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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.

The use of the cholinergic system is widespread in the animal kingdom. It controls different processes, including reproduction and neural transmission. However, its evolutionary history is not yet well understood. For instance, the role played by the cholinergic system in the nervous system of basal bilaterian taxa, where the first signs of architectural complexity appear, is still unknown. Here, we describe the structure of the cholinergic system during the development and regeneration of the acoel flatworm Symsagittifera roscoffensis , using acetylcholinesterase (AchE) activity as a marker. In this species, AchE activity is observed at all developmental stages, including in the early embryos. The juvenile and adult patterns reveal the presence of a complex nervous system that includes three pairs of longitudinal neurite bundles, which are connected to an anterior centralized mass of neurons and neural processes formed by two pairs of connectives and four commissures. The power of the technique also allows the detection of newly born neurons as they are incorporated into the growing nervous system (during regeneration).

The neuroarchitecture of Acoela has been at the center of morphological debates. Some authors, using immunochemical tools, suggest that the nervous system in Acoela is organized as a commissural brain that bears little resemblance to the central, ganglionic type brain of other flatworms, and bilaterians in general. Others, who used histological staining on paraffin sections, conclude that it is a compact structure (an endonal brain; e.g., Raikova 2004; von Graff 1891; Delage Arch Zool Exp Gén 4:109-144, 1886). To address this question with modern tools, we have obtained images from serial transmission electron microscopic sections of the entire hatchling of Symsagittifera roscoffensis. In addition, we obtained data from wholemounts of hatchlings labeled with markers for serotonin and tyrosinated tubulin. Our data show that the central nervous system of a juvenile S. roscoffensis consists of an anterior compact brain, formed by a dense, bilobed mass of neuronal cell bodies surrounding a central neuropile. The neuropile flanks the median statocyst and contains several types of neurites, classified according to their types of synaptic vesicles. The neuropile issues three pairs of nerve cords that run at different dorso-ventral positions along the whole length of the body. Neuronal cell bodies flank the cords, and neuromuscular synapses are abundant. The TEM analysis also reveals different classes of peripheral sensory neurons and provides valuable information about the spatial relationships between neurites and other cell types within the brain and nerve cords. We conclude that the acoel S. roscoffensis has a central brain that is comparable in size and architecture to the brain of other (rhabditophoran) flatworms.