Data-Driven Insights into Hyperkinetic Disorders in Neurodevelopmental Syndromes and Epileptic Encephalopathies

Area of Science:

• Genetics
• Neurology
• Pediatrics

Background:

• Childhood-onset hyperkinetic movement disorders are linked to various genetic conditions.
• Monogenic disorders associated with neurodevelopmental delay (NDD) and developmental and epileptic encephalopathies (DEE) increasingly present with hyperkinetic movement disorders.
• The full spectrum of genotypes and phenotypes for these conditions remains underexplored.

Purpose of the Study:

• To comprehensively review literature identifying monogenic NDD and DEE disorders associated with hyperkinetic movement disorders (dystonia, chorea, dyskinesia).
• To analyze the frequency of neurological, extra-neurological, and phenomenological features in these disorders.
• To develop data-driven phenotypic groupings for diagnostic strategies.

Main Methods:

• Comprehensive literature review.
• Cluster analysis to identify phenotypic groupings.
• Analysis of neurological, extra-neurological, and phenomenological features.

Main Results:

• 210 monogenic conditions were identified, with 131 segregating into NDD or DEE clusters.
• Dystonia was the most frequent movement disorder, followed by chorea, ataxia, and dyskinesia.
• Specific features like paroxysmal movement disorders and alternating hemiplegia of childhood were identified as diagnostic clues.

Conclusions:

• A clinical and syndromic diagnostic framework is proposed for NDD, DEE, and hyperkinetic movement disorders.
• This framework can assist clinicians, especially in resource-limited settings.
• The approach supports reverse phenotyping to enhance diagnostic precision and genomic data interpretation.