# CTNNB1-related disorders: clinical and radiological contributions from a French cohort

## TL;DR

This study describes the clinical and radiological features of individuals with CTNNB1-related disorders, highlighting a complex motor phenotype and brain anomalies.

## Contribution

The study expands the known phenotypic spectrum of CTNNB1-related disorders through a detailed analysis of a French cohort.

## Key findings

- CTNNB1-related disorders are characterized by global developmental delay, microcephaly, and motor phenotypes including gait disturbances and hypertonia.
- Brain MRI findings include thickening of the anterior commissure, frontal lobe hypoplasia, and corpus callosum anomalies.
- Exaggerated startle reactions and sleep disturbances are common features in CTNNB1-related disorders.

## Abstract

CTNNB1 monoallelic pathogenic variants account for up to 4% of genetically determined cerebral palsy cases, yet their phenotypic spectrum remains poorly defined. We retrospectively analyzed 25 individuals with pathogenic CTNNB1 variants using medical records and a questionnaire. Data included genetic variants, perinatal history, developmental milestones, behavioral characteristics, head growth, feeding, sleep difficulties, neurological and ophthalmological assessments. Brain MRIs were reviewed by expert neuroradiologists. Twenty-two distinct heterozygous variants were identified. Microcephaly occurred in 16/22 patients. All exhibited global developmental delay, independent walking was achieved at a mean age of 2.1 years, with regression in 4/16 independent walkers. Behavioral disorders were frequent, as were oral sensorimotor disorders (21/25) and sleep disturbances (13/21). Lower limb hypertonia was present in 22/25 patients [spastic (8) and/or dystonic (11)]. Unstable gait were common among ambulatory patients. Exaggerated startle reactions, often since birth, were reported in 16/21. Exudative vitreoretinopathy was identified in 3/5 patients with retinal angiography. Brain MRI (19 patients) showed: thickening of anterior commissure (8), frontal lobe hypoplasia (9), widening of superior vermian sulci (10) and corpus callosum anomalies (7). This study broadens the spectrum of CTNNB1-related syndrome, reporting a complex motor phenotype combining (i) gait disturbances related to dystonic or non-dystonic hypertonia and unsteadiness, sometimes associated to dystonia in other body parts (ii) possible deterioration of motor achievements over the course of the disease (iii) an exaggerated startle reflex. New non-specific brain anomalies are precisely described. Our work underscores the need for registries and longitudinal studies to refine characterization and guide future therapies.