Category: Choreas (Non-Huntington's Disease)
Objective: To analyze the clinical spectrum, genotype-phenotype correlations, and prognostic factors in NKX2-1-related disorders (NKX2-1-RD) through a multicenter study, providing insights for improved diagnosis and management.
Background: NKX2-1-RD, also known as Brain-Lung-Thyroid syndrome, is caused by NKX2-1 gene variants, essential for brain, lung, and thyroid development. The disorder typically presents with movement disorders, hypothyroidism, and neonatal respiratory distress syndrome (NRDS). However, its phenotypic spectrum and genotype-phenotype correlations remain poorly understood, necessitating large-scale studies.
Method: This multicenter, cross-sectional, observational study recruited patients with NKX2-1-RD via referral physicians and networks such as the ERN-RND, ERN-ITHACA, and MDS-Pediatric SIG. Clinical and genetic data, including neurological, respiratory, and endocrine assessments, were collected through RedCap at Hospital Sant Joan de Déu, Barcelona. Statistical analyses were conducted with a significance threshold of p<0.05.
Results: A total of 68 individuals with NKX2-1-RD were included, with a mean age at last follow-up of 16 years (±12.3; range, 2–60). The mean age at symptom onset was 0.87 years (±1.47; range, 0–8), with motor delay being the most common initial feature (41.8%). Delayed gait (median 29.5 months) correlated with intellectual disability (p=0.021) and neurodevelopmental impairment (p<0.001). Hypotonia (p=0.002) and untreated hypothyroidism (p=0.032) worsened chorea. Females had more hypotonia (p=0.011), while males showed worse MACS but better chorea evolution (p=0.035). Myoclonus correlated with dystonia (p<0.05), anxiety, and depression (p<0.01). Gait abnormalities were strongly linked to dysarthria (p<0.05). NRDS predicted later respiratory symptoms (87% vs. 45%, p=0.001). Higher AIMS scores correlated with worse MACS (rho=0.414, p=0.003) and GMFCS (rho=0.294, p=0.035). Variants vs. deletions increased respiratory symptoms (p=0.016). Chorea-specific treatments were used in 55.6% of cases, with variable efficacy and retention rates.
Conclusion: This study, the largest NKX2-1-RD cohort to date, highlights early neurological manifestations, genotype-specific outcomes, and novel associations, such as myoclonus with mental health conditions. These findings enhance clinical understanding and offer guidance for future research and patient management.
To cite this abstract in AMA style:
JD. Ortigoza-Escobar, L. Nou-Fontanet, C. Ravelli, S. Balsells Mejia, E. Roman Schiffels, A. Innocenti, B. Villafuerte, A. Salazar, V. Quiroz, A. Sariego Jamardo, G. Bonato, A. Díaz-Gomez, A. Afenjar, C. Vilain, P. Dumke Dasilva, D. Garcia-Navas Nuñez, M. Krygier, MJ. Molnar, L. Milanowski, K. Ounap, M. Pauni, R. Borie, P. Vega, M. Villamil, S. Yilmaz, D. Zádori, M. Zawadzka, TS. Barakat, N. Sebastian, D. Natera Debenito, L. Soliani, CM. de Gusmao, G. Garone, N. Specchio, M. Carecchio, JC. Moreno, F. Magrinelli, D. Ebrahimi-Fakhari, C. Castiglioni, M. Kurian, JN. Carvalho, R. Pons, E. Flamand-Roze, D. Doummar. Unraveling NKX2-1-related disorders: clinical, genetic, and neuroimaging insights from a global cohort [abstract]. Mov Disord. 2025; 40 (suppl 1). https://www.mdsabstracts.org/abstract/unraveling-nkx2-1-related-disorders-clinical-genetic-and-neuroimaging-insights-from-a-global-cohort/. Accessed October 5, 2025.« Back to 2025 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/unraveling-nkx2-1-related-disorders-clinical-genetic-and-neuroimaging-insights-from-a-global-cohort/