, and differs from A-T by the absence of telangiectasia and oculomotor apraxia, the early absence of tendon reflexes, a normal AFP , the frequent presence of scoliosis, and abnormal features on the EKG."

The review provides direct distinguishing features for Friedreich ataxia.

📊

Related Datasets

1

NETSseq Reveals Inflammatory and Aging Mechanisms in Distinct Cell Types Driving Cerebellar Decline in Ataxia Telangiectasia geo:GSE282079

The cellular and molecular changes driving the neurological abnormalities associated with the loss or functional deficiency of the ataxia–telangiectasia mutated (ATM) protein are not well understood. In this study, we applied our proprietary Nuclear Enriched Transcript Sort sequencing (NETSseq) platform to investigate changes in cell type composition and gene expression patterns in human cerebellar post-mortem tissue from ataxia–telangiectasia (A-T) donors and non-neurodegenerative disease control donors. Compared to single-cell technologies, NETSseq provided a more robust detection of lowly expressed and differentially expressed genes.

human BULK RNA SEQ n=318

PMID:40959764

Identified by GEO DataSets index search for Ataxia-telangiectasia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

🔬

Clinical Trials

4

NCT06193200 PHASE_III COMPLETED

NEAT was an international randomized, double-blind, placebo-controlled phase 3 trial of intravenous EryDex every 28 days for neurologic symptoms.

Target Phenotypes: Progressive cerebellar ataxia HP:0002073

Show evidence (1 reference)

clinicaltrials:NCT06193200 SUPPORT Human Clinical

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

The registry defines the intervention, design, phase, and neurologic target.

NCT06673056 PHASE_III ACTIVE_NOT_RECRUITING

Randomized, double-blind, placebo-controlled crossover phase 3 study of N-acetyl-L-leucine (IB1001) in participants age four and older with confirmed A-T.

Target Phenotypes: Progressive cerebellar ataxia HP:0002073

Show evidence (1 reference)

clinicaltrials:NCT06673056 SUPPORT Human Clinical

"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..."

The current registry summary defines the study population, design, and objectives.

NCT04870866 PHASE_II ACTIVE_NOT_RECRUITING

Open-label proof-of-concept phase 2 study of nicotinamide riboside supplementation in children, focused on neurologic symptoms and exploratory biomarkers.

Target Phenotypes: Progressive cerebellar ataxia HP:0002073

Show evidence (1 reference)

clinicaltrials:NCT04870866 SUPPORT Human Clinical

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

The registry supports the pediatric NR intervention and neurologic focus.

NCT07215416 PHASE_I RECRUITING

Phase 1/2 first-in-human study of intrathecal atipeksen, a mutation-targeted antisense oligonucleotide for A-T caused by the recurrent ATM c.7865C>T variant.

Target Phenotypes: Progressive cerebellar ataxia HP:0002073

Show evidence (1 reference)

clinicaltrials:NCT07215416 SUPPORT Human Clinical

"This project aims to evaluate the safety and efficacy of precision genetic therapy for patients with Ataxia-telangiectasia (A-T), a rare neurodegenerative disease caused by mutations in the ATM gene."

The registry establishes the precision-therapy trial scope and intent.

{ }

Source YAML

click to show

name: Ataxia-telangiectasia
creation_date: '2026-03-15T23:04:29Z'
category: Mendelian
synonyms:
- Louis-Bar syndrome
- A-T
description: >-
  Ataxia-telangiectasia (A-T) is a rare autosomal recessive multisystem
  disorder caused by biallelic pathogenic variants in ATM. Deficient ATM
  kinase signaling impairs the response to DNA double-strand breaks and other
  cellular stresses, producing progressive neurologic disease, variable
  immunodeficiency and pulmonary disease, cellular radiosensitivity, and a
  high risk of malignancy. The phenotype is a continuum from childhood-onset
  classic A-T, usually associated with absent ATM kinase activity, to
  later-onset variant A-T, often associated with residual activity. The
  mechanisms connecting ATM loss to selective neurodegeneration,
  telangiectasia, and elevated alpha-fetoprotein remain incompletely resolved.
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: Classic ataxia-telangiectasia
  description: >-
    The severe end of the ATM-related spectrum. Progressive cerebellar ataxia
    begins in early childhood and is followed by extrapyramidal involvement,
    sensorimotor neuropathy, variable combined immunodeficiency, pulmonary
    disease, and early malignancy risk. ATM kinase activity is usually absent
    or extremely low, but clinical severity should not be inferred from variant
    class alone.
  genes:
  - preferred_term: ATM
    term:
      id: hgnc:795
      label: ATM
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK26468/
    reference_title: Ataxia-Telangiectasia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      childhood onset of progressive
      neurologic manifestations (initially cerebellar ataxia, followed
      typically by extrapyramidal involvement and peripheral sensorimotor
      neuropathy), immunodeficiency (variably associated with abnormalities of
      humoral immunity, cellular immunity, or combined immune deficiency),
      pulmonary disease (resulting from recurrent infections, immune
      deficiency, aspiration, interstitial lung disease, and neurologic
      abnormalities), and increased risk of malignancy.
    explanation: >-
      The current GeneReviews revision defines the principal manifestations of
      classic A-T without treating every feature as universal.
  - reference: PMID:22213089
    reference_title: "Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients without ATM kinase activity showed the classical phenotype.
    explanation: >-
      A human genotype-phenotype cohort links absent kinase activity to classic
      disease while leaving room for individual variability.
- name: Variant ataxia-telangiectasia
  description: >-
    The milder end of the ATM-related spectrum, commonly associated with
    residual ATM kinase activity. Onset and neurologic progression are later or
    slower; dystonia, tremor, or axonal neuropathy may dominate and cerebellar
    ataxia can be absent. Immune and pulmonary manifestations are generally
    less prominent, but malignancy risk remains increased and may present in
    adulthood.
  genes:
  - preferred_term: ATM
    term:
      id: hgnc:795
      label: ATM
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK26468/
    reference_title: Ataxia-Telangiectasia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      While cerebellar ataxia can be absent, extrapyramidal movement disorders are common
      (typically dystonia and dystonic tremor) and most individuals have
      manifestations of axonal sensorimotor polyneuropathy.
    explanation: >-
      GeneReviews defines variant A-T as part of the same ATM-related continuum
      and describes its distinguishing neurologic pattern.
  - reference: PMID:22213089
    reference_title: "Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Residual kinase activity correlated with a milder and essentially
      different neurological phenotype, absence of telangiectasia, normal
      endocrine and pulmonary function, normal immunoglobulins, significantly
      lower X-ray hypersensitivity in lymphocytes, and extended lifespan.
    explanation: >-
      Human data associate residual kinase activity with a milder phenotype;
      this is a correlation rather than an absolute genotype rule.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    A-T results from biallelic pathogenic ATM variants. When both parents are
    heterozygous, each pregnancy has a 25% probability of an affected child, a
    50% probability of a heterozygous child, and a 25% probability of a child
    who inherited neither familial variant.
  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. 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: >-
      The human case report's background directly states both autosomal
      recessive inheritance and the biallelic ATM requirement.
prevalence:
- population: Global live births
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_low: 1.0
  rate_high: 2.5
  notes: >-
    The frequently cited worldwide birth-prevalence estimate is one in 40,000
    to one in 100,000, equivalent to 1.0-2.5 per 100,000 live births. Founder
    populations can have higher local frequencies, and ascertainment is
    incomplete.
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    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: >-
      The clinical review supplies the standard worldwide range, normalized
      here to cases per 100,000 live births.
progression:
- phase: Classic A-T - early childhood onset
  subtype: Classic ataxia-telangiectasia
  age_range: Infancy to early childhood
  notes: >-
    Postural instability and progressive ataxia usually become apparent when a
    child begins sitting or walking; telangiectasia can emerge later, so its
    absence early does not exclude A-T.
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Neurological symptoms most often first appear in early childhood when
      children begin to sit or walk.
    explanation: The review places typical neurologic onset in early childhood.
- phase: Classic A-T - progressive neurologic disability
  subtype: Classic ataxia-telangiectasia
  age_range: School age through adolescence
  notes: >-
    Gait, eye-movement, speech, extrapyramidal, and peripheral nerve
    abnormalities progress. Many affected children require a wheelchair around
    the beginning of the second decade; dysphagia commonly emerges during that
    decade.
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Around the beginning of their second decade children with classic A-T
      start using a wheelchair in the community setting [4].
    explanation: >-
      This gives a representative functional milestone for classic A-T, not an
      invariant deadline.
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      Dysphagia is common in A-T and typically appears
      during the second decade of life because of the neuro-
    explanation: >-
      The clinical review describes dysphagia as a later neurologic
      complication.
- phase: Classic A-T - later multisystem morbidity
  subtype: Classic ataxia-telangiectasia
  age_range: Childhood through adulthood
  notes: >-
    Cancer, chronic lung disease, and infection drive premature mortality.
    Improved supportive care has extended survival, so adult pulmonary,
    metabolic, hepatic, and solid-tumor complications are increasingly
    encountered.
  evidence:
  - reference: PMID:21665257
    reference_title: Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract
      infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently
      associated with mortality.
    explanation: >-
      A 240-patient cohort identifies cancer and respiratory infection as major
      mortality determinants.
- phase: Variant A-T - slower and later course
  subtype: Variant ataxia-telangiectasia
  age_range: Childhood to adulthood
  notes: >-
    Neurologic decline is generally slower and life expectancy longer than in
    classic A-T. Immunodeficiency and pulmonary disease may be absent, whereas
    cancer risk persists and malignancy can precede recognition of A-T.
  evidence:
  - reference: PMID:22213089
    reference_title: "Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, the phenotypic manifestations in A-T show a continuous spectrum
      from severe classical childhood-onset A-T to a relatively mild adult-onset
      disorder, depending on the presence of ATM protein and kinase activity.
    explanation: >-
      This cohort supports a continuum rather than sharply separated diseases.
clinical_burden:
  burden_level: HIGH
  rationale: >-
    Classic A-T causes progressive loss of motor independence together with
    recurrent infection, chronic pulmonary morbidity, feeding impairment,
    marked treatment-related radiosensitivity, and early cancer risk. Variant
    A-T can be substantially milder, but no part of the spectrum is free of
    malignancy risk or the need for lifelong multidisciplinary surveillance.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK26468/
    reference_title: Ataxia-Telangiectasia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Life expectancy is significantly reduced due to cancer, pulmonary
      disease, and infections.
    explanation: >-
      GeneReviews directly identifies the major life-limiting complications of
      classic A-T.
pathophysiology:
- name: ATM kinase deficiency and defective DNA-damage signaling
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Biallelic pathogenic ATM variants reduce or abolish ATM kinase function.
    ATM normally coordinates signaling after DNA double-strand breaks and
    oxidative or genotoxic stress, including checkpoint activation and repair.
    Its deficiency is the established proximal lesion; downstream tissue
    selectivity is not explained by the DNA-damage response alone.
  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
    modifier: DECREASED
  biological_processes:
  - preferred_term: DNA damage response
    term:
      id: GO:0006974
      label: DNA damage response
    modifier: DECREASED
  - preferred_term: double-strand break repair
    term:
      id: GO:0006302
      label: double-strand break repair
    modifier: DECREASED
  - preferred_term: cell cycle checkpoint signaling
    term:
      id: GO:0000075
      label: cell cycle checkpoint signaling
    modifier: DECREASED
  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: >-
      The review defines the central DNA-damage and stress-signaling role of ATM.
  - 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 molecular diagnoses link biallelic ATM loss of function to classic
      A-T.
  downstream:
  - target: Genomic instability, radiosensitivity, and cancer predisposition
    description: >-
      Failure of ATM-dependent double-strand-break signaling impairs repair and
      checkpoints, permitting chromosomal instability and hypersensitivity to
      DNA-break-inducing radiation.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27884168
      reference_title: "Ataxia telangiectasia: a review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In the absence of the ATM protein, the signaling network that responds
        to DNA DSBs is defective, and responses to other types of genotoxic
        stress are reduced to various degrees.
      explanation: >-
        This directly links ATM absence to defective double-strand-break
        signaling and genotoxic-stress responses.
  - target: Adaptive immune-development and antibody-production defects
    description: >-
      ATM-dependent repair is required when lymphocyte antigen-receptor and
      class-switch recombination create programmed DNA breaks.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired repair of programmed DNA breaks during V(D)J and class-switch recombination.
    evidence:
    - reference: PMID:27884168
      reference_title: "Ataxia telangiectasia: a review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        As lymphocytes develop they undergo gene rearrange-
        ments to generate clonal diversity and class switch
        recombination, processes which generate DSBs. In the
        absence of ATM, the effective repair of these DSBs is
        difficult [111 – 113].
      explanation: >-
        The review supplies the known recombination intermediate between ATM
        loss and adaptive immune dysfunction.
  - target: Progressive cerebellar and peripheral neurodegeneration
    description: >-
      ATM deficiency ultimately causes selective progressive neurologic injury,
      but the necessary molecular intermediates are not established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27884168
      reference_title: "Ataxia telangiectasia: a review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The cause of this cell death is not known, though many hypotheses have
        been proposed (reviewed in [11]).
      explanation: >-
        The review explicitly supports modeling this causal bridge as indirect
        with unknown intermediates.
  - target: Oxidative stress and microglial neuroinflammation
    description: >-
      ATM loss is associated with oxidative stress and an inflammatory
      microglial state, a plausible contributor to neuronal injury rather than
      an established sole cause.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:38159274
      reference_title: ATM-deficiency-induced microglial activation promotes neurodegeneration in ataxia-telangiectasia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        While ATM loss of function has long been identified as the genetic cause
        of ataxia-telangiectasia (A-T), how it leads to selective and
        progressive degeneration of cerebellar Purkinje and granule neurons
        remains unclear.
      explanation: >-
        The study motivates investigation of microglia while explicitly
        acknowledging that the ATM-to-neuron bridge remains unclear.
  - target: Telangiectasia
    description: >-
      Telangiectasia belongs to the ATM-deficiency phenotype, but the causal
      tissue pathway is unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27884168
      reference_title: "Ataxia telangiectasia: a review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        sia or dilated, enlarged blood vessels in the absence of
        the ATM protein is not yet known.
      explanation: >-
        This explicitly justifies an unknown-intermediate edge rather than a
        speculative vascular mechanism.
  - target: Elevated circulating alpha-fetoprotein concentration
    description: >-
      Persistent AFP elevation is strongly associated with A-T after early
      childhood, although its mechanistic link to ATM loss is unknown.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27884168
      reference_title: "Ataxia telangiectasia: a review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Why the majority of individuals with A-T have elevated levels of AFP
        remains unknown.
      explanation: >-
        The review supports the phenotype association while preventing a false
        causal mechanism from being asserted.
- name: Genomic instability, radiosensitivity, and cancer predisposition
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Defective double-strand-break repair and checkpoint signaling permit
    spontaneous and induced chromosome breaks and rearrangements. Ionizing
    radiation and radiomimetic agents therefore cause disproportionate
    cytotoxicity. Genomic instability also promotes malignancy, especially
    lymphoid cancers in children; solid tumors comprise a larger share in
    adults and in variant A-T.
  biological_processes:
  - preferred_term: double-strand break repair
    term:
      id: GO:0006302
      label: double-strand break repair
    modifier: DECREASED
  - preferred_term: cell cycle checkpoint signaling
    term:
      id: GO:0000075
      label: cell cycle checkpoint signaling
    modifier: DECREASED
  - preferred_term: chromosome organization
    term:
      id: GO:0051276
      label: chromosome organization
    modifier: ABNORMAL
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The result is genomic instability which can lead to the development of
      cancers [6].
    explanation: >-
      This directly links the defective ATM stress response to genomic
      instability and cancer.
  - 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: >-
      A large contemporary cohort quantifies the cancer burden and spectrum.
  downstream:
  - target: Increased sensitivity to ionizing radiation
    description: >-
      Ionizing radiation produces DNA lesions whose repair is severely impaired
      without ATM.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27884168
      reference_title: "Ataxia telangiectasia: a review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Irradiation (e.g. radiation therapy for cancers) and radiomimetic
        compounds (e.g. those used in cancer chemotherapy protocols) induce DSBs
        and other DNA lesions whose repair is severely impaired when ATM is
        absent.
      explanation: >-
        This identifies impaired repair of radiation-induced lesions as the
        direct basis of radiosensitivity.
  - target: Neoplasm
    description: >-
      Accumulated genomic instability permits malignant transformation across
      hematologic and solid tissues.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Persistence and clonal selection of cells with oncogenic chromosome damage.
    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: >-
        The cohort demonstrates primary cancers across both hematologic and
        solid-organ compartments.
  - target: Lymphoma
    description: >-
      Aberrant repair during lymphocyte antigen-receptor rearrangement can
      generate oncogenic translocations, contributing to the characteristic
      lymphoma risk.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Oncogenic chromosome rearrangements in developing lymphocytes.
    evidence:
    - reference: PMID:27884168
      reference_title: "Ataxia telangiectasia: a review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        tions can occur as a result of aberrant DSB repair,
        making these cells prone to the development of cancer
        (lymphomas and leukemias)
      explanation: >-
        The review provides the known lymphocyte-translocation intermediate.
- name: Oxidative stress and microglial neuroinflammation
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Patient cerebellar single-nucleus data show inflammatory microglial states,
    while patient-derived co-cultures show microglia-associated neuronal
    cytotoxicity. Oxidative stress and microglial signaling are therefore
    represented as a provisional contributing pathway, not as the unique or
    sufficient explanation for A-T neurodegeneration.
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar 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
  evidence:
  - 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 identify microglial inflammation.
  - 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: >-
      Patient-derived co-culture provides functional evidence while remaining
      an in-vitro model.
  downstream:
  - target: Progressive cerebellar and peripheral neurodegeneration
    description: >-
      Neurotoxic microglial signaling may contribute to Purkinje and granule
      neuron injury within the broader, multifactorial neurologic mechanism.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Neurotoxic cytokine signaling from activated microglia to cerebellar neurons.
    evidence:
    - 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 transcriptomic ordering supports, but does not by itself prove,
        a contributing microglia-to-neuron pathway.
- name: Progressive cerebellar and peripheral neurodegeneration
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Progressive loss and dysfunction of cerebellar Purkinje and granule neurons
    produce cerebellar atrophy and ataxia. Eye-movement, speech, swallowing,
    extrapyramidal, and peripheral nerve abnormalities broaden with age. The
    clinical neurodegenerative process is established, but no single upstream
    molecular hypothesis fully explains its selectivity.
  cell_types:
  - preferred_term: Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  biological_processes:
  - preferred_term: neuron apoptotic process
    term:
      id: GO:0051402
      label: neuron apoptotic process
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      guably some of the most devastating symptoms of A-T
      are a result of progressive cerebellar degeneration, char-
      acterized by the gradual loss and/or aberrant location of
      PCs and, to a lesser extent, the gradual loss of granule
      cells [122, 123].
    explanation: >-
      The review establishes the anatomic substrate while separately
      acknowledging uncertainty about its cause.
  downstream:
  - target: Progressive cerebellar ataxia
    description: Cerebellar neuronal dysfunction and loss produce progressive ataxia.
    causal_link_type: DIRECT
    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: >-
        The mouse-study article's clinical background links cerebellar neuronal
        degeneration to progressive ataxia; its source is classified by the
        study's Atm-deficient mouse evidence.
    - reference: PMID:27884168
      reference_title: "Ataxia telangiectasia: a review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Ataxia telangiectasia (A-T) is an autosomal recessive disorder primarily
        characterized by cerebellar degeneration, telangiectasia,
        immunodeficiency, cancer susceptibility and radiation sensitivity.
      explanation: The human clinical review independently establishes cerebellar degeneration as a primary A-T feature.
  - target: Cerebellar atrophy
    description: Progressive loss of cerebellar neurons produces macroscopic atrophy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27884168
      reference_title: "Ataxia telangiectasia: a review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Cerebellar atrophy detected by MRI
      explanation: The review lists MRI-detected cerebellar atrophy as a characteristic abnormality.
  - target: Oculomotor apraxia
    description: Progressive neurologic dysfunction impairs voluntary saccadic initiation and coordination.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    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: >-
        Human clinical evidence places ocular apraxia within the
        neurodegenerative phenotype; the exact circuit intermediate is not
        asserted.
  - target: Dysarthria
    description: Progressive motor-system dysfunction impairs speech production.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired coordination of bulbar and respiratory speech musculature.
    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: The clinical review identifies dysarthria as a common neurologic manifestation.
  - target: Abnormal extrapyramidal motor function
    description: Basal-ganglia and connected motor-system involvement produces dystonia, tremor, chorea, or parkinsonism.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK26468/
      reference_title: Ataxia-Telangiectasia - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        While cerebellar ataxia can be absent, extrapyramidal movement disorders
        are common (typically dystonia and dystonic tremor)
      explanation: >-
        GeneReviews supports the motor phenotype, especially in variant A-T,
        without resolving the affected circuit.
  - target: Peripheral axonal neuropathy
    description: Progressive peripheral nerve involvement produces an axonal sensorimotor neuropathy.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK26468/
      reference_title: Ataxia-Telangiectasia - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        most individuals have manifestations of axonal sensorimotor
        polyneuropathy.
      explanation: GeneReviews supports peripheral axonal neuropathy in variant A-T.
  - target: Dysphagia
    description: Progressive bulbar incoordination compromises safe swallowing.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired coordination of oral and pharyngeal movement.
    evidence:
    - reference: PMID:27884168
      reference_title: "Ataxia telangiectasia: a review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Dysphagia is common in A-T and typically appears
        during the second decade of life because of the neuro-
        logical changes which interfere with the coordination of
        mouth and pharynx movements necessary for safe and
        efficient swallowing [64].
      explanation: The review provides the neurologic intermediate for dysphagia.
  - target: Multifactorial chronic pulmonary injury
    description: Bulbar weakness and dysphagia contribute to aspiration and impaired airway clearance.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Aspiration and weak or discoordinated cough.
    evidence:
    - reference: PMID:27884168
      reference_title: "Ataxia telangiectasia: a review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Pulmonary disease In addition to the neurological deficits
        which contribute to bulbar weakness and the immunodefi-
        ciencies which can contribute to susceptibility to chronic
        sinopulmonary infections, several other factors may influ-
        ence the development of pulmonary disease in A-T.
      explanation: >-
        The review identifies neurologic and immune intermediates but also
        emphasizes the multifactorial nature of lung disease.
- name: Adaptive immune-development and antibody-production defects
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Impaired repair of programmed DNA breaks during lymphocyte development
    reduces lymphocyte number and repertoire diversity and can disrupt
    immunoglobulin class switching. Immune findings vary from selective
    antibody deficiency to combined immunodeficiency; variant A-T often has
    normal immune function.
  cell_types:
  - preferred_term: B cell
    term:
      id: CL:0000236
      label: B cell
  - preferred_term: T cell
    term:
      id: CL:0000084
      label: T cell
  biological_processes:
  - preferred_term: V(D)J recombination
    term:
      id: GO:0033151
      label: V(D)J recombination
    modifier: DECREASED
  - preferred_term: immunoglobulin isotype switching
    term:
      id: GO:0045190
      label: isotype switching
    modifier: DECREASED
  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: >-
      A multicenter human cohort demonstrates both humoral deficiency and
      lymphopenia.
  - 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: >-
      Functional testing identifies defective class-switch recombination in the
      hyper-IgM subset and also demonstrates that it is not universal.
  downstream:
  - target: Combined immunodeficiency
    description: Variable B- and T-cell abnormalities can produce combined immune deficiency.
    causal_link_type: DIRECT
    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: Human immune profiling supports combined immunodeficiency as a core manifestation.
  - target: Decreased circulating IgA concentration
    description: Defective B-cell maturation and class switching commonly reduce serum IgA.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired immunoglobulin class-switch recombination and B-cell repertoire formation.
    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%.
      explanation: The cohort quantifies IgA deficiency in A-T.
  - target: Recurrent respiratory infections
    description: Antibody deficiency and lymphopenia increase susceptibility to recurrent airway infection.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired mucosal antibody and cellular immune defense.
    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: >-
        The clinical association supports immune deficiency as one contributor
        to recurrent airway infection.
  - target: Multifactorial chronic pulmonary injury
    description: Recurrent infection and impaired immune clearance contribute to cumulative lung injury.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Repeated sinopulmonary infection and inflammation.
    evidence:
    - reference: PMID:27884168
      reference_title: "Ataxia telangiectasia: a review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Pulmonary disease In addition to the neurological deficits
        which contribute to bulbar weakness and the immunodefi-
        ciencies which can contribute to susceptibility to chronic
        sinopulmonary infections, several other factors may influ-
        ence the development of pulmonary disease in A-T.
      explanation: >-
        The evidence supports immune contribution while cautioning that lung
        disease is multifactorial.
- name: Multifactorial chronic pulmonary injury
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Pulmonary disease reflects interacting recurrent infection,
    immunodeficiency, aspiration and weak cough from neurologic disease,
    interstitial injury, and tissue stress. Patient-derived airway epithelial
    cells also show oxidative and inflammasome abnormalities, but that
    cell-intrinsic pathway is not assumed to explain all clinical lung disease.
  cell_types:
  - preferred_term: respiratory tract 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: innate immune response
    term:
      id: GO:0045087
      label: innate immune response
  - preferred_term: response to oxidative stress
    term:
      id: GO:0006979
      label: response to oxidative stress
  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: >-
      Patient-derived epithelial experiments support one local contributor;
      PARTIAL prevents generalizing the cell model to the entire pulmonary
      phenotype.
  downstream:
  - target: Recurrent respiratory infections
    description: Impaired immune defense and airway integrity permit repeated sinopulmonary infection.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Impaired systemic and epithelial host defense.
    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: The article summarizes the recurrent-infection pulmonary phenotype.
  - target: Bronchiectasis
    description: Repeated airway infection and injury can produce permanent bronchial dilation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Recurrent infection, inflammation, secretion retention, and airway remodeling.
    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: >-
        The clinical background identifies bronchiectasis as a major pulmonary
        complication.
phenotypes:
- name: Progressive cerebellar ataxia
  category: Neurologic
  frequency: VERY_FREQUENT
  notes: >-
    Usually the presenting manifestation of classic A-T in early childhood;
    ataxia can be mild, delayed, or absent in variant A-T.
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  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: Progressive cerebellar ataxia is a defining classic A-T manifestation.
- name: Cerebellar atrophy
  category: Neurologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Cerebellar atrophy detected by MRI
    explanation: The review lists MRI-detected cerebellar atrophy among characteristic abnormalities.
- name: Oculomotor apraxia
  category: Neurologic
  frequency: VERY_FREQUENT
  notes: >-
    Common and progressive in classic A-T, but it can appear later or remain
    absent in variant A-T.
  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: The human genetic report lists ocular apraxia as a characteristic feature.
- 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: The clinical review identifies dysarthria as a common neurologic feature.
- name: Abnormal extrapyramidal motor function
  category: Neurologic
  frequency: FREQUENT
  notes: >-
    Dystonia, dystonic tremor, chorea, myoclonus, or parkinsonism can occur;
    extrapyramidal disease may dominate variant A-T.
  phenotype_term:
    preferred_term: Abnormality of extrapyramidal motor function
    term:
      id: HP:0002071
      label: Abnormality of extrapyramidal motor function
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK26468/
    reference_title: Ataxia-Telangiectasia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      While cerebellar ataxia can be absent, extrapyramidal movement disorders
      are common (typically dystonia and dystonic tremor)
    explanation: GeneReviews emphasizes extrapyramidal manifestations in variant A-T.
- 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: The clinical review identifies axonal neuropathy as a common neurologic feature.
- name: Dysphagia
  category: Neurologic
  frequency: FREQUENT
  notes: >-
    Often emerges during the second decade in classic A-T and contributes to
    aspiration, prolonged meals, and inadequate nutrition.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      Dysphagia is common in A-T and typically appears
      during the second decade of life because of the neuro-
      logical changes which interfere with the coordination of
      mouth and pharynx movements necessary for safe and
      efficient swallowing [64].
    explanation: The review describes the timing and neurologic basis of dysphagia.
- name: Telangiectasia
  category: Vascular
  frequency: FREQUENT
  notes: >-
    Ocular and cutaneous telangiectasias often appear after neurologic onset;
    they may be absent in variant A-T.
  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: The review supports oculocutaneous telangiectasia as a characteristic feature.
- name: Combined immunodeficiency
  category: Immunologic
  frequency: FREQUENT
  notes: >-
    Immune abnormalities are heterogeneous and can involve humoral, cellular,
    or combined immunity; immune function is often normal in variant A-T.
  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: Human immune profiling supports combined immunodeficiency in A-T.
- name: Decreased circulating IgA concentration
  category: Immunologic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Decreased circulating IgA concentration
    term:
      id: HP:0002720
      label: Decreased circulating IgA concentration
  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: The multicenter cohort reports IgA deficiency in 60.8% of patients.
  - 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: IgA deficiency also stratifies prognosis in classic A-T cohorts.
- name: Recurrent respiratory infections
  category: Respiratory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: 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: >-
      Most patients presented recurrent airway infections, which was
      significantly associated with IgA deficiency.
    explanation: The cohort supports recurrent airway infection and its association with IgA deficiency.
- 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: The clinical background identifies bronchiectasis as an important complication.
- name: Elevated circulating alpha-fetoprotein concentration
  category: Laboratory
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: >-
    Serum AFP is usually elevated and slowly rises after age two in classic
    A-T; normal AFP does not exclude variant A-T.
  phenotype_term:
    preferred_term: Elevated circulating alpha-fetoprotein concentration
    term:
      id: HP:0006254
      label: Elevated circulating alpha-fetoprotein concentration
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      mately 95% of people with A-T have elevated serum
      AFP levels after the age of two, and measured levels of
      AFP appear to increase slowly over time [137].
    explanation: The review provides the approximate frequency and age qualification.
  reports_on:
  - target: ATM kinase deficiency and defective DNA-damage signaling
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Persistent AFP elevation after early childhood is a useful diagnostic
      clue, but it is not a direct assay of ATM function and can be normal in
      variant A-T.
- name: Increased sensitivity to ionizing radiation
  category: Cellular
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Increased sensitivity to ionizing radiation
    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: The review supports radiosensitivity as a core A-T feature.
- name: Neoplasm
  category: Oncologic
  frequency: OCCASIONAL
  notes: >-
    A contemporary cohort found primary cancer in 16.5% of 508 individuals.
    Hematologic malignancies predominate in childhood; solid tumors become more
    prominent in adults and in variant A-T. This frequency is cohort- and
    age-dependent rather than lifetime penetrance.
  phenotype_term:
    preferred_term: Neoplasm
    term:
      id: HP:0002664
      label: Neoplasm
  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: The contemporary cohort quantifies cancer prevalence and spectrum.
- name: Lymphoma
  category: Oncologic
  frequency: OCCASIONAL
  notes: >-
    Non-Hodgkin lymphoma was the most common individual cancer in a 508-person
    cohort; OCCASIONAL reflects its patient-level frequency, not its share among
    cancers.
  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: The cohort identifies non-Hodgkin lymphoma as the most frequent cancer type.
- name: Insulin-resistant diabetes mellitus
  category: Metabolic
  frequency: OCCASIONAL
  notes: >-
    Insulin-resistant diabetes affects a minority of people with A-T and
    typically appears late in disease progression.
  phenotype_term:
    preferred_term: Insulin-resistant diabetes mellitus
    term:
      id: HP:0000831
      label: Insulin-resistant diabetes mellitus
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A minority of patients with A-T suffer from insulin resistant diabetes which typically appears as a late event during disease progression."
    explanation: >-
      The review directly supports an OCCASIONAL frequency band and late onset.
- name: Chromosome breakage
  category: Laboratory
  diagnostic: true
  notes: >-
    Spontaneous and radiation-induced chromosome breaks and rearrangements in
    cultured lymphocytes and fibroblasts are a diagnostic laboratory finding in
    A-T. The source does not quantify frequency or specify 7;14 translocations,
    so those stronger claims are intentionally omitted.
  phenotype_term:
    preferred_term: Chromosome breakage
    term:
      id: HP:0040012
      label: Chromosome breakage
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Spontaneous and X-ray induced chromosomal breaks and rearrangements in cultured lymphocytes and fibroblasts"
    explanation: >-
      The finding appears in the review's table of laboratory abnormalities in A-T.
genetic:
- name: ATM
  gene_term:
    preferred_term: ATM
    term:
      id: hgnc:795
      label: ATM
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  inheritance:
  - name: Autosomal recessive inheritance
    inheritance_term:
      preferred_term: autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  notes: >-
    Biallelic germline pathogenic variants in ATM cause A-T. Truncating alleles
    are commonly associated with absent kinase activity and classic disease;
    hypomorphic missense or splice variants can preserve activity and produce
    variant A-T. These are probabilistic genotype-phenotype correlations:
    residual kinase activity is more informative than variant class alone, and
    cancer risk remains increased across the spectrum.
  evidence:
  - 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 autosomal-recessive ATM-A-T relationship as definitive.
  - 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 molecular diagnosis supports biallelic ATM loss of function.
  - reference: PMID:22213089
    reference_title: "Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The genotypes of severely affected patients generally included truncating
      mutations resulting in total absence of ATM kinase activity, while
      patients with milder phenotypes harbored at least one missense or splice
      site mutation resulting in expression of ATM with some kinase activity.
    explanation: >-
      The genotype-phenotype cohort supports, but does not make absolute, the
      relationship between residual kinase activity and milder disease.
treatments:
- name: Multidisciplinary rehabilitation
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: >-
    Physical, occupational, and speech-language therapy, together with
    rehabilitation medicine, are supportive care. They aim to preserve safe
    mobility, communication, participation, and independence but have not been
    shown to stop neurodegeneration.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  - preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  - preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK26468/
    reference_title: Ataxia-Telangiectasia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Supportive care to improve quality of life, maximize function, and reduce
      complications ideally involves multidisciplinary care
    explanation: >-
      Current GeneReviews recommends multidisciplinary supportive care rather
      than claiming a disease-modifying rehabilitation effect.
  - 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: >-
      A single-child case report provides low-certainty evidence of functional
      benefit and is therefore marked PARTIAL.
- name: Immunology-guided infection prevention and immunoglobulin replacement
  action_category: THERAPEUTIC
  therapeutic_modality: PROTEIN_REPLACEMENT
  description: >-
    Vaccination, antimicrobial prophylaxis, and intravenous or subcutaneous
    immunoglobulin are individualized according to immunoglobulin levels,
    vaccine responses, lymphocyte status, and infection history. Live rubella
    vaccine should be avoided in severe immunodeficiency; management should be
    directed by an immunodeficiency specialist.
  treatment_term:
    preferred_term: immunoglobulin infusion therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_phenotypes:
  - preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  - preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  target_mechanisms:
  - target: Adaptive immune-development and antibody-production defects
    treatment_effect: BYPASSES
    description: >-
      Replacement immunoglobulin supplies antibody function without correcting
      the underlying ATM-dependent lymphocyte-development defect.
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      The need for additional im-
      munizations (especially with pneumococcal and influenza
      vaccines), antibiotics to provide prophylaxis from infec-
      tions, and/or gamma globulin therapy should be deter-
      mined by an expert in the field of immunodeficiency or
      infectious diseases.
    explanation: >-
      The review recommends individualized specialist-directed preventive and
      replacement therapy.
- name: Airway clearance and pulmonary care
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: >-
    Pulmonary follow-up addresses secretion retention, infection, weak cough,
    aspiration, and restrictive or interstitial disease. Manual chest therapy,
    oscillating devices, or a chest physiotherapy vest can be used when
    secretions are increased, with cough-assist support when needed.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  - preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  target_mechanisms:
  - target: Multifactorial chronic pulmonary injury
    treatment_effect: MODULATES
    description: Airway-clearance techniques reduce retained secretions and secondary airway injury.
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      Children and adults with increased bronchial secre-
      tions may benefit from routine chest therapy using the
      manual method, and a cappella device or a chest physio-
      therapy vest.
    explanation: The review supports airway-clearance therapy when secretions are increased.
- name: Swallowing and nutritional support
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  description: >-
    Speech-language and nutrition teams adapt food texture, meal support, and
    caloric intake. Gastrostomy is considered when oral intake cannot sustain
    growth or weight, aspiration is problematic, or meals are excessively long
    and stressful.
  treatment_term:
    preferred_term: nutritional support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  target_phenotypes:
  - preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      A gastrostomy tube (G-tube or feeding tube) is recom-
      mended when any of the following occur: a child cannot
      eat enough to grow or a person of any age cannot eat
      enough to maintain weight; aspiration is problematic;
      mealtimes are stressful or too long, interfering with
      other activities [161].
    explanation: >-
      The review states clinical thresholds for escalation to gastrostomy rather
      than recommending it universally.
- name: Malignancy surveillance
  action_category: SCREENING
  description: >-
    Lifelong clinical and laboratory surveillance is required because cancer
    can occur in childhood or adulthood. Evaluation is symptom- and
    age-directed, and imaging choices should minimize ionizing radiation.
  treatment_term:
    preferred_term: surveillance for malignancies
    term:
      id: NCIT:C15406
      label: Cancer Screening
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK26468/
    reference_title: Ataxia-Telangiectasia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Eval for clinical manifestations of malignancy (e.g., lymphadenopathy)
    explanation: >-
      GeneReviews includes malignancy assessment in recommended evaluation and
      surveillance; the record does not imply a validated universal imaging
      protocol.
- name: Avoidance of ionizing radiation and radiotherapy
  description: >-
    Diagnostic x-rays and CT should be limited to medically necessary
    situations and non-ionizing alternatives used when suitable. Therapeutic
    radiation is contraindicated in affected individuals because severe
    radiosensitivity can cause major complications. This restriction does not
    automatically apply to heterozygous relatives.
  treatment_term:
    preferred_term: therapeutic procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_phenotypes:
  - preferred_term: Increased sensitivity to ionizing radiation
    term:
      id: HP:0011133
      label: Increased sensitivity to ionizing radiation
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK26468/
    reference_title: Ataxia-Telangiectasia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Ionizing radiation (x-ray and gamma ray) is contraindicated, due to
      increased sensitivity
    explanation: Current GeneReviews explicitly advises avoidance in affected individuals.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK26468/
    reference_title: Ataxia-Telangiectasia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Radiation therapy is contraindicated because increased radiosensitivity
      may lead to very severe complications
    explanation: GeneReviews separately identifies therapeutic radiation as contraindicated.
- name: ATM-activity-adapted treatment of hematologic malignancy
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  description: >-
    Cancer therapy requires an A-T-experienced oncology team and avoidance of
    standard radiotherapy. A 2024 international cohort suggests de-escalated
    leukemia or lymphoma therapy when ATM kinase activity is absent and
    near-standard regimens when residual activity is present; this is
    risk-adapted evidence, not a universal protocol.
  treatment_term:
    preferred_term: therapeutic procedure
    term:
      id: NCIT:C49236
      label: Therapeutic Procedure
  target_phenotypes:
  - preferred_term: Neoplasm
    term:
      id: HP:0002664
      label: Neoplasm
  - preferred_term: Lymphoma
    term:
      id: HP:0002665
      label: Lymphoma
  evidence:
  - 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: >-
      The authors propose kinase-activity-stratified therapy; PARTIAL preserves
      the observational and non-protocol nature of the recommendation.
- name: Genetic counseling
  action_category: COUNSELING_INFORMATIONAL
  description: >-
    Counseling covers autosomal recessive recurrence risk, testing of relatives
    for familial ATM variants, reproductive options, and the distinct cancer
    implications of heterozygosity.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK26468/
    reference_title: Ataxia-Telangiectasia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: including discussion of potential risks to offspring and reproductive options
    explanation: GeneReviews explicitly includes offspring risk and reproductive options in counseling.
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      Genetic counseling: Genetic counseling can help family members of a patient with A-T understand when genetic
      testing for A-T is feasible, and how the test results should be interpreted.
    explanation: The clinical review supports family counseling about the availability and interpretation of testing.
- name: Intra-erythrocyte dexamethasone sodium phosphate (EryDex)
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    EryDex is an investigational erythrocyte-delivered corticosteroid for
    neurologic symptoms. The published ATTeST phase 3 trial did not meet its
    primary efficacy endpoint overall, although safety was acceptable and an
    age-defined subgroup signal was explored. The separate NEAT phase 3 trial
    (NCT06193200) is completed; no disease-modifying efficacy should be inferred
    until results are available.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  target_mechanisms:
  - target: Progressive cerebellar and peripheral neurodegeneration
    treatment_effect: MODULATES
    description: The clinical program tests symptomatic neurologic modulation rather than proven ATM restoration.
  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: SUPPORT
    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: >-
      The phase 3 result supports continued investigation but not established
      efficacy.
- name: Triheptanoin
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  description: >-
    Triheptanoin is investigational anaplerotic therapy studied in a 31-person
    phase 2a/b dose-escalation trial. Respiratory epithelial-cell death and
    selected neurologic, speech, and swallowing measures improved, but 38% of
    participants had gastrointestinal adverse events and dosing was capped.
    These early outcomes do not establish routine use.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  - preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:40616902
    reference_title: "Phase 2a/b randomised placebo-controlled dose-escalation trial of triheptanoin for ataxia-telangiectasia: treating mitochondrial dysfunction with anaplerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Adverse events including abdominal pain, nausea, vomiting, and diarrhoea,
      requiring dose capping at 20%, were observed in 12 (38%) participants.
    explanation: >-
      The phase 2 trial documents tolerability limitations; efficacy remains
      preliminary.
- name: Hematopoietic stem cell transplantation
  action_category: THERAPEUTIC
  therapeutic_modality: CELL_THERAPY
  description: >-
    Allogeneic HSCT can reconstitute hematopoietic immunity in selected
    individuals, but experience is limited to single cases and small series,
    neurologic outcomes are divergent, and transplant conditioning is hazardous
    in a radiosensitive DNA-repair disorder. It remains investigational rather
    than standard preventive therapy.
  treatment_term:
    preferred_term: hematopoietic stem cell transplantation
    term:
      id: NCIT:C15431
      label: Hematopoietic Cell Transplantation
  target_phenotypes:
  - preferred_term: Combined immunodeficiency
    term:
      id: HP:0005387
      label: Combined immunodeficiency
  target_mechanisms:
  - target: Adaptive immune-development and antibody-production defects
    treatment_effect: RESTORES
    description: Donor hematopoiesis can restore lymphocyte and antibody function but not ATM in neural tissue.
  evidence:
  - reference: PMID:30420857
    reference_title: Pre-emptive Allogeneic Hematopoietic Stem Cell Transplantation in Ataxia Telangiectasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our manuscript provides a proof-of-concept of alloHSCT as an individual
      pre-emptive treatment strategy from which some A-T patients might benefit.
    explanation: >-
      The publication itself frames the evidence as individual proof of concept,
      so routine use is not supported.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK26468/
    reference_title: Ataxia-Telangiectasia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      in A-T has been conducted in single cases and small case series, with
      divergent results regarding effect on neurologic functioning
    explanation: Current GeneReviews emphasizes the small evidence base and divergent neurologic outcomes.
- name: Atipeksen for ATM c.7865C>T
  action_category: THERAPEUTIC
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  aso_details:
    aso_mechanism: SPLICE_MODULATION_EXON_INCLUSION
    target_gene:
      preferred_term: ATM
      term:
        id: hgnc:795
        label: ATM
    target_transcript: ATM pre-mRNA carrying the c.7865C>T-created aberrant splice donor
    target_exon: 64-nucleotide segment lost through c.7865C>T-driven aberrant splicing
    aso_chemistry: TWO_PRIME_O_METHOXYETHYL
  description: >-
    Atipeksen is an investigational intrathecal antisense oligonucleotide
    designed for individuals carrying the recurrent ATM c.7865C>T variant. The
    first phase 1/2 study is recruiting with an estimated August 2026 start; the
    intervention is mutation-specific and has no established clinical efficacy.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  target_mechanisms:
  - target: ATM kinase deficiency and defective DNA-damage signaling
    treatment_effect: RESTORES
    description: The mutation-targeted program is intended to restore ATM function in the eligible genotype.
  evidence:
  - reference: PMID:37438524
    reference_title: A framework for individualized splice-switching oligonucleotide therapy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Several of these ASOs were effective in restoring normal splicing on
      allele-specific RT–PCR in patient fibroblasts (Supplementary Table 14),
      with two designs (AT007 and AT008) showing the most promise.
    explanation: >-
      Patient-fibroblast experiments directly support atipeksen/AT008 as a
      splice-restoring ASO for this ATM variant.
  - reference: clinicaltrials:NCT07215416
    reference_title: A Phase 1/2 Study of Antisense Oligonucleotide Therapy for Treatment of Ataxia-Telangiectasia
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: >-
      The registry documents the intended mutation-specific mechanism and trial
      plan, not demonstrated clinical benefit.
clinical_trials:
- name: NCT06193200
  phase: PHASE_III
  status: COMPLETED
  description: >-
    NEAT was an international randomized, double-blind, placebo-controlled phase
    3 trial of intravenous EryDex every 28 days for neurologic symptoms.
  target_phenotypes:
  - preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  notes: >-
    ClinicalTrials.gov status reviewed 2026-07-20: COMPLETED; actual enrollment
    105, actual start 2024-06-24, actual completion 2025-12-17, last update
    posted 2026-04-30. No outcome result is asserted here.
  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
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is an international, multi-center, randomized, prospective,
      double-blind, placebo-controlled, Phase 3 study, designed to assess the
      effect of EryDex
    explanation: The registry defines the intervention, design, phase, and neurologic target.
- name: NCT06673056
  phase: PHASE_III
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Randomized, double-blind, placebo-controlled crossover phase 3 study of
    N-acetyl-L-leucine (IB1001) in participants age four and older with
    confirmed A-T.
  target_phenotypes:
  - preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  notes: >-
    ClinicalTrials.gov status reviewed 2026-07-20: ACTIVE_NOT_RECRUITING;
    estimated enrollment 60, actual start 2025-03-18, estimated completion
    2028-06-01, last update posted 2025-07-03.
  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
    evidence_source: HUMAN_CLINICAL
    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: The current registry summary defines the study population, design, and objectives.
- name: NCT04870866
  phase: PHASE_II
  status: ACTIVE_NOT_RECRUITING
  description: >-
    Open-label proof-of-concept phase 2 study of nicotinamide riboside
    supplementation in children, focused on neurologic symptoms and exploratory
    biomarkers.
  target_phenotypes:
  - preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  notes: >-
    ClinicalTrials.gov status reviewed 2026-07-20: ACTIVE_NOT_RECRUITING; actual
    enrollment 13, actual start 2019-06-05, estimated completion 2027-06-16,
    last update posted 2022-08-17.
  evidence:
  - reference: clinicaltrials:NCT04870866
    reference_title: NAD Supplementation to Prevent Progressive Neurological Disease in Ataxia Telangiectasia
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: The registry supports the pediatric NR intervention and neurologic focus.
- name: NCT07215416
  phase: PHASE_I
  status: RECRUITING
  description: >-
    Phase 1/2 first-in-human study of intrathecal atipeksen, a
    mutation-targeted antisense oligonucleotide for A-T caused by the recurrent
    ATM c.7865C>T variant.
  target_phenotypes:
  - preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  notes: >-
    ClinicalTrials.gov status reviewed 2026-07-20: RECRUITING; estimated
    enrollment 10, estimated start 2026-08, estimated completion 2036-12, last
    update posted 2026-05-28. PHASE_I is used in the structured slot because the
    schema has no combined phase I/II value; the description preserves phase
    1/2.
  evidence:
  - reference: clinicaltrials:NCT07215416
    reference_title: A Phase 1/2 Study of Antisense Oligonucleotide Therapy for Treatment of Ataxia-Telangiectasia
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This project aims to evaluate the safety and efficacy of precision genetic
      therapy for patients with Ataxia-telangiectasia (A-T), a rare
      neurodegenerative disease caused by mutations in the ATM gene.
    explanation: The registry establishes the precision-therapy trial scope and intent.
diagnosis:
- name: Molecular confirmation of biallelic ATM pathogenic variants
  description: >-
    Diagnosis is established in a person with suggestive findings by identifying
    biallelic pathogenic variants in ATM. Sequence analysis should be
    complemented by deletion/duplication analysis when needed.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: Biallelic pathogenic or likely pathogenic ATM variants establish the molecular diagnosis.
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      A diagnosis
      of A-T can be confirmed by the finding of an absence or deficiency of the ATM
      protein or its kinase activity in cultured cell lines, and/or identification of
      the pathological mutations in the ATM gene.
    explanation: The clinical review identifies ATM mutation detection as a confirmatory diagnostic route.
  - 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: |-
      radiosensitivity and cancer predisposition. 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: The human genetic report supports the biallelic ATM requirement.
- name: Clinical and laboratory evaluation for suspected A-T
  description: >-
    Progressive ataxia and abnormal eye movements raise suspicion. Supporting
    clues include telangiectasia, recurrent sinopulmonary infection, elevated
    AFP after age two, immunoglobulin deficiency, and lymphopenia. No single
    supporting clue substitutes for molecular confirmation.
  results: A convergent neurologic, immunologic, and laboratory pattern supports targeted ATM testing.
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diagnosis of A-T is usually suspected by the combination of neurologic
      clinical features (ataxia, abnormal control of eye movement, and postural
      instability) with one or more of the following which may vary in their
      appearance: telangiectasia, frequent sinopulmonary infections and specific
      laboratory abnormalities (e.g. IgA deficiency, lymphopenia especially
      affecting T lymphocytes and increased alpha-fetoprotein levels).
    explanation: The review defines the clinical and laboratory suspicion pattern.
- name: ATM protein and kinase functional testing
  description: >-
    When molecular findings are incomplete or phenotype classification matters,
    specialized laboratories can assess ATM protein abundance and kinase
    activity in cultured cells. Cellular radiosensitivity and chromosome-break
    assays can support the diagnosis but are not substitutes for variant
    interpretation.
  results: Absent or deficient ATM protein or kinase activity supports A-T and helps distinguish classic from variant disease.
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A diagnosis of A-T can be confirmed by the finding of an absence or
      deficiency of the ATM protein or its kinase activity in cultured cell
      lines, and/or identification of the pathological mutations in the ATM
      gene.
    explanation: The review identifies specialized protein and kinase assays as confirmatory tests.
- name: SCID newborn-screen signal
  description: >-
    TREC-based newborn screening for severe combined immunodeficiency can detect
    lymphopenic classic A-T before neurologic manifestations, but sensitivity is
    incomplete and a positive screen requires specialist evaluation and
    molecular diagnosis.
  results: Reduced T-cell receptor excision circles can trigger evaluation for A-T among causes of neonatal lymphopenia.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK26468/
    reference_title: Ataxia-Telangiectasia - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      newborn screening (NBS) for severe combined immunodeficiency (SCID) that
      relies on the identification of reduced T-cell receptor excision circle
      (TREC) levels in blood spots most likely identifies about 50% of children
      with classic A-T
    explanation: GeneReviews quantifies the incomplete sensitivity of TREC screening for classic A-T.
differential_diagnoses:
- name: Ataxia-telangiectasia-like disorder 1
  disease_term:
    preferred_term: ataxia-telangiectasia-like disorder 1
    term:
      id: MONDO:0024557
      label: ataxia-telangiectasia-like disorder 1
  description: >-
    Biallelic MRE11 deficiency can produce progressive ataxia, oculomotor
    abnormalities, cerebellar atrophy, and cellular radiosensitivity that
    resemble A-T.
  distinguishing_features:
  - Telangiectasia, immunodeficiency, elevated AFP, and cancer predisposition are absent or less prominent than in classic A-T.
  - Molecular testing identifies biallelic MRE11 rather than ATM variants.
  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: OTHER
    snippet: >-
      Atypical presentations can be found in A-T-like disease or in Nijmegen
      breakage syndrome, caused by deficiency of mre11 or nibrin proteins,
      respectively.
    explanation: The review identifies MRE11-deficient A-T-like disease as a phenocopy.
- name: Nijmegen breakage syndrome
  disease_term:
    preferred_term: Nijmegen breakage syndrome
    term:
      id: MONDO:0009623
      label: Nijmegen breakage syndrome
  description: >-
    Biallelic NBN deficiency overlaps through immunodeficiency,
    radiosensitivity, chromosome instability, growth failure, and cancer risk.
  distinguishing_features:
  - Progressive microcephaly and characteristic facies are typical, whereas progressive cerebellar neurodegeneration is not.
  - Molecular testing identifies biallelic NBN rather than ATM variants.
  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: OTHER
    snippet: >-
      Atypical presentations can be found in A-T-like disease or in Nijmegen
      breakage syndrome, caused by deficiency of mre11 or nibrin proteins,
      respectively.
    explanation: The review identifies nibrin deficiency as the basis of this overlapping disorder.
- name: Ataxia with oculomotor apraxia type 1
  disease_term:
    preferred_term: ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia
    term:
      id: MONDO:0008842
      label: ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia
  description: >-
    Biallelic APTX disease overlaps through childhood-onset ataxia, oculomotor
    apraxia, and axonal neuropathy.
  distinguishing_features:
  - Hypoalbuminemia and hypercholesterolemia favor AOA1.
  - AFP is generally normal, and telangiectasia, immunodeficiency, radiosensitivity, and cancer predisposition are not typical.
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These include: ataxia oculomotor apraxia type 1 (AOA1), ataxia oculomotor
      apraxia type 2 (AOA2, also known as SCAR1), ataxia telangiectasia like
      disorder (ATLD) and Nijmegen breakage syndrome (NBS).
    explanation: The clinical review explicitly includes AOA1 in the A-T differential.
- name: Ataxia with oculomotor apraxia type 2
  disease_term:
    preferred_term: spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
    term:
      id: MONDO:0018996
      label: spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
  description: >-
    Biallelic SETX disease overlaps through progressive ataxia, axonal
    sensorimotor neuropathy, occasional oculomotor apraxia, and elevated AFP.
  distinguishing_features:
  - Onset is usually later than classic A-T and immunodeficiency, telangiectasia, radiosensitivity, and cancer predisposition are not typical.
  - Molecular testing identifies biallelic SETX rather than ATM variants.
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      These include: ataxia oculomotor apraxia type 1 (AOA1), ataxia oculomotor
      apraxia type 2 (AOA2, also known as SCAR1), ataxia telangiectasia like
      disorder (ATLD) and Nijmegen breakage syndrome (NBS).
    explanation: The clinical review explicitly includes AOA2 in the A-T differential.
- name: Friedreich ataxia
  disease_term:
    preferred_term: Friedreich ataxia
    term:
      id: MONDO:0100339
      label: Friedreich ataxia
  description: >-
    Biallelic FXN disease is a common recessive childhood or adolescent ataxia
    and can overlap through progressive gait and peripheral nerve dysfunction.
  distinguishing_features:
  - Telangiectasia and oculomotor apraxia are absent; AFP is normal.
  - Early areflexia, sensory proprioceptive loss, scoliosis, and cardiomyopathy favor Friedreich ataxia.
  evidence:
  - reference: PMID:27884168
    reference_title: "Ataxia telangiectasia: a review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In FRDA, ataxia typically appears between 10 and 15 years of age, and
      differs from A-T by the absence of telangiectasia and oculomotor apraxia,
      the early absence of tendon reflexes, a normal AFP , the frequent presence
      of scoliosis, and abnormal features on the EKG.
    explanation: The review provides direct distinguishing features for Friedreich ataxia.
discussions:
- discussion_id: gap_at_selective_neurodegeneration
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#ATM kinase deficiency and defective DNA-damage signaling
  - pathophysiology#Oxidative stress and microglial neuroinflammation
  - pathophysiology#Progressive cerebellar and peripheral neurodegeneration
  prompt: >-
    Which ATM-dependent failure is necessary and sufficient for selective
    Purkinje and granule neuron degeneration in human A-T, and how much is
    driven by neuronal DNA-damage responses versus oxidative, mitochondrial,
    epigenetic, or microglial pathways?
  rationale: >-
    Human cerebellar single-nucleus data and patient-derived co-cultures support
    microglial involvement, but the ATM-to-selective-neuron causal chain remains
    unresolved and multiple hypotheses may coexist. The graph therefore marks
    the microglial branch provisional and the root-to-neurodegeneration edge as
    indirect with unknown intermediates.
  evidence:
  - reference: PMID:38159274
    reference_title: ATM-deficiency-induced microglial activation promotes neurodegeneration in ataxia-telangiectasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      While ATM loss of function has long been identified as the genetic cause
      of ataxia-telangiectasia (A-T), how it leads to selective and progressive
      degeneration of cerebellar Purkinje and granule neurons remains unclear.
    explanation: The recent human study explicitly states the unresolved causal problem.
- discussion_id: gap_at_neurologic_disease_modification
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Intra-erythrocyte dexamethasone sodium phosphate (EryDex)
  - treatments#Triheptanoin
  - treatments#Atipeksen for ATM c.7865C>T
  prompt: >-
    Which intervention can produce durable, clinically meaningful slowing of
    neurologic decline across age and ATM-function strata rather than a
    short-term scale or biomarker change?
  rationale: >-
    ATTeST missed its overall primary endpoint, the triheptanoin study was small
    and dose-limited, and atipeksen is mutation-specific and just entering
    first-in-human evaluation. No therapy is yet established to arrest the
    neurodegenerative course.
  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: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although there were no safety concerns, the primary efficacy endpoint was
      not met
    explanation: The largest published phase 3 neurologic study did not establish overall efficacy.
  - reference: clinicaltrials:NCT07215416
    reference_title: A Phase 1/2 Study of Antisense Oligonucleotide Therapy for Treatment of Ataxia-Telangiectasia
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    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: The registry shows both the early trial stage and narrow genotype eligibility.
- discussion_id: gap_at_hsct_net_benefit
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - treatments#Hematopoietic stem cell transplantation
  - pathophysiology#Adaptive immune-development and antibody-production defects
  - pathophysiology#Progressive cerebellar and peripheral neurodegeneration
  prompt: >-
    Which individuals, if any, obtain a net survival benefit from pre-emptive
    allogeneic HSCT once immune reconstitution, malignancy risk, conditioning
    toxicity, and continued neurodegeneration are considered together?
  rationale: >-
    Small reports show immune reconstitution, but they cannot establish
    prevention of malignancy or neurologic benefit and conditioning is
    especially consequential in a DNA-repair disorder. HSCT is therefore
    retained as investigational, not standard preventive care.
  evidence:
  - reference: PMID:30420857
    reference_title: Pre-emptive Allogeneic Hematopoietic Stem Cell Transplantation in Ataxia Telangiectasia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      It is a matter of discussion whether pre-emptive allogeneic hematopoietic
      stem cell transplantation (alloHSCT) using a reduced intensity
      conditioning regimen would be an option to restore immune-competence and
      prevent malignancy
    explanation: The proof-of-concept report itself frames the indication as unsettled.
references:
- reference: PMID:20301790
  title: Ataxia-Telangiectasia.
  tags:
  - GeneReviews
review_notes: >-
  Comprehensive re-review completed 2026-07-20. Scope was narrowed to the
  biallelic ATM disease spectrum: classic and variant A-T remain subtypes,
  whereas MRE11-, APTX-, SETX-, PCNA-, and TDP1-related disorders are not A-T
  subtypes. Key supported phenocopies are represented as differential
  diagnoses; the differential list is intentionally not exhaustive. The causal
  graph now distinguishes established ATM/DNA-break, immune, pulmonary,
  radiosensitivity, and cancer mechanisms from provisional microglial evidence
  and explicitly unknown causal bridges. Supportive and preventive management
  is separated from investigational EryDex, triheptanoin, HSCT, and
  mutation-specific atipeksen. ClinicalTrials.gov recruitment states were
  checked on 2026-07-20. The prior broad top-level reference ledger was removed;
  the tagged GeneReviews record is retained for discoverability. Unsupported
  clinical placement of pioglitazone and alpha-ketoglutarate was also removed.
datasets:
- accession: geo:GSE282079
  title: NETSseq Reveals Inflammatory and Aging Mechanisms in Distinct Cell Types Driving Cerebellar Decline in Ataxia Telangiectasia
  description: The cellular and molecular changes driving the neurological abnormalities associated with the loss or functional deficiency of the ataxia–telangiectasia mutated (ATM) protein are not well understood. In this study, we applied our proprietary Nuclear Enriched Transcript Sort sequencing (NETSseq) platform to investigate changes in cell type composition and gene expression patterns in human cerebellar post-mortem tissue from ataxia–telangiectasia (A-T) donors and non-neurodegenerative disease control donors. Compared to single-cell technologies, NETSseq provided a more robust detection of lowly expressed and differentially expressed genes.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: BULK_RNA_SEQ
  sample_count: 318
  publication: PMID:40959764
  notes: Identified by GEO DataSets index search for Ataxia-telangiectasia (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.

📚

References & Deep Research

References

1

PMID:20301790

Ataxia-Telangiectasia.

No top-level findings curated for this source.

Deep Research

2

Falcon ▸

1. Disease Information

Edison Scientific Literature 24 citations 2026-04-25T16:50:51.075479

1. Disease Information

1.1 Concise overview

Ataxia‑telangiectasia (A‑T) is a rare, autosomal recessive, multisystem disorder caused by biallelic pathogenic variants (PVs) in ATM, characterized by progressive cerebellar neurodegeneration (ataxia), oculocutaneous telangiectasia, immunodeficiency with recurrent infections, marked radiosensitivity, and elevated cancer risk. (pereira2024ataxiatelangiectasiainlatin pages 1-6, nakano2024updateonrecommendations pages 1-2, collyer2024ataxiatelangiectasia pages 3-5)

1.2 Key identifiers and controlled vocabulary

OMIM: 208900 (pereira2024ataxiatelangiectasiainlatin pages 1-6, tiet2024exploringneurodegenerationin pages 9-16)
MeSH: Ataxia Telangiectasia (ClinicalTrials.gov condition browse) (NCT06193200 chunk 2)
ICD‑10 / ICD‑11: Not identified in retrieved sources (gap)
Orphanet (ORPHA): Not identified in retrieved sources (gap)
MONDO: Not identified in retrieved sources (gap)

1.3 Synonyms / alternative names

Louis‑Bar syndrome (NCT06193200 chunk 1)
Cerebello‑oculocutaneous telangiectasia (NCT06193200 chunk 1)

1.4 Evidence source type

The report integrates: - Aggregated disease-level resources / consensus guidance (AACR Childhood Cancer Predisposition Workshop update in Clinical Cancer Research, 2024) (nakano2024updateonrecommendations pages 1-2) - Large multi-center human cohort evidence (Latin America, n=218) (pereira2024ataxiatelangiectasiainlatin pages 1-6) - Mechanistic primary research (Cell Reports 2024 microglia study) (lai2024atmdeficiencyinducedmicroglialactivation pages 1-3) - ClinicalTrials.gov interventional trial records for real‑world implementation of investigational therapies (NCT06193200 chunk 1, NCT04870866 chunk 1, NCT06673056 chunk 1, NCT07215416 chunk 1)

Summary identifiers & diagnostic anchors

Item	Value	Source (with DOI/URL if present)	Publication year
Disease name	Ataxia-telangiectasia (A-T)	Tiet dissertation, DOI: https://doi.org/10.17863/cam.112012 (tiet2024exploringneurodegenerationin pages 9-16)	2024
OMIM identifier	OMIM 208900	Tiet dissertation, DOI: https://doi.org/10.17863/cam.112012 (tiet2024exploringneurodegenerationin pages 9-16)	2024
Common synonyms	Louis-Bar syndrome; cerebello-oculocutaneous telangiectasia	ClinicalTrials.gov NEAT trial keywords, NCT06193200: https://clinicaltrials.gov/study/NCT06193200 (NCT06193200 chunk 1)	2024
Inheritance	Autosomal recessive	Nakano et al., Clin Cancer Res, DOI: https://doi.org/10.1158/1078-0432.CCR-24-1098 (nakano2024updateonrecommendations pages 1-2)	2024
Causal gene	ATM (biallelic pathogenic variants)	Pereira et al., Immunologic Research, DOI: https://doi.org/10.1007/s12026-024-09494-5 (pereira2024ataxiatelangiectasiainlatin pages 1-6)	2024
Gene locus	ATM located at 11q22.3	Pereira et al., Immunologic Research, DOI: https://doi.org/10.1007/s12026-024-09494-5 (pereira2024ataxiatelangiectasiainlatin pages 1-6)	2024
Core molecular function	ATM is a serine/threonine kinase central to DNA double-strand break response/repair and cell-cycle checkpoint signaling	Lai et al., Cell Reports, DOI: https://doi.org/10.1016/j.celrep.2023.113622 (lai2024atmdeficiencyinducedmicroglialactivation pages 1-3)	2024
Genetic testing approach	Sequencing including deletion/duplication assessment of ATM	Nakano et al., Clin Cancer Res, DOI: https://doi.org/10.1158/1078-0432.CCR-24-1098 (nakano2024updateonrecommendations pages 1-2)	2024
Chromosome instability test	Chromosome breakage analysis; radiation-induced chromosomal breakage used diagnostically	Nakano et al., Clin Cancer Res, DOI: https://doi.org/10.1158/1078-0432.CCR-24-1098; Pereira et al., Immunologic Research, DOI: https://doi.org/10.1007/s12026-024-09494-5 (nakano2024updateonrecommendations pages 1-2, pereira2024ataxiatelangiectasiainlatin pages 1-6)	2024
Immunoblotting	Immunoblotting listed as a diagnostic laboratory method	Nakano et al., Clin Cancer Res, DOI: https://doi.org/10.1158/1078-0432.CCR-24-1098 (nakano2024updateonrecommendations pages 1-2)	2024
Alpha-fetoprotein (AFP)	Elevated AFP is a key laboratory biomarker	Nakano et al., Clin Cancer Res, DOI: https://doi.org/10.1158/1078-0432.CCR-24-1098 (nakano2024updateonrecommendations pages 1-2)	2024
Immunodeficiency profile	Lymphopenia and low immunoglobulins are characteristic; reduced TREC may be seen on newborn screening	Nakano et al., Clin Cancer Res, DOI: https://doi.org/10.1158/1078-0432.CCR-24-1098 (nakano2024updateonrecommendations pages 1-2)	2024
Common immunoglobulin abnormalities	IgA deficiency, IgG deficiency, and frequent T- and B-lymphopenia	Pereira et al., Immunologic Research, DOI: https://doi.org/10.1007/s12026-024-09494-5 (pereira2024ataxiatelangiectasiainlatin pages 1-6)	2024
Characteristic karyotype finding	Abnormal karyotype involving chromosomes 7 and 14	Nakano et al., Clin Cancer Res, DOI: https://doi.org/10.1158/1078-0432.CCR-24-1098 (nakano2024updateonrecommendations pages 1-2)	2024

Table: This table compiles core identifiers, synonyms, inheritance, ATM gene information, and the main laboratory diagnostics used for ataxia-telangiectasia. It is useful as a concise reference for disease knowledge base curation and diagnostic annotation.

2. Etiology

2.1 Disease causal factors

Genetic: A‑T is caused by biallelic PVs in ATM, which encodes a serine/threonine kinase central to the DNA damage response, particularly double‑strand break (DSB) signaling/repair and cell‑cycle checkpoints. (pereira2024ataxiatelangiectasiainlatin pages 1-6, lai2024atmdeficiencyinducedmicroglialactivation pages 1-3, nakano2024updateonrecommendations pages 1-2)

Molecular role: Upon DNA damage, ATM activation phosphorylates regulators of cell‑cycle arrest, DNA repair, and apoptosis (lai2024atmdeficiencyinducedmicroglialactivation pages 1-3). ATM also has cytoplasmic/redox and organelle functions (mitochondrial redox sensing, lysosomal trafficking, autophagy modulation), which are increasingly implicated in neurodegeneration and systemic complications. (lai2024atmdeficiencyinducedmicroglialactivation pages 1-3, amirifar2019ataxia‐telangiectasiaareview pages 6-9)

2.2 Risk factors

Genetic risk factors (causal variants): - ATM (11q22.3); biallelic PVs cause classic A‑T. (pereira2024ataxiatelangiectasiainlatin pages 1-6)

Environmental/iatrogenic risk factors (gene–environment interaction): - Ionizing radiation (clinical radiosensitivity) is a major risk due to the underlying DNA repair defect; exposure can cause toxicity and is generally avoided. (collyer2024ataxiatelangiectasia pages 3-5) - Radiomimetic chemotherapy (example noted: bleomycin) is also discouraged/avoided in A‑T due to hypersensitivity. (collyer2024ataxiatelangiectasia pages 3-5)

2.3 Protective factors

Not identified in the retrieved evidence (gap).

2.4 Gene–environment interactions

A‑T is a canonical gene–environment interaction disorder where ATM deficiency → impaired response to radiation‑induced DNA damage, motivating diagnostic radiation‑induced chromosomal breakage testing and clinical avoidance of ionizing radiation exposures when feasible. (pereira2024ataxiatelangiectasiainlatin pages 1-6, nakano2024updateonrecommendations pages 1-2, collyer2024ataxiatelangiectasia pages 3-5)

3. Phenotypes (with HPO suggestions)

3.1 Neurologic phenotypes (symptoms/signs)

Progressive cerebellar ataxia (childhood onset; progressive; major cause of disability) - Quantitative natural history proxy: classic patients often develop symptoms ~2 years and may need ambulatory assistance between ~8–12 years (reviewed trial landscape). (kuhn2023ataxiatelangiectasiaclinicaltrial pages 1-3) - Review notes many patients lose ambulation by adolescence. (collyer2024ataxiatelangiectasia pages 5-7) - HPO: HP:0001251 (Ataxia); HP:0001272 (Cerebellar atrophy)

Oculomotor abnormalities / oculomotor apraxia - HPO: HP:0000641 (Oculomotor apraxia); HP:0000612 (Oculogyration / abnormal eye movements; placeholder—use most specific term per phenotype)

Movement disorders (e.g., dystonia/chorea in some presentations) - HPO: HP:0001332 (Dystonia); HP:0002072 (Chorea)

3.2 Vascular/skin phenotype

Telangiectasia (oculocutaneous) - HPO: HP:0001083 (Telangiectasia)

3.3 Immunologic and infectious phenotypes (with frequencies)

In a 2024 multicenter Latin American cohort (n=218): - Recurrent airway infections: 66.9% (pereira2024ataxiatelangiectasiainlatin pages 1-6) - IgA deficiency: 60.8% (pereira2024ataxiatelangiectasiainlatin pages 1-6) - IgG deficiency: 28.6% (pereira2024ataxiatelangiectasiainlatin pages 1-6) - HPO: HP:0002721 (Immunodeficiency); HP:0002719 (Recurrent infections); HP:0002720 (IgA deficiency)

3.4 Pulmonary disease

Pulmonary disease is common and reported to affect ~70% in a recent pediatric neurology review; pulmonary function testing is recommended beginning around 5–6 years. (collyer2024ataxiatelangiectasia pages 3-5) - HPO: HP:0006536 (Recurrent respiratory infections); HP:0002204 (Pulmonary fibrosis—if present); HP:0002099 (Asthma—if present)

3.5 Hepatic / metabolic phenotypes (recent data)

Hepatic fibrosis / chronic liver disease - Cross‑sectional study (2023; n=25, ages 5–31) found significant hepatic fibrosis in 5/25 (20%) by non‑invasive biomarkers and elastography. (barreto2023hepaticfibrosisa pages 1-2) - HPO: HP:0001394 (Hepatic fibrosis); HP:0001397 (Hepatomegaly—if present)

3.6 Cancer predisposition

A pediatric neurology review reported malignancy risk estimates with a minimum ~10% and ceiling 25–38%, with hematologic neoplasms predominating in younger individuals; reported hematologic categories include T‑ALL and T‑PLL. (collyer2024ataxiatelangiectasia pages 3-5) - HPO: HP:0003002 (Neoplasm)

3.7 Quality‑of‑life impact

A‑T is progressive and disabling; clinical trials and biomarker reviews emphasize the need for validated outcome measures and biomarkers due to functional decline and multisystem disease burden. (kuhn2023ataxiatelangiectasiaclinicaltrial pages 1-3)

4. Genetic / Molecular Information

4.1 Causal gene

ATM (ataxia‑telangiectasia mutated), locus 11q22.3. (pereira2024ataxiatelangiectasiainlatin pages 1-6)

4.2 Pathogenic variant classes and functional consequences

The retrieved evidence supports that disease is due to biallelic ATM PVs leading to defective ATM kinase function and impaired DSB response, plus broader redox/mitochondrial/lysosomal effects. (lai2024atmdeficiencyinducedmicroglialactivation pages 1-3, nakano2024updateonrecommendations pages 1-2)

Variant‑level details (e.g., recurrent founder variants, allele frequencies in gnomAD, ACMG classifications from ClinVar) were not extracted from the retrieved corpus and remain a gap for this report.

4.3 Modifier genes

Not identified in the retrieved evidence (gap).

4.4 Epigenetic information

Not identified in the retrieved evidence (gap).

4.5 Chromosomal abnormalities

Consensus guidance lists “abnormal karyotype involving chromosomes 7 and 14” among laboratory abnormalities used in diagnostic workup for A‑T. (nakano2024updateonrecommendations pages 1-2)

5. Environmental Information

5.1 Environmental factors

The dominant environmental sensitivity is ionizing radiation exposure, due to impaired DSB repair; clinical reviews explicitly recommend avoiding ionizing radiation when possible. (collyer2024ataxiatelangiectasia pages 3-5)

5.2 Lifestyle factors

Not identified in retrieved evidence (gap).

5.3 Infectious agents

No single pathogen is causal; however, recurrent respiratory infections are common and linked to immunodeficiency. (pereira2024ataxiatelangiectasiainlatin pages 1-6)

6. Mechanism / Pathophysiology

6.1 Core pathway concepts (current understanding)

DNA double‑strand break response / cell‑cycle checkpoint: ATM is a kinase activated by DNA damage and phosphorylates key regulators of DNA repair, cell‑cycle arrest, and apoptosis. (lai2024atmdeficiencyinducedmicroglialactivation pages 1-3)
Oxidative stress and organelle dysfunction: Reviews emphasize ATM’s roles beyond nuclear DSB repair, including oxidative stress response and metabolic signaling; oxidative stress is proposed as a contributor to multisystem pathology. (amirifar2019ataxia‐telangiectasiaareview pages 6-9, barreto2023hepaticfibrosisa pages 1-2)

Suggested pathway/ontology mappings (illustrative): - GO: DNA damage response, signal transduction by p53 class mediator; double‑strand break repair; cell cycle checkpoint signaling; regulation of intrinsic apoptotic signaling pathway.

6.2 Neurodegeneration and neuroinflammation (recent development: 2024)

A 2024 Cell Reports study provides mechanistic evidence that ATM deficiency drives microglial activation that promotes neurodegeneration. Key findings include: - Enriched ATM expression in microglia and snRNA‑seq evidence of microglial inflammation in A‑T cerebellum. (lai2024atmdeficiencyinducedmicroglialactivation pages 1-3) - Temporal ordering: pseudotime analyses suggesting microglial activation precedes neuronal apoptosis‑related gene upregulation. (lai2024atmdeficiencyinducedmicroglialactivation pages 1-3) - Cell-intrinsic immune activation: iPSC‑derived A‑T microglia show activation of innate immune pathways; co‑culture with neurons increases cytotoxicity (LDH release; p<0.001). (lai2024atmdeficiencyinducedmicroglialactivation pages 10-11) - Upstream pathway: cell‑intrinsic activation includes cGAS–STING, NF‑κB, and type I interferon programs. (lai2024atmdeficiencyinducedmicroglialactivation pages 10-11)

Suggested cell type ontology mappings: - CL: microglial cell; Purkinje cell; cerebellar granule cell.

6.3 Liver/metabolic pathophysiology

A 2023 Orphanet Journal of Rare Diseases cohort emphasizes that liver disease is an emerging later complication with histopathologic correlates (NASH, cirrhosis, HCC reported in the literature) and identified 20% significant hepatic fibrosis by non‑invasive tests, associated with metabolic alterations and greater ataxia severity. (barreto2023hepaticfibrosisa pages 1-2)

7. Anatomical Structures Affected (with UBERON/GO-CC suggestions)

7.1 Organ systems

Central nervous system: cerebellum (neurodegeneration) (pereira2024ataxiatelangiectasiainlatin pages 1-6, lai2024atmdeficiencyinducedmicroglialactivation pages 1-3)
UBERON: cerebellum
Immune system: combined immunodeficiency features (lymphopenia, hypogammaglobulinemia/IgA deficiency) (pereira2024ataxiatelangiectasiainlatin pages 1-6, nakano2024updateonrecommendations pages 1-2)
UBERON: thymus; bone marrow; lymph node
Respiratory system: chronic sinopulmonary disease (~70% reported) (collyer2024ataxiatelangiectasia pages 3-5)
UBERON: lung
Liver/metabolic: hepatic fibrosis in a subset (barreto2023hepaticfibrosisa pages 1-2)
UBERON: liver

7.2 Subcellular localization (suggested)

GO cellular component: nucleus (DNA repair foci), mitochondrion (redox/mitochondrial dysfunction), lysosome (perinuclear lysosome accumulation), consistent with ATM’s described roles. (lai2024atmdeficiencyinducedmicroglialactivation pages 1-3)

8. Temporal Development (onset and progression)

8.1 Onset

In the 2024 Latin American cohort (n=218), median/mean timing was: - Symptom onset: mean 1.6 ± 1.1 years - Diagnosis: mean 5.7 ± 3.5 years (pereira2024ataxiatelangiectasiainlatin pages 1-6)

8.2 Progression

A‑T is progressive with functional decline; neurological manifestations worsen over time, and multi‑system complications (pulmonary, malignancy, metabolic/liver) accumulate, contributing to premature mortality. (collyer2024ataxiatelangiectasia pages 3-5, pereira2024ataxiatelangiectasiainlatin pages 1-6)

9. Inheritance and Population

9.1 Inheritance

Autosomal recessive, caused by biallelic ATM PVs. (nakano2024updateonrecommendations pages 1-2)

9.2 Epidemiology

Estimated prevalence range in a 2023 clinical-trial landscape review: 1/40,000–1/100,000 live births (kuhn2023ataxiatelangiectasiaclinicaltrial pages 1-3)
A 2024 dissertation summarizes a lower prevalence estimate (~1:400,000) and an estimate of ~200 UK cases (lower-authority source; thesis) (tiet2024exploringneurodegenerationin pages 9-16)

9.3 Population genetics

Carrier frequency and founder effects were not identified in the retrieved evidence (gap).

10. Diagnostics

10.1 Core diagnostic tests (consensus guidance; 2024)

The 2024 AACR workshop update lists A‑T diagnostic testing/lab abnormalities including: - Genetic testing (sequencing including deletion/duplication assessment) - Chromosome breakage analysis - Immunoblotting - Elevated alpha‑fetoprotein (AFP) - Abnormal karyotype involving chromosomes 7 and 14 - Immunodeficiency (lymphopenia, low immunoglobulin levels, reduced TREC in newborn screening) (nakano2024updateonrecommendations pages 1-2)

10.2 Practical diagnostic criteria used in a large cohort

In the Latin American cohort, diagnostic biomarkers/criteria included: progressive cerebellar ataxia plus AFP >2 SD for age, low IgA (≥2 SD below), and radiation-induced chromosomal breakage; definitive diagnosis required biallelic disabling ATM variants plus chromosome breakage or progressive ataxia. (pereira2024ataxiatelangiectasiainlatin pages 1-6)

10.3 Differential diagnosis

AT‑like disorders affecting DNA damage response/repair can mimic A‑T and should be considered (e.g., A‑T‑like disorder due to MRE11; other DDR disorders). (collyer2024ataxiatelangiectasia pages 3-5)

11. Outcome / Prognosis

11.1 Survival and mortality (recent cohort data)

In the 2024 Latin American cohort (n=218): - Mean survival: 24.2 years - Kaplan–Meier 20‑year survival: 52.6% - Higher mortality association: low IgG (HR 2.1, 95% CI 1.11–3.93); sex association reported (HR 0.52 for males in one analysis). (pereira2024ataxiatelangiectasiainlatin pages 1-6)

11.2 Major causes of death

Cancer was reported as the leading cause of death, with infections also contributing substantially. (pereira2024ataxiatelangiectasiainlatin pages 13-16)

12. Treatment

12.1 Current standard-of-care (supportive, real-world implementations)

A‑T currently lacks curative therapy; care is primarily supportive and multidisciplinary. (pereira2024ataxiatelangiectasiainlatin pages 1-6, kuhn2023ataxiatelangiectasiaclinicaltrial pages 1-3)

Implemented supportive strategies with cohort utilization data: - Antibiotic prophylaxis: 57.7% of patients (Latin American cohort) (pereira2024ataxiatelangiectasiainlatin pages 1-6) - Immunoglobulin replacement therapy (IgRT): 49.1% (pereira2024ataxiatelangiectasiainlatin pages 1-6) - Pulmonary monitoring: PFTs recommended starting ~5–6 years (collyer2024ataxiatelangiectasia pages 3-5)

MAXO suggestions (illustrative): - Immunoglobulin replacement therapy; antibiotic prophylaxis; pulmonary function testing; physical therapy/occupational therapy/speech therapy.

12.2 Investigational / emerging therapies and clinical trials

Erythrocyte-encapsulated dexamethasone (EryDex)

NEAT trial: Phase 3, randomized placebo-controlled; monthly infusions (every 28 days) (NCT06193200; first posted 2024‑01‑05; start 2024‑06‑24; completion 2025‑12‑17; status verified 2026‑01). Primary endpoint: change in RmICARS over ~6 months (baseline to Visit 9). (NCT06193200 chunk 1)

NAD+ boosting via nicotinamide ribonucleoside (NR)

Phase 2, open-label proof-of-concept in A‑T: NR 300 mg/day for 2 years; endpoints include NAD metabolome in blood, SARA/ICARS/AT‑NEST and exploratory AFP and metabolic markers (NCT04870866; first posted 2021‑05‑04; estimated primary completion 2024‑09‑03). (NCT04870866 chunk 1)

N‑acetyl‑L‑leucine (IB1001; levacetylleucine)

Phase 3 randomized placebo-controlled cross‑over study in patients age ≥4 years; primary endpoint SARA (NCT06673056; first posted 2024‑11‑04). (NCT06673056 chunk 1)

Precision genetic therapy (mutation-specific ASO)

Phase 1/2 ASO therapy (atipeksen) for recurrent ATM c.7865C>T splice variant; intrathecal dosing; endpoints include AT‑NEST and structured A‑T CGI and exploratory biomarkers including neurofilament light chain and AFP (NCT07215416; first posted 2025‑10‑10; not yet recruiting as of 2025‑10). (NCT07215416 chunk 1)

12.3 Expert analysis (trial readiness obstacles)

A 2023 Expert Opinion review emphasizes barriers to successful A‑T trials including phenotype variability, delayed diagnosis, lack of validated biomarkers/outcome measures, incomplete understanding of neurologic injury, and rarity that limits randomized trial size. (kuhn2023ataxiatelangiectasiaclinicaltrial pages 1-3)

13. Prevention

13.1 Primary/tertiary prevention

Avoid/limit ionizing radiation exposure and radiomimetic agents due to radiosensitivity. (collyer2024ataxiatelangiectasia pages 3-5)

13.2 Vaccination considerations

In the large Latin American cohort, no live-vaccine complications were reported, supporting that vaccination practices can be feasible but must be individualized to immune status. (pereira2024ataxiatelangiectasiainlatin pages 1-6)

13.3 Genetic counseling

Autosomal recessive inheritance and consensus recommendations for genetic testing imply a central role for genetic counseling and cascade testing, but specific prenatal/carrier screening protocols were not retrieved in this evidence set (gap). (nakano2024updateonrecommendations pages 1-2)

14. Other Species / Natural Disease

Naturally occurring A‑T in non‑human species was not identified in the retrieved evidence (gap).

15. Model Organisms

15.1 Key models and what they capture

ATM-null mouse models: reported limitation—do not recapitulate human cerebellar degeneration well. (lai2024atmdeficiencyinducedmicroglialactivation pages 1-3)
Human iPSC-derived microglia/neuron co-culture models: show microglia-driven inflammatory activation and neuronal cytotoxicity, enabling mechanistic dissection and candidate therapeutic testing of neuroinflammatory pathways. (lai2024atmdeficiencyinducedmicroglialactivation pages 10-11)

Direct quotes from abstracts (supporting key statements)

1) Large human cohort (2024; Immunologic Research): - “Ataxia-telangiectasia (AT) is a rare genetic disorder leading to neurological defects, telangiectasias, and immunodeficiency.” (pereira2024ataxiatelangiectasiainlatin pages 1-6) - “Median (IQR) ages at symptom onset and diagnosis were 1.0 (1.0-2.0) years, respectively.” (pereira2024ataxiatelangiectasiainlatin pages 1-6)

2) Trial landscape review (2023; Expert Opinion on Investigational Drugs): - “Ataxia telangiectasia (A-T) is a life-limiting autosomal recessive disease characterized by cerebellar degeneration, ocular telangiectasias, and sinopulmonary disease.” (kuhn2023ataxiatelangiectasiaclinicaltrial pages 1-3)

Data gaps and curation notes

MONDO / Orphanet / ICD‑10/ICD‑11 identifiers were not retrieved via the current tool evidence set and should be filled from OMIM/Orphanet/MONDO cross-references in a subsequent curation pass.
Variant-level spectrum, ClinVar assertions, allele frequencies (gnomAD), founder effects, and carrier frequency were not captured in retrieved sources.
Detailed cancer surveillance modality and schedule for A‑T beyond diagnostic recognition was not extracted (although AACR 2024 paper establishes A‑T within genomic instability disorders and diagnostic testing framework). (nakano2024updateonrecommendations pages 1-2)

References

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Ataxia-Telangiectasia: Comprehensive Disease Characterization Report

openscientist-autonomous 46 citations 2026-05-05T07:46:59.040347

Ataxia-Telangiectasia: Comprehensive Disease Characterization Report

Summary

Ataxia-telangiectasia (A-T) is an autosomal recessive, multisystem disorder caused by biallelic loss-of-function mutations in the ATM gene (chromosome 11q22.3), which encodes a 3,056-amino-acid serine/threonine protein kinase of the phosphatidylinositol 3-kinase-related kinase (PIKK) family. ATM is the master regulator of the cellular DNA double-strand break (DSB) response, and its absence disrupts DNA repair, cell cycle checkpoints, apoptosis, redox homeostasis, and mitochondrial function. The disease presents as a phenotypic continuum from severe classical childhood-onset A-T—characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, combined immunodeficiency, a 56-fold increased cancer risk, and progressive pulmonary disease—to milder adult-onset variant forms, with disease severity determined by residual ATM kinase activity.

Epidemiologically, A-T affects approximately 1 in 40,000 to 1 in 100,000 live births worldwide, with autosomal recessive inheritance and a carrier frequency of approximately 1–3% in the general population. The Kaplan-Meier 20-year survival rate is 53.4%, with cancer and respiratory tract infections independently associated with mortality. Patients with null ATM mutations experience earlier cancer onset (primarily hematologic malignancies), while those with hypomorphic mutations more often succumb to respiratory infections. There is no curative therapy, but multidisciplinary supportive care—including immunoglobulin replacement, aggressive pulmonary management, and cancer surveillance—improves quality of life. Emerging therapies including triheptanoin (targeting mitochondrial dysfunction) and intra-erythrocyte dexamethasone (sustained corticosteroid delivery) have shown promise in clinical trials.

The pathophysiology involves interconnected mechanisms of defective DSB repair, oxidative stress targeting cerebellar Purkinje cells, mitochondrial dysfunction with impaired ER-mitochondrial connectivity, neuroinflammation via the cGAS-STING pathway driven by cytosolic DNA accumulation, and impaired V(D)J/class-switch recombination leading to immunodeficiency. This report provides a comprehensive characterization across 15 disease dimensions with ontology annotations and evidence citations to support knowledge base population.

1. Disease Information

Overview

Ataxia-telangiectasia (A-T), also known as Louis-Bar syndrome, is a rare autosomal recessive neurodegenerative disorder first described in 1926 and later characterized by Madame Louis-Bar in 1941. It is classified as both a primary immunodeficiency and a genomic instability syndrome. A-T is characterized by progressive cerebellar ataxia typically manifesting in early childhood, oculocutaneous telangiectasia, variable immunodeficiency, radiosensitivity, susceptibility to malignancies, and metabolic abnormalities including insulin resistance and endocrine dysfunction. As summarized in a comprehensive review: "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. 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" (PMID: 30685876).

Key Identifiers

Database	Identifier
OMIM	#208900 (phenotype); *607585 (ATM gene)
Orphanet	ORPHA:100
ICD-10	G11.3 (Cerebellar ataxia with defective DNA repair)
ICD-11	8A03.11
MeSH	D001260
MONDO	MONDO:0008840
GARD	5862

Synonyms and Alternative Names

Ataxia-telangiectasia (A-T)
Louis-Bar syndrome
Boder-Sedgwick syndrome
ATM syndrome / ATM deficiency
Cerebello-oculocutaneous telangiectasia

Data Sources

This report is derived from aggregated disease-level resources including OMIM, Orphanet, GeneReviews, ClinVar, published cohort studies (particularly European A-T registries from France, Netherlands, Germany, and the UK), clinical trials, and primary research literature comprising 78 reviewed papers.

2. Etiology

Disease Causal Factors

A-T is a monogenic Mendelian disorder caused exclusively by biallelic pathogenic variants in the ATM gene (OMIM *607585), located on chromosome 11q22.3. ATM encodes a 3,056-amino-acid serine/threonine protein kinase belonging to the phosphatidylinositol 3-kinase-related kinase (PIKK) family. The ATM protein is the master regulator of the cellular DNA damage response (DDR), specifically activated by DNA double-strand breaks (DSBs). "ATM is a central kinase that activates an extensive network of responses to cellular stress via a signaling role. ATM is activated by DNA double strand breaks (DSBs) and by oxidative stress, subsequently phosphorylating a plethora of target proteins" (PMID: 34573351). The disease is genetic in origin with no environmental or infectious causative factors (PMID: 9735376).

Genetic Risk Factors

Causal variants: Over 600 distinct pathogenic variants reported in ATM, including truncating (nonsense, frameshift), splice-site, missense, and large genomic rearrangements (e.g., a 90-kb duplication spanning exons 17–61; PMID: 30888062)
Genotype-phenotype correlation: The definitive genotype-phenotype study of 51 patients established that "patients without ATM kinase activity showed the classical phenotype. The presence of ATM protein, correlated with slightly better immunological function. Residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan" (PMID: 22213089)
Founder mutations: Population-specific founder mutations identified in North Caucasus ethnic groups (PMID: 37851290), Kyrgyzstan (homozygous c.5932G>A; PMID: 41451872), Ashkenazi Jewish, and other populations
Consanguinity: Significantly increases risk; "the findings confirm that consanguineous unions increase the risk of developing Louis-Bar syndrome, as they elevate the likelihood of inheriting identical mutant alleles" (PMID: 41451872)
Modifier genes: The DNA damage checkpoint gene HUS1 modifies A-T severity; simultaneous ATM and HUS1 defects cause synthetic lethality in mice (PMID: 22575700)

Heterozygous Carrier Risk

ATM heterozygous carriers (~1–3% of the general population) have a moderately increased cancer risk. "ATM germline pathogenic variants (GPVs) are associated with a moderately increased risk of female breast cancer, pancreatic cancer, and prostate cancer" (PMID: 39636577). The pooled prevalence of ATM variants in breast cancer patients was 7% (95% CI: 5–8%) (PMID: 34493284).

Environmental Risk Factors

Ionizing radiation: A-T patients are exquisitely radiosensitive; exposure to therapeutic radiation can cause severe, potentially fatal toxicity. Diagnostic imaging with ionizing radiation should be avoided when possible; radiation-free techniques (US, MRI) are recommended (PMID: 36186632)
Genotoxic chemicals: Radiomimetic agents and topoisomerase inhibitors pose increased risk due to defective DSB repair

Protective Factors

Residual ATM kinase activity: The single most important modifier; even small amounts of residual kinase activity significantly ameliorate disease course (PMID: 22213089)
Antioxidants: The antioxidant CTMIO was shown to correct neurobehavioral deficits and reduce oxidative damage to Purkinje cells in Atm−/− mice, dramatically delaying thymic lymphoma onset (PMID: 16934683)
NAD+ supplementation: Boosting intracellular NAD+ alleviates senescence phenotypes and mitochondrial dysfunction in ATM-deficient cells (PMID: 33734555)

Gene-Environment Interactions

ATM heterozygotes carrying rare missense variants of uncertain significance showed increased risk of radiation-associated contralateral breast cancer (carriers with RT: RR = 2.98, 95% CI 1.31–6.80 vs. without RT: RR = 0.38, 95% CI 0.09–1.55), suggesting gene-radiation interaction (PMID: 32119081). In homozygous A-T patients, elevated Cu/Zn-SOD paradoxically exacerbated radiosensitivity and hematopoietic abnormalities, consistent with oxidative stress contributing to the phenotype (PMID: 11285218).

3. Phenotypes

Neurological Phenotypes

Phenotype	HPO Term	Onset	Frequency	Progression
Progressive cerebellar ataxia	HP:0001251	1–4 years	>95%	Progressive, wheelchair by age 10–12
Oculomotor apraxia	HP:0000657	Early childhood	~90%	Progressive
Dysarthria/slurred speech	HP:0001260	Childhood	>80%	Progressive
Choreoathetosis	HP:0001266	Variable	30–50%	Variable
Dystonia	HP:0001332	Variable	20–40%	May predominate in variant A-T (PMID: 37009283)
Peripheral neuropathy	HP:0009830	Late childhood	50–70%	Progressive
Cognitive slowing	HP:0100543	Adolescence	Variable	Progressive

Dermatological Phenotypes

Phenotype	HPO Term	Onset	Frequency
Oculocutaneous telangiectasia	HP:0000989, HP:0000565	Age 3–6 years	~80–90% classical; absent in variant
Café-au-lait spots	HP:0000957	Variable	10–30%
Cutaneous granulomas	HP:0100764	Variable	5–10%
Premature graying of hair	HP:0002216	Adolescence	Variable
Progeric skin changes	HP:0007495	Variable	Variable

Immunological Phenotypes

Phenotype	HPO Term	Onset	Frequency
IgA deficiency	HP:0004313	Congenital	60–80%
IgG subclass deficiency	HP:0004315	Congenital	50–70%
Hyper-IgM phenotype	HP:0002790	Variable	10–20%
T-cell lymphopenia	HP:0001888	Congenital	>80%
Decreased switched memory B cells	HP:0002846	Congenital	>80%
Recurrent sinopulmonary infections	HP:0002783	Early childhood	>80%

Detailed immunological analysis confirmed that "patients with AT have a broad spectrum of cellular and humoral deficiencies" (PMID: 33052516), and "immunoglobulin deficiency in AT is caused by disturbed development of class-switched memory B cells. ATM deficiency affects both germinal center reaction and choice of DNA-repair pathway in class switching" (PMID: 38280573).

Pulmonary Phenotypes

Phenotype	HPO Term	Onset	Frequency
Recurrent respiratory infections	HP:0002205	Early childhood	>80%
Bronchiectasis	HP:0002110	Childhood–adolescence	40–60%
Restrictive lung disease	HP:0002091	Progressive	>70%
Interstitial lung disease	HP:0006530	Variable	20–30%
Bronchiolitis obliterans	HP:0011946	Variable	Documented at autopsy (PMID: 9083516)

FVC declines from 67 ± 8% predicted while walking to 19 ± 6% predicted at end-stage. A sharp elevation in FEF25-75/FVC ratio was observed when FEV1 was ~45% predicted, approximately 2 years prior to death (PMID: 26033643). Lung disease in A-T "shows similarities to the lung disease seen in cystic fibrosis" (PMID: 23761391).

Oncological Phenotypes

Cancer risk is 56-fold increased overall (SIR = 56, 95% CI: 33–88) in a population-based German cohort: "Among the 160 patients with AT, we observed 19 cases of childhood cancer (15 cases of lymphoma, three cases of leukemia, and one case of medulloblastoma) versus 0.32 expected" (PMID: 34597127). Non-Hodgkin lymphoma SIR = 470 (95% CI: 225–865); Hodgkin lymphoma SIR = 215 (95% CI: 58–549). Approximately 14% of patients develop cancer by age 18.

Endocrine and Metabolic Phenotypes

Phenotype	HPO Term	Onset	Frequency
Growth failure	HP:0001510	After age 8	>60%
Insulin resistance/diabetes	HP:0000855	Adolescence	20–40%
Gonadal failure	HP:0000135	Puberty	Variable (PMID: 40270454)

Mean weight, height, and BMI Z-scores were −1.0, −1.2, and −0.4 respectively, with 35/101 children having weight Z-scores below −2. Decline was most obvious after age 8 (PMID: 27573920).

Laboratory Abnormalities

Finding	HPO Term	Frequency
Elevated alpha-fetoprotein	HP:0006254	>95%
Elevated transaminases	HP:0002910	40–60%
Chromosomal instability	HP:0003220	Universal
Radiosensitivity	HP:0200144	Universal

Quality of Life Impact

A-T profoundly impacts quality of life across multiple domains: progressive loss of ambulation (typically by age 10–12), speech deterioration, swallowing difficulty, increasing dependence for all activities of daily living, chronic respiratory symptoms, frequent infections, fatigue, and social isolation. Cancer treatment is further complicated by radiosensitivity.

4. Genetic/Molecular Information

Causal Gene

Gene: ATM (Ataxia-Telangiectasia Mutated)
HGNC ID: HGNC:795
NCBI Gene ID: 472
OMIM: *607585
Chromosomal location: 11q22.3
Gene structure: 66 exons spanning ~150 kb of genomic DNA
Protein: 3,056 amino acids, ~370 kDa

ATM belongs to the PIKK family, sharing structural features including N-terminal HEAT repeats, FAT domain, kinase domain, and C-terminal FATC domain. "A characteristic PIKK member comprises of an N-terminal HEAT domain, followed by FAT domain, a highly conserved kinase catalytic domain, and a C-terminal FATC domain" (PMID: 32114444). "The FATC domain of ATM mediates the interaction between ATM and Tip60, a histone acetyltransferase that regulates activation of ATM" (PMID: 16603769). The three-dimensional structure reveals that "the highly conserved C-terminal PIKK catalytic domain forms a central structure from which FAT and FATC domains protrude" (PMID: 15698568).

Pathogenic Variants

Variant types: Truncating (~85% in classical A-T: nonsense, frameshift), splice-site (~15%), missense (~10% overall), large deletions/duplications
Classification: >800 variants in ClinVar; majority classified as pathogenic or likely pathogenic
Novel variants: Continuously identified, including a 90-kb duplication spanning exons 17–61 detected by NGS (PMID: 30888062) and compound heterozygous mutations in diverse populations (PMID: 37009283; PMID: 41044616)
Functional consequence: Predominantly loss-of-function; null mutations abolish kinase activity (classical A-T); hypomorphic mutations retain residual activity (variant A-T)
Somatic vs. germline: A-T is caused by germline biallelic mutations. Somatic ATM mutations are frequent in various cancers; approximately 3% of lung cancers harbor biallelic ATM mutations (PMID: 38807759)
Population frequency: Carrier frequency ~1–3% (1 in 50–100). Individually rare variants but collectively common

Modifier Genes

HUS1: Modifies A-T severity; simultaneous ATM and HUS1 defects cause synthetic lethality, while partial Hus1 impairment with Atm loss produces synergistic increases in genomic instability and developmental defects (PMID: 22575700)
SOD1: Elevated Cu/Zn-SOD exacerbates the A-T phenotype, suggesting redox balance is a modifier (PMID: 11285218)

Epigenetic Information

ATM deficiency leads to impaired DNA damage-induced histone modifications, particularly γH2AX phosphorylation. ATM regulates chromatin remodeling through its interaction with the Tip60 histone acetyltransferase and through phosphorylation of KAP1/TRIM28. ATM phosphorylates SPOP at Ser119, promoting non-degradative ubiquitination of HIPK2, which then phosphorylates HP1γ to promote dissociation from H3K9me3 marks for DNA damage repair (PMID: 34133717). ATM-mediated senescence involves STING-dependent pathways and SASP (PMID: 33734555).

Chromosomal Abnormalities

Characteristic cytogenetic findings include inversions and translocations involving chromosomes 7 and 14 at TCR and immunoglobulin gene loci: inv(7)(p14q35), t(7;14)(p14;q11.2), t(14;14)(q11.2;q32). "At the cellular level, one of the most prominent features of A-T cells is chromosome rearrangement, especially that in T lymphocytes" (PMID: 34440406).

5. Environmental Information

Environmental Factors

Ionizing radiation: The most critical environmental factor. A-T patients are extremely radiosensitive; diagnostic imaging should use non-ionizing methods (US, MRI) whenever possible (PMID: 36186632)
Genotoxic chemicals: Radiomimetic agents and topoisomerase inhibitors pose increased risk

Lifestyle Factors

Nutrition: Growth failure is progressive; PEG tube feeding should be considered proactively from age 8 (PMID: 27573920)
Physical activity: Adapted exercise encouraged for respiratory and general health; limited by progressive ataxia
Respiratory care: Avoidance of respiratory irritants is critical given pulmonary vulnerability

Infectious Agents

A-T patients are susceptible to common bacterial respiratory pathogens due to immunodeficiency. In younger patients (<15 years), Staphylococcus aureus, Haemophilus influenzae, and Streptococcus pneumoniae predominate (25/27 cultured positive), while in older patients, Pseudomonas aeruginosa becomes prevalent (35/47 cultured positive). "Opportunistic infections of the lungs were not observed" (PMID: 23761391). Chronic EBV infection has been associated with more severe outcomes in hyper-IgM A-T patients (PMID: 36340711).

6. Mechanism / Pathophysiology

Molecular Pathways

ATM is the central kinase of the DSB response. Upon DSB induction, the MRN complex (MRE11-RAD50-NBS1) recognizes breaks and recruits ATM, which undergoes autophosphorylation and monomerization. Active ATM phosphorylates >1,000 downstream substrates including H2AX (γH2AX), CHK2 (Thr68), p53 (Ser15), SMC1 (Ser966), KAP1/TRIM28 (Ser824), BRCA1, and NBS1.

Key disrupted pathways: DNA damage response (GO:0006974), p53 signaling (KEGG: hsa04115), homologous recombination (KEGG: hsa03440), non-homologous end joining (KEGG: hsa03450), V(D)J recombination (GO:0033151), and cell cycle checkpoint control (GO:0000077).

Cellular Processes and Causal Chains

DNA Repair Deficiency (Upstream)

ATM-deficient neurons exhibit "defective repair of DNA double-strand breaks (DSBs) and repressed phosphorylation of ATM substrates (e.g., γH2AX, Smc1-S966, Kap1-S824, Chk2-T68, p53-S15), but normal repair of single-strand breaks" and "abnormal accumulation of topoisomerase 1-DNA covalent complexes (Top1-ccs)" (PMID: 25032865).

Oxidative Stress (Parallel/Amplifying)

"Organs which develop pathologic changes in the Atm-deficient mice are targets of oxidative damage, and cerebellar Purkinje cells are particularly affected" (PMID: 10449794). Chronic oxidative stress involves endogenous ROS overproduction, NADPH oxidase 4 (NOX4) activation, and impaired antioxidant defense (PMID: 28063379).

Mitochondrial Dysfunction (Intermediate)

"A-T cells demonstrate defective endoplasmic reticulum-mitochondrial connectivity disrupting calcium homoeostasis and mitochondrial fusion, which are corrected in vitro by the triheptanoin metabolite, heptanoate" (PMID: 40616902). Senescence phenotypes and SASP in ATM-deficient cells are mediated through STING and involve ectopic cytoplasmic DNA (PMID: 33734555).

Neuroinflammation via cGAS-STING (Downstream)

"Loss of Atm in neurons and glia leads to accumulation of cytosolic DNA, increased cytokine production and constitutive activation of microglia consistent with a neuroinflammatory phenotype. Rats lacking ATM had significant loss of motor neurons and microgliosis in the spinal cord, consistent with onset of paralysis" (PMID: 28007901).

Impaired Class-Switch Recombination (Downstream)

"Immunoglobulin deficiency in AT is caused by disturbed development of class-switched memory B cells. ATM deficiency affects both germinal center reaction and choice of DNA-repair pathway in class switching" (PMID: 38280573).

Pathophysiology Model

ATM Gene Mutation (Biallelic Loss-of-Function)
 │
 ▼
    Loss of ATM Kinase Activity
 │
    ┌────┼────────────────────┬──────────────────────────┐
    ▼    ▼                    ▼                          ▼
Defective   Impaired Redox   Impaired V(D)J    Defective Cell
DSB Repair  Regulation        & CSR             Cycle Checkpoints
    │         │                  │                    │
    ▼         ▼                  ▼                    ▼
Genomic     Oxidative         Immunodeficiency   Radiosensitivity
Instability Stress            ↓IgA, IgG, Hyper-IgM
    │         │                  │
    ▼         ▼                  ▼
Cancer     Mitochondrial     Recurrent Infections
Predisposition Dysfunction    Pulmonary Disease
    │         │                  │
    │         ▼                  ▼
    │    Cytosolic DNA       Respiratory Failure
    │    Accumulation
    │         │
    │         ▼
    │    cGAS-STING Activation
    │    Neuroinflammation
    │         │
    │         ▼
    │    Progressive Cerebellar
    │    Neurodegeneration
    └─────────┘
 │
 ▼
   Multisystem Disease

Cell Types Involved

Cell Type	CL Term	Role
Purkinje cell	CL:0000121	Primary target of cerebellar neurodegeneration
Microglial cell	CL:0000129	Constitutive activation drives neuroinflammation
T lymphocyte	CL:0000084	Impaired development, V(D)J recombination defects
B lymphocyte	CL:0000236	Defective class-switch recombination
Naive B cell	CL:0000788	Decreased numbers
Class-switched memory B cell	CL:0000972	Severely reduced
Motor neuron	CL:0000100	Loss documented in ATM-deficient rats
Respiratory epithelial cell	CL:0002368	Increased cell death
Endothelial cell	CL:0000115	Telangiectasia formation

GO Terms for Key Processes

GO:0006302 — Double-strand break repair
GO:0006974 — Cellular response to DNA damage stimulus
GO:0000723 — Telomere maintenance
GO:0007050 — Cell cycle arrest
GO:0006915 — Apoptotic process
GO:0006955 — Immune response
GO:0033151 — V(D)J recombination
GO:0045087 — Innate immune response (cGAS-STING)
GO:0006979 — Response to oxidative stress
GO:0000077 — DNA damage checkpoint signaling

Metabolic Changes

A-T patients exhibit insulin resistance and glucose intolerance. Mitochondrial dysfunction leads to altered energy metabolism. Chronic DNA damage activates PARP, depleting NAD+ stores (PMID: 33734555). Triheptanoin provides heptanoate to bypass ER-mitochondrial connectivity disruption through anaplerosis (PMID: 40616902).

Biochemical Abnormalities

Elevated serum AFP (>95% of patients; mechanism not fully understood)
Absent or reduced ATM protein (Western blot) and kinase activity
Deficient γH2AX foci formation after radiation
Radioresistant DNA synthesis (absent intra-S phase checkpoint)
Elevated liver transaminases (40–60%)

7. Anatomical Structures Affected

Organ Level

Organ/System	UBERON Term	Involvement	Details
Cerebellum	UBERON:0002037	Primary	Progressive atrophy, Purkinje/granule cell loss
Thymus	UBERON:0002370	Primary	Hypoplasia, impaired T cell production
Lungs	UBERON:0002048	Primary	Bronchiectasis, fibrosis, infections
Liver	UBERON:0002107	Secondary	Steatosis, granulomatous disease, elevated AFP
Skin/Conjunctiva	UBERON:0001811	Primary	Telangiectasia, granulomas
Bone marrow	UBERON:0002371	Primary	Impaired lymphopoiesis
Gonads	UBERON:0000991	Primary	Gonadal dysgenesis/failure
Spinal cord	UBERON:0002240	Secondary	Motor neuron loss (documented in rat model)

Subcellular Level

Compartment	GO CC Term	Role
Nucleus	GO:0005634	DSB sensing and repair; γH2AX foci
Mitochondria	GO:0005739	Dysfunction, ROS overproduction
Cytoplasm	GO:0005737	Cytosolic DNA accumulation → cGAS-STING
Endoplasmic reticulum	GO:0005783	Impaired ER-mitochondrial connectivity
Chromatin	GO:0000785	Defective H2AX phosphorylation, KAP1 regulation

Localization

Neurological and vascular manifestations are bilateral and symmetric: cerebellar atrophy (UBERON:0002129), conjunctival telangiectasia (UBERON:0001811), and bronchial disease (UBERON:0001555) all affect both sides.

8. Temporal Development

Onset

Typical age: 1–4 years for gait ataxia (insidious onset)
Variant A-T: Later onset (adolescence to adulthood); dystonia may be initial symptom (PMID: 37009283)

Progression

Stage	Age (Classical)	Key Features
Early	1–5 years	Gait ataxia, frequent falls, early infections
Intermediate	5–12 years	Wheelchair dependence, telangiectasia, speech deterioration
Advanced	12–20 years	Severe dysarthria, dysphagia, progressive lung disease
End-stage	>20 years	Respiratory failure, severe disability, high cancer risk

Progression rate: Relentlessly progressive for neurological features; respiratory decline accelerates in adolescence
Disease course: Progressive, chronic, lifelong; no remissions
Historical median survival: ~19–25 years for classical A-T

Critical Periods

Age 8 years: Growth decline accelerates; proactive nutritional intervention recommended (PMID: 27573920)
Adolescence: Cancer risk peaks; pulmonary function rapidly declines
FVC ~45% predicted: Sharp elevation in FEF25-75/FVC ratio signals imminent respiratory decompensation, approximately 2 years prior to death (PMID: 26033643)

9. Inheritance and Population

Epidemiology

Measure	Value
Prevalence	1:40,000–1:100,000 live births
Carrier frequency	~1–3% (~1 in 50–100)

Inheritance

Pattern: Autosomal recessive (AR)
Penetrance: Complete for biallelic null mutations; variable for hypomorphic alleles
Expressivity: Variable; correlates with residual ATM kinase activity
Genetic anticipation: Not observed (not a repeat expansion disorder)
Consanguinity: Important factor, particularly in Central Asian and Middle Eastern communities (PMID: 41451872)

Founder Effects

Population-specific founder mutations documented in: - North Caucasus ethnic groups (BRCA1/ATM; PMID: 37851290) - Kyrgyz population (c.5932G>A; PMID: 41451872) - Ashkenazi Jewish, Amish/Mennonite, Japanese, and other populations

Population Demographics

Sex ratio: Approximately 1:1 (autosomal recessive, no sex predilection)
Ethnic distribution: All ethnicities affected; higher in consanguineous populations
Geographic distribution: Worldwide; registries in Europe, North America, and other regions

10. Diagnostics

Clinical Tests

Test	Finding	Utility
Serum AFP	Elevated (>10 ng/mL, often >50)	>95% sensitive screening test
Immunoglobulins	Low IgA, IgG subclasses; variable IgM	Immune function assessment
Lymphocyte subsets	T cell lymphopenia, ↓naive/memory B cells	Immune profiling (PMID: 33052516)
ATM protein (Western blot)	Absent or reduced	Diagnostic confirmation
Radiosensitivity assay	Increased sensitivity	Functional confirmation
Brain MRI	Cerebellar atrophy	Non-ionizing; progressive finding
Lung US/MRI	Bronchiectasis, consolidations	Preferred over CT (PMID: 36186632)
Spirometry	Progressive restrictive/obstructive pattern	Monitoring (PMID: 26033643)
Karyotype	7;14 translocations	Diagnostic support

Genetic Testing

The recommended approach is: 1. Clinical suspicion based on progressive ataxia + elevated AFP ± immunodeficiency 2. ATM gene sequencing (Sanger or NGS) as confirmatory test 3. MLPA or array CGH for large deletions/duplications 4. WES/WGS for atypical presentations

"Next-generation sequencing (NGS) revealed two novel heterozygous mutations in the ATM gene... demonstrating the utility of targeted NGS in the detection of copy number variation" (PMID: 30888062).

Differential Diagnosis

Condition	Distinguishing Features
Ataxia-telangiectasia-like disorder (ATLD)	MRE11 mutations; similar but milder; no telangiectasia
Nijmegen breakage syndrome (NBS)	NBS1/NBN mutations; microcephaly; no ataxia
Ataxia with oculomotor apraxia types 1/2	No telangiectasia or immunodeficiency; AOA2 has elevated AFP
Friedreich ataxia	FXN GAA expansion; cardiomyopathy; sensory neuropathy
Cerebral palsy	Non-progressive; may initially mimic early A-T

Screening

Newborn screening: Not standard; TREC-based SCID screening may incidentally identify severe cases
Carrier screening: ATM included in expanded carrier screening panels
Prenatal testing: Available for families with known mutations (CVS, amniocentesis)
PGD: Available for carrier couples

11. Outcome/Prognosis

Survival and Mortality

The French cohort of 240 A-T patients demonstrated: "the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954. Life expectancy was lower among patients with mutations in ATM that caused total loss of expression or function of the gene product (null mutations) compared with that seen in patients with hypomorphic mutations because of earlier onset of cancer (mainly hematologic malignancies). Cancer (hazard ratio, 2.7; 95% CI, 1.6-4.5) and respiratory tract infections (hazard ratio, 2.3; 95% CI, 1.4-3.8) were independently associated with mortality" (PMID: 21665257).

The Dutch cohort confirmed: "classical AT patients had a shorter survival than variant patients (HR 5.9, 95%CI 2.0-17.7), especially once a malignancy was diagnosed (HR 2.5, 95%CI 1.1-5.5, compared to classical AT patients without malignancy)" (PMID: 28126470).

Genotype-Stratified Mortality

Cause of Death	Overall HR	Null Mutations HR	Hypomorphic Mutations HR
Cancer	2.7 (95% CI 1.6–4.5)	5.8 (95% CI 2.9–11.6)	—
Respiratory infections	2.3 (95% CI 1.4–3.8)	—	4.1 (95% CI 1.8–9.1)

Prognostic Factors

Factor	Impact
ATM genotype (null vs. hypomorphic)	Most important prognostic factor
Residual ATM kinase activity	Higher activity → milder disease, longer survival
Hyper-IgM phenotype	Significantly worsens prognosis (PMID: 28126470)
Baseline FVC	Lower FVC predicts worse respiratory outcome
Cancer development	Once diagnosed, survival significantly shortened

12. Treatment

Pharmacotherapy

There is currently no curative pharmacotherapy for A-T. Treatment is primarily supportive and multidisciplinary.

Treatment	MAXO Term	Purpose
Immunoglobulin replacement (IVIG/SCIG)	MAXO:0001298	Immunodeficiency management
Prophylactic antibiotics	MAXO:0000747	Infection prevention
Bronchodilators	MAXO:0000165	Airway management
Corticosteroids	MAXO:0000609	Neurological improvement (transient)

Advanced Therapeutics

Triheptanoin (Phase 2a/b trial, 31 participants): An anaplerotic medium-chain triglyceride targeting mitochondrial dysfunction. Results showed significant improvements at maximum dose vs. placebo (PMID: 40616902): - Nasal cell death: MD = −9.7% (95% CI −16.0, −4.6) - SARA kinetic function: MD = −5.8 (95% CI −10.4, −1.2) - ICARS gait: MD = −0.5 (95% CI −0.9, −0.1) - Speech intelligibility: MD = −12.8 (95% CI −21.2, −4.3) - Swallowing safety: MD = −0.9 (95% CI −1.6, −0.3)

Intra-erythrocyte dexamethasone (ATTeST Phase 3 trial): "Corticosteroids can improve neurological functioning in patients with the disorder but adrenal suppression and symptom recurrence on treatment discontinuation has limited their use, prompting the development of novel steroid delivery systems." Multicentre, randomised, double-blind, placebo-controlled at 22 centres in 12 countries (PMID: 39152028).

Antioxidant therapy: CTMIO "dramatically delays the onset of thymic lymphomas in Atm(−/−) mice" and "corrects neurobehavioral deficits in these mice and reduces oxidative damage to Purkinje cells" (PMID: 16934683).

NAD+ supplementation: Ameliorates senescence and mitochondrial dysfunction in ATM-deficient cells through STING pathway modulation (PMID: 33734555).

Cell therapy: Adipose-derived MSCs explored for pulmonary tissue regeneration (PMID: 32531978).

Supportive and Rehabilitative Care

Intervention	MAXO Term	Details
Physical therapy	MAXO:0000487	Maintain mobility, prevent contractures
Occupational therapy	MAXO:0000536	Adaptive equipment, independence
Speech therapy	MAXO:0000930	Dysphagia management, communication aids
PEG tube feeding	MAXO:0001001	From age 8 proactively (PMID: 27573920)
Chest physiotherapy	MAXO:0000168	Airway clearance

Cancer Treatment Considerations

Radiation therapy: Must be avoided or drastically reduced; standard doses can be fatal
Chemotherapy: Modified protocols; radiomimetic agents require dose modification
PARP inhibitors: Show synthetic lethality with ATM loss in cancer cells, relevant for somatic ATM-mutant tumors (PMID: 38807759)

13. Prevention

Primary Prevention

Genetic counseling (MAXO:0000079): Essential for families with affected children and consanguineous populations
Carrier screening: ATM included in expanded carrier screening panels
Prenatal diagnosis: CVS or amniocentesis available when familial mutations known
Preimplantation genetic diagnosis (PGD): Available for carrier couples

Secondary Prevention

Elevated AFP + ataxia → immediate ATM genetic testing; "early ATM genetic testing should be considered for those patients with predominant dystonia, despite without accompanying ataxia or telangiectasia" (PMID: 37009283)
TREC-based newborn screening: May incidentally identify severe cases
Cancer surveillance: Regular clinical assessment; avoid ionizing radiation; use US/MRI (PMID: 39264246)

Tertiary Prevention

Complication	Prevention Strategy
Respiratory infections	IVIG, prophylactic antibiotics, vaccination (inactivated only)
Nutritional failure	Proactive PEG from age 8
Cancer	Enhanced surveillance; minimize radiation
Radiation injury	Strict avoidance; medical alert identification

ATM Heterozygote Cancer Screening

"ATM GPV heterozygotes should generally be offered enhanced breast surveillance according to their personalized risk estimate and country-specific guidelines and, generally, risk-reducing mastectomy is not recommended. Prostate cancer surveillance should be considered. Pancreatic cancer surveillance should be considered based on assessment of family history" (PMID: 39636577).

14. Other Species / Natural Disease

Orthologous Genes

Species	Gene	NCBI Gene ID	Notes
Mus musculus (mouse)	Atm	11920	Knockout models available
Rattus norvegicus (rat)	Atm	300711	Superior neurological model
Danio rerio (zebrafish)	atm	403065	Developmental studies
Drosophila melanogaster	tefu	42953	ATM ortholog
Saccharomyces cerevisiae	TEL1	854225	Yeast ATM ortholog
Caenorhabditis elegans	atm-1	172394	Genetic studies

Comparative Biology

ATM function is evolutionarily ancient and conserved from yeast to humans. In S. cerevisiae, "the Tel1 kinase (ortholog of human ATM) is activated at DNA double-strand breaks (DSBs) and short telomeres" and controls "telomere maintenance, suppression of chromosomal rearrangements, activation of cell cycle checkpoints, and repair of DSBs" (PMID: 39826692). Novel phosphoproteomic analysis revealed a D/E-S/T motif unique to Tel1 signaling, providing insights into specialized ATM functions.

A-T has not been widely documented as a naturally occurring disease in companion animals. The disease is not zoonotic.

15. Model Organisms

Mouse Models (Atm−/−)

Types: Conventional knockouts (multiple alleles), conditional knockouts
Phenotype recapitulation:
✅ Thymic lymphomas (100% penetrance by ~4–6 months)
✅ Immunodeficiency (T/B cell defects, CSR impairment)
✅ Radiosensitivity, growth retardation, infertility, chromosomal instability
❌ Does NOT recapitulate progressive cerebellar degeneration (major limitation)
⚠️ Subtle neurobehavioral deficits and oxidative damage to Purkinje cells detectable (PMID: 10449794)
Antioxidant studies: CTMIO "dramatically delays the onset of thymic lymphomas" and "corrects neurobehavioral deficits" (PMID: 16934683)
Modifier studies: Hus1 impairment + Atm loss → synthetic lethality or synergistic genomic instability (PMID: 22575700); SOD1 overexpression exacerbates phenotype (PMID: 11285218)

Rat Models

Superior neurological model: "Loss of Atm in neurons and glia leads to accumulation of cytosolic DNA, increased cytokine production and constitutive activation of microglia consistent with a neuroinflammatory phenotype. Rats lacking ATM had significant loss of motor neurons and microgliosis in the spinal cord, consistent with onset of paralysis" (PMID: 28007901)
✅ Neuroinflammation, motor neuron loss, cytosolic DNA accumulation, paralysis

Cellular Models

iPSC-derived neurons: Recapitulate DSB repair defects, repressed ATM substrate phosphorylation, Top1-cc accumulation (PMID: 25032865)
Brain-derived and iPSC-derived neural stem cells: Model neurodegeneration (PMID: 23598976)
Patient fibroblasts: Show mitochondrial dysfunction, senescence, SASP (PMID: 33734555)

Yeast (S. cerevisiae)

TEL1 ortholog: Telomere maintenance, DSB signaling; novel D/E-S/T motif identified (PMID: 39826692)

Model Limitations

Model	Key Limitation
Atm−/− mouse	No cerebellar degeneration
Atm−/− rat	Spinal cord rather than cerebellar pathology
iPSC neurons	In vitro; lacks tissue context
Yeast (TEL1)	No multicellular phenotypes

Key Findings — Detailed Evidence

Finding 1: Biallelic ATM Mutations Cause A-T with Genotype-Phenotype Correlation

The ATM gene on chromosome 11q22.3 encodes a 3,056-amino-acid serine/threonine kinase that is the master regulator of the DNA double-strand break response. Biallelic loss-of-function mutations cause autosomal recessive A-T. A landmark genotype-phenotype study of 51 patients demonstrated that patients without ATM kinase activity display classical A-T, while "residual kinase activity correlated with a milder and essentially different neurological phenotype, absence of telangiectasia, normal endocrine and pulmonary function, normal immunoglobulins, significantly lower X-ray hypersensitivity in lymphocytes, and extended lifespan" (PMID: 22213089). This genotype-phenotype correlation—centered on residual ATM kinase activity—is the single most important prognostic factor and has transformed our understanding of A-T as a disease continuum rather than a single entity. Prevalence is estimated at 1:40,000–1:100,000 live births, with a cancer risk 56-fold increased (SIR = 56; PMID: 34597127).

Finding 2: Cerebellar Neurodegeneration Driven by DNA Damage and cGAS-STING Neuroinflammation

The most debilitating feature of A-T—progressive cerebellar degeneration—results from a cascade beginning with defective DSB repair and culminating in neuroinflammation. ATM-deficient neurons show "defective repair of DNA double-strand breaks (DSBs) and repressed phosphorylation of ATM substrates" and "abnormal accumulation of topoisomerase 1-DNA covalent complexes" (PMID: 25032865). Cerebellar Purkinje cells are selectively vulnerable to oxidative damage (PMID: 10449794). Unrepaired DNA leads to cytosolic DNA accumulation that activates the cGAS-STING innate immune pathway: "Loss of Atm in neurons and glia leads to accumulation of cytosolic DNA, increased cytokine production and constitutive activation of microglia" (PMID: 28007901). The nitroxide antioxidant CTMIO "corrects neurobehavioral deficits in these mice and reduces oxidative damage to Purkinje cells" (PMID: 16934683), confirming oxidative stress as a tractable therapeutic target.

Finding 3: Survival Determined by Cancer and Respiratory Infections with Genotype Stratification

In the French cohort of 240 A-T patients, "the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954." Cancer (HR 2.7, 95% CI 1.6–4.5) and respiratory tract infections (HR 2.3, 95% CI 1.4–3.8) were independently associated with mortality. For null mutations, cancer is the major risk factor (HR 5.8, 95% CI 2.9–11.6); for hypomorphic mutations, respiratory infections lead (HR 4.1, 95% CI 1.8–9.1) (PMID: 21665257). The Dutch cohort confirmed that "classical AT patients had a shorter survival than variant patients (HR 5.9, 95% CI 2.0–17.7)" (PMID: 28126470).

Finding 4: Immunodeficiency from Defective Class-Switch Recombination

The immunodeficiency in A-T reflects fundamental defects in lymphocyte development and function. "Immunoglobulin deficiency in AT is caused by disturbed development of class-switched memory B cells. ATM deficiency affects both germinal center reaction and choice of DNA-repair pathway in class switching" (PMID: 38280573). Comprehensive analysis revealed "a broad spectrum of cellular and humoral deficiencies" (PMID: 33052516). The hyper-IgM phenotype is particularly significant as a poor prognostic marker, associated with chronic EBV expansion and liver failure (PMID: 36340711).

Finding 5: Triheptanoin and Intra-Erythrocyte Dexamethasone Show Clinical Promise

Two therapeutic approaches have advanced to clinical trials. Triheptanoin showed significant improvements in a Phase 2a/b trial across multiple endpoints (nasal cell death MD = −9.7%, SARA kinetic MD = −5.8, speech intelligibility MD = −12.8), targeting mitochondrial dysfunction as "A-T cells demonstrate defective endoplasmic reticulum-mitochondrial connectivity disrupting calcium homoeostasis and mitochondrial fusion, which are corrected in vitro by the triheptanoin metabolite, heptanoate" (PMID: 40616902). The ATTeST Phase 3 trial of intra-erythrocyte dexamethasone leverages corticosteroid neurological benefits while minimizing systemic effects through encapsulated delivery (PMID: 39152028).

Evidence Base

Landmark Papers

PMID	Key Contribution
9735376	Foundational ATM gene-to-function review
22213089	Definitive genotype-phenotype correlation (n=51)
21665257	French cohort survival analysis (n=240)
28126470	Dutch cohort survival and prognostic factors
28007901	Rat model: cGAS-STING neuroinflammation
10449794	Oxidative damage targeting Purkinje cells
34597127	Population-based cancer risk (SIR=56, German registry)
38280573	Mechanism of immunoglobulin deficiency via CSR
40616902	Triheptanoin Phase 2a/b trial results
39152028	ATTeST Phase 3 trial of intra-erythrocyte dexamethasone
30685876	Comprehensive A-T clinical and molecular review
25032865	iPSC-derived A-T neuron functional defects
16934683	Antioxidant therapy in Atm−/− mice
33734555	NAD+ supplementation for mitochondrial dysfunction
39636577	ACMG guidelines for ATM heterozygote management

Evidence Types

The evidence base comprises 78 papers spanning: - Human clinical data: Cohort studies from France (n=240; PMID: 21665257), Netherlands (PMID: 28126470), Germany (n=160; PMID: 34597127), and multinational clinical trials - Model organism data: Mouse (PMID: 10449794; PMID: 16934683), rat (PMID: 28007901), yeast (PMID: 39826692) - In vitro data: iPSC-derived neurons (PMID: 25032865), patient fibroblasts (PMID: 33734555) - Clinical trials: Triheptanoin Phase 2a/b (PMID: 40616902), ATTeST Phase 3 (PMID: 39152028)

Ontology Term Summary

HPO Terms (Phenotype)

HP:0001251 (Cerebellar ataxia), HP:0000657 (Oculomotor apraxia), HP:0000989 (Telangiectasia), HP:0000565 (Conjunctival telangiectasia), HP:0002721 (Immunodeficiency), HP:0002664 (Neoplasm), HP:0006254 (Elevated AFP), HP:0200144 (Radiosensitivity), HP:0003220 (Chromosomal instability), HP:0001260 (Dysarthria), HP:0001332 (Dystonia), HP:0001266 (Choreoathetosis), HP:0009830 (Peripheral neuropathy), HP:0001888 (Lymphopenia), HP:0004313 (↓IgA), HP:0004315 (↓IgG), HP:0002790 (Hyper-IgM), HP:0002205 (Recurrent respiratory infections), HP:0002110 (Bronchiectasis), HP:0001510 (Growth delay), HP:0000855 (Insulin resistance), HP:0000135 (Hypogonadism), HP:0007495 (Premature aging)

GO Terms (Biological Process)

GO:0006302 (DSB repair), GO:0006974 (DNA damage response), GO:0000077 (DNA damage checkpoint), GO:0006915 (Apoptosis), GO:0033151 (V(D)J recombination), GO:0045087 (Innate immune response), GO:0006979 (Oxidative stress response), GO:0000723 (Telomere maintenance)

GO Terms (Cellular Component)

GO:0005634 (Nucleus), GO:0005739 (Mitochondrion), GO:0005783 (ER), GO:0005737 (Cytoplasm), GO:0000785 (Chromatin)

CL Terms (Cell Types)

CL:0000121 (Purkinje cell), CL:0000084 (T cell), CL:0000236 (B cell), CL:0000129 (Microglia), CL:0000100 (Motor neuron), CL:0000788 (Naive B cell), CL:0000972 (Class-switched memory B cell), CL:0002368 (Respiratory epithelial cell), CL:0000115 (Endothelial cell)

UBERON Terms (Anatomy)

UBERON:0002037 (Cerebellum), UBERON:0002370 (Thymus), UBERON:0002048 (Lung), UBERON:0001811 (Conjunctiva), UBERON:0002107 (Liver), UBERON:0002240 (Spinal cord), UBERON:0002371 (Bone marrow), UBERON:0000991 (Gonad)

MAXO Terms (Treatment)

MAXO:0001298 (Immunoglobulin replacement), MAXO:0000747 (Antimicrobial therapy), MAXO:0000079 (Genetic counseling), MAXO:0001001 (Gastrostomy), MAXO:0000487 (Physical therapy), MAXO:0000536 (Occupational therapy), MAXO:0000930 (Speech therapy)

MONDO Term

MONDO:0008840 (Ataxia-telangiectasia)

Limitations and Knowledge Gaps

Neurodegeneration mechanism: The precise reason why cerebellar Purkinje cells are selectively vulnerable to ATM loss remains incompletely understood. The relative contributions of DSB repair failure, oxidative stress, mitochondrial dysfunction, and neuroinflammation are still debated (PMID: 32871349).
Mouse model limitations: Atm knockout mice do not develop progressive cerebellar ataxia or Purkinje cell loss, making preclinical neurological studies challenging. The rat model is superior but still shows spinal cord rather than cerebellar pathology (PMID: 28007901; PMID: 23598976).
Stagnant prognosis: Despite decades of study, "the prognosis for these patients has not changed since 1954" (PMID: 21665257), highlighting the urgent need for disease-modifying therapies.
Limited trial data: Clinical trials are constrained by small sample sizes inherent to rare diseases (triheptanoin trial: n=31). Long-term efficacy data are lacking for all emerging therapies.
Variant A-T underdiagnosis: Atypical presentations (dystonia-predominant, adult-onset) are likely underdiagnosed; the full phenotypic spectrum of hypomorphic ATM mutations is not yet defined (PMID: 37009283).
Heterozygote cancer risk: Precise penetrance estimates for different ATM variant types and cancer types remain uncertain (PMID: 39636577).
Multi-omic characterization: Comprehensive epigenomic, proteomic, and metabolomic profiling of A-T tissues—particularly at single-cell resolution—is still limited.
Pulmonary pathogenesis: The etiology of progressive pulmonary deterioration beyond immunodeficiency is unclear; direct ATM roles in respiratory epithelium require investigation (PMID: 17524020).

Proposed Follow-up Experiments/Actions

Single-cell transcriptomics of A-T cerebellum: Profile Purkinje cells, granule cells, and microglia from A-T patient post-mortem tissue to define cell-type-specific transcriptional changes and validate the cGAS-STING neuroinflammation axis in human tissue.
STING inhibitor trials: Given demonstrated cGAS-STING involvement in neuroinflammation (PMID: 28007901), evaluate STING pathway inhibitors in the ATM-deficient rat model.
NAD+ supplementation clinical trial: Translate preclinical findings that NAD+ boosting ameliorates senescence and mitochondrial dysfunction (PMID: 33734555) into a clinical trial.
Long-term triheptanoin follow-up: Extend the Phase 2a/b trial to assess disease progression rate modification and survival benefit.
Global genotype-phenotype registry: Establish a registry linking detailed ATM genotype (including residual kinase activity) with longitudinal clinical outcomes.
Biomarker development: Develop non-invasive biomarkers (neurofilament light chain, cytokine panels, circulating cytosolic DNA) for disease monitoring and clinical trial design.
Gene therapy approaches: Investigate dual-AAV, lentiviral, or base editing strategies for ATM restoration in neural progenitors and HSCs.
ATM heterozygote prospective cohort: Establish prospective surveillance to refine cancer penetrance estimates.

Report generated: 2026-05-05 Data sources: OMIM, Orphanet, ClinVar, PubMed, and 78 reviewed publications Evidence quality: High for genetic/molecular mechanisms; moderate for clinical outcomes; emerging for therapeutic interventions

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Diagnosis

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References & Deep Research

References

Deep Research

1. Disease Information

1.1 Concise overview

1.2 Key identifiers and controlled vocabulary

1.3 Synonyms / alternative names

1.4 Evidence source type

Summary identifiers & diagnostic anchors

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes (with HPO suggestions)

3.1 Neurologic phenotypes (symptoms/signs)

3.2 Vascular/skin phenotype

3.3 Immunologic and infectious phenotypes (with frequencies)

3.4 Pulmonary disease

3.5 Hepatic / metabolic phenotypes (recent data)

3.6 Cancer predisposition

3.7 Quality‑of‑life impact

4. Genetic / Molecular Information

4.1 Causal gene

4.2 Pathogenic variant classes and functional consequences

4.3 Modifier genes

4.4 Epigenetic information

4.5 Chromosomal abnormalities

5. Environmental Information

5.1 Environmental factors

5.2 Lifestyle factors

5.3 Infectious agents

6. Mechanism / Pathophysiology

6.1 Core pathway concepts (current understanding)

6.2 Neurodegeneration and neuroinflammation (recent development: 2024)

6.3 Liver/metabolic pathophysiology

7. Anatomical Structures Affected (with UBERON/GO-CC suggestions)

7.1 Organ systems

7.2 Subcellular localization (suggested)

8. Temporal Development (onset and progression)

8.1 Onset

8.2 Progression

9. Inheritance and Population

9.1 Inheritance

9.2 Epidemiology

9.3 Population genetics

10. Diagnostics

10.1 Core diagnostic tests (consensus guidance; 2024)

10.2 Practical diagnostic criteria used in a large cohort

10.3 Differential diagnosis

11. Outcome / Prognosis

11.1 Survival and mortality (recent cohort data)

11.2 Major causes of death

12. Treatment

12.1 Current standard-of-care (supportive, real-world implementations)

12.2 Investigational / emerging therapies and clinical trials

Erythrocyte-encapsulated dexamethasone (EryDex)

NAD+ boosting via nicotinamide ribonucleoside (NR)

N‑acetyl‑L‑leucine (IB1001; levacetylleucine)

Precision genetic therapy (mutation-specific ASO)

12.3 Expert analysis (trial readiness obstacles)

13. Prevention