Post-mortem Characterisation of a Case With an ACTG1 Variant, Agenesis of the Corpus Callosum and Neuronal Heterotopia.

Shu Yau,Suzanne Lillis,Mary A Rutherford,Veena G Supramaniam,Mattias Jansson,Claire Thornton,Alice Davidson,Regina Vontell,Muriel Holder-Espinasse,Andreas Marnerides,Henrik E Hagberg

doi:10.3389/fphys.2019.00623

Abstract

Cytoplasmic Actin Gamma 1 (ACTG1) gene variant are autosomal dominant and can cause CNS anomalies (Baraitser Winter Malformation Syndrome; BWMS). ACTG1 anomalies in offspring include agenesis of the corpus callosum (ACC) and neuronal heterotopia which are ectopic nodules of nerve cells that failed to migrate appropriately. Subcortical and periventricular neuronal heterotopia have been described previously in association with ACC. In this case report, we investigated a neonatal brain with an ACTG1 gene variant and a phenotype of ACC, and neuronal heterotopia (ACC-H) which was diagnosed on antenatal MR imaging and was consistent with band heterotopia seen on post-mortem brain images. Histologically clusters of neurons were seen in both the subcortical and periventricular white matter (PVWM) brain region that coincided with impaired abnormalities in glial formation. Immunohistochemistry was performed on paraffin-embedded brain tissue blocks from this case with ACTG1 variant and an age-matched control. Using tissue sections from the frontal lobe, we examined the distribution of neuronal cells (HuC/HuD, calretinin, and parvalbumin), growth cone (drebrin), and synaptic proteins (synaptophysin and SNAP-25). Additionally, we investigated how the ACTG1 variant altered astroglia (nestin, GFAP, vimentin); oligodendroglia (OLIG2) and microglia (Iba-1) in the corpus callosum, cortex, caudal ganglionic eminence, and PVWM. As predicted in the ACTG1 variant case, we found a lack of midline radial glia and glutamatergic fibers. We also found disturbances in the cortical region, in glial cells and a lack of extracellular matrix components in the ACTG1 variant. The caudal ganglionic eminence and the PVWM regions in the ACTG1 variant lacked several cellular components that were identified in a control case. Within the neuronal heterotopia, we found evidence of glutamatergic and GABAergic neurons with apparent synaptic connections. The data presented from this case study with BWMS with variants in the ACTG1 gene provides insight as to the composition of neuronal heterotopia, and how disturbances of important migratory signals may dramatically affect ongoing brain development.

Highlights

Baraitser Winter malformation syndrome (BWMS) is associated with variants in the Cytoplasmic Actin Gamma 1 genes ACTB or ACTG1, which encodes β- and γ-actins (Verloes et al, 2014)
We have shown that in this case of the ACTG1 gene variant, there are disruptions in radial glia, which are comorbid with a loss of axonal fiber density in the corpus callosum
We found disturbances in the subcortical and intermediate zone radial glia composition and a dramatic decrease in cortical neurons In the ACTG1 variant, there is a marked lack of proliferative signals (MIB1) and guidance structures, which are normally found in the caudal ganglionic eminence

Summary

Introduction

Baraitser Winter malformation syndrome (BWMS) is associated with variants in the Cytoplasmic Actin Gamma 1 genes ACTB or ACTG1, which encodes β- and γ-actins (Verloes et al, 2014). Common CNS anomalies are pachygyria, subcortical band heterotopia and agenesis of the corpus callosum (ACC) (Verloes et al, 2014). ACC represents one of the most common antenatally diagnosed malformations of the brain and may be isolated or associated with other cerebral or non-cerebral abnormalities. The failure of neuronal migration due to genetic variants that interfere with glial structure and function are associated with the presence of neuronal heterotopias (Marcorelles et al, 2010; Kato, 2015; Ibanez and Andressoo, 2016). Neurodevelopmental impairments in isolated ACC are variable but are more severe in the presence of additional anomalies, and the occurrence of overt neuronal heterotopia is associated with poorer outcomes (Edwards et al, 2014; Ishii et al, 2015)

Methods

Results

Conclusion