Clinical trial NCT06566066: Register for Patients With Thyroid Hormone Resistance.
Official title: Deep Geno- and Phenotyping of Patients With Thyroid Hormone Resistance, a Register Study.
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Hypothyroidism
Global Developmental Delay
Intellectual Disability
Dystonia
Muscle Hypotonia
Seizures
Allan-Herndon-Dudley Syndrome
Microcephalus
Keywords: Thyroid hormone
Thyroid hormone resistance
MCT8
SLC16A2
THRA deficiency
Myelination
Lead sponsor: Charite University, Berlin, Germany
Sponsor class: OTHER
First posted: 2024-08-22
Enrollment: 200
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: OTHER
Sampling method: NON_PROBABILITY_SAMPLE
Study population: * Patients with THRα deficiency =\> Patients in whom a coding or non-coding pathogenic mutation was found in the THRA-gene or its regulating genomic regions (e.g. enhancers, promoters)
* Patients with MCT8 deficiency =\> Patients in whom a coding or non-coding pathogenic mutation was found in the SLC16A2-gene or its regulating genomic regions (e.g. enhancers, promoters)

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.

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

Primary outcomes:
measure: Description of infant motor and language development
timeFrame: 5 years
measure: Description of neurological abnormalities
timeFrame: 5 years
measure: Description of motor development
timeFrame: 5 years
Secondary outcomes:
measure: body weight
timeFrame: 5 years
measure: body length
timeFrame: 5 years
measure: head circumference
timeFrame: 5 years
measure: Reponse to therapies (e.g. Triac, DIPTA, levodopa/carbidopa)
timeFrame: 5 years
measure: T3
timeFrame: 5 years
measure: T4
timeFrame: 5 years
measure: fT3
timeFrame: 5 years
measure: fT4
timeFrame: 5 years
measure: TSH
timeFrame: 5 years
measure: CSF fT3
timeFrame: 5 years
measure: CSF fT4
timeFrame: 5 years
measure: CSF levodopa
timeFrame: 5 years
measure: CSF homovanillic acid (HVA)
timeFrame: 5 years
measure: CSF 5-hydroxyindoleacetic acid (5-HIAA)
timeFrame: 5 years
measure: Quantification of dystonia
timeFrame: 5 years
measure: Quantification of parkinsonism in children
timeFrame: 5 years
measure: Quanitification of cerebral palys symptomes
timeFrame: 5 years
Other outcomes:
Locations:
city: Berlin
country: Germany
facility: Charite - Universitaetsmedizin Berlin
Study officials:
affiliation: Charite University, Berlin, Germany
name: Heiko Krude, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wilpert NM, Krueger M, Opitz R, Sebinger D, Paisdzior S, Mages B, Schulz A, Spranger J, Wirth EK, Stachelscheid H, Mergenthaler P, Vajkoczy P, Krude H, Kuhnen P, Bechmann I, Biebermann H. Spatiotemporal Changes of Cerebral Monocarboxylate Transporter 8 Expression. Thyroid. 2020 Sep;30(9):1366-1383. doi: 10.1089/thy.2019.0544. Epub 2020 Apr 17.
citation: 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.
citation: Remerand G, Boespflug-Tanguy O, Tonduti D, Touraine R, Rodriguez D, Curie A, Perreton N, Des Portes V, Sarret C; RMLX/AHDS Study Group. Expanding the phenotypic spectrum of Allan-Herndon-Dudley syndrome in patients with SLC16A2 mutations. Dev Med Child Neurol. 2019 Dec;61(12):1439-1447. doi: 10.1111/dmcn.14332. Epub 2019 Aug 13.
citation: Groeneweg S, Peeters RP, Moran C, Stoupa A, Auriol F, Tonduti D, Dica A, Paone L, Rozenkova K, Malikova J, van der Walt A, de Coo IFM, McGowan A, Lyons G, Aarsen FK, Barca D, van Beynum IM, van der Knoop MM, Jansen J, Manshande M, Lunsing RJ, Nowak S, den Uil CA, Zillikens MC, Visser FE, Vrijmoeth P, de Wit MCY, Wolf NI, Zandstra A, Ambegaonkar G, Singh Y, de Rijke YB, Medici M, Bertini ES, Depoorter S, Lebl J, Cappa M, De Meirleir L, Krude H, Craiu D, Zibordi F, Oliver Petit I, Polak M, Chatterjee K, Visser TJ, Visser WE. Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019 Sep;7(9):695-706. doi: 10.1016/S2213-8587(19)30155-X. Epub 2019 Jul 31.
citation: 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.
citation: 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.
citation: 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.
citation: Wilpert NM, Tonduti D, Vaia Y, Krude H, Sarret C, Schuelke M. Establishing Patient-Centered Outcomes for MCT8 Deficiency: Stakeholder Engagement and Systematic Literature Review. Neuropsychiatr Dis Treat. 2023 Oct 20;19:2195-2216. doi: 10.2147/NDT.S379703. eCollection 2023.