Clinical, Behavioral and Neuroradiological Phenotype in an Italian Cohort of Patients With Xia Gibbs Syndrome: A Multicenter Cross‐Sectional Study and Systematic Literature Review

Heterozygous variants in the AHDC1 gene are associated with Xia Gibbs Syndrome (XGS), a genetic disorder with a highly variable phenotype. Cognitive impairment, motor delay, language delay, neonatal hypotonia, and sleep apnea are considered "cardinal" signs of the disease. In a multicenter cross-sectional study, we analyzed the genetic, epileptological, behavioral, and neuroradiological features of 15 patients with XGS harboring heterozygous variants in AHDC1. The phenotype of our patient cohort is almost overlapping with that already reported in the literature. Seizures begin between 2 and 9 years, while EEG is generally characterized by normal background activity with paroxysmal abnormalities in the posterior areas increased by sleep. We systematically analyzed brain imaging findings as the most frequent brain alteration: the thinning of the corpus callosum, followed by posterior fossa malformation and lateral ventricle morphology abnormalities. Regarding psychiatric disorders, we observed neurodevelopmental disorders such as ID, language disorders, Autism spectrum disorders (ASD), and ADHD in preschoolers, followed by a prevalence of externalizing problems during childhood and adolescence. Our study showed that epilepsy and brain anomalies are very common among XGS individuals. MRI changes are nonspecific, but their association with other clinical features of the syndrome can guide early diagnosis. EEG abnormalities are present in all epileptic patients in the temporal-occipital regions with the same characteristics, so we could hypothesize that these abnormalities could represent a recognizable EEG pattern of XGS. Behavioral disorders represent an important problem, and longitudinal evaluations are needed to improve the classification of the psychopathological spectrum in XGS.