RELN and VLDLR mutations underlie two distinguishable clinico-radiological phenotypes

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Pontocerebellar hypoplasias (PCH) are a group of neurodevelopmental disorders affecting cerebellum and brainstem development.
• The Reelin signaling pathway plays a crucial role in neuronal migration during brain development.

Purpose of the Study:

• To investigate the role of the Reelin pathway genes (RELN and VLDLR) in patients presenting with atypical Pontocerebellar Hypoplasia.
• To differentiate clinical and neuroimaging phenotypes associated with RELN versus VLDLR mutations in PCH.

Main Methods:

• Clinical assessment and Magnetic Resonance Imaging (MRI) of five patients with PCH.
• Genetic screening for mutations in RELN and VLDLR genes.
• Comparison of patient phenotypes with previously reported cases.

Main Results:

• Five patients with PCH exhibited cerebellar hypoplasia, flattened pons, and neocortical abnormalities on MRI.
• One patient with severe phenotype and lissencephaly had a homozygous RELN splicing mutation.
• Four patients with milder phenotypes (consistent with CARMQ1) had VLDLR mutations, showing distinct cortical abnormalities.

Conclusions:

• Mutations in RELN and VLDLR genes are associated with distinct PCH phenotypes.
• MRI findings and clinical severity can help distinguish between RELN- and VLDLR-related PCH.
• This study highlights the importance of the Reelin pathway in cerebellar and neocortical development.