Arterial tortuosity syndrome is a rare autosomal recessive connective tissue disorder caused by biallelic pathogenic variants in SLC2A10. It is characterized by elongation and tortuosity of large and medium-sized arteries, with variable stenosis, aneurysm formation, respiratory, skeletal, cutaneous, and hernia-associated manifestations.
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name: Arterial Tortuosity Syndrome
creation_date: "2026-05-04T22:23:50Z"
updated_date: "2026-05-05T16:40:30Z"
description: >-
Arterial tortuosity syndrome is a rare autosomal recessive connective tissue
disorder caused by biallelic pathogenic variants in SLC2A10. It is
characterized by elongation and tortuosity of large and medium-sized arteries,
with variable stenosis, aneurysm formation, respiratory, skeletal, cutaneous,
and hernia-associated manifestations.
category: Mendelian
disease_term:
preferred_term: arterial tortuosity syndrome
term:
id: MONDO:0008818
label: arterial tortuosity syndrome
synonyms:
- ATS
- ATORS
parents:
- Vascular disorder
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
ATS is caused by biallelic SLC2A10 variants and is inherited as an
autosomal recessive disorder.
evidence:
- reference: PMID:37619836
reference_title: "Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue
disease caused by biallelic variants in the SLC2A10 gene (NG_016284.1) and characterised
by tortuosity and elongation of the aorta and medium-sized arteries.
explanation: This abstract directly states autosomal recessive inheritance and biallelic SLC2A10 causation.
pathophysiology:
- name: SLC2A10/GLUT10 loss-of-function connective tissue defect
conforms_to: "aortopathy_tgfbeta_dysregulation#Aortic Wall ECM or Contractile Apparatus Defect"
description: >-
Biallelic SLC2A10 pathogenic variants disrupt GLUT10-dependent
connective-tissue and arterial-wall homeostasis, creating the molecular
basis for downstream vessel-wall matrix abnormalities.
cell_types:
- preferred_term: vascular smooth muscle cell
term:
id: CL:0000359
label: vascular associated smooth muscle cell
biological_processes:
- preferred_term: extracellular matrix organization
modifier: ABNORMAL
term:
id: GO:0030198
label: extracellular matrix organization
evidence:
- reference: PMID:29323665
reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
PURPOSE: We delineate the clinical spectrum and describe the histology in arterial
tortuosity syndrome (ATS), a rare connective tissue disorder characterized by
tortuosity of the large and medium-sized arteries, caused by mutations in SLC2A10.
explanation: This review defines ATS as SLC2A10-associated arterial tortuosity of large and medium arteries.
downstream:
- target: Arterial-wall TGF-beta pathway upregulation
description: >-
GLUT10 deficiency is associated with upregulation of the TGF-beta pathway
in the arterial wall, the conserved aortopathy hub also seen in
Loeys-Dietz syndrome.
- target: Fragmented elastic fibers and collagen deposition
description: SLC2A10/GLUT10 loss is linked to the abnormal elastic-fiber and collagen matrix phenotype.
- name: Arterial-wall TGF-beta pathway upregulation
conforms_to: "aortopathy_tgfbeta_dysregulation#TGF-beta Signaling Dysregulation"
description: >-
GLUT10 deficiency is associated with upregulation of the TGF-beta signaling
pathway in the arterial wall, mirroring the dysregulated TGF-beta activity
seen in Loeys-Dietz syndrome and the other heritable aortopathies. (Of note,
one large series found that skin and end-stage diseased vascular tissue did
not show increased TGF-beta signaling, so the upregulation is most evident
earlier in the arterial-wall disease process.)
cell_types:
- preferred_term: vascular smooth muscle cell
term:
id: CL:0000359
label: vascular associated smooth muscle cell
biological_processes:
- preferred_term: transforming growth factor beta receptor signaling pathway
modifier: INCREASED
term:
id: GO:0007179
label: transforming growth factor beta receptor signaling pathway
evidence:
- reference: PMID:16550171
reference_title: "Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
GLUT10 deficiency is associated with upregulation of the TGFbeta pathway in the arterial wall, a finding also observed in Loeys-Dietz syndrome
explanation: >-
The gene-discovery paper establishes arterial-wall TGF-beta pathway
upregulation as the conserved aortopathy mechanism in ATS, shared with
Loeys-Dietz syndrome.
- reference: PMID:18630721
reference_title: "New insights in the pathogenesis of aortic aneurysms."
supports: SUPPORT
evidence_source: OTHER
snippet: >-
In analogy to LDS, we demonstrated an upregulation of TGFbeta in ATS.
explanation: >-
This review confirms TGF-beta upregulation in ATS by analogy to
Loeys-Dietz syndrome, supporting the conserved TGF-beta hub. Evidence
source is OTHER because this is a review synthesizing human and mouse data.
- reference: PMID:29323665
reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Skin and end-stage diseased vascular tissue do not indicate increased TGF-β signaling.
explanation: >-
Provides the important nuance that increased TGF-beta signaling is not
detectable in skin or end-stage vascular tissue, so the upregulation is
stage-dependent; included to represent the mechanism faithfully.
downstream:
- target: Fragmented elastic fibers and collagen deposition
description: >-
Dysregulated TGF-beta signaling contributes to the elastic-fiber
fragmentation and disordered collagen matrix of the arterial media.
- name: Fragmented elastic fibers and collagen deposition
conforms_to: "aortopathy_tgfbeta_dysregulation#Aortic Medial Degeneration and Wall Weakening"
description: >-
Histologic studies of skin and vascular tissue show elastic-fiber
fragmentation and increased collagen deposition, supporting a structural
vessel-wall matrix mechanism.
cell_types:
- preferred_term: vascular smooth muscle cell
term:
id: CL:0000359
label: vascular associated smooth muscle cell
biological_processes:
- preferred_term: extracellular matrix organization
modifier: ABNORMAL
term:
id: GO:0030198
label: extracellular matrix organization
evidence:
- reference: PMID:29323665
reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Skin and vascular biopsies show fragmented elastic fibers (EF) and increased
collagen deposition.
explanation: This abstract directly supports abnormal elastic-fiber and collagen matrix organization in ATS tissues.
downstream:
- target: Arterial wall structural failure and tortuosity
description: Elastic-fiber fragmentation and collagen deposition weaken arterial structure and lead to tortuosity, stenosis, and aneurysm formation.
- name: Arterial wall structural failure and tortuosity
conforms_to: "aortopathy_tgfbeta_dysregulation#Progressive Aortic Dilation and Aneurysm"
description: >-
Matrix disorganization compromises arterial-wall structure, producing
tortuosity with associated stenosis and aneurysm formation across affected
large and medium-sized arteries.
cell_types:
- preferred_term: vascular smooth muscle cell
term:
id: CL:0000359
label: vascular associated smooth muscle cell
biological_processes:
- preferred_term: extracellular matrix organization
modifier: ABNORMAL
term:
id: GO:0030198
label: extracellular matrix organization
evidence:
- reference: PMID:29323665
reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Stenoses, tortuosity, and aneurysm formation are widespread occurrences.
explanation: This supports the structural vascular consequences downstream of the histologic matrix abnormality.
downstream:
- target: Arterial tortuosity
description: Arterial-wall structural failure manifests as arterial elongation and tortuosity.
phenotypes:
- category: Cardiovascular
name: Arterial tortuosity
diagnostic: true
description: Elongation and tortuosity of the aorta and medium-sized arteries are defining vascular features.
phenotype_term:
preferred_term: Arterial tortuosity
term:
id: HP:0005116
label: Arterial tortuosity
evidence:
- reference: PMID:37619836
reference_title: "Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue
disease caused by biallelic variants in the SLC2A10 gene (NG_016284.1) and characterised
by tortuosity and elongation of the aorta and medium-sized arteries.
explanation: The defining vascular phenotype is tortuosity and elongation of the aorta and medium-sized arteries.
- category: Cardiovascular
name: Arterial stenosis
description: Stenosis can occur in affected arterial beds but appears variable across reported patients.
phenotype_term:
preferred_term: Arterial stenosis
term:
id: HP:0100545
label: Arterial stenosis
evidence:
- reference: PMID:29323665
reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Stenoses, tortuosity, and aneurysm formation are widespread occurrences.
explanation: The large review identifies stenosis as part of the widespread vascular phenotype.
- category: Cardiovascular
name: Pulmonary artery stenosis
description: Pulmonary artery stenosis is a recognized vascular manifestation within the ATS stenosis spectrum.
phenotype_term:
preferred_term: Pulmonary artery stenosis
term:
id: HP:0004415
label: Pulmonary artery stenosis
evidence:
- reference: PMID:29323665
reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
Stenoses, tortuosity, and aneurysm formation are widespread occurrences.
explanation: The abstract supports stenoses as widespread in ATS, although it does not isolate pulmonary artery stenosis in the quoted sentence.
- category: Cardiovascular
name: Aortic root aneurysm
description: Aortic root aneurysm is a severe vascular complication requiring early monitoring.
phenotype_term:
preferred_term: Aortic root aneurysm
term:
id: HP:0002616
label: Aortic root aneurysm
evidence:
- reference: PMID:29323665
reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Severe but rare vascular complications include early and aggressive aortic root
aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation.
explanation: This supports aortic root aneurysm as a severe ATS complication.
- category: Respiratory
name: Infant respiratory distress syndrome
description: Infant respiratory distress syndrome is frequently observed in ATS and should be monitored early in life.
phenotype_term:
preferred_term: Infant respiratory distress syndrome
term:
id: HP:0002098
label: Respiratory distress
evidence:
- reference: PMID:29323665
reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS)
are frequently observed.
explanation: This directly supports frequent respiratory distress syndrome in ATS.
- category: Respiratory
name: Diaphragmatic hernia
description: Diaphragmatic hernia is a recurrent nonvascular ATS feature reported in cohort review.
phenotype_term:
preferred_term: Congenital diaphragmatic hernia
term:
id: HP:0000776
label: Congenital diaphragmatic hernia
evidence:
- reference: PMID:29323665
reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Of note, diaphragmatic hernia and infant respiratory distress syndrome (IRDS)
are frequently observed.
explanation: This directly supports diaphragmatic hernia as a frequent ATS manifestation.
histopathology:
- name: Fragmented elastic fibers with increased collagen deposition
description: >-
Skin and vascular biopsies show elastic-fiber fragmentation, increased
collagen deposition, and disease-specific ultrastructural abnormalities.
evidence:
- reference: PMID:29323665
reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Skin and vascular biopsies show fragmented elastic fibers (EF) and increased
collagen deposition.
explanation: This directly supports the histopathologic matrix abnormality.
genetic:
- name: SLC2A10
association: Causative
presence: Positive
gene_term:
preferred_term: SLC2A10
term:
id: hgnc:13444
label: SLC2A10
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
notes: >-
SLC2A10 encodes GLUT10. Reported ATS variants include nonsense and missense
alleles, with biallelic pathogenic variants required for disease.
evidence:
- reference: PMID:37619836
reference_title: "Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A not previously described variant (NM_030777.4:c.899T>G (p.Leu300Trp)) was
detected in a proband; it has an allegedly deleterious effect in compound heterozygous
state with the pathogenic variant c.417T>A (p.Tyr139Ter).
explanation: This identifies a novel SLC2A10 variant in compound heterozygous state with a pathogenic allele.
- reference: CGGV:assertion_80a24753-e6d3-41cb-85ba-85a2eae3ddb6-2024-11-07T170000.000Z
reference_title: "SLC2A10 / arterial tortuosity syndrome (Definitive)"
supports: SUPPORT
evidence_source: OTHER
snippet: "SLC2A10 | HGNC:13444 | arterial tortuosity syndrome | MONDO:0008818 | AR | Definitive"
explanation: ClinGen classifies the SLC2A10-arterial tortuosity syndrome gene-disease relationship as definitive with autosomal recessive inheritance.
diagnosis:
- name: Vascular imaging surveillance
description: >-
Extensive vascular imaging is recommended after diagnosis because tortuosity,
stenosis, and aneurysm formation can involve multiple arterial beds.
diagnosis_term:
preferred_term: diagnostic imaging
results: Imaging may show arterial elongation, tortuosity, stenosis, or aneurysm.
evidence:
- reference: PMID:29323665
reference_title: "Arterial tortuosity syndrome: 40 new families and literature review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring
of the aortic root early in life, and extensive vascular imaging afterwards.
explanation: The review recommends early aortic-root monitoring and subsequent extensive vascular imaging.
treatments:
- name: Beta-adrenergic blockade
description: >-
Beta-blockers have been used clinically to reduce hemodynamic stress on the
arterial wall, although evidence remains limited and supportive.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: Beta-Adrenergic Antagonist
term:
id: NCIT:C29576
label: Beta-Adrenergic Antagonist
evidence:
- reference: PMID:37619836
reference_title: "Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
To reduce hemodynamic stress on the arterial wall, beta-adrenergic blocking
treatment was prescribed.
explanation: This supports reported clinical use of beta-blockade but does not establish efficacy.
references:
- reference: DOI:10.1186/s13019-024-02905-6
title: 'Total pulmonary arterial reconstruction in a patient with arterial tortuosity syndrome affecting the pulmonary artery: a case report and review of the literature'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-falcon.md
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: Arterial tortuosity syndrome is a rare Autosomal recessive disease that leads to a loss of function of the connective tissues of the body, this happens due to a mutation in the solute carrier family 2 member 10 (SLC2A10) gene.
supporting_text: Arterial tortuosity syndrome is a rare Autosomal recessive disease that leads to a loss of function of the connective tissues of the body, this happens due to a mutation in the solute carrier family 2 member 10 (SLC2A10) gene.
- reference: DOI:10.21203/rs.3.rs-2594978/v1
title: 'Arterial tortuosity syndrome: phenotypic and cardiovascular features in 4 newly identified patients'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-falcon.md
findings:
- statement: Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disease caused by biallelic variants in the SLC2A10gene and characterized by tortuosity and elongation of the aorta and medium-sized arteries.
supporting_text: Arterial tortuosity syndrome (ATS) is an autosomal recessive connective tissue disease caused by biallelic variants in the SLC2A10gene and characterized by tortuosity and elongation of the aorta and medium-sized arteries.
- reference: DOI:10.22468/cvia.2020.00129
title: 'Arterial Tortuosity Syndrome: A Case Report and Literature Review'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-falcon.md
findings:
- statement: 'Arterial Tortuosity Syndrome: A Case Report and Literature Review'
supporting_text: 'Arterial Tortuosity Syndrome: A Case Report and Literature Review'
- reference: DOI:10.3390/biomedicines13010159
title: 'Understanding the Spectrum of Mild Clinical Outcomes and Novel Findings in Arterial Tortuosity Syndrome Among Qatari Patients: Implications of SLC2A10 Mutation'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-falcon.md
findings:
- statement: Arterial Tortuosity Syndrome (ATS) is a rare, autosomal recessive connective tissue disorder characterized by arterial twists, abnormal bulges, constriction, and tears.
supporting_text: Arterial Tortuosity Syndrome (ATS) is a rare, autosomal recessive connective tissue disorder characterized by arterial twists, abnormal bulges, constriction, and tears.
- reference: DOI:10.3390/ijms252011173
title: Identification of Genetic Variants Associated with Hereditary Thoracic Aortic Diseases (HTADs) Using Next Generation Sequencing (NGS) Technology and Genotype–Phenotype Correlations
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-falcon.md
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: Hereditary thoracic aorta diseases (HTADs) are a heterogeneous group of rare disorders whose major manifestation is represented by aneurysm and/or dissection frequently located at the level of the ascending thoracic aorta.
supporting_text: Hereditary thoracic aorta diseases (HTADs) are a heterogeneous group of rare disorders whose major manifestation is represented by aneurysm and/or dissection frequently located at the level of the ascending thoracic aorta.
- reference: DOI:10.7759/cureus.99989
title: 'Radiologic Diagnosis of Arterial Tortuosity Syndrome in a Pediatric Patient: A Case Report'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-falcon.md
findings:
- statement: 'Radiologic Diagnosis of Arterial Tortuosity Syndrome in a Pediatric Patient: A Case Report'
supporting_text: 'Radiologic Diagnosis of Arterial Tortuosity Syndrome in a Pediatric Patient: A Case Report'
- reference: PMID:16550171
title: Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome.
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2006 Apr;38(4):452-7. doi: 10.1038/ng1764.'
supporting_text: '2006 Apr;38(4):452-7. doi: 10.1038/ng1764.'
- reference: PMID:18630721
title: New insights in the pathogenesis of aortic aneurysms.
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: Aortic aneurysms are an important cause of mortality in the western world.
supporting_text: Aortic aneurysms are an important cause of mortality in the western world.
- reference: PMID:18693279
title: Absence of arterial phenotype in mice with homozygous slc2A10 missense substitutions.
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2008 Aug;46(8):385-9. doi: 10.1002/dvg.20409.'
supporting_text: '2008 Aug;46(8):385-9. doi: 10.1002/dvg.20409.'
- reference: PMID:18818946
title: A novel non-sense mutation in the SLC2A10 gene of an arterial tortuosity syndrome patient of Kurdish origin.
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2009 Jul;168(7):867-70. doi: 10.1007/s00431-008-0839-2.'
supporting_text: '2009 Jul;168(7):867-70. doi: 10.1007/s00431-008-0839-2.'
- reference: PMID:22116938
title: GLUT10 is required for the development of the cardiovascular system and the notochord and connects mitochondrial function to TGFβ signaling.
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2012 Mar 15;21(6):1248-59. doi: 10.1093/hmg/ddr555.'
supporting_text: '2012 Mar 15;21(6):1248-59. doi: 10.1093/hmg/ddr555.'
- reference: PMID:25373504
title: 'Arterial Tortuosity Syndrome: homozygosity for two novel and one recurrent SLC2A10 missense mutations in three families with severe cardiopulmonary complications in infancy and a literature review.'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: 'Arterial Tortuosity Syndrome: homozygosity for two novel and one recurrent SLC2A10 missense mutations in three families with severe cardiopulmonary complications in infancy and a literature review'
supporting_text: Arterial Tortuosity Syndrome (ATS) is a very rare autosomal recessive connective tissue disorder (CTD) characterized by tortuosity and elongation of the large- and medium-sized arteries and a propensity for aneurysm formation and vascular dissection.
- reference: PMID:25821090
title: Differential diagnosis and diagnostic flow chart of joint hypermobility syndrome/ehlers-danlos syndrome hypermobility type compared to other heritable connective tissue disorders.
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2015 Mar;169C(1):6-22. doi: 10.1002/ajmg.c.31429.'
supporting_text: '2015 Mar;169C(1):6-22. doi: 10.1002/ajmg.c.31429.'
- reference: PMID:26376865
title: GLUT10 deficiency leads to oxidative stress and non-canonical αvβ3 integrin-mediated TGFβ signalling associated with extracellular matrix disarray in arterial tortuosity syndrome skin fibroblasts.
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2015 Dec 1;24(23):6769-87. doi: 10.1093/hmg/ddv382.'
supporting_text: '2015 Dec 1;24(23):6769-87. doi: 10.1093/hmg/ddv382.'
- reference: PMID:27153185
title: Glucose transporter type 10-lacking in arterial tortuosity syndrome-facilitates dehydroascorbic acid transport.
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2016 Jun;590(11):1630-40. doi: 10.1002/1873-3468.12204.'
supporting_text: '2016 Jun;590(11):1630-40. doi: 10.1002/1873-3468.12204.'
- reference: PMID:29587413
title: Multifaced Roles of the αvβ3 Integrin in Ehlers-Danlos and Arterial Tortuosity Syndromes' Dermal Fibroblasts.
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2018 Mar 26;19(4):982. doi: 10.3390/ijms19040982.'
supporting_text: '2018 Mar 26;19(4):982. doi: 10.3390/ijms19040982.'
- reference: PMID:29979900
title: Pharmacological resources, diagnostic approach and coordination of care in joint hypermobility-related disorders.
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2018 Jul;11(7):689-703. doi: 10.1080/17512433.2018.1497973.'
supporting_text: '2018 Jul;11(7):689-703. doi: 10.1080/17512433.2018.1497973.'
- reference: PMID:31203799
title: 'Comprehensive in silico Study of GLUT10: Prediction of Possible Substrate Binding Sites and Interacting Molecules.'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2020;21(2):117-130. doi: 10.2174/1389201020666190613152030.'
supporting_text: '2020;21(2):117-130. doi: 10.2174/1389201020666190613152030.'
- reference: PMID:31621376
title: 'Arterial Tortuosity Syndrome: An Ascorbate Compartmentalization Disorder?'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2021 Apr 10;34(11):875-889. doi: 10.1089/ars.2019.7843.'
supporting_text: '2021 Apr 10;34(11):875-889. doi: 10.1089/ars.2019.7843.'
- reference: PMID:32307537
title: Slc2a10 knock-out mice deficient in ascorbic acid synthesis recapitulate aspects of arterial tortuosity syndrome and display mitochondrial respiration defects.
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2020 Jun 3;29(9):1476-1488. doi: 10.1093/hmg/ddaa071.'
supporting_text: '2020 Jun 3;29(9):1476-1488. doi: 10.1093/hmg/ddaa071.'
- reference: PMID:34384376
title: 'Two fetuses in one family of arterial tortuosity syndrome: prenatal ultrasound diagnosis.'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: Arterial tortuosity syndrome (ATS) is a rare autosomal recessive connective tissue disorder chiefly characterized by elongated and tortuosity of the large and medium sized arteries and anomalies of the vascular elastic fibers.
supporting_text: Arterial tortuosity syndrome (ATS) is a rare autosomal recessive connective tissue disorder chiefly characterized by elongated and tortuosity of the large and medium sized arteries and anomalies of the vascular elastic fibers.
- reference: PMID:34847858
title: 'Arterial tortuosity syndrome causing recurrent transient ischemic attacks in young adult: a case report.'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: Arterial Tortuosity Syndrome (ATS) is a rare autosomal recessive disorder characterized by elongated and tortuous arteries.
supporting_text: Arterial Tortuosity Syndrome (ATS) is a rare autosomal recessive disorder characterized by elongated and tortuous arteries.
- reference: PMID:35302653
title: Ultrastructure abnormalities of collagen and elastin in Arab patients with arterial tortuosity syndrome.
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2022 Jul;49(7):618-622. doi: 10.1111/cup.14228.'
supporting_text: '2022 Jul;49(7):618-622. doi: 10.1111/cup.14228.'
- reference: PMID:36578839
title: 'Arterial Tortuosity Syndrome in a Newborn: A Case Report With Literature Review.'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2022 Dec 24;14(12):e32899. doi: 10.7759/cureus.32899. eCollection 2022 Dec.'
supporting_text: '2022 Dec 24;14(12):e32899. doi: 10.7759/cureus.32899. eCollection 2022 Dec.'
- reference: PMID:37692180
title: 'Arterial Tortuosity Syndrome: Unraveling a Rare Vascular Disorder.'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2023 Sep 8;15(9):e44906. doi: 10.7759/cureus.44906. eCollection 2023 Sep.'
supporting_text: '2023 Sep 8;15(9):e44906. doi: 10.7759/cureus.44906. eCollection 2023 Sep.'
- reference: PMID:39827853
title: 'A Rare Case of Dichorionic Twins Concordant for Arterial Tortuosity Syndrome: Case Report and Review of the Literature.'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2025;52(4):371-376. doi: 10.1159/000543596.'
supporting_text: '2025;52(4):371-376. doi: 10.1159/000543596.'
- reference: PMID:40027906
title: 'Arterial Tortuosity Syndrome: Keys to Early Diagnosis and Report of a New Mutation.'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2024 Dec 15;9(1):30-35. doi: 10.1016/j.case.2024.09.009. eCollection 2025 Jan.'
supporting_text: '2024 Dec 15;9(1):30-35. doi: 10.1016/j.case.2024.09.009. eCollection 2025 Jan.'
- reference: PMID:40613586
title: 'Arterial Tortuosity Syndrome: A Longitudinal Assessment of Cardiovascular Features and Interventions From the Collaborative for Longitudinal Aortic Research in the Young (CLARITY).'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings:
- statement: '2025 Nov;197(11):e64159. doi: 10.1002/ajmg.a.64159.'
supporting_text: '2025 Nov;197(11):e64159. doi: 10.1002/ajmg.a.64159.'
- reference: DOI:10.1016/j.ejmg.2023.104823
title: 'Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-falcon.md
findings: []
- reference: DOI:10.1038/gim.2017.253
title: 'Arterial tortuosity syndrome: 40 new families and literature review'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-falcon.md
findings: []
- reference: DOI:10.21203/rs.3.rs-2321263/v1
title: 'Arterial tortuosity syndrome: phenotypic features and cardiovascular manifestations in 4 newly identified patients.'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-falcon.md
findings: []
- reference: PMID:29323665
title: 'Arterial tortuosity syndrome: 40 new families and literature review.'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings: []
- reference: PMID:37619836
title: 'Arterial tortuosity syndrome: Phenotypic features and cardiovascular manifestations in 4 newly identified patients.'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings: []
- reference: PMID:38987788
title: 'Total pulmonary arterial reconstruction in a patient with arterial tortuosity syndrome affecting the pulmonary artery: a case report and review of the literature.'
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings: []
- reference: PMID:39456956
title: Identification of Genetic Variants Associated with Hereditary Thoracic Aortic Diseases (HTADs) Using Next Generation Sequencing (NGS) Technology and Genotype-Phenotype Correlations.
found_in:
- Arterial_Tortuosity_Syndrome-deep-research-openscientist.md
findings: []
Question: You are an expert researcher providing comprehensive, well-cited information.
Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies
Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.
Please provide a comprehensive research report on Arterial Tortuosity Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.
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For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype
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Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease
This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details
Arterial Tortuosity Syndrome is an autosomal recessive connective tissue disorder caused by biallelic pathogenic variants in SLC2A10 (GLUT10) and characterized by elongation and tortuosity of large- and medium-sized arteries, often accompanied by stenoses and a variable risk of aneurysm formation and ischemic complications (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5). Extra-vascular connective tissue features (craniofacial, skeletal, cutaneous, ocular, and hernia phenotypes) are common and provide diagnostic clues (beyens2018arterialtortuositysyndrome pages 8-9, esmelvilomara2023arterialtortuositysyndromea pages 5-8).
| Knowledge-base field | Summary | Key details / frequencies / examples | Source details |
|---|---|---|---|
| Disease name / identifiers | Arterial Tortuosity Syndrome (ATS); OMIM #208050 | Rare autosomal recessive connective-tissue disorder with elongation/tortuosity of large- and medium-sized arteries; also termed ATORS in some recent literature (beyens2018arterialtortuositysyndrome pages 1-2, butnariu2024identificationofgenetic pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5) | Beyens et al., Genetics in Medicine, published 2018-01-11 online / Oct 2018; DOI: https://doi.org/10.1038/gim.2017.253 (beyens2018arterialtortuositysyndrome pages 1-2). Butnariu et al., Int J Mol Sci, 2024-10-17; DOI: https://doi.org/10.3390/ijms252011173 (butnariu2024identificationofgenetic pages 1-2) |
| Synonyms / alternative names | Arterial tortuosity syndrome, ATS, ATORS | Some resources/papers use “arterial tortuosity syndrome”; HTAD-focused paper abbreviates as ATORS (butnariu2024identificationofgenetic pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5) | Butnariu et al. 2024 https://doi.org/10.3390/ijms252011173; Esmel-Vilomara et al. preprint posted 2022-12-05 / journal article 2023-08 https://doi.org/10.21203/rs.3.rs-2321263/v1 and https://doi.org/10.1016/j.ejmg.2023.104823 (butnariu2024identificationofgenetic pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5) |
| Core evidence type | Aggregated disease-level and cohort/case-series evidence | Information in the table is derived from aggregated disease cohorts/reviews and individual case series, not EHR-only data (beyens2018arterialtortuositysyndrome pages 1-2, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 1-5) | Beyens 2018; Rahmath et al., Biomedicines, 2025-01 https://doi.org/10.3390/biomedicines13010159; Esmel-Vilomara 2023 (beyens2018arterialtortuositysyndrome pages 1-2, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 1-5) |
| Causal gene | SLC2A10 (encodes GLUT10) | Loss-of-function / biallelic pathogenic variants cause ATS; GLUT10 is described as an intracellular transporter involved in dehydroascorbic acid/ascorbate biology and connective-tissue homeostasis (beyens2018arterialtortuositysyndrome pages 1-2, beyens2018arterialtortuositysyndrome pages 2-4, esmelvilomara2023arterialtortuositysyndromea pages 1-5) | Beyens 2018 https://doi.org/10.1038/gim.2017.253; Esmel-Vilomara 2023 https://doi.org/10.1016/j.ejmg.2023.104823 (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5) |
| Inheritance | Autosomal recessive | Frequently associated with parental consanguinity: 24/48 (50%) in Beyens cohort/review (beyens2018arterialtortuositysyndrome pages 8-9) | Beyens et al. 2018 https://doi.org/10.1038/gim.2017.253 (beyens2018arterialtortuositysyndrome pages 8-9) |
| Epidemiology / rarity | Extremely rare | Reported incidence <1:1,000,000 live births; Esmel-Vilomara notes 106 genetically confirmed individuals identified to date at time of study (esmelvilomara2023arterialtortuositysyndromea pages 1-5) | Esmel-Vilomara preprint/journal 2022/2023 https://doi.org/10.21203/rs.3.rs-2321263/v1 and https://doi.org/10.1016/j.ejmg.2023.104823 (esmelvilomara2023arterialtortuositysyndromea pages 1-5) |
| Key vascular phenotype: aortic tortuosity | Hallmark feature | 37/41 (90%) in Beyens 2018; 21/21 (100%) in Qatari cohort with p.Ser81Arg (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6) | Beyens 2018 https://doi.org/10.1038/gim.2017.253; Rahmath 2025 https://doi.org/10.3390/biomedicines13010159 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6) |
| Key vascular phenotype: tortuosity of other arteries | Very common multisite arterial involvement | 38/42 (90%) in Beyens; 20/21 (95%) in Rahmath cohort; severe intracranial tortuosity highlighted in 4-patient 2023 series (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 1-5, esmelvilomara2023arterialtortuositysyndromea pages 5-8) | Beyens 2018; Rahmath 2025; Esmel-Vilomara 2023 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 1-5, esmelvilomara2023arterialtortuositysyndromea pages 5-8) |
| Pulmonary artery involvement | Common and clinically important | Pulmonary artery stenosis 23/42 (55%) in Beyens; pulmonary artery tortuosity 19/21 (90%) in Rahmath; severe PAS can cause RV hypertension and need intervention (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, alshair2024totalpulmonaryarterial pages 1-2, alshair2024totalpulmonaryarterial pages 2-5) | Beyens 2018 https://doi.org/10.1038/gim.2017.253; Rahmath 2025 https://doi.org/10.3390/biomedicines13010159; Alshair 2024 https://doi.org/10.1186/s13019-024-02905-6 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, alshair2024totalpulmonaryarterial pages 1-2, alshair2024totalpulmonaryarterial pages 2-5) |
| Aortic root aneurysm / aneurysms | Present in a subset, not universal | Aortic root aneurysm 9/42 (21%) in Beyens overall table; 2/21 (9%) in Qatari p.Ser81Arg cohort; 2023 4-patient series found no aneurysms in their cases (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 5-8) | Beyens 2018; Rahmath 2025; Esmel-Vilomara 2023 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 5-8) |
| Arterial dissections | Rare / not documented in major series cited | 0/37 (0%) in Beyens summary; 2023 series notes no confirmed dissections to date in reviewed ATS literature (beyens2018arterialtortuositysyndrome pages 8-9, esmelvilomara2023arterialtortuositysyndrome pages 8-11) | Beyens 2018 https://doi.org/10.1038/gim.2017.253; Esmel-Vilomara 2023 https://doi.org/10.21203/rs.3.rs-2594978/v1 (beyens2018arterialtortuositysyndrome pages 8-9, esmelvilomara2023arterialtortuositysyndrome pages 8-11) |
| Craniofacial features | Frequent syndromic clues | Long face 32/49 (65%), high-arched palate 29/44 (66%), micrognathia 23/45 (51%), sagging cheeks 27/49 (55%) in Beyens (beyens2018arterialtortuositysyndrome pages 8-9) | Beyens 2018 https://doi.org/10.1038/gim.2017.253 (beyens2018arterialtortuositysyndrome pages 8-9) |
| Skin / connective tissue features | Common extra-vascular signs | Hyperextensible skin 27/46 (50%), cutis laxa 21/41 (51%), velvety skin 26/41 (63%) in Beyens; Rahmath found cutaneous findings in 12/21, including hyperextensible skin in 8/21 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6) | Beyens 2018; Rahmath 2025 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6) |
| Skeletal / musculoskeletal features | Common | Joint laxity 36/42 (86%) in Beyens; Rahmath reported skeletal abnormalities in 15/21, including joint hypermobility 8/21, muscular hypotonia 8/21, pectus excavatum 3/21, scoliosis 2/21 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6) | Beyens 2018; Rahmath 2025 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6) |
| Ocular features | Important but variably expressed | Myopia 15/36 (42%) and keratoconus 3/38 (8%) in Beyens; Rahmath: ocular anomalies 7/21, including astigmatism 5/21, myopia 2/21; ophthalmologic baseline exam with keratometry recommended (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6) | Beyens 2018 https://doi.org/10.1038/gim.2017.253; Rahmath 2025 https://doi.org/10.3390/biomedicines13010159 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6) |
| Hernias / GI-GU findings | Recurrent nonvascular clues | Diaphragmatic hernia 19/65 (29%), inguinal hernia 35/92 (38%), urogenital abnormalities 11/56 (20%) in Beyens; Rahmath: inguinal hernia 8/21, diaphragmatic hernia 7/21, GERD 5/21 (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 5-8) | Beyens 2018; Rahmath 2025; Esmel-Vilomara 2023 detailed GU examples (pyelectasis/megaureter) (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 5-8) |
| Respiratory manifestations | Clinically relevant in infancy/childhood | Beyens: respiratory symptoms 10/67 (15%) and frequent attention to IRDS; Rahmath: respiratory manifestations 13/21, recurrent chest infections 8/21, respiratory distress syndrome 5/21 (beyens2018arterialtortuositysyndrome pages 1-2, rahmath2025understandingthespectrum pages 4-6, beyens2018arterialtortuositysyndrome pages 8-9) | Beyens 2018 https://doi.org/10.1038/gim.2017.253; Rahmath 2025 https://doi.org/10.3390/biomedicines13010159 (beyens2018arterialtortuositysyndrome pages 1-2, rahmath2025understandingthespectrum pages 4-6, beyens2018arterialtortuositysyndrome pages 8-9) |
| Example pathogenic / likely pathogenic variants | Representative recurrent and novel alleles | c.510G>A (p.Trp170Ter) homozygous in 3 siblings; c.417T>A (p.Tyr139Ter) pathogenic; c.899T>G (p.Leu300Trp) novel/likely deleterious in compound heterozygosity; c.243C>G (p.Ser81Arg) in 21-patient Qatari cohort associated with relatively mild outcomes (esmelvilomara2023arterialtortuositysyndromea pages 1-5, esmelvilomara2023arterialtortuositysyndromea pages 5-8, rahmath2025understandingthespectrum pages 4-6) | Esmel-Vilomara 2023 https://doi.org/10.1016/j.ejmg.2023.104823 and preprint https://doi.org/10.21203/rs.3.rs-2321263/v1; Rahmath 2025 https://doi.org/10.3390/biomedicines13010159 (esmelvilomara2023arterialtortuositysyndromea pages 1-5, esmelvilomara2023arterialtortuositysyndromea pages 5-8, rahmath2025understandingthespectrum pages 4-6) |
| Recent HTAD testing implementation | ATS detectable via NGS / WES in broader aortopathy workups | 2024 HTAD study identified compound heterozygous SLC2A10 pathogenic variants in a patient with ATS using NGS/WES, reinforcing inclusion of SLC2A10 in syndromic aortopathy testing (butnariu2024identificationofgenetic pages 1-2) | Butnariu et al., Int J Mol Sci, 2024-10-17 https://doi.org/10.3390/ijms252011173 (butnariu2024identificationofgenetic pages 1-2) |
| Recommended baseline diagnostic evaluation | Comprehensive vascular and multisystem baseline work-up | Suggested by Beyens: detailed clinical exam, echocardiography, head-to-pelvis MRA, ophthalmologic exam with keratometry, and renal artery ultrasound for every ATS patient (beyens2018arterialtortuositysyndrome pages 8-9) | Beyens 2018 https://doi.org/10.1038/gim.2017.253 (beyens2018arterialtortuositysyndrome pages 8-9) |
| Surveillance / monitoring | Serial vascular surveillance required | Case-based radiology review recommends echocardiography every 3 months until age 5 and then individualized but annual imaging; serial multimodal imaging (CTA/MRA/US) for progression and complications (alkooheji2025radiologicdiagnosisof pages 5-6) | Alkooheji et al., Cureus, 2025-12 https://doi.org/10.7759/cureus.99989 (alkooheji2025radiologicdiagnosisof pages 5-6) |
| Imaging hallmarks in practice | CTA/MRA are central real-world diagnostic tools | Radiologic signs include meandering vessel sign, cluster-of-vessels sign, aortic elongation sign, and pulmonary bifurcation “V/inverted V” signs; coronal MIP CTA can show tortuous arch branches and thoracic aorta (alkooheji2025radiologicdiagnosisof pages 5-6, kumar2021arterialtortuositysyndrome media cf1c0f36, kumar2021arterialtortuositysyndrome media 75462c90) | Kumar 2021 https://doi.org/10.22468/cvia.2020.00129; Alkooheji 2025 https://doi.org/10.7759/cureus.99989 (kumar2021arterialtortuositysyndrome media cf1c0f36, kumar2021arterialtortuositysyndrome media 75462c90, alkooheji2025radiologicdiagnosisof pages 5-6) |
| Real-world intervention: medical | Empiric beta-blocker use | 2023 4-patient series: beta-adrenergic blocking treatment prescribed to reduce hemodynamic stress; authors note efficacy is unproven and management is largely expert-opinion based (esmelvilomara2023arterialtortuositysyndromea pages 1-5, esmelvilomara2023arterialtortuositysyndrome pages 8-11) | Esmel-Vilomara 2023 https://doi.org/10.1016/j.ejmg.2023.104823 and https://doi.org/10.21203/rs.3.rs-2594978/v1 (esmelvilomara2023arterialtortuositysyndromea pages 1-5, esmelvilomara2023arterialtortuositysyndrome pages 8-11) |
| Real-world intervention: surgery | Pulmonary artery reconstruction for severe PAS | In a 2-year-old with ATS, surgical reconstruction performed for severe PAS: pre-op LPA gradient 73 mmHg, velocity 4.3 m/s; RPA gradient 46 mmHg, velocity 3.4 m/s; post-repair both branch PA gradients 20 mmHg at follow-up (alshair2024totalpulmonaryarterial pages 1-2, alshair2024totalpulmonaryarterial pages 2-5) | Alshair et al., J Cardiothorac Surg, 2024-07 https://doi.org/10.1186/s13019-024-02905-6 (alshair2024totalpulmonaryarterial pages 1-2, alshair2024totalpulmonaryarterial pages 2-5) |
| Real-world intervention: catheter-based | Balloon dilation can be used for residual focal stenosis | Same 2024 case: postoperative proximal LPA stenosis treated with 8×40 mm Sterling balloon, reducing peak gradient from about 25 mmHg to 14 mmHg (alshair2024totalpulmonaryarterial pages 2-5) | Alshair et al. 2024 https://doi.org/10.1186/s13019-024-02905-6 (alshair2024totalpulmonaryarterial pages 2-5) |
| Prognosis | More variable and often milder than first reports suggested | Historical reports cited mortality up to 40% before age 5, but larger later cohorts indicate a milder course and no mortality in the 21-patient Qatari p.Ser81Arg cohort (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5, rahmath2025understandingthespectrum pages 4-6) | Beyens 2018; Esmel-Vilomara 2023; Rahmath 2025 (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5, rahmath2025understandingthespectrum pages 4-6) |
Table: This table summarizes core disease-knowledge fields for Arterial Tortuosity Syndrome, including identifiers, genetics, phenotype frequencies, diagnostics, surveillance, and real-world interventions. It is useful as a structured evidence-backed snapshot for populating a rare disease knowledge base entry.
Recent developments (2023–2024 emphasis): New variant reports and expanded phenotype capture via modern sequencing (clinical exome/WES) and systematic imaging were described in 2023, and incorporation of SLC2A10 into broader HTAD NGS/WES workflows was explicitly illustrated in 2024 (esmelvilomara2023arterialtortuositysyndromea pages 1-5, butnariu2024identificationofgenetic pages 1-2).
ATS often presents in infancy/childhood, including neonatal manifestations such as pulmonary artery stenosis and respiratory distress in some patients (alshair2024totalpulmonaryarterial pages 2-5, beyens2018arterialtortuositysyndrome pages 1-2). Natural history is heterogeneous; early reports described high early mortality, but later cohorts suggest a milder course in many patients (beyens2018arterialtortuositysyndrome pages 1-2, esmelvilomara2023arterialtortuositysyndromea pages 1-5).
From a large cohort/literature synthesis (Beyens 2018): - Aortic tortuosity: 37/41 (90%) (beyens2018arterialtortuositysyndrome pages 8-9) - Tortuosity of other arteries: 38/42 (90%) (beyens2018arterialtortuositysyndrome pages 8-9) - Pulmonary artery stenosis: 23/42 (55%) (beyens2018arterialtortuositysyndrome pages 8-9) - Aortic root aneurysm: 9/42 (21%) (beyens2018arterialtortuositysyndrome pages 8-9) - Arterial dissections: 0/37 (0%) (beyens2018arterialtortuositysyndrome pages 8-9)
From a 21-patient genetically confirmed Qatari cohort (Rahmath 2025; homozygous p.Ser81Arg): - Aortic tortuosity: 21/21 (100%) - Other arterial tortuosity: 20/21 (95%) - Pulmonary artery tortuosity: 19/21 (90%) - Aortic root aneurysm: 2/21 (9%) - Cardiovascular interventions: 2/21 (9%) (rahmath2025understandingthespectrum pages 4-6)
Below are common phenotypes and representative HPO terms (examples; not exhaustive).
Craniofacial / dysmorphism (common diagnostic clues) - Long face HP:0000276; hypertelorism HP:0000316; downslanted palpebral fissures HP:0000494; high arched/narrow palate HP:0002705; micrognathia HP:0000347; sagging cheeks HP:0034273 (beyens2018arterialtortuositysyndrome pages 8-9, esmelvilomara2023arterialtortuositysyndromea pages 5-8).
Cutaneous / connective tissue - Hyperextensible skin HP:0000974; cutis laxa HP:0000973; velvety skin texture (phenotyped in cohort tables) (beyens2018arterialtortuositysyndrome pages 8-9).
Musculoskeletal - Joint hypermobility HP:0001382; pectus excavatum HP:0000767; scoliosis HP:0002650; pes planus HP:0001763; pes valgus HP:0008081 (beyens2018arterialtortuositysyndrome pages 8-9, esmelvilomara2023arterialtortuositysyndromea pages 5-8).
Ocular - Myopia HP:0000545; keratoconus HP:0000563; keratoglobus (as reported in cohort tables); exotropia HP:0000577; myopic astigmatism HP:0500041 (beyens2018arterialtortuositysyndrome pages 8-9, esmelvilomara2023arterialtortuositysyndromea pages 5-8).
Hernias / GI - Diaphragmatic hernia HP:0000776; inguinal hernia HP:0000023; gastroesophageal reflux disease (GERD) (reported in cohort summaries) (beyens2018arterialtortuositysyndrome pages 8-9, rahmath2025understandingthespectrum pages 4-6, esmelvilomara2023arterialtortuositysyndromea pages 5-8).
Genitourinary / renal - Dilatation of renal pelvis HP:0010946; congenital megaureter HP:0008676; cryptorchidism HP:0000028; urogenital abnormalities (reported at cohort level) (beyens2018arterialtortuositysyndrome pages 8-9, esmelvilomara2023arterialtortuositysyndromea pages 5-8).
Neurologic / imaging-associated findings - Intracranial/cerebrovascular tortuosity HP:0005116 (vascular HPO); corpus callosum hypoplasia HP:0002079; temporal cortical atrophy HP:0007112 in individual cases (esmelvilomara2023arterialtortuositysyndromea pages 5-8).
No validated QoL instrument outcomes (e.g., SF-36/EQ-5D) were reported in the retrieved ATS-specific sources. However, vascular stenosis (especially pulmonary arteries) can produce major functional limitation via right ventricular hypertension and reduced exercise tolerance (alshair2024totalpulmonaryarterial pages 2-5).
Variant interpretation framework: The 2022/2023 series describes ACMG-guideline-based classification and segregation testing (Sanger) after exome sequencing (esmelvilomara2023arterialtortuositysyndromea pages 1-5).
ATS is a Mendelian disorder; no specific toxins, lifestyle factors, or infectious triggers were established as causal or modifying factors in the retrieved sources.
A convergent model from cohort and case-series sources is: 1) SLC2A10 (GLUT10) deficiency → perturbed intracellular handling of dehydroascorbic acid/ascorbate (hypothesis) (esmelvilomara2023arterialtortuositysyndromea pages 1-5, beyens2018arterialtortuositysyndrome pages 2-4). 2) In the endoplasmic reticulum, reduced ascorbate cofactor availability may impair prolyl/lysyl hydroxylase activity and collagen/elastin maturation/crosslinking (esmelvilomara2023arterialtortuositysyndromea pages 1-5). 3) In mitochondria, altered ascorbate biology may impair redox homeostasis and reactive oxygen species scavenging (esmelvilomara2023arterialtortuositysyndromea pages 1-5, beyens2018arterialtortuositysyndrome pages 2-4). 4) These perturbations contribute to extracellular matrix (ECM) homeostasis defects and elastic lamellar integrity loss, leading to fragmentation of elastic fibers/lamellae in arterial walls (beyens2018arterialtortuositysyndrome pages 1-2, beyens2018arterialtortuositysyndrome pages 2-4). 5) Structural arterial wall weakness + abnormal remodeling → arterial elongation/tortuosity, stenosis (potentially via smooth muscle proliferation), and variable aneurysm risk (beyens2018arterialtortuositysyndrome pages 8-9, beyens2018arterialtortuositysyndrome pages 1-2).
GO biological processes (examples): - extracellular matrix organization (GO) - elastic fiber assembly (GO) - collagen fibril organization (GO) - response to oxidative stress (GO) - transforming growth factor beta receptor signaling pathway (GO; mechanistic hypothesis/uncertain directionality)
Cell types (CL, examples): - vascular smooth muscle cell (CL) - endothelial cell (CL) - fibroblast (CL)
Anatomy (UBERON, examples): - aorta (UBERON) - pulmonary artery (UBERON) - carotid artery / cerebral arteries (UBERON) - renal artery (UBERON)
Chemical entities (ChEBI, examples): - ascorbic acid (vitamin C) / dehydroascorbic acid (ChEBI)
Classic radiologic patterns include markedly tortuous great vessels and pulmonary artery branching signs (“V/inverted V”), visualized by CTA/MRA (kumar2021arterialtortuositysyndrome media cf1c0f36, kumar2021arterialtortuositysyndrome media 75462c90).
Syndromic pattern recognition—arterial tortuosity with characteristic craniofacial/connective tissue findings and hernias—should prompt genetic evaluation (beyens2018arterialtortuositysyndrome pages 8-9, esmelvilomara2023arterialtortuositysyndromea pages 1-5).
A large ATS cohort recommends baseline evaluation including: - detailed clinical exam, - echocardiography, - “head-to-pelvis” MR angiography, - ophthalmologic exam with keratometry, - renal artery ultrasound (beyens2018arterialtortuositysyndrome pages 8-9).
Key differentials for arterial tortuosity with syndromic features include: - Loeys–Dietz syndrome, Marfan syndrome, vascular Ehlers–Danlos syndrome, cutis laxa, and homocystinuria (alkooheji2025radiologicdiagnosisof pages 5-6).
MAXO suggestions (examples): beta-adrenergic antagonist therapy; cardiovascular surveillance.
A 2024 surgical case illustrates management of severe pulmonary artery stenosis in ATS: - Preoperative echo gradients: LPA 73 mmHg (4.3 m/s); RPA 46 mmHg (3.4 m/s) with right ventricular hypertension; surgical reconstruction performed at age 2 (alshair2024totalpulmonaryarterial pages 1-2). - Postoperative: branch PA gradients ~20 mmHg (alshair2024totalpulmonaryarterial pages 1-2). - Residual proximal LPA stenosis was treated via balloon angioplasty (8×40 mm) with peak gradient reduced from ~25 mmHg to 14 mmHg (alshair2024totalpulmonaryarterial pages 2-5).
MAXO suggestions (examples): pulmonary artery reconstruction; balloon angioplasty; perioperative cardiopulmonary bypass.
No ATS-specific interventional trials were retrieved. A large observational aortopathy biorepository/genetics study explicitly includes ATS among conditions studied: - NCT03440697 (Yale University; first posted 2018-02-22, last update posted 2026-02-13; start 2015-12-10; estimated completion 2030-12-31) (NCT03440697 chunk 1).
No naturally occurring ATS orthologous disease in other species was identified in the retrieved sources.
The retrieved full-text sources in this run provided DOIs/URLs and detailed data but did not expose PubMed IDs within the accessible text. For knowledge-base ingestion requiring PMIDs, the recommended next step is to map these DOIs to PMIDs via PubMed/NCBI records during curation.
References
(beyens2018arterialtortuositysyndrome pages 1-2): Aude Beyens, Juliette Albuisson, Annekatrien Boel, Mazen Al-Essa, Waheed Al-Manea, Damien Bonnet, Ozlem Bostan, Odile Boute, Tiffany Busa, Nathalie Canham, Ergun Cil, Paul J. Coucke, Margot A. Cousin, Majed Dasouki, Julie De Backer, Anne De Paepe, Sofie De Schepper, Deepthi De Silva, Koenraad Devriendt, Inge De Wandele, David R. Deyle, Harry Dietz, Sophie Dupuis-Girod, Eudice Fontenot, Björn Fischer-Zirnsak, Alper Gezdirici, Jamal Ghoumid, Fabienne Giuliano, Neus Baena Diéz, Mohammed Z. Haider, Joshua S. Hardin, Xavier Jeunemaitre, Eric W. Klee, Uwe Kornak, Manuel F. Landecho, Anne Legrand, Bart Loeys, Stanislas Lyonnet, Helen Michael, Pamela Moceri, Shehla Mohammed, Laura Muiño-Mosquera, Sheela Nampoothiri, Karin Pichler, Katrina Prescott, Anna Rajeb, Maria Ramos-Arroyo, Massimiliano Rossi, Mustafa Salih, Mohammed Z. Seidahmed, Elise Schaefer, Elisabeth Steichen-Gersdorf, Sehime Temel, Fahrettin Uysal, Marine Vanhomwegen, Lut Van Laer, Lionel Van Maldergem, David Warner, Andy Willaert, Tom R. Collins, Andrea Taylor, Elaine C. Davis, Yuri Zarate, and Bert Callewaert. Arterial tortuosity syndrome: 40 new families and literature review. Genetics in Medicine, 20:1236-1245, Oct 2018. URL: https://doi.org/10.1038/gim.2017.253, doi:10.1038/gim.2017.253. This article has 113 citations and is from a highest quality peer-reviewed journal.
(esmelvilomara2023arterialtortuositysyndromea pages 1-5): Roger Esmel-Vilomara, Irene Valenzuela, Lucía Riaza, Benjamín Rodríguez-Santiago, Ferran Rosés-Noguer, Susana Boronat, and Anna Sabaté-Rotés. Arterial tortuosity syndrome: phenotypic features and cardiovascular manifestations in 4 newly identified patients. European journal of medical genetics, pages 104823, Aug 2023. URL: https://doi.org/10.1016/j.ejmg.2023.104823, doi:10.1016/j.ejmg.2023.104823. This article has 1 citations and is from a peer-reviewed journal.
(beyens2018arterialtortuositysyndrome pages 8-9): Aude Beyens, Juliette Albuisson, Annekatrien Boel, Mazen Al-Essa, Waheed Al-Manea, Damien Bonnet, Ozlem Bostan, Odile Boute, Tiffany Busa, Nathalie Canham, Ergun Cil, Paul J. Coucke, Margot A. Cousin, Majed Dasouki, Julie De Backer, Anne De Paepe, Sofie De Schepper, Deepthi De Silva, Koenraad Devriendt, Inge De Wandele, David R. Deyle, Harry Dietz, Sophie Dupuis-Girod, Eudice Fontenot, Björn Fischer-Zirnsak, Alper Gezdirici, Jamal Ghoumid, Fabienne Giuliano, Neus Baena Diéz, Mohammed Z. Haider, Joshua S. Hardin, Xavier Jeunemaitre, Eric W. Klee, Uwe Kornak, Manuel F. Landecho, Anne Legrand, Bart Loeys, Stanislas Lyonnet, Helen Michael, Pamela Moceri, Shehla Mohammed, Laura Muiño-Mosquera, Sheela Nampoothiri, Karin Pichler, Katrina Prescott, Anna Rajeb, Maria Ramos-Arroyo, Massimiliano Rossi, Mustafa Salih, Mohammed Z. Seidahmed, Elise Schaefer, Elisabeth Steichen-Gersdorf, Sehime Temel, Fahrettin Uysal, Marine Vanhomwegen, Lut Van Laer, Lionel Van Maldergem, David Warner, Andy Willaert, Tom R. Collins, Andrea Taylor, Elaine C. Davis, Yuri Zarate, and Bert Callewaert. Arterial tortuosity syndrome: 40 new families and literature review. Genetics in Medicine, 20:1236-1245, Oct 2018. URL: https://doi.org/10.1038/gim.2017.253, doi:10.1038/gim.2017.253. This article has 113 citations and is from a highest quality peer-reviewed journal.
(esmelvilomara2023arterialtortuositysyndromea pages 5-8): Roger Esmel-Vilomara, Irene Valenzuela, Lucía Riaza, Benjamín Rodríguez-Santiago, Ferran Rosés-Noguer, Susana Boronat, and Anna Sabaté-Rotés. Arterial tortuosity syndrome: phenotypic features and cardiovascular manifestations in 4 newly identified patients. European journal of medical genetics, pages 104823, Aug 2023. URL: https://doi.org/10.1016/j.ejmg.2023.104823, doi:10.1016/j.ejmg.2023.104823. This article has 1 citations and is from a peer-reviewed journal.
(butnariu2024identificationofgenetic pages 1-2): Lăcrămioara Ionela Butnariu, Georgiana Russu, Alina-Costina Luca, Constantin Sandu, Laura Mihaela Trandafir, Ioana Vasiliu, Setalia Popa, Gabriela Ghiga, Laura Bălănescu, and Elena Țarcă. Identification of genetic variants associated with hereditary thoracic aortic diseases (htads) using next generation sequencing (ngs) technology and genotype–phenotype correlations. International Journal of Molecular Sciences, 25:11173, Oct 2024. URL: https://doi.org/10.3390/ijms252011173, doi:10.3390/ijms252011173. This article has 4 citations.
(rahmath2025understandingthespectrum pages 4-6): Muhammed Riyas K. Rahmath, Haytham Ibrahim, Muhammad Faiyaz-Ul-Haque, Zafar Nawaz, Ahmad Zitoun, Ahmed Hussein, Ahmed Sadek, Ayman El-Menyar, Reema Kamal, Hassan Al-Thani, and Gulab Sher. Understanding the spectrum of mild clinical outcomes and novel findings in arterial tortuosity syndrome among qatari patients: implications of slc2a10 mutation. Biomedicines, 13:159, Jan 2025. URL: https://doi.org/10.3390/biomedicines13010159, doi:10.3390/biomedicines13010159. This article has 2 citations.
(beyens2018arterialtortuositysyndrome pages 2-4): Aude Beyens, Juliette Albuisson, Annekatrien Boel, Mazen Al-Essa, Waheed Al-Manea, Damien Bonnet, Ozlem Bostan, Odile Boute, Tiffany Busa, Nathalie Canham, Ergun Cil, Paul J. Coucke, Margot A. Cousin, Majed Dasouki, Julie De Backer, Anne De Paepe, Sofie De Schepper, Deepthi De Silva, Koenraad Devriendt, Inge De Wandele, David R. Deyle, Harry Dietz, Sophie Dupuis-Girod, Eudice Fontenot, Björn Fischer-Zirnsak, Alper Gezdirici, Jamal Ghoumid, Fabienne Giuliano, Neus Baena Diéz, Mohammed Z. Haider, Joshua S. Hardin, Xavier Jeunemaitre, Eric W. Klee, Uwe Kornak, Manuel F. Landecho, Anne Legrand, Bart Loeys, Stanislas Lyonnet, Helen Michael, Pamela Moceri, Shehla Mohammed, Laura Muiño-Mosquera, Sheela Nampoothiri, Karin Pichler, Katrina Prescott, Anna Rajeb, Maria Ramos-Arroyo, Massimiliano Rossi, Mustafa Salih, Mohammed Z. Seidahmed, Elise Schaefer, Elisabeth Steichen-Gersdorf, Sehime Temel, Fahrettin Uysal, Marine Vanhomwegen, Lut Van Laer, Lionel Van Maldergem, David Warner, Andy Willaert, Tom R. Collins, Andrea Taylor, Elaine C. Davis, Yuri Zarate, and Bert Callewaert. Arterial tortuosity syndrome: 40 new families and literature review. Genetics in Medicine, 20:1236-1245, Oct 2018. URL: https://doi.org/10.1038/gim.2017.253, doi:10.1038/gim.2017.253. This article has 113 citations and is from a highest quality peer-reviewed journal.
(alshair2024totalpulmonaryarterial pages 1-2): Fahad M. Alshair, Amal S. Alsulami, Mohammad S. Shihata, Osman O. Alradi, Ragab S. Debis, Abdullah H. Baghaffar, and Mazin A. Fatani. Total pulmonary arterial reconstruction in a patient with arterial tortuosity syndrome affecting the pulmonary artery: a case report and review of the literature. Journal of Cardiothoracic Surgery, Jul 2024. URL: https://doi.org/10.1186/s13019-024-02905-6, doi:10.1186/s13019-024-02905-6. This article has 2 citations and is from a peer-reviewed journal.
(alshair2024totalpulmonaryarterial pages 2-5): Fahad M. Alshair, Amal S. Alsulami, Mohammad S. Shihata, Osman O. Alradi, Ragab S. Debis, Abdullah H. Baghaffar, and Mazin A. Fatani. Total pulmonary arterial reconstruction in a patient with arterial tortuosity syndrome affecting the pulmonary artery: a case report and review of the literature. Journal of Cardiothoracic Surgery, Jul 2024. URL: https://doi.org/10.1186/s13019-024-02905-6, doi:10.1186/s13019-024-02905-6. This article has 2 citations and is from a peer-reviewed journal.
(esmelvilomara2023arterialtortuositysyndrome pages 8-11): Roger Esmel-Vilomara, Irene Valenzuela, Lucia Riaza, Benjamin Rodriguez-Santiago, Ferran Roses-Noguer, Susana Boronat, and Anna Sabate-Rotes. Arterial tortuosity syndrome: phenotypic and cardiovascular features in 4 newly identified patients. Feb 2023. URL: https://doi.org/10.21203/rs.3.rs-2594978/v1, doi:10.21203/rs.3.rs-2594978/v1.
(alkooheji2025radiologicdiagnosisof pages 5-6): Amina Salah Alkooheji, Neale Nicola Kalis, G. Koç, Suad R. Alamer, and Vimalarani Arulselvam. Radiologic diagnosis of arterial tortuosity syndrome in a pediatric patient: a case report. Cureus, Dec 2025. URL: https://doi.org/10.7759/cureus.99989, doi:10.7759/cureus.99989. This article has 0 citations.
(kumar2021arterialtortuositysyndrome media cf1c0f36): Parveen Kumar. Arterial tortuosity syndrome: a case report and literature review. Cardiovascular Imaging Asia, 5:9, Jan 2021. URL: https://doi.org/10.22468/cvia.2020.00129, doi:10.22468/cvia.2020.00129. This article has 4 citations.
(kumar2021arterialtortuositysyndrome media 75462c90): Parveen Kumar. Arterial tortuosity syndrome: a case report and literature review. Cardiovascular Imaging Asia, 5:9, Jan 2021. URL: https://doi.org/10.22468/cvia.2020.00129, doi:10.22468/cvia.2020.00129. This article has 4 citations.
(NCT03440697 chunk 1): Pathogenetic Basis of Aortopathy and Aortic Valve Disease. Yale University. 2015. ClinicalTrials.gov Identifier: NCT03440697
Arterial Tortuosity Syndrome is a rare, monogenic connective tissue disorder primarily affecting the vascular system. It was first described clinically approximately 55 years ago (Ertugrul, 1967) and its genetic basis was elucidated in 2006 when Coucke et al. identified mutations in SLC2A10 as the causative defect (PMID: 16550171). ATS is characterized by generalized tortuosity, elongation, and stenosis of large and medium-sized arteries, with a propensity for aneurysm formation. Patients also display connective tissue features overlapping with Ehlers-Danlos syndromes and Loeys-Dietz syndrome.
| Database | Identifier |
|---|---|
| OMIM | #208050 |
| Orphanet | ORPHA:3342 |
| MONDO | MONDO:0009005 |
| ICD-10 | Q27.8 (Other specified congenital malformations of peripheral vascular system) |
| MeSH | C537373 |
| Gene (HGNC) | SLC2A10 (HGNC:13445) |
| NCBI Gene | 81031 |
| UniProt | O95528 (GTR10_HUMAN) |
| Chromosomal Location | 20q13.12 |
Information is derived from aggregated disease-level resources (OMIM, Orphanet, GeneReviews) and individual case reports/series from published literature. The largest systematic cohort study encompasses 102 patients from 92 families (Beyens et al. 2018, PMID: 29323665). A 2025 longitudinal study (CLARITY) provides the most recent prospective cardiovascular data on 14 patients (PMID: 40613586).
ATS is a monogenic (Mendelian) disorder caused by biallelic (homozygous or compound heterozygous) loss-of-function mutations in the SLC2A10 gene. There are no known environmental or infectious causes.
As stated in the original discovery paper: "Mutations in one of these genes, SLC2A10, encoding the facilitative glucose transporter GLUT10, were identified in six ATS families. GLUT10 deficiency is associated with upregulation of the TGFbeta pathway in the arterial wall" (PMID: 16550171).
The interplay between GLUT10 deficiency and the human inability to synthesize ascorbic acid represents a critical gene–environment (nutrient) interaction that likely determines disease severity. Mice with intact ascorbic acid synthesis via Gulo are protected from the full disease phenotype even when lacking GLUT10, while Gulo;Slc2a10 double knockout mice that cannot synthesize ascorbate show compromised ECM and mitochondrial defects: "Altogether, our data add evidence that ATS is an ascorbate compartmentalization disorder, but additional factors underlying the observed phenotype in humans remain to be determined" (PMID: 32307537).
| Phenotype | HPO Term | Frequency | Onset | Severity | Progression |
|---|---|---|---|---|---|
| Arterial tortuosity (large/medium arteries) | HP:0005116 | >95% | Congenital/neonatal | Moderate-severe | Stable to progressive |
| Aortic root dilation/aneurysm | HP:0002616 | ~71.4% (CLARITY) | Infancy-childhood | Variable | Progressive (stable z-scores) |
| Pulmonary artery stenosis | HP:0004415 | Frequent | Infancy | Moderate-severe | May require intervention |
| Aortic coarctation | HP:0001680 | Occasional | Congenital | Severe | May require surgery |
| Intracranial arterial tortuosity | HP:0005116 | Common | Congenital | Variable | Stable |
| Ischemic stroke | HP:0002140 | Rare | Childhood-young adult | Severe | Episodic |
| Neonatal intracranial bleeding | HP:0007420 | Rare | Neonatal | Severe | Acute |
The CLARITY longitudinal study reported that "aortic root dilation was present in 71.4%; branch pulmonary artery (BPA) dimensions were mixed between dilated and hypoplastic" (PMID: 40613586). The largest cohort study documented: "Stenoses, tortuosity, and aneurysm formation are widespread occurrences. Severe but rare vascular complications include early and aggressive aortic root aneurysms, neonatal intracranial bleeding, ischemic stroke, and gastric perforation" (PMID: 29323665).
| Phenotype | HPO Term | Frequency | Onset | Severity |
|---|---|---|---|---|
| Skin hyperextensibility | HP:0001030 | Very frequent | Congenital | Mild-moderate |
| Joint hypermobility | HP:0001382 | Very frequent | Congenital | Mild-moderate |
| Dysmorphic facial features | HP:0001999 | Frequent | Congenital | Mild |
| Keratoconus | HP:0000563 | Occasional | Childhood-adolescence | Progressive |
| Diaphragmatic hernia | HP:0000776 | Frequent (~15-20%) | Congenital/neonatal | Severe |
| Inguinal/umbilical hernia | HP:0000023 / HP:0001537 | Frequent | Infancy | Mild-moderate |
| Skeletal abnormalities | HP:0000924 | Frequent | Childhood | Variable |
| Microcephaly | HP:0000252 | Occasional | Congenital | Mild |
| Congenital contractures | HP:0002803 | Occasional | Congenital | Variable |
| Phenotype | HPO Term | Frequency | Onset | Severity |
|---|---|---|---|---|
| Infant respiratory distress syndrome (IRDS) | HP:0002643 | Frequent | Neonatal | Severe |
| Dyspnea/cyanosis (from PA involvement) | HP:0002094 | Occasional | Infancy | Variable |
| Phenotype | HPO Term | Frequency |
|---|---|---|
| Complex uropathy | HP:0000079 | Rare |
| Bilateral hip dislocation | HP:0001374 | Rare |
| Stomach displacement into thorax | HP:0002579 | Rare |
| Gastric perforation | — | Very rare |
"A patient with microcephaly and a complex uropathy and two cases with diaphragmatic hernia are noticed." (PMID: 37619836)
ATS significantly impacts quality of life, particularly in childhood, due to: - Cardiovascular surveillance burden (repeated imaging, echocardiography) - Potential need for surgical interventions (pulmonary artery reconstruction, aortopexy) - Joint laxity affecting mobility and musculoskeletal function - Risk of cerebrovascular events limiting physical activity - Respiratory complications in the neonatal period - Psychosocial burden of a chronic rare disease
No formal QoL studies (EQ-5D, SF-36, PROMIS) specific to ATS have been published. This represents a significant gap in the literature.
ATS-causing variants span the full spectrum of loss-of-function mutations:
| Variant (cDNA) | Protein Change | Type | Population | Reference |
|---|---|---|---|---|
| c.243C>G | p.Ser81Arg (rs80358230) | Missense | Arab | PMID: 36578839 |
| c.173C>T | p.Ala58Val | Missense | — | PMID: 40027906 |
| c.899T>G | p.Leu300Trp | Missense | — | PMID: 37619836 |
| c.1309G>A | p.Glu437Lys | Missense | — | PMID: 31203799 |
| c.417T>A | p.Tyr139Ter | Nonsense | — | PMID: 37619836 |
| c.510G>A | p.Trp170Ter | Nonsense | — | PMID: 37619836 |
| c.756C>A | p.Cys252Ter | Nonsense | Kurdish | PMID: 18818946 |
Additional frameshift and splice-site variants have been reported (see ClinVar entries for SLC2A10).
All known pathogenic variants result in loss of function of GLUT10 through: - Premature protein truncation (nonsense, frameshift) - Misfolding or impaired membrane insertion (missense) - Loss of substrate transport activity - Re-expression of GLUT10 in patient fibroblasts rescues the cellular phenotype (PMID: 26376865)
All pathogenic variants are germline in origin. No somatic mutations have been reported.
No specific modifier genes have been identified in humans. However, the variable expressivity observed even among siblings with identical mutations suggests genetic modifiers or stochastic developmental factors influence disease severity. At the species level, GULO (L-gulonolactone oxidase) status serves as a major modifier — humans are pseudogene carriers (non-functional GULO), exacerbating GLUT10 deficiency effects compared to mice that retain functional Gulo (PMID: 32307537).
No specific epigenetic modifications (DNA methylation, histone modifications, chromatin changes) have been described in ATS. Transcriptomic studies show dysregulation of genes involved in oxidative stress response and ECM homeostasis, but dedicated epigenomic profiling has not been performed.
ATS is not caused by chromosomal abnormalities. No large-scale structural variants (aneuploidy, translocations, inversions) are associated with the disease. All causative mutations are point mutations or small indels within SLC2A10.
ATS is a purely genetic disorder. No environmental toxins, radiation, pollution, or occupational exposures are known to cause or contribute to disease development.
While no lifestyle factors cause ATS, clinical management recommends: - Avoidance of contact sports and intense isometric exercise to reduce hemodynamic stress on weakened arterial walls - Blood pressure management to reduce risk of aneurysm progression - Adequate vitamin C intake may be theoretically important given the ascorbate compartmentalization hypothesis, but this remains clinically unvalidated
Not applicable. ATS is not caused or triggered by any infectious agent.
The pathogenesis of ATS involves a multi-layered molecular cascade from the primary genetic defect to clinical manifestation:
SLC2A10 biallelic mutations
↓
GLUT10 protein loss-of-function
↓
Impaired dehydroascorbic acid (DAA) transport across endomembranes
↓
Reduced intracellular ascorbate in ER/mitochondria
↓
┌───────────────────┬────────────────────────┬──────────────────────┐
│ │ │ │
▼ ▼ ▼ ▼
Defective collagen Impaired elastin Oxidative stress Mitochondrial
hydroxylation assembly (↑ ROS, ↑ lipid dysfunction
(↓ prolyl/lysyl (fragmented peroxidation) (compromised
hydroxylase elastic fibers) via altered PPARγ respiration in
activity) VSMCs)
│ │ │ │
└───────────────────┴────────────────────────┘ │
↓ │
ECM disorganization │
(↑ collagen deposition, │
↓ elastic fiber integrity) │
↓ │
Non-canonical TGF-β signaling ←────────────────────────────┘
(αvβ3 integrin → p125FAK → p60Src → p38 MAPK)
↓
Vascular wall weakening
↓
Arterial tortuosity, elongation, stenosis, aneurysm
The original discovery paper demonstrated "GLUT10 deficiency is associated with upregulation of the TGFbeta pathway in the arterial wall" (PMID: 16550171). However, subsequent work has significantly refined this understanding. In ATS fibroblasts, the primary TGF-β dysregulation occurs through a non-canonical pathway mediated by the αvβ3 integrin, involving p125FAK, p60Src, and p38 MAPK signaling, rather than the canonical SMAD2/3 pathway (PMID: 29587413; PMID: 26376865).
Importantly, histological analysis of end-stage skin and vascular tissue from ATS patients did not show increased canonical TGF-β signaling markers (pSMAD2/CTGF) (PMID: 29323665), and TGF-β signaling was unaltered in the Gulo;Slc2a10 double knockout mouse (PMID: 32307537). This suggests tissue-specific and temporal differences in TGF-β pathway involvement, and that canonical TGF-β upregulation may not be the primary driver of disease in all contexts.
GLUT10 has been confirmed as a DAA transporter: "The present results demonstrate that GLUT10 is a DAA transporter and DAA transport is diminished in the endomembranes of fibroblasts from ATS patients" (PMID: 27153185). Intracellular ascorbate is required as a cofactor for prolyl and lysyl hydroxylases that catalyze collagen cross-linking and for enzymes involved in elastin assembly. ATS has accordingly been characterized as an "ascorbate compartmentalization disorder" (PMID: 31621376; PMID: 32307537).
Studies on ATS fibroblasts demonstrated "a marked increase in ROS-induced lipid peroxidation sustained by altered PPARγ function, which contributes to the redox imbalance and the compensatory antioxidant activity of ALDH1A1" (PMID: 26376865). The oxidative stress is a direct consequence of impaired intracellular ascorbate, which normally serves as a major intracellular antioxidant.
In ATS fibroblasts, the αvβ3 integrin is preferentially recruited due to loss of the fibronectin-ECM and its canonical α5β1 integrin receptor. This integrin activates downstream signaling through p125FAK, p60Src, and p38 MAPK, contributing to ECM disarray and altered cell behavior (PMID: 29587413).
Electron microscopy of ATS skin biopsies revealed: "Large spaces were observed among the collagen fibrils…suggesting disorganization of the collagen structures. Furthermore, elastin fiber contents and their thickness are reduced…In small muscular arteries in the skin from ATS patients, discontinuous internal elastic lamina, lack of myofilaments, and disorganized medial smooth muscle cells with vacuolated cytoplasm are present" (PMID: 35302653). The largest cohort study confirmed: "EM of skin EF shows a fragmented elastin core and a peripheral mantle of microfibrils of random directionality" (PMID: 29323665).
Zebrafish studies showed that "a large proportion of the genes, which were specifically dysregulated after glut10 depletion gene and not by tgfbr1 inhibition, play a major role in mitochondrial function" (PMID: 22116938). The Gulo;Slc2a10 double knockout mouse confirmed compromised mitochondrial respiration in smooth muscle cells (PMID: 32307537).
GLUT10 is a 541-amino acid transmembrane protein with 12 predicted transmembrane domains. In silico modeling identified potential substrate binding site residues including PRO531, GLU507, GLU437, and TRP432, with a highly recurrent point mutation (c.1309G>A, p.Glu437Lys) located directly in the predicted binding site region (PMID: 31203799).
No primary immune dysfunction is described in ATS. Arterial wall inflammation may be secondary to ECM disruption and oxidative stress, but this has not been formally studied.
| Cell Type | CL Term | Role in Pathogenesis |
|---|---|---|
| Vascular smooth muscle cell | CL:0000359 | Primary affected cell; mitochondrial dysfunction, ECM production defects, disorganized morphology |
| Fibroblast | CL:0000057 | Oxidative stress, non-canonical TGF-β signaling, ECM disarray, altered integrin signaling |
| Vascular endothelial cell | CL:0002543 | Altered angiogenesis, hemodynamic stress response |
| Organ System | Structures | UBERON Term |
|---|---|---|
| Cardiovascular | Aorta, pulmonary arteries, carotid arteries, subclavian arteries, intracranial arteries | UBERON:0000947 (aorta), UBERON:0002012 (pulmonary artery) |
| Integumentary | Skin (hyperextensibility) | UBERON:0002097 (skin of body) |
| Musculoskeletal | Joints (hypermobility), skeleton | UBERON:0000982 (skeletal joint) |
| Organ System | Structures | Mechanism |
|---|---|---|
| Respiratory | Lungs (IRDS), diaphragm (hernia) | Connective tissue defect, pulmonary artery stenosis |
| Nervous | Brain (stroke, intracranial bleeding) | Cerebrovascular complications from tortuosity |
| Ocular | Cornea (keratoconus) | Connective tissue weakness |
| Gastrointestinal | Stomach (perforation, displacement) | Connective tissue defect |
| Urogenital | Kidneys/ureters (uropathy) | Connective tissue defect |
Body systems involved: Cardiovascular (primary), musculoskeletal, integumentary, ocular, respiratory, gastrointestinal, nervous (secondary).
Specific cell populations targeted: - Vascular smooth muscle cells (CL:0000359): Disorganized, vacuolated, lacking myofilaments - Fibroblasts (CL:0000057): Altered ECM production, oxidative stress - Endothelial cells (CL:0002543): Secondary to vascular wall disruption
Critical period: The neonatal and infancy period (first 1-2 years of life) is the most critical for life-threatening events. As stated by Callewaert et al.: "Our data confirm that the cardiovascular prognosis in ATS is less severe than previously reported and that the first years of life are the most critical for possible life-threatening events" (PMID: 25373504).
| Feature | Detail |
|---|---|
| Inheritance pattern | Autosomal recessive (AR); HP:0000007 |
| Penetrance | Complete for vascular features (tortuosity) in individuals with biallelic variants |
| Expressivity | Highly variable — even among siblings with identical mutations |
| Genetic anticipation | Not observed (not a repeat expansion disorder) |
| Germline mosaicism | Not documented, though theoretically possible |
| Consanguinity role | Significant — many reported families are consanguineous |
| Carrier frequency | Unknown; extremely low given disease rarity |
"Arterial tortuosity syndrome (ATS) is a rare congenital disorder characterized by elongation and tortuosity of the aorta and mid-sized arteries. Additional features typical of connective tissue disorders are usually present, but the clinical presentation of the syndrome can extensively change." (PMID: 39827853)
The p.Ser81Arg (c.243C>G, rs80358230) variant appears to be a founder mutation in Arab populations. Faiyaz-Ul-Haque et al. studied 48 patients with this specific mutation from Arab families (PMID: 35302653; PMID: 36578839). Enrichment of ATS cases in populations with high rates of consanguinity (Middle Eastern, North African, South Asian, Mediterranean) is well documented.
Skin biopsy with electron microscopy shows disease-specific abnormalities: - Fragmented elastic fibers with fragmented elastin core - Peripheral mantle of microfibrils with random directionality - Disorganized collagen fibrils with increased inter-fibrillar spacing - In small muscular arteries: discontinuous internal elastic lamina, lack of myofilaments, disorganized medial smooth muscle cells with vacuolated cytoplasm (PMID: 35302653)
CMA, karyotyping, FISH, mitochondrial DNA testing, and repeat expansion testing are not applicable to ATS diagnosis.
No formal standardized diagnostic criteria (e.g., Ghent-like criteria) exist for ATS. Diagnosis is based on: 1. Clinical features: Generalized arterial tortuosity on imaging + connective tissue features 2. Genetic confirmation: Biallelic pathogenic variants in SLC2A10
Key differential diagnoses:
| Condition | Distinguishing Features | Gene(s) |
|---|---|---|
| Loeys-Dietz syndrome | AD inheritance; hypertelorism, cleft palate/bifid uvula, more aggressive aortopathy | TGFBR1, TGFBR2, SMAD3, TGFB2, TGFB3 |
| Marfan syndrome | AD inheritance; lens subluxation, tall stature, arachnodactyly | FBN1 |
| Vascular EDS (type IV) | AD; thin translucent skin, arterial/organ rupture | COL3A1 |
| Cutis laxa syndromes | More prominent skin laxity, may have systemic features | ELN, FBLN4, FBLN5, ATP6V0A2 |
| Homocystinuria | AR; intellectual disability, lens subluxation, thromboembolism | CBS |
(PMID: 25821090; PMID: 29979900; PMID: 37692180)
Beta-blockers (e.g., atenolol, propranolol) are first-line pharmacological treatment to reduce hemodynamic stress on arterial walls. "To reduce hemodynamic stress on the arterial wall, beta-adrenergic blocking treatment was prescribed" (PMID: 37619836). The rationale is extrapolated from management of Marfan syndrome and other aortopathies — reducing heart rate and blood pressure decreases shear stress on tortuous and dilated vessels.
Losartan (angiotensin II type 1 receptor blocker) has been proposed based on its TGF-β antagonist properties and efficacy in Marfan syndrome mouse models: "In transgenic mouse models it was shown that losartan, an angiotensin II type 1 receptor with known inhibiting effects on TGFbeta, rescues the aortic phenotype" (PMID: 18630721). Clinical efficacy in ATS specifically is not yet established.
May be considered for secondary prevention of cerebrovascular events. One case report described treatment with recombinant tissue plasminogen activator (r-TPA) at 0.9 mg/kg for TIA with complete recovery (PMID: 34847858).
No pharmacogenomic data specific to ATS are available.
Management requires a multidisciplinary approach (PMID: 37692180): - Close monitoring of aortic root early in life - Extensive vascular imaging afterwards - Surveillance and prevention are key - "Our findings warrant attention for IRDS and diaphragmatic hernia, close monitoring of the aortic root early in life, and extensive vascular imaging afterwards" (PMID: 29323665)
Relevant MAXO terms: - MAXO:0000502 — Counseling - MAXO:0000127 — Echocardiography - MAXO:0000004 — Surgical procedure - MAXO:0010033 — Medical management - MAXO:0001298 — Beta-adrenergic antagonist therapy - MAXO:0000079 — Genetic counseling
As a Mendelian genetic disorder, primary prevention of disease occurrence is limited to: - Genetic counseling (MAXO:0000079) for consanguineous families and known carriers - Preimplantation genetic diagnosis (PGD) for families with known mutations - Prenatal genetic testing (CVS, amniocentesis) when familial mutations are established - Carrier screening in populations with known founder mutations (e.g., p.Ser81Arg in Arab populations)
Not applicable — ATS is not an infectious or immune-mediated disorder.
Given the ultra-rare nature of ATS (<1/1,000,000), population-level public health interventions are not practical. Awareness among pediatric cardiologists, geneticists, and prenatal sonographers is the most impactful public health measure.
No naturally occurring animal disease equivalent to human ATS has been reported in veterinary literature or in the OMIA database. This is likely because most animals (including mice, rats, dogs, cats) retain functional L-gulonolactone oxidase (Gulo) and can synthesize ascorbic acid endogenously, compensating for any GLUT10 dysfunction.
| Species | Gene Symbol | NCBI Taxon |
|---|---|---|
| Human (Homo sapiens) | SLC2A10 | 9606 |
| Mouse (Mus musculus) | Slc2a10 | 10090 |
| Zebrafish (Danio rerio) | slc2a10 | 7955 |
| Rat (Rattus norvegicus) | Slc2a10 | 10116 |
The SLC2A10/GLUT10 gene is highly conserved across vertebrates, suggesting an essential role in development. A critical species difference is that mice (but not humans) can synthesize their own ascorbic acid via the gulonolactone oxidase (Gulo) pathway. This likely explains why simple Slc2a10 mutant mice fail to recapitulate the human vascular phenotype, while the Gulo;Slc2a10 double knockout (which eliminates both GLUT10 and endogenous ascorbate synthesis) shows a more informative phenotype (PMID: 32307537).
Guinea pigs and some primates share the human inability to synthesize ascorbic acid (non-functional GULO) and could theoretically manifest ATS-like phenotypes if SLC2A10 were disrupted, but no such models exist.
Not applicable — ATS is a non-infectious genetic disorder with no zoonotic potential or cross-species transmission.
| Model | Species | Vascular Phenotype | ECM Defects | TGF-β Change | Overall Utility |
|---|---|---|---|---|---|
| Slc2a10 G128E/S150F | Mouse | None | None | Not observed | Limited |
| Gulo;Slc2a10 DKO | Mouse | Mild | Yes | Unaltered | Moderate |
| slc2a10 MO | Zebrafish | Yes (CV abnormalities) | Yes (notochord) | Reduced | Good (developmental) |
| Patient fibroblasts | Human | N/A | Yes | Non-canonical ↑ | Good (mechanistic) |
No single model fully recapitulates the severe human vascular phenotype of ATS. This suggests that additional human-specific factors — including the obligate dependence on dietary ascorbate, hemodynamic forces during human cardiovascular development, and perhaps differences in elastic fiber assembly — contribute to disease manifestation.
Synthesizing all available evidence, ATS is best understood as an ascorbate compartmentalization disorder with multi-pathway downstream consequences:
The canonical TGF-β/SMAD pathway, while highlighted in the original discovery paper, appears to be a secondary or context-dependent phenomenon rather than the primary driver. This is supported by: (a) absence of pSMAD2/CTGF upregulation in patient tissues, (b) unaltered TGF-β signaling in the Gulo;Slc2a10 double knockout mouse, and (c) non-canonical rather than canonical pathway activation in patient fibroblasts.
| Paper | PMID | Key Contribution |
|---|---|---|
| Coucke et al. 2006, Nat Genet | 16550171 | Discovery of SLC2A10 as causative gene |
| Beyens et al. 2018, Hum Mutat | 29323665 | Largest cohort (102 patients, 40 new families); comprehensive phenotyping |
| Callewaert et al. 2008, Hum Mutat | 18693279 | Mouse model demonstrating species-specific differences |
| Willaert et al. 2012, Hum Mol Genet | 22116938 | Zebrafish model; mitochondrial function link |
| Németh et al. 2016, FEBS Lett | 27153185 | GLUT10 confirmed as DAA transporter |
| Boel et al. 2020, Hum Mol Genet | 32307537 | Double KO mouse model; ascorbate compartmentalization |
| Zoppi et al. 2015, Hum Mol Genet | 26376865 | Oxidative stress mechanism and non-canonical TGF-β in fibroblasts |
| Callewaert et al. 2008, J Med Genet | 25373504 | Prognosis better than expected; infancy most critical |
| CLARITY study 2025 | 40613586 | Longitudinal cardiovascular data; 71.4% aortic root dilation |
| Al-Khawaga et al. 2022, Eur J Med Genet | 35302653 | Ultrastructural analysis of collagen and elastin in Arab patients |
| Zoppi et al. 2018, Int J Mol Sci | 29587413 | αvβ3 integrin role in ATS fibroblasts |
| Hosen et al. 2020, ACS Omega | 31203799 | In silico GLUT10 structure and substrate binding prediction |
| Paper | PMID | Contribution |
|---|---|---|
| Esmel-Vilomara et al. 2023 | 37619836 | 4 new patients; novel variant p.Leu300Trp; supra-aortic involvement |
| Ekhator et al. 2023 | 37692180 | Comprehensive review of ATS |
| Cotti Piccinelli et al. 2021 | 34847858 | TIA in young adult with ATS; first r-TPA use |
| Liang et al. 2021 | 34384376 | Prenatal ultrasound diagnosis in 2 siblings |
| Alshair et al. 2024 | 38987788 | Pulmonary arterial reconstruction case report |
| Tunks et al. 2025 | 40027906 | Novel p.Ala58Val variant; prenatal diagnosis keys |
| Ponziani et al. 2025 | 39827853 | Concordant dichorionic twins with ATS |
| Debette & Germain 2014 | 24365320 | Neurologic manifestations of connective tissue disorders |
| Al-Habeeb et al. 2024 | 36578839 | Neonatal ATS case; p.Ser81Arg founder mutation |
| Loeys & De Paepe 2008 | 18630721 | TGF-β pathway and losartan in aortic aneurysms |
Ultra-rare disease with limited natural history data: With only ~106 confirmed patients, long-term outcomes, genotype-phenotype correlations, and rare complications may be underestimated or incompletely characterized.
No adequate animal model: No single animal model fully recapitulates human ATS. Mouse models are limited by endogenous ascorbate synthesis, and zebrafish models are limited by developmental and anatomical differences.
Pathomechanism incompletely understood: The relative contributions of ascorbate compartmentalization, TGF-β signaling (canonical vs. non-canonical), oxidative stress, and mitochondrial dysfunction remain unclear. The observation that end-stage tissue shows no canonical TGF-β upregulation creates an apparent contradiction with the original discovery that needs resolution.
No validated biomarkers: No circulating biomarkers exist for disease monitoring, progression prediction, or treatment response assessment.
No formal diagnostic criteria: Unlike Marfan syndrome (Ghent criteria) or EDS (2017 criteria), ATS lacks standardized clinical diagnostic criteria.
Treatment evidence is anecdotal: No clinical trials have been conducted for any intervention. Beta-blocker and losartan use is extrapolated from other aortopathies. The potential role of ascorbate supplementation is speculative.
No quality-of-life studies: Formal patient-reported outcome measures (EQ-5D, SF-36, PROMIS) have not been applied to ATS cohorts.
Omics data are sparse: No large-scale transcriptomic, proteomic, metabolomic, or epigenomic profiling of ATS patient tissues has been published. Single-cell approaches have not been applied.
Genotype-phenotype correlation poorly defined: While variable expressivity is well documented, specific relationships between mutation type/position and disease severity have not been systematically analyzed.
Prenatal natural history: Few cases have been diagnosed prenatally, limiting understanding of fetal disease progression and optimal prenatal management strategies.
International ATS Registry: Establish a prospective, multicenter registry to systematically collect phenotypic, genotypic, treatment, and outcome data across all known patients, building on the CLARITY initiative framework.
Genotype-Phenotype Correlation Study: Using registry data, analyze whether specific mutation types (truncating vs. missense), positions within SLC2A10, or zygosity status (homozygous vs. compound heterozygous) predict disease severity, complication rates, or specific phenotypic features.
Circulating Biomarker Discovery: Profile serum/plasma from ATS patients using targeted proteomics and metabolomics to identify potential biomarkers for disease activity (e.g., ECM turnover markers such as desmosine/isodesmosine for elastin degradation, oxidative stress markers such as 8-isoprostane, TGF-β pathway markers).
Patient-Derived iPSC Vascular Models: Generate iPSC lines from ATS patients, differentiate into vascular smooth muscle cells and endothelial cells, and use these to study vascular pathomechanisms and screen potential therapeutics in a human-relevant system.
Improved Mouse Model: Generate a conditional Slc2a10 knockout on a Gulo-null background with vascular-specific and temporally controlled deletion, combined with controlled dietary ascorbate restriction, to better model human ATS.
Ascorbate Supplementation Pilot Study: Design a controlled clinical study evaluating high-dose ascorbic acid supplementation in ATS patients, monitoring aortic root dimensions, arterial stiffness, vascular tortuosity indices, and circulating biomarkers as endpoints.
Single-Cell RNA Sequencing: Perform scRNA-seq on ATS patient skin biopsies and available vascular tissue to identify cell-type-specific transcriptional signatures, prioritize therapeutic targets, and understand the cellular heterogeneity of disease.
TGF-β Pathway Dissection: Use patient-derived fibroblasts and iPSC-derived vascular cells to systematically dissect canonical vs. non-canonical TGF-β signaling across different cell types and developmental stages, resolving the apparent contradiction between in vitro and in vivo findings.
Gene Therapy Development: Explore AAV-mediated SLC2A10 gene replacement in vascular smooth muscle cells, first validating in the improved mouse model, then progressing toward clinical translation. The in vitro proof-of-concept (GLUT10 re-expression rescuing fibroblast phenotype) is encouraging.
Clinical Treatment Trial: Based on biomarker and mechanistic data, design a randomized controlled trial of pharmacological intervention (losartan, high-dose ascorbate, or novel targeted therapy) in ATS patients, leveraging the international registry for recruitment.
Formal Diagnostic Criteria Development: Convene an international expert panel to establish standardized diagnostic criteria for ATS, analogous to Ghent criteria for Marfan syndrome, incorporating clinical, imaging, and genetic features.
Report generated: 2026-05-05 | Based on analysis of 39 published studies and structured database resources | MONDO:0009005 | OMIM #208050