An international study improves clinical prediction in genetic disorders related to NKX2-1

An international multicenter study has analyzed the largest cohort published so far of people with NKX2-1-related disorders. The work, titled International Registry of NKX2-1-Related Disorders: Clinical, Genetic, and Imaging Perspectives, published in the scientific journal Movement Disorders, included 68 patients with genetically confirmed diagnosis and collected clinical, genetic and neuroimaging information through an international registry coordinated from SJD Barcelona Children's Hospital in Barcelona. The main finding is that early motor delay is the most frequent initial manifestation and that there are relevant associations between the type of genetic variant and the clinical evolution, especially in relation to respiratory involvement and chorea, a movement disorder characterized by involuntary, abrupt and irregular movements that can affect the face, arms or legs.

NKX2-1-related disorders

NKX2-1-related disorders are genetic diseases caused by alterations in the NKX2-1 gene. This gene is essential for the development of the brain, lungs and thyroid gland.

Traditionally they are described by the involvement of three main organs:
- Brain (movement disorder, especially chorea)
- Lungs (respiratory problems, often from birth)
- Thyroid (hypothyroidism)

However, the clinical expression is variable, which makes diagnosis and prediction of prognosis difficult.

Main results of the study

• Study design: International multicenter observational research that included 68 patients with genetically confirmed diagnosis, with standardized collection of clinical and genetic data.
• Key genetic findings: Most patients presented small changes in the NKX2-1 gene. Some types of genetic alterations that affect the functioning of the gene more intensely were related to greater respiratory involvement. In contrast, alterations located in a specific region of the gene (called the homeobox domain, in exon 3) were associated with a more stable evolution of the movement disorder (chorea), that is, with less worsening over time.
• Main clinical impact: Chorea, a movement disorder characterized by involuntary movements, appeared in the vast majority of patients and began in the first years of life. In addition, newborns who presented respiratory difficulty at birth had a higher probability of developing lung problems later on. On the other hand, patients with deletions (loss of a fragment of genetic material) showed, in general, better capacity to perform broad movements such as walking or maintaining balance.
• Other relevant findings: Only approximately half presented the complete classic triad; psychiatric comorbidities were frequent and brain magnetic resonance imaging was normal in most cases.

Laia Nou, MD, pediatric neurologist at SJD Barcelona Children's Hospital (HSJD) and first author of the article, and Dario Ortigoza, MD, PhD, researcher of the Epilepsy and Movement Disorders in Pediatrics research group at the Institut de Recerca Sant Joan de Déu (IRSJD), pediatric neurologist at SJD Barcelona Children's Hospital (HSJD) and author of the article, comment that this study redefines our clinical expectations in NKX2-1-related disorders. It shows that early motor delay may precede chorea and that certain genetic variants are associated with specific clinical trajectories. These findings make it possible to move towards earlier diagnosis and personalized care based on genotype.

Importance for future research

The results highlight the need to carry out long-term follow-up studies, with periodic and standardized evaluations of the neurological, respiratory and endocrine status of patients. In addition, the observed relationship between the type of genetic alteration and clinical symptoms opens new opportunities to improve care and research, such as:

• Being able to better anticipate the evolution of the disease according to the type of genetic variant.
• Deepening research to understand why some alterations of the gene cause different symptoms than others.
• Designing more personalized clinical trials, adapted to the genetic and clinical profile of each patient.
• Establishing clear protocols for hormonal follow-up and early detection of possible respiratory problems.

In short, the study shows that early motor delay is usually the first sign of the disease, even before chorea appears. In addition, it confirms that the type of genetic alteration can help anticipate the clinical evolution. These findings facilitate earlier diagnosis and more personalized care.