Pathogenic SATB2 missense variants affecting p.Gly392 have variable functional implications and result in diverse clinical phenotypes.

SATB2-associated syndrome (SAS) is caused by pathogenic variants in SATB2, which encodes an evolutionarily conserved transcription factor. Despite the broad range of phenotypic manifestations and variable severity related to this syndrome, haploinsufficiency has been assumed to be the primary molecular explanation.In this study, we describe eight individuals with SATB2 variants that affect p.Gly392 (four women, age range 2-16 years; p.Gly392Arg, p.Gly392Glu and p.Gly392Val). Of these, individuals with p.Gly392Arg substitutions were found to have more severe neurodevelopmental phenotypes based on an established rubric scoring system when compared with individuals with p.Gly392Glu, p.Gly392Val and other previously reported causative SATB2 missense variants. Consistent with the observations at the phenotypic level, using human cell-based and model organism functional data, we documented that while all three described p.Gly392 variants affect the same residue and seem to all have a partial loss-of-function effect, some effects on SATB2 protein function appear to be variant-specific. Our results indicate that genotype-phenotype correlations in SAS are more complex than originally thought, and variant-specific genotype-phenotype correlations are needed.

Glycopyrronium 320 µg/mL in children and adolescents with severe sialorrhoea and neurodisabilities: A randomized, double-blind, placebo-controlled trial.

AIM: To investigate the efficacy, safety, and impact on quality of life (QoL) of an oral formulation of 320 µg/mL glycopyrronium designed for children. METHOD: A double-blind, placebo-controlled SALIVA (Sialanar plus orAl rehabiLitation against placebo plus oral rehabilitation for chIldren and adolescents with seVere sialorrhoeA and neurodisabilities) trial was conducted. Children (3-17 years) with neurodisabilities and severe sialorrhoea (modified Teachers Drooling Scale ≥6) were randomized to 320 µg/mL glycopyrronium or placebo, in addition to non-pharmacological standard care. RESULTS: Of 87 participants, 44 were aged 10 years or under and 43 had cerebral palsy. The primary endpoint, change in total Drooling Impact Scale (DIS) score from baseline to day 84, was significantly greater (improved) with 320 µg/mL glycopyrronium versus placebo (median [quartile 1, quartile 3] -29.5 [-44.5, 0] vs -1 [-16, 5]; p < 0.001), an effect also observed at day 28 (median - 25 vs -2; p < 0.01). Significant reduction in bibs/clothes used per day was seen with glycopyrronium versus placebo at day 84 (median - 2 vs 0; p < 0.01). Glycopyrronium significantly improved DIS items 9 and 10 related to the extent that drooling affects the child's and family's life (p ≤ 0.03). Adverse events were reported by 77.3% and 69.8% of children with glycopyrronium and placebo respectively; the most common treatment-related adverse event was constipation (20.5% and 16.3%). INTERPRETATION: The formulation of 320 µg/mL glycopyrronium significantly improved drooling and reduced its impact on QoL, with good tolerability in children with neurodisabilities. WHAT THIS PAPER ADDS: The formulation of 320 µg/mL glycopyrronium significantly improved Drooling Impact Scale score versus placebo at day 84. The formulation reduced the impact of drooling on the child's and family's quality of life. There were no safety or tolerability concerns with this specific formulation.

Delineating FOXG1 syndrome: From congenital microcephaly to hyperkinetic encephalopathy.

OBJECTIVE: To provide new insights into the FOXG1-related clinical and imaging phenotypes and refine the phenotype-genotype correlation in FOXG1 syndrome. METHODS: We analyzed the clinical and imaging phenotypes of a cohort of 45 patients with a pathogenic or likely pathogenic FOXG1 variant and performed phenotype-genotype correlations. RESULTS: A total of 37 FOXG1 different heterozygous mutations were identified, of which 18 are novel. We described a broad spectrum of neurodevelopmental phenotypes, characterized by severe postnatal microcephaly and developmental delay accompanied by a hyperkinetic movement disorder, stereotypes and sleep disorders, and epileptic seizures. Our data highlighted 3 patterns of gyration, including frontal pachygyria in younger patients (26.7%), moderate simplified gyration (24.4%) and mildly simplified or normal gyration (48.9%), corpus callosum hypogenesis mostly in its frontal part, combined with moderate-to-severe myelination delay that improved and normalized with age. Frameshift and nonsense mutations in the N-terminus of FOXG1, which are the most common mutation types, show the most severe clinical features and MRI anomalies. However, patients with recurrent frameshift mutations c.460dupG and c.256dupC had variable clinical and imaging presentations. CONCLUSIONS: These findings have implications for genetic counseling, providing evidence that N-terminal mutations and large deletions lead to more severe FOXG1 syndrome, although genotype-phenotype correlations are not necessarily straightforward in recurrent mutations. Together, these analyses support the view that FOXG1 syndrome is a specific disorder characterized by frontal pachygyria and delayed myelination in its most severe form and hypogenetic corpus callosum in its milder form.

Comparison in outcomes at two-years of age of very preterm infants born in 2000, 2005 and 2010.

OBJECTIVE: To investigate alteration in 2-year neurological/behavioral outcomes of very preterm infants born in a French level three neonatal intensive care unit. METHODS: We conducted a prospective, comparative study of very preterm infants born before 33 weeks' gestation at 5-year intervals in 2000, 2005 and 2010 at Rouen University Hospital. Neonatal mortality/morbidities, ante- and neonatal treatments, and at age 2 years motor, cognitive and behavioral data were collected by standardized questionnaires. RESULTS: We included 536 very preterm infants. Follow-up rates at two years old were 78% in 2000, 93% in 2005 and 92% in 2010 respectively. No difference in gestational age, birthweight, neonatal mortality/morbidities was observed except a decrease in low grade subependymal/intraventricular hemorrhages. Care modifications concerned use of antenatal magnesium sulfate, breast-feeding and post-natal corticosteroid therapy. Significant improvement in motor outcome and dramatic decrease in cerebral palsy rates (12% in 2000, 6% in 2005, 1% in 2010, p<0.001) were observed, as were improvements in feeding behavior. Although a non significant difference to better psychosocial behavior was reported, there was no difference in cognitive outcome. CONCLUSIONS: Improvement in neuromotor outcome and behavior was reported. This could be due to multiple modifications in care: including administration of magnesium sulfate to women at risk of preterm birth, increase in breast-feeding, decrease in low grade subependymal/intraventricular hemorrhages, and decrease in post-natal corticosteroid therapy, all of which require further investigation in other studies. Extended follow-up until school age is mandatory for better detection of cognitive, learning and behavioral disorders.

Compared outcomes of very preterm infants born in 2000 and 2005.

AIM: To compare neonatal and 2-year outcomes in very premature infants born 5 years apart. METHODS: Prospective observational study of infants born before 33 weeks' gestation in 2000 or 2005 admitted to a neonatal intensive care unit in France. We collected perinatal data and evaluated motor, cognitive, neurosensory and behavioural outcomes at 2 years of age. RESULTS: We included 170 infants in 2000 and 173 in 2005. The significant differences in neonatal outcomes were decreases in postnatal corticosteroid use and in percentage of infants with head circumference below the 3rd percentile on days 7 (25% vs. 13%) and 30 (30% vs. 17%). At 2 years of age, rates of follow-up were 87% in 2000 and 94% in 2005. The cerebral palsy rate was 6% in both cohorts. The overall rate of motor disabilities diminished from 30% (41/137) to 18% (26/142), and the rate of mild motor disabilities decreased from 24% to 12%. Rates of cognitive, behavioural and neurosensorial impairments were similar. CONCLUSION: Between 2000 and 2005, motor impairments at 2 years of age diminished in very preterm children (but not cerebral palsy rates). We observed a reduced use of postnatal corticosteroids and a decreased percentage of neonates with head circumference below the third percentile.