Clinical Cases and the Molecular Profiling of a Novel Childhood Encephalopathy-Causing GNAO1 Mutation P170R.

De novo mutations in GNAO1, the gene encoding the major neuronal G protein Gαo, cause a spectrum of pediatric encephalopathies with seizures, motor dysfunction, and developmental delay. Of the >80 distinct missense pathogenic variants, many appear to uniformly destabilize the guanine nucleotide handling of the mutant protein, speeding up GTP uptake and deactivating GTP hydrolysis. Zinc supplementation emerges as a promising treatment option for this disease, as Zn2+ ions reactivate the GTP hydrolysis on the mutant Gαo and restore cellular interactions for some of the mutants studied earlier. The molecular etiology of GNAO1 encephalopathies needs further elucidation as a prerequisite for the development of efficient therapeutic approaches. In this work, we combine clinical and medical genetics analysis of a novel GNAO1 mutation with an in-depth molecular dissection of the resultant protein variant. We identify two unrelated patients from Norway and France with a previously unknown mutation in GNAO1, c.509C>G that results in the production of the Pro170Arg mutant Gαo, leading to severe developmental and epileptic encephalopathy. Molecular investigations of Pro170Arg identify this mutant as a unique representative of the pathogenic variants. Its 100-fold-accelerated GTP uptake is not accompanied by a loss in GTP hydrolysis; Zn2+ ions induce a previously unseen effect on the mutant, forcing it to lose the bound GTP. Our work combining clinical and molecular analyses discovers a novel, biochemically distinct pathogenic missense variant of GNAO1 laying the ground for personalized treatment development.

Functional MRI in prenatally opioid-exposed children during a working memory-selective attention task.

BACKGROUND: Opioid induced cerebral changes may contribute to neuropsychological difficulties, like attention problems, frequently reported in prenatally opioid-exposed children. Reduced regional brain volumes have been shown after prenatal opioid exposure, but no study to date has explored the possible impact of prenatal opioids on brain activation patterns. MATERIALS AND METHODS: A hospital-based sample of prenatally opioid-exposed school-aged children (n = 11) and unexposed controls (n = 12) underwent functional magnetic resonance imaging (fMRI) during a combined working memory-selective attention task. Within-group- and between-group analyses of blood-oxygen-level-dependent (BOLD) activation were performed using the SPM12 software package and group differences in task performance were analyzed using Cox proportional hazards modeling. RESULTS: Overall, similar patterns of task related parietal and prefrontal BOLD activations were found in both groups. The opioid-exposed group showed impaired task performance, and during the most cognitive demanding versions of the working memory-selective attention task, increased activation in prefrontal cortical areas was found in the opioid-exposed group compared to controls. CONCLUSION: Our findings suggest that prenatal opioids affect later brain function, visible through changes in BOLD activation patterns. However, results should be considered preliminary until replicated in larger samples better suited to control for potential confounding factors.

Cerebral Magnetic Resonance Imaging in Children With Prenatal Drug Exposure.

This study aimed to evaluate cerebral magnetic resonance imaging (MRI) scans of children with prenatal drug exposure in a clinical context. A hospital-based cohort of 10- to 14-year-old children, prenatally exposed to alcohol, opioids, and polysubstances, and a group of sex- and age-matched controls were examined with cerebral MRI. Scans obtained from 34 exposed children and 40 controls were scored based on the presence and degree of pathology by an experienced pediatric neuroradiologist blinded to the participants' background. Overall visual detectable MRI pathology was found in 35% of the exposed children and 33% of the controls (odds ratio = 1.08; 95% confidence interval = 0.36-3.25). No specific imaging pattern following prenatal drug exposure was seen by the means of simple visual analysis of cerebral MRI scans. Although cerebral MRI is feasible, it is probably of limited value in the clinical assessment of children with prenatal drug exposure.

Cerebral magnetic resonance imaging findings in children born extremely preterm, very preterm, and at term.

BACKGROUND: The aim of this study was to compare findings on cerebral MRI scans of infants born extremely preterm (i.e., gestation < 28 weeks, very preterm; gestation 28-31 weeks) and at term. METHODS: MRI scans obtained in a cohort of 29 extremely preterm children at 11 years, 51 very preterm young adults at 19 years, and respective term-born controls were scored according to presence and degree of MRI pathology. RESULTS: MRI pathology was found in 76% of the extremely preterm children vs 31% of their controls (odds ratio 4.3; 95% confidence interval, 1.5-137.5) and in 55% of the very preterm group vs 19% of their controls (odds ratio 5.2; 95% confidence interval, 2.5-10.9). The distribution of moderate and severe pathology did not differ among the groups. CONCLUSIONS: The extremely preterm, very preterm, and term subjects shared the same morphological pathology, revealing no specific preterm MRI pattern, but both premature cohorts had higher frequencies. Differences were mainly limited to mild pathology. Whether MRI lesions were more common in the extremely preterm than in the very preterm group is uncertain as the difference in frequency was similar in the two control groups, suggesting a lack of objective criteria for differentiating mild pathology from normality or that MRI scans normally differ at 11 and 19 years of age.