CLN6-related continuum phenotype caused by aberrant splicing.

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Rare Diseases

Background:

• Neuronal ceroid lipofuscinoses (NCLs) are a group of rare, inherited neurodegenerative diseases.
• CLN6-related NCLs manifest in various forms, including late-infantile and adult myoclonic types.
• Understanding genotype-phenotype correlations is crucial for diagnosing and managing NCLs.

Purpose of the Study:

• To investigate a case of CLN6-related NCL with an atypical presentation.
• To analyze the genetic variants and their impact on CLN6 gene expression and clinical phenotype.
• To explore the concept of a phenotypic continuum in CLN6 disease.

Main Methods:

• Clinical evaluation of a 21-year-old patient with progressive neurological symptoms.
• Skin biopsy for ultrastructural analysis of storage material (curvilinear and fingerprint profiles).
• Brain MRI to assess cortical atrophy.
• Genetic analysis to identify variants in the CLN6 gene.
• Allele-specific expression analysis.

Main Results:

• The patient presented with mild developmental delay, occipital seizures, cognitive decline, and myoclonus, consistent with progressive myoclonus epilepsy.
• Genetic analysis revealed compound heterozygosity for a known missense variant (c.722T>C, p.(Met241Thr)) and a novel intronic splice site variant (c.486+28T>C) in the CLN6 gene.
• The novel intronic variant led to aberrant splicing, but the overall CLN6 expression was partially preserved, potentially explaining a milder phenotype compared to the classic late-infantile form.

Conclusions:

• The identified genetic variants and their impact on CLN6 expression contribute to a continuum of clinical phenotypes in CLN6-related NCLs.
• This case highlights the importance of comprehensive genetic analysis in understanding the variability of NCL presentations.
• The findings suggest that CLN6 disease exists on a spectrum, bridging the late-infantile and adult forms.