Cerebellar Abnormalities in the Neuroimaging Spectrum of CLTC-Related Disorder

Area of Science:

• Neurogenetics
• Developmental Neuroscience
• Neuroradiology

Background:

• Pathogenic variants in CLTC, encoding the clathrin heavy chain, are linked to rare neurodevelopmental disorders.
• These disorders present with global developmental delay, intellectual disability, and brain abnormalities, often involving the corpus callosum and white matter.
• The full spectrum of neuroimaging findings in CLTC-related disorders remains incompletely characterized.

Purpose of the Study:

• To systematically review and expand the understanding of the neuroimaging spectrum associated with CLTC variants.
• To report a patient with a novel CLTC variant and unique brain MRI findings.
• To explore potential genotype-phenotype correlations in CLTC-related neurodevelopmental disorders.

Main Methods:

• Comprehensive literature review of CLTC-related neurodevelopmental disorders.
• Re-evaluation of neuroimaging data from published cases and a novel case.
• Analysis of clinical and genetic data from 30 individuals.

Main Results:

• Pontine hypoplasia and cerebellar atrophy were identified as rare but significant neuroimaging findings in CLTC-related disorder.
• These findings expand the known neuroimaging phenotype beyond commonly reported corpus callosum and white matter anomalies.
• A cohort of 30 individuals, including a novel case, was analyzed for neuroimaging characteristics.

Conclusions:

• Pontine hypoplasia and cerebellar atrophy represent important additions to the neuroimaging spectrum of CLTC-related disorder.
• The findings suggest a potential genotype-phenotype correlation, with missense variants possibly linked to more severe clinical presentations.
• Systematic review of neuroimaging is crucial for a comprehensive understanding of rare genetic neurodevelopmental disorders.