Bertini, Enrico

Abstract DDX3X dysfunction causes an X-linked multisystem disorder with high penetrance and variable expressivity. The phenotypic spectrum spans from learning disability without somatic involvement to profound intellectual disability with severe impairments in the central nervous system and other organs. A few multicenter studies and single case reports have previously highlighted some common phenotypic patterns but were unable to delineate correlations between underlying DDX3X variants and phenotypic findings.From the second largest patient cohort published to date, we analysed clinical, psychometric and diagnostic findings of 52 female and 7 male individuals, harbouring de novo and inherited DDX3X variants. These female patients revealed previously unknown quantitative correlations between variant type and localization and specific phenotypic findings (growth features, epilepsy, brain anomalies, dysmorphisms, motor-focused neurological findings). Moreover, by analysing the in silico folding and RNA binding capability of mutant DDX3X monomers, we were able to delineate novel correlations between DDX3X monomer misfolding grade and phenotypic severity.

Background: RNA polymerase III (POLR3)-related leukodystrophy is a rare, neurodegenerative disorder characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism. Despite the challenges of caring for a child with POLR3-related leukodystrophy, few studies have examined parents’ disease burden. We sought to investigate quality of life and stress levels amongst parents of children with POLR3-related leukodystrophy. Methods: 43 parents of 32 children completed questionnaires on demographics, stress, quality of life, coping mechanisms, and experience of injustice. Detailed clinical data was collected from all patients. Results: Mothers ( t[27] = –8.66, P < .001) and fathers (t[16] = –4.47, P < .001) had lower quality of life scores compared to the normative population, yet 80% of parents’ stress scores fell within the normal stress range. Parents’ experience of injustice scores were high (>60). Correlations were found between and within parents’ scores. Years since disease onset and certain life circumstances correlated to mothers’ quality of life scores; however, no correlation was found between modifiable factors and fathers’ quality of life scores. Helpful coping mechanisms included those that allowed parents to be involved in their child's life. Conclusions: This is the first study to assess stress and quality of life in this population. These results shed light on the importance of implementing services and social support to improve the well-being of parents.