Objective: NKX2-1-related disorders encompass a spectrum extending from benign hereditary chorea (BHC) to choreoathetosis, hypothyroidism, neonatal respiratory distress. The prevalence of chorea remains undetermined, albeit 28 affected individuals from 13 families harboring a heterozygous NKX2-1 pathogenic variant exhibited chorea and hypotonia.

Background: We present a case detailing a patient exhibiting a unique mutation within the NKX2-1 gene.

Method: A 24-year-old male patient was admitted presenting with symptoms of involuntary movements. Progressive neurological impairment was observed, manifested initially as difficulties in walking and balance, with developmental delays noted as early as 1.5 years of age. Over time, these difficulties became increasingly apparent. Neurological examination revealed increased deep tendon reflexes, chorea in the left upper and lower limbs, moderate hypotonia, truncal ataxia, and impaired tandem gait. His antistreptolysin-O (ASO) titers and peripheral blood analysis for acanthocytes, yielded negative results. MRI demonstrated cerebellar atrophy. A family history revealed similar clinical features in the patient’s mother, characterized by choreathetoid movements in all limbs, global hypotonia, and tandem gait impairment, along with cerebellar atrophy evident on MRI. Given the patient’s clinical presentation, developmental trajectory, and familial correlation, a diagnosis of genetically inherited chorea was considered. The patient underwent genetic analysis. Clinical exome sequencing identified a genetic alteration resulting in a c.200_225dup, p.(Alz76Argfs*34) protein change due to a frameshift mutation located at chr14:36988427 in the NKX2-1 gene and NM_001079668 transcript.

Results: This genomic alteration was identified in association with benign hypotonia. Notably, a number sign (#) is utilized in the OMIM (Online Mendelian Inheritance in Man) entry, denoting that certain individuals with BHC exhibit heterozygous mutations within the NKX2-1 gene (600635), responsible for encoding thyroid transcription factor-1 (TITF1), located on chromosome 14q13.

Conclusion: Enhanced comprehension of the breadth of clinical manifestations and underlying pathogenic mechanisms associated with this mutation necessitates forthcoming collaborative multicenter longitudinal investigations, establishment of novel laboratory disease models, and implementation of expansive clinical trial initiatives.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/a-novel-mutation-of-nkx2-1-gene-a-rare-presentation-of-chorea/