Renaud, Deborah L.

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.

Introduction: BRCA1-associated ataxia-telangiectasia–mutated activator-1 (BRAT1) is responsible for cell cycle surveillance and mitochondrial function. The implications of adult-onset BRAT1-variant and the resulting phenotypic neurocognitive and imaging features have not been previously described. Case Report: A 66-year-old man with a recent diagnosis of classic Hodgkin lymphoma was referred to neuro-oncology for cognitive and motor decline, and progressive cerebral white matter changes noted on magnetic resonance imaging (MRI). A neurological examination revealed global weakness, broad-based gait, and bilateral extensor plantar responses. Brain MRI demonstrated periventricular, deep, and subcortical white matter T2/FLAIR hyperintensities without contrast enhancement. Cerebral spinal fluid studies were unremarkable. A GeneDX genetic leukodystrophy panel conduction revealed a pathogenic variant (c.294dupA; p.L99TfsX92) resulting in a truncated protein of BRAT1, along with a variant of uncertain significance (c.746A>G;p.E249G). A presumptive diagnosis of late-onset leukoencephalopathy secondary to the BRAT1 variant was made. In an attempt to combat his mitochondrial dysfunction, he was initiated on a mitochondrial cocktail, including B-100 complex and coenzyme Q10. He began lymphoma-directed combination chemotherapy and developed precipitous functional decline after 2 cycles of therapy. Compared with prechemotherapy imaging, repeat positron emission tomography/computed tomography metabolic imaging showed a response after 3 cycles of chemotherapy; however, repeat brain MRI showed worsening diffuse white matter hyperintensities and cerebral atrophy. Conclusion: Given the variability in phenotypes and clinical onset, leukodystrophies can be a diagnostic challenge. This case demonstrated progressive BRAT1-associated leukodystrophy exacerbated by chemotherapy-induced toxic leukoencephalopathy. Mitochondrial energy deficiency in the context of multiple metabolic insults was likely underlying the progressive neurological decline observed in this case of genetic leukodystrophy.

Limited information is known about neuropsychological outcomes in Alexander disease, a rare leukodystrophy. Two pediatric cases are summarized. Case 1 (evaluations at 6, 7, 9, and 12 years of age) represents Type I Alexander disease with associated seizures. Case 2 (evaluations at 12, 13, and 16 years of age) represents Type II Alexander disease without additional complications. Case 1 experienced declines in intellectual functioning, visual motor skills, receptive vocabulary, verbal memory, and academic achievement. Case 2 experienced variable neurocognitive change and academic functioning, with average word reading and spelling. Verbal memory also remained intact. Taken together, individuals with Alexander disease may experience cognitive decline to variable degrees. Type I Alexander disease, associated with earlier onset and additional neurological complications, may presage greater cognitive decline than Type II. Due to variability in functioning over time, it is critical to follow individuals across development to make recommendations for educational and treatment planning.

AbstractThe study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro‐behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low‐hanging columella. The presented data will inform clinical management of individuals with ASXL3‐related syndrome and improve interpretation of new ASXL3 sequence variants.