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Last update 08 May 2025

ATR-X Syndrome

Last update 08 May 2025

Basic Info

Synonyms

ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED, ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, NONDELETION TYPE, ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED

+ [34]

Introduction

A rare, X-linked recessive inherited syndrome caused by mutations in the ATRX gene. It is characterized by intellectual disability, developmental delays, hypotonia, widely spaced eyes, small nose, low-set ears, tented upper lip, skeletal abnormalities, and a mild form of alpha thalassemia.

Drugs associated with ATR-X Syndrome

Cutamesine Hydrochloride

Target

σ1 receptor

Mechanism

σ1 receptor agonists

Active Org.

M's Science Corp. [+2]

Originator Org.

Santen SAS

Active Indication

Amyotrophic Lateral Sclerosis [+3]

Inactive Indication

Acute Ischemic Stroke [+3]

Drug Highest PhasePhase 1

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

Clinical Trials associated with ATR-X Syndrome

JPRN-jRCT2051220062

/ Not yet recruitingPhase 2IIT

Exploratory study to investigate the safety and efficacy of NPJ005 in patients with ATR-X syndrome. - IACT21003

Start Date14 Jul 2022

Sponsor / Collaborator-

NCT03377556

/ CompletedPhase 2IIT

A Phase II Study of Talazoparib (BMN 673) in Patients With Homologous Recombination Repair Deficiency Positive Stage IV Squamous Cell Lung Cancer (Lung-Map Sub-Study)

This phase II trial studies how well talazoparib works in treating patients with homologous recombination repair deficiency (HRRD) positive stage IV squamous cell lung cancer that has come back after previous treatment. Talazoparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Start Date03 Mar 2017

Sponsor / Collaborator

National Cancer Institute

NCT04957069

/ CompletedNot ApplicableIIT

Comparison of Surgical Outcomes Between Avulsion Fracture of the Achilles Tendon and Conventional Achilles Tendon Rupture--a Retrospective Study

To compare the surgical outcomes between avulsion fracture of the Achilles tendon and conventional Achilles tendon rupture, collected and analysed information of patients preoperatively and postoperatively.

Start Date01 Jan 2013

Sponsor / Collaborator

Peking University Third Hospital

100 Clinical Results associated with ATR-X Syndrome

100 Translational Medicine associated with ATR-X Syndrome

0 Patents (Medical) associated with ATR-X Syndrome

269

Literatures (Medical) associated with ATR-X Syndrome

01 Mar 2025·Clinical Imaging

MRI-derived radiomics and end-to-end deep learning models for predicting glioma ATRX status: a systematic review and meta-analysis of diagnostic test accuracy studies

Review

Author: Bathla, Girish ; Ahmadzadeh, Amir Mahmoud ; Sotoudeh, Houman ; Ashoobi, Mohammad Amin ; Lomer, Nima Broomand

We aimed to systematically review and meta-analyze the predictive value of magnetic resonance imaging (MRI)-derived radiomics/end-to-end deep learning (DL) models in predicting glioma alpha thalassemia/mental retardation syndrome X-linked (ATRX) status. We conducted a comprehensive search across four major databases-Web of Science, PubMed, Scopus, and Embase. All the studies that assessed the performance of radiomics and/or end-to-end DL models for predicting glioma ATRX status were included. Quality assessment was performed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) criteria and the METhodological RadiomICs Score (METRICS). Pooled estimates for performance metrics were calculated. I-squared was used to assess heterogeneity, while subgroup and sensitivity analyses were performed to find its potential sources. Publication bias was assessed using Deeks' funnel plots. Seventeen and eleven studies were included in the systematic review and meta-analysis, respectively. Most of the studies had a low risk of bias and low concern for applicability according to the QUADAS-2. Also, most of them had good quality according to the METRICS. Meta-analysis showed a pooled sensitivity of 0.80 (95%CI: 0.71-0.96), a specificity of 0.82 (95%CI: 0.67-0.93), a positive diagnostic likelihood ratio (DLR) of 6.77 (95%CI: 4.67-9.82), a negative DLR of 0.15 (95%CI: 0.06-0.38), a diagnostic odds ratio of 30.36 (95%CI: 15.87-58.05), and an area under the curve (AUC) of 0.92 (95%CI: 0.89-0.94). Subgroup analysis revealed significant intergroup differences based on several factors. Radiomics models can accurately predict ATRX status in gliomas, enhancing non-invasive tumor characterization and guiding treatment strategies.

08 Feb 2025·Nucleic Acids Research

Elevated reactive oxygen species can drive the alternative lengthening of telomeres pathway in ATRX-null cancers

Article

Author: Goncalves, Tomas ; Kent, Thomas ; Cunniffe, Siobhan ; Clynes, David ; Rose, Andrew W ; Geiller, Helene E B ; Gibbons, Richard J ; Mattis, Natalie ; Mole, David R ; Humphrey, Timothy C ; van Bijsterveldt, Linda ; Rose, Anna M ; Ma, Tiffany S ; Hammond, Ester M

AbstractThe alternative lengthening of telomeres (ALT) pathway is a telomerase-independent mechanism for immortalization in cancer cells and is commonly activated in low-grade and high-grade glioma, as well as osteosarcoma. The ALT pathway can be activated under various conditions and has often been shown to include mutational loss of ATRX. However, this is insufficient in isolation and so other cellular event must also be implicated. It has been shown that excessive accumulation of DNA:RNA hybrid structures (R-loops) and/or formation of DNA–protein crosslinks (DPCs) can be other important driving factors. The underlying cellular events leading to R-loop and DPC formation in ALT cancer cells to date remain unclear. Here, we demonstrate that excessive cellular reactive oxygen species (ROS) is an important causative factor in the evolution of ALT-telomere maintenance in ATRX-deficient glioma. We identified three sources of elevated ROS in ALT-positive gliomas: co-mutation of SETD2, downregulation of DRG2, and hypoxic tumour microenvironment. We demonstrate that elevated ROS leads to accumulation of R-loops and, crucially, resolution of R-loops by the enzyme RNase H1 prevents ALT pathway activity in cells exposed to elevated ROS. Further, we found a possible causal link between the formation of R-loops and the accumulation of DPCs, in particular, formation of TOP1 complexes covalently linked to DNA (Top1cc). We also demonstrate that elevation of ROS can trigger over-activity of the ALT pathway in osteosarcoma and glioma cell lines, resulting in excessive DNA damage and cell death. This work presents important mechanistic insights into the endogenous origin of excessive R-loops and DPCs in ALT-positive cancers, as well as highlighting potential novel therapeutic approaches in these difficult-to-treat cancer types.

06 Jan 2025·Clinical Cancer Research

A Translational Study of the ATR Inhibitor Berzosertib as Monotherapy in Four Molecularly Defined Cohorts of Advanced Solid Tumors

Article

Author: Bullock, Andrea ; Zou, Lee ; Gao, Xin ; Kochupurakkal, Bose S. ; Cleary, James M. ; Muzikansky, Alona ; Cote, Gregory M. ; Shapiro, Geoffrey I. ; Do, Khanh ; Weekes, Colin D. ; McLoughlin, Daniel E. ; Park, Jong Chul ; Cheng, Michael L. ; Parikh, Aparna ; Yeku, Oladapo

AbstractPurpose:Preclinical studies have identified molecular correlates of sensitivity to ATR inhibition. This translational study was designed to test the ATR inhibitor berzosertib in patients with advanced solid tumors carrying alterations in ATRX, ataxia-telangiectasia–mutated (ATM), genes conferring replication stress (RS), or SDH.Patients and Methods:Patients were recruited to four cohorts: T1: ATRX-mutant leiomyosarcoma; T2: ATM-mutant solid tumors; T3: solid tumors with mutations in RS-associated genes; and T4: SDH-deficient gastrointestinal stromal tumors (GIST). Patients were treated with berzosertib 240 mg/m2 intravenously twice per week. Pretreatment and on-treatment biopsies were obtained in cohorts T1 to T3.Results:Patients with SDH-mutant GIST had the longest median progression-free survival (PFS; 229 days) with stable disease as the best response. Patients in the other cohorts experienced progressive disease within 4 months. There was no significant difference in PFS comparing outcomes in patients with/without mutations in ATM or RS genes. Decreased pS345-CHK1 levels in on-treatment biopsies indicated target engagement by berzosertib and were accompanied by substantial increases in levels of DNA damage (γ-H2AX) and RS (pKAP1) markers in a subset of patients. However, these biomarker changes did not translate to clinical benefit. In contrast, in cohorts T1 to T3, increased expression of SLFN11 on treatment correlated with clinical benefit (HR = 0.045; 95% confidence interval, 0.005–0.400).Conclusions:Across cohorts, only patients with SDH-mutant GIST experienced prolonged disease control. Despite evidence of target engagement, patients enrolled to all other cohorts had short PFS, suggesting rapid adaptation to ATR inhibitor monotherapy. Among these patients, those with tumors expressing SLFN11 during berzosertib exposure derived the most clinical benefit.

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ATR-X Syndrome

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