CLN8 – Neuronal Ceroid Lipofuscinosis 8 Northern Epilepsy Variant

Neuronal ceroid lipofuscinosis 8 northern epilepsy variant (MONDO:0012391) is an autosomal recessive neurodegenerative disorder characterized by childhood-onset seizures, progressive psychomotor deterioration, visual impairment, and premature death. Initial MRI and somatosensory evoked field studies in Finnish patients demonstrated minimal cerebral neuronal loss compared with other NCL subtypes (PMID:11588991).

Genetic studies in Finnish Northern epilepsy pedigrees identified homozygosity at the CLN8 locus, and subsequent screening of Turkish variant late‐infantile NCL families revealed multiple homozygous and compound heterozygous CLN8 mutations, confirming allelism to Finnish Northern epilepsy (PMID:15024724). Extended exome sequencing in a large Turkish consanguineous family uncovered a novel homozygous CLN8 mutation, c.677T>C (p.Leu226Pro), in five affected individuals (PMID:27844444).

The variant spectrum includes missense, nonsense, frameshift, splice‐site, and UTR changes. A representative pathogenic variant is c.109_112dup (p.Val38fs) (PMID:15024724). No recurrent founder mutation has been established, reflecting allelic heterogeneity across Finnish and Turkish populations.

Functional assessment of CLN8 knockdown in neuronal and non‐neuronal models revealed enlarged Golgi, increased endo‐lysosomal mobility, lysosomal alkalinization, and reduced dendritic complexity, indicating a role in endo‐lysosomal dynamics and somatodendritic development consistent with NCL pathogenesis (PMID:34021618).

An early homozygosity‐mapping effort in Turkish variant LINCL families did not identify CLN8 coding or non‐coding mutations, suggesting genetic heterogeneity for vLINCL in this population (PMID:11589000).

Collectively, biallelic CLN8 variants across multiple populations, supportive segregation in consanguineous pedigrees, and concordant functional data establish a strong gene–disease relationship. CLN8 sequencing should be considered in patients with early‐onset epilepsy, psychomotor decline, and visual loss.

References

• European Journal of Paediatric Neurology • 2001 • Northern epilepsy syndrome (NES, CLN8)--MRI and electrophysiological studies. PMID:11588991
• Human Mutation • 2004 • Variant late infantile neuronal ceroid lipofuscinosis in a subset of Turkish patients is allelic to Northern epilepsy. PMID:15024724
• Acta Neurologica Belgica • 2017 • Exome sequencing identifies a novel homozygous CLN8 mutation in a Turkish family with Northern epilepsy. PMID:27844444
• Biology of the Cell • 2021 • The neuronal ceroid lipofuscinosis-related protein CLN8 regulates endo-lysosomal dynamics and dendritic morphology. PMID:34021618

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