NKX2-1 – Hereditary Progressive Chorea Without Dementia

NKX2-1 (thyroid transcription factor-1) is causally linked to benign hereditary chorea, clinically defined as autosomal dominant, early-onset, nonprogressive chorea without cognitive decline. The disorder, also known as hereditary progressive chorea without dementia, exhibits pleiotropy with variable respiratory and thyroid involvement. Pathogenic variants in NKX2-1 have been identified in multiple unrelated families worldwide, establishing a robust gene–disease relationship.

Initial familial reports described a heterozygous nonsense variant c.745C>T (p.Gln249Ter) segregating with chorea in a mother–son pair ([PMID:16220345]) and a de novo c.619G>T (p.Glu207Ter) in a UK mother–daughter duo presenting chorea, ataxia, hypothyroidism, and pituitary cyst ([PMID:24930029]). A Norwegian four-generation kindred with eight affected members carrying c.671T>G (p.Leu224Arg) highlighted intrafamilial phenotypic variability, including motor delay, dystonia, and myoclonus ([PMID:26839702]). Larger series involving 28 mutated patients from 13 families confirmed private loss-of-function and missense variants in >100 probands ([PMID:22832740]).

The variant spectrum spans nonsense, frameshift, splice-site, missense, and regulatory deletions. Most variants are unique to individual families; recurrent alleles are rare. Functional studies uniformly demonstrate impaired DNA binding and transcriptional activation of thyroid and surfactant promoters. For instance, the R178X mutant fails to bind DNA or activate promoters, resulting in cytoplasmic mislocalization and haploinsufficiency ([PMID:17765926]).

Mechanistically, NKX2-1 haploinsufficiency underlies the choreic phenotype via loss of homeodomain-mediated transcriptional regulation. Dominant-negative effects have been reported, with certain variants exhibiting impaired synergism with PAX8 and TAZ co-factors, modulating thyroid and lung manifestations. Animal models heterozygous for Ttf1 deletion recapitulate coordination deficits and TSH elevation, supporting haploinsufficiency as a key driver of disease ([PMID:11854318]).

One study found no TITF1/NKX2-1 variants in sporadic or late-onset chorea cases, suggesting that NKX2-1 screening is most informative in early-onset, nonprogressive chorea with thyroid or pulmonary features ([PMID:16830318]).

Collectively, genetic and functional data fulfill ClinGen criteria for a Strong clinical validity classification. NKX2-1 testing is recommended in patients with early-onset chorea, especially when accompanied by thyroid or respiratory signs. Identification of pathogenic variants informs prognosis, guides surveillance for multi-organ involvement, and supports genetic counseling.

References

• Neurogenetics • 2005 • Nonsense mutation in TITF1 in a Portuguese family with benign hereditary chorea. PMID:16220345
• Cerebellum & ataxias • 2016 • Benign hereditary chorea, not only chorea: a family case presentation. PMID:26839702
• Cerebellum (London, England) • 2014 • A novel de novo mutation of the TITF1/NKX2-1 gene causing ataxia, benign hereditary chorea, hypothyroidism and a pituitary mass in a UK family and review of the literature. PMID:24930029
• Journal of neurology, neurosurgery, and psychiatry • 2012 • Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene. PMID:22832740
• Journal of the neurological sciences • 2008 • Functional characterization of a novel mutation in TITF-1 in a patient with benign hereditary chorea. PMID:17765926
• Movement disorders : official journal of the Movement Disorder Society • 2006 • Mutations in TITF1 are not relevant to sporadic and familial chorea of unknown cause. PMID:16830318

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