Lithium as a possible therapeutic strategy for Cornelia de Lange syndrome

Paolo Grazioli,Raffaella Adami,Jolanta Wierzba,Aida Zulueta,Angelo Selicorni,Romano Tenconi,Elisabetta Di Fede,Milena Mariani,Chiara Parodi,Daniele Bottai,Laura Avagliano,Valentina Massa,Cristina Gervasini,Anna Cereda,Paola Francesca Ajmone,Thomas Vaccari,Maria Iascone

doi:10.1038/s41420-021-00414-2

Abstract

Cornelia de Lange Syndrome (CdLS) is a rare developmental disorder affecting a multitude of organs including the central nervous system, inducing a variable neurodevelopmental delay. CdLS malformations derive from the deregulation of developmental pathways, inclusive of the canonical WNT pathway. We have evaluated MRI anomalies and behavioral and neurological clinical manifestations in CdLS patients. Importantly, we observed in our cohort a significant association between behavioral disturbance and structural abnormalities in brain structures of hindbrain embryonic origin. Considering the cumulative evidence on the cohesin-WNT-hindbrain shaping cascade, we have explored possible ameliorative effects of chemical activation of the canonical WNT pathway with lithium chloride in different models: (I) Drosophila melanogaster CdLS model showing a significant rescue of mushroom bodies morphology in the adult flies; (II) mouse neural stem cells restoring physiological levels in proliferation rate and differentiation capabilities toward the neuronal lineage; (III) lymphoblastoid cell lines from CdLS patients and healthy donors restoring cellular proliferation rate and inducing the expression of CyclinD1. This work supports a role for WNT-pathway regulation of CdLS brain and behavioral abnormalities and a consistent phenotype rescue by lithium in experimental models.

Highlights

Introduction Cornelia de LangeSyndrome (CdLS, OMIM #122470,#300590, #610759, #614701, #300882, # 611192, #608749) is a rare genetic disorder affecting a variety of organs, including the Central Nervous System (CNS)
We sought to ascertain if alterations in cognitive, neurological, and behavioral aspects of Cornelia de Lange Syndrome (CdLS) patients could be associated with morphological abnormalities in hindbrain-derived structures[24]
Subdividing magnetic resonance imaging (MRI) data according to individual behavioral assessment, we observed a significant correlation between CNS abnormalities and autism-spectrum disorder (ASD) (Fig. 1B, C)

Summary

Introduction

Introduction Cornelia de LangeSyndrome (CdLS, OMIM #122470,#300590, #610759, #614701, #300882, # 611192, #608749) is a rare genetic disorder affecting a variety of organs, including the Central Nervous System (CNS). The recent International Consensus Statement[1] has defined the phenotypes classified as CdLS as a spectrum including the classic CdLS phenotype with or without a pathogenic variant in a gene involved in cohesin functioning, The prevalence of CdLS is estimated to be 1:10.000–30.000 newborns but, most likely this represents an underestimation, as milder cases may not be recognized[2]. The features of this disorder vary widely among affected individuals and range from relatively mild to severe. CdLS patients are characterized by intellectual disabilities and behavior of the autism-spectrum indicating neural development alterations[3,4]

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Conclusion