Register for Patients With Thyroid Hormone Resistance.

NCT06566066 | Recruiting

• 1 other identifier: EA2_026_20
• Study Type: observational
• Target: 200
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (3)

• Description of infant motor and language development

  Bayley Scales of Infant and Toddler Development III =\> (Units on a Scale and Sum Score)

  5 years

• Description of neurological abnormalities

  Hammersmith Infant Neurological Examination (HINE) =\> (Units on a Scale and Sum Score)

  5 years

• Description of motor development

  Gross Motor Function Measure (GMFM-88) =\> (Units on a Scale and Sum Score)

  5 years

Secondary Outcomes (17)

• body weight

  5 years

• body length

  5 years

• head circumference

  5 years

• Reponse to therapies (e.g. Triac, DIPTA, levodopa/carbidopa)

  5 years

• T3

  5 years

Study Arms (2)

Patients with mutations in SLC16A2

Text

Other: no intervention

Patients with mutations in THRA

Text

Other: no intervention

Interventions

no intervention OTHER

register study without intervention

Also known as: does not apply

Patients with mutations in SLC16A2; Patients with mutations in THRA

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• 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)

You may qualify if:

• 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

You may not qualify if:

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

Sponsors & Collaborators

• Charite University, Berlin, Germany: lead

Study Sites (1)

Charite - Universitaetsmedizin Berlin

Berlin, 13353, Germany

RECRUITING

Related Publications (8)

• 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.

  PMID: 32143555 BACKGROUND

• 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.

  PMID: 15488219 BACKGROUND

• 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.

  PMID: 31410843 BACKGROUND

• 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.

  PMID: 31377265 BACKGROUND

• 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.

  PMID: 32559475 BACKGROUND

• 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.

  PMID: 22805248 BACKGROUND

• 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.

  PMID: 34969638 RESULT

• 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.

  PMID: 37881807 RESULT

MeSH Terms

Conditions

Hypothyroidism; Learning Disabilities; Intellectual Disability; Dystonia; Muscle Hypotonia; Seizures; Allan-Herndon-Dudley syndrome; Microcephaly; Thyroid Hormone Resistance Syndrome

Condition Hierarchy (Ancestors)

Thyroid Diseases; Endocrine System Diseases; Communication Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Neurodevelopmental Disorders; Mental Disorders; Dyskinesias; Neuromuscular Manifestations; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Musculoskeletal Diseases; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Hyperthyroxinemia

Study Officials

• Heiko Krude, MD

  Charite University, Berlin, Germany

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Nina-Maria Wilpert

CONTACT

+49 30 450; nina-maria.wilpert@charite.de

Markus Schülke-Gerstenfeld, MD

CONTACT

+49 30 450; markus.schuelke@charite.de

Study Design

• Study Type: observational
• Observational Model: CASE ONLY
• Time Perspective: OTHER
• Target Duration: 5 Years
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Prof. Dr. med. Markus Schülke-Gerstenfeld

Study Record Dates

• First Submitted: August 11, 2024
• First Posted: August 22, 2024
• Study Start: July 1, 2021
• Primary Completion (Estimated): July 14, 2029
• Study Completion (Estimated): July 31, 2029
• Last Updated: August 22, 2024

Record last verified: 2024-08

Locations

DE (1)