Ignite Creation Date:
2024-05-06 @ 8:15 PM
Last Modification Date:
2024-10-26 @ 3:23 PM
Study NCT ID:
NCT06307990
Status:
RECRUITING
Last Update Posted:
2024-03-13
First Post:
2024-03-06
Brief Title:
Understanding Diagnosis and Monitoring of Thyroid Hormone Action Defects
Sponsor:
Istituto Auxologico Italiano
Organization:
Istituto Auxologico Italiano
Study Overview
Official Title:
Advancing Understanding Diagnosis and Monitoring of Thyroid Hormone Action Defects ADAM-THAD
Status:
RECRUITING
Status Verified Date:
2024-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ADAM-THAD
Brief Summary:
The goal of this observational study is to learn about the neurological and cardiological phenotype of patients with resistance to thyroid hormone RTH syndromes beta and alpha RTHß and RTHa due to dominant negative variants in the genes encoding the thyroid hormone receptors alpha THRA and beta THRB
The main questions it aims to answer are
Define frequency and improve early diagnosis for RTH syndromes
Developing tools to accelerate diagnosis of RTH syndromes
Development and validation of monitoring tools
Participants recruited at neonatal screening or from cohorts of patients with unexplained specific neuro-cognitive or cardiovascular phenotypes will be submitted to biochemical and genetic investigations In addition pluripotent stem cells will be generated from peripheral blood cells of RTHs patients and studied in vitro to understand the molecular mechanisms underlying neurological and cardiovascular consequences In vitro and clinical data will be correlated to identify biomarkers for monitoring treatment
The main questions it aims to answer are
Define frequency and improve early diagnosis for RTH syndromes
Developing tools to accelerate diagnosis of RTH syndromes
Development and validation of monitoring tools
Participants recruited at neonatal screening or from cohorts of patients with unexplained specific neuro-cognitive or cardiovascular phenotypes will be submitted to biochemical and genetic investigations In addition pluripotent stem cells will be generated from peripheral blood cells of RTHs patients and studied in vitro to understand the molecular mechanisms underlying neurological and cardiovascular consequences In vitro and clinical data will be correlated to identify biomarkers for monitoring treatment
Detailed Description:
TH action defects THAD are a group of rare syndromes characterized by abnormal thyroid hormone TH cell signaling due to defective transport metabolism or action of TH via binding with nuclear receptors TRs there are two TRs the alpha TRa and beta TRß receptors Among them mutations of THRA or THRB genes cause two distinct syndromes with Resistance to Thyroid Hormone RTH action whose incidence was estimated 120000-50000 newborns likely representing the most frequent THAD forms RTHa is due to dominant negative DN heterozygous mutations in THRA and characterized by dramatic manifestations in TRa-expressing tissues resembling untreated congenital hypothyroidism CH
RTHß is due to DN heterozygous THRB mutations which cause variable TH resistance in TRß-expressing tissues hypothalamus pituitary liver resulting in distinctive biochemical signature high free TH and unsuppressed TSH together with additional features like deafness impaired color vision and thyrotoxic-related symptoms goiter tachyarrhythmias osteoporosis anxiety and Attention-DeficitHyperactivity Disorder ADHD
Outstandingly early treatment with TH or its analogues is expected to reduce most of the adverse consequences of RTHs but earlyneonatal diagnosis is presently not feasible due to the lack of accurate biomarkers Indeed uniform characterization is essential for a rare disease and establishment of clear-cut endocrine fingerprints for RTHa and RTHß are essential for a timely diagnosis
In addition the wide application of next generation sequencing NGS has yielded an unprecedented wealth of genetic information calling for proper instruments to distinguish benign from pathogenic variants
Finally biomarkers for monitoring treatment of these conditions have not been established or validated
This study aim to
1 develop neonatal screening strategies for THAD and give unprecedented epidemiological characterization of RTHs in Italy
2 understand the pathogenicity of newly discovered THRB or THRA variants in in vivo model or identify new mechanisms
3 generate induced pluripotent stem cells from RTH patients to understand the molecular mechanisms underlying neurological and cardiovascular consequences and correlate in vitro and clinical data with the final goal to identify potential biomarkers for monitoring treatment of these rare diseases
RTHß is due to DN heterozygous THRB mutations which cause variable TH resistance in TRß-expressing tissues hypothalamus pituitary liver resulting in distinctive biochemical signature high free TH and unsuppressed TSH together with additional features like deafness impaired color vision and thyrotoxic-related symptoms goiter tachyarrhythmias osteoporosis anxiety and Attention-DeficitHyperactivity Disorder ADHD
Outstandingly early treatment with TH or its analogues is expected to reduce most of the adverse consequences of RTHs but earlyneonatal diagnosis is presently not feasible due to the lack of accurate biomarkers Indeed uniform characterization is essential for a rare disease and establishment of clear-cut endocrine fingerprints for RTHa and RTHß are essential for a timely diagnosis
In addition the wide application of next generation sequencing NGS has yielded an unprecedented wealth of genetic information calling for proper instruments to distinguish benign from pathogenic variants
Finally biomarkers for monitoring treatment of these conditions have not been established or validated
This study aim to
1 develop neonatal screening strategies for THAD and give unprecedented epidemiological characterization of RTHs in Italy
2 understand the pathogenicity of newly discovered THRB or THRA variants in in vivo model or identify new mechanisms
3 generate induced pluripotent stem cells from RTH patients to understand the molecular mechanisms underlying neurological and cardiovascular consequences and correlate in vitro and clinical data with the final goal to identify potential biomarkers for monitoring treatment of these rare diseases
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None