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Review
. 2024 Sep;131(9):1013-1024.
doi: 10.1007/s00702-024-02800-3. Epub 2024 Jun 25.

Differential diagnosis of Huntington's disease- neurological aspects of NKX2-1-related disorders

Julia Skwara  1 , Maciej Nowicki  1 , Lucia Sharif  1 , Łukasz Milanowski  2 , Jarosław Dulski  3   4 , Ewelina Elert-Dobkowska  5 , Katarzyna Skrzypek  6 , Dorota Hoffman-Zacharska  6 , Dariusz Koziorowski  7 , Jarosław Sławek  3   8
Affiliations
Review

Differential diagnosis of Huntington's disease- neurological aspects of NKX2-1-related disorders

Julia Skwara et al. J Neural Transm (Vienna). 2024 Sep.

Abstract

Benign hereditary chorea (BHC) is an inherited neurological disorder consisting of childhood-onset, nonprogressive chorea, generally without any other manifestations. In most reported cases, the inheritance of BHC is autosomal dominant but both incomplete penetrance and variable expressivity are observed and can be caused by NKX2-1 mutations. The spectrum contains choreoathetosis, congenital hypothyroidism, and neonatal respiratory distress syndrome. The neurological symptoms can be misdiagnosed as Huntington's disease (HD). The two Polish families were diagnosed with NKX2-1 gene mutations and a literature review concerning the NKX2-1-related disorders was conducted. All family members were examined by experienced movement disorders specialists. PubMed database was searched to obtain previously described NKX2-1 cases. Whole exome sequencing (WES) was performed in one proband (Family A) and direct NKX2-1 sequencing in the second (Family B). Two Polish families were diagnosed with NKX2-1 gene mutations (p.Trp208Leu and p.Cys117Alafs*8). In one family, the co-occurrence of HD was reported. Forty-nine publications were included in the literature review and symptoms of 195 patients with confirmed NKX2-1 mutation were analyzed. The most common symptoms were chorea and choreiform movements, and delayed motor milestones. The NKX2-1 mutation should always be considered as a potential diagnosis in families with chorea, even with a family history of HD. Lack of chorea does not exclude the NKX2-1-related disorders.

Keywords: NKX2-1; NKX2-1-related disorders; Benign hereditary chorea; Brain-lung-thyroid syndrome; Dystonia; Huntington’s disease.

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Conflict of interest statement

The authors have no relevant financial or non-financial interests to disclose.

Figures

Fig. 1
Fig. 1
Phenotypes of NKX2-1-related disorders. It may manifest in one organ, or any combination, with all three being the “brain-lung-thyroid” syndrome. Created with BioRender.com
Fig. 2
Fig. 2
Upstream and downstream targets of NKX2-1. * activation in cooperation with PAX8. ** inhibits NKX2-1 in inflammation. SP, surfactant protein; CCSP, clara cell secretory protein; BMP-4, bone morphogenic protein 4; URP-1, uteroglobin related protein 1; NestBS, nestin binding site; ABCA, ATP-binding cassette sub-family A; RET, rearranged during transfection gene; SCGB3A2, secretoglobin 3A2. Based on Atlas of Genetics and Cytogenetics in Oncology and Haematology (Wilbertz et al. 2010). Created with BioRender.com
Fig. 3
Fig. 3
Pedigree of two described families carrying the NKX2-1 mutations Family A (p.Thr208Leu) and Family B (p.Cys117Alafs*8).
See this image and copyright information in PMC

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