Register for Patients With Thyroid Hormone Resistance.

NCT ID: NCT06566066

Last Updated: 2024-08-22

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 200 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2021-07-01
• Study Completion Date: 2029-07-31

Brief Summary

Thyroid hormones (TH) play a pivotal role in the development and function of the mammalian brain. Patients with impaired thyroid hormone transport into the brain tissue or in the case of defective local thyroid hormone receptor (collectively referred to as thyroid hormone resistance) subsequently experience psychomotor disabilities.

The "DEEPTYPE" registry has been established with the objective of intensifying the genotyping and, in particular, the neurological phenotyping of patients exhibiting deficiencies in either the thyroid hormone transporter (MCT8) or the thyroid hormone receptor alpha (THRα). The objective of this registry-based study is to enhance the diagnostic yield for MCT8 and THRα deficiencies by employing the serum fT3/fT4 ratio as a more sophisticated screening parameter. Furthermore, the investigators will study the genomic regulation of both genes and attempt to identify further coding and non-coding mutations that result in TH resistance. The patient registry "DEEPTYPE" will document the retrospective and prospective clinical data of identified children in a comprehensive manner. This will enable the identification of three key groups: (i) patients with non-coding mutations, (ii) patients with milder phenotypes presenting only with a subset of symptoms seen in both "classic" conditions, and (iii) patients who are ready for clinical trials.

Detailed Description

Thyroid hormones (TH) are of vital importance in the development and functioning of the brain. A deficiency in fetal thyroid hormone (TH) supply has been linked to significant psychomotor retardation in children born in regions with inadequate iodine supply. Insufficient postnatal production of thyroid hormones (TH) can result in intellectual and motor disabilities. These can be prevented by L-thyroxine (T4) supplementation in children with congenital hypothyroidism immediately after birth.

However, in the event of impaired transport of thyroid hormones into the brain tissue or in the case of defective local thyroid hormone receptors, the cerebral action of these hormones is impeded despite the presence of a sufficient thyroid hormone production. Such conditions may result from mutations in either SLC16A2, which encodes the monocarboxylate transporter 8 (MCT8), or THRA, which codes for the thyroid hormone receptor alpha (THRα). THRα is widely expressed in the central nervous system (CNS). In both instances, the absence of local TH action results in severe intellectual disability, developmental delay, movement disorders, and decreased brain volumes. In contrast to the outcomes observed in cases of congenital hypothyroidism, treatment trials involving the substitution of TH were ineffective in preventing the neurological phenotype in these children.

The full genotypic and phenotypic spectrum of these children has yet to be explored. It is anticipated that both conditions will be significantly underdiagnosed, given that awareness of these differential diagnoses within the pediatric community remains limited. As the standard screening parameters, such as thyroid-stimulating hormone (TSH), are not altered, the condition is frequently overlooked and is most often only "accidentally" diagnosed through next-generation sequencing.

The sole endocrine irregularity is a relative elevation of 3,3',5-triiodothyronine (T3) in comparison to T4. However, this is not a parameter that is routinely measured. More often the concentrations of the free plasma concentrations of these hormones, e.g. fT3 and fT4, are measured.

To date, only patients with mutations in the coding regions of the respective loci have been described. It can be reasonably assumed that mutations in the non-coding regulatory regions will result in disruption of the tissue-specific TH action in the MCT8/THRα-deficient brain. Similarly, disruptions in gene expression resulting from mutant regulatory enhancer sequences have recently been identified in other endocrine disorders, including congenital diabetes and brain developmental disorders.

The objective of this study is to enhance the diagnostic yield for MCT8 and THRα deficiencies by employing the serum fT3/fT4 ratio as a potentially more sophisticated screening parameter. Furthermore, the investigators will study the genomic regulation of both genes. The patient registry "DEEPTYPE" will be used to comprehensively document retrospective and prospective clinical data of identified children with coding or non-coding mutations. This will enable the investigators to identify patients with non-coding mutations and discover patients with milder phenotypes presenting only with a subset of symptoms seen in both "classic" conditions.

Conditions

Hypothyroidism; Global Developmental Delay; Intellectual Disability; Dystonia; Muscle Hypotonia; Seizures; Allan-Herndon-Dudley Syndrome; Microcephalus

Study Design

• Observational Model Type: CASE_ONLY
• Study Time Perspective: OTHER

Study Groups

Patients with mutations in SLC16A2

Text

no intervention

Intervention Type: OTHER

register study without intervention

Patients with mutations in THRA

Text

no intervention

Intervention Type: OTHER

register study without intervention

Interventions

no intervention

register study without intervention

Intervention Type: OTHER

Other Intervention Names

does not apply

Eligibility Criteria

Inclusion Criteria

• Presence of a coding or non-coding mutation in SLC16A2
• Presence of a coding or non-coding mutation in THRA
• Abnormal fT3/fT4 ratio in the serum
• Written informed consent of the caregivers for participation in the register study

Exclusion Criteria

• Withdrawal of consent
• Correction/change of the molecular diagnosis

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Charite University, Berlin, Germany

OTHER

Sponsor Role: lead

Responsible Party

Markus Schuelke, M.D.

Prof. Dr. med. Markus Schülke-Gerstenfeld

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Heiko Krude, MD

Role: PRINCIPAL_INVESTIGATOR

Charite University, Berlin, Germany

Locations

Charite - Universitaetsmedizin Berlin

Berlin, , Germany

Site Status: RECRUITING

Countries

Germany

Central Contacts

Nina-Maria Wilpert

Role: CONTACT

nina-maria.wilpert@charite.de

+49 30 450 ext. 616207

Markus Schülke-Gerstenfeld, MD

Role: CONTACT

markus.schuelke@charite.de

+49 30 450 ext. 566112

Facility Contacts

Nina M Wilpert, MD/PhD

Role: primary

nina-maria.wilpert@charite.de

+49 30 450 616207

Markus Schülke, MD

Role: backup

markus.schuelke@charite.de

+49 30 4505 66112

References

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Reference Type: BACKGROUND

PMID: 32143555 (View on PubMed)

Friesema EC, Grueters A, Biebermann H, Krude H, von Moers A, Reeser M, Barrett TG, Mancilla EE, Svensson J, Kester MH, Kuiper GG, Balkassmi S, Uitterlinden AG, Koehrle J, Rodien P, Halestrap AP, Visser TJ. Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet. 2004 Oct 16-22;364(9443):1435-7. doi: 10.1016/S0140-6736(04)17226-7.

Reference Type: BACKGROUND

PMID: 15488219 (View on PubMed)

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Reference Type: BACKGROUND

PMID: 31410843 (View on PubMed)

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Reference Type: BACKGROUND

PMID: 31377265 (View on PubMed)

Groeneweg S, van Geest FS, Abaci A, Alcantud A, Ambegaonkar GP, Armour CM, Bakhtiani P, Barca D, Bertini ES, van Beynum IM, Brunetti-Pierri N, Bugiani M, Cappa M, Cappuccio G, Castellotti B, Castiglioni C, Chatterjee K, de Coo IFM, Coutant R, Craiu D, Crock P, DeGoede C, Demir K, Dica A, Dimitri P, Dolcetta-Capuzzo A, Dremmen MHG, Dubey R, Enderli A, Fairchild J, Gallichan J, George B, Gevers EF, Hackenberg A, Halasz Z, Heinrich B, Huynh T, Klosowska A, van der Knaap MS, van der Knoop MM, Konrad D, Koolen DA, Krude H, Lawson-Yuen A, Lebl J, Linder-Lucht M, Lorea CF, Lourenco CM, Lunsing RJ, Lyons G, Malikova J, Mancilla EE, McGowan A, Mericq V, Lora FM, Moran C, Muller KE, Oliver-Petit I, Paone L, Paul PG, Polak M, Porta F, Poswar FO, Reinauer C, Rozenkova K, Menevse TS, Simm P, Simon A, Singh Y, Spada M, van der Spek J, Stals MAM, Stoupa A, Subramanian GM, Tonduti D, Turan S, den Uil CA, Vanderniet J, van der Walt A, Wemeau JL, Wierzba J, de Wit MY, Wolf NI, Wurm M, Zibordi F, Zung A, Zwaveling-Soonawala N, Visser WE. Disease characteristics of MCT8 deficiency: an international, retrospective, multicentre cohort study. Lancet Diabetes Endocrinol. 2020 Jul;8(7):594-605. doi: 10.1016/S2213-8587(20)30153-4.

Reference Type: BACKGROUND

PMID: 32559475 (View on PubMed)

Tonduti D, Vanderver A, Berardinelli A, Schmidt JL, Collins CD, Novara F, Genni AD, Mita A, Triulzi F, Brunstrom-Hernandez JE, Zuffardi O, Balottin U, Orcesi S. MCT8 deficiency: extrapyramidal symptoms and delayed myelination as prominent features. J Child Neurol. 2013 Jun;28(6):795-800. doi: 10.1177/0883073812450944. Epub 2012 Jul 17.

Reference Type: BACKGROUND

PMID: 22805248 (View on PubMed)

Masnada S, Sarret C, Antonello CE, Fadilah A, Krude H, Mura E, Mordekar S, Nicita F, Olivotto S, Orcesi S, Porta F, Remerand G, Siri B, Wilpert NM, Amir-Yazdani P, Bertini E, Schuelke M, Bernard G, Boespflug-Tanguy O, Tonduti D. Movement disorders in MCT8 deficiency/Allan-Herndon-Dudley Syndrome. Mol Genet Metab. 2022 Jan;135(1):109-113. doi: 10.1016/j.ymgme.2021.12.003. Epub 2021 Dec 16.

Reference Type: RESULT

PMID: 34969638 (View on PubMed)

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Reference Type: RESULT

PMID: 37881807 (View on PubMed)

Other Identifiers

EA2_026_20

Identifier Type: -

Identifier Source: org_study_id