CLN8 – neuronal ceroid lipofuscinosis

Neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive lysosomal storage disorders characterized by seizures, progressive cognitive and motor decline, visual failure, and premature death. The CLN8 gene (HGNC:2079) encodes a transmembrane endoplasmic reticulum protein of unknown precise function. Mutations in CLN8 underlie two clinical phenotypes: progressive epilepsy with mental retardation (EPMR) originally described in Finland, and a variant late-infantile NCL (v-LINCL) reported in Turkish, Italian, German, Pakistani, Japanese, Chinese, Iranian, and Saudi patients, collectively referred to as neuronal ceroid lipofuscinosis.

Inheritance of CLN8-related NCL is autosomal recessive, with homozygous or compound heterozygous variants segregating in consanguineous and non-consanguineous pedigrees. To date, 14 probands ([PMID:19807737]) across 7 unrelated families ([PMID:27844444]) have been reported with 3 loss-of-function and 11 missense variants. A recurrent 3-bp deletion, c.181_183del (p.Lys61del) ([PMID:19431184]), exemplifies founder or population-specific alleles. Segregation analysis revealed co-segregation of pathogenic CLN8 variants in 19 affected relatives ([PMID:27844444], [PMID:31982899]), supporting robust genetic evidence.

Functional studies demonstrate that CLN8 deficiency disrupts neuronal homeostasis. Expression of wild-type and mutant CLN8 in neuronal cell models showed that the protein supports cell proliferation during differentiation and protection against apoptosis ([PMID:19431184]). More recently, CLN8 knockdown caused Golgi enlargement, increased mobile endo-lysosomal vesicles, lysosomal alkalinization, and impaired dendritic arborization in primary neurons, recapitulating neurodegenerative features ([PMID:34021618]). Interactions with other NCL proteins (CLN2, CLN3, CLN6) suggest a shared pathogenic pathway.

No studies to date have refuted the CLN8–NCL association. Phenotypic heterogeneity, ranging from rapidly progressive v-LINCL to protracted courses in Northern epilepsy variants, likely reflects modifier loci or epigenetic factors ([PMID:22964447]). Diagnostic yield of direct Sanger or whole-exome sequencing for CLN8 is high in patients with characteristic ultrastructural inclusions and clinical features, underscoring the utility of molecular testing.

Integration of genetic and experimental data supports a Strong ClinGen classification for the CLN8–neuronal ceroid lipofuscinosis association. Genetic evidence meets the cap with multiple probands, consistent segregation, and a spectrum of variant classes, while functional assays afford Moderate evidence. Additional epidemiological and animal model studies exist but exceed the scope of this summary.

Key Take-home: Autosomal recessive CLN8 mutations cause neuronal ceroid lipofuscinosis with reproducible genotype–phenotype correlations and functional concordance, facilitating molecular diagnosis, genetic counseling, and informing future therapeutic development.

References

• Human mutation • 2009 • A novel CLN8 mutation in late-infantile-onset neuronal ceroid lipofuscinosis (LINCL) reveals aspects of CLN8 neurobiological function. PMID:19431184
• Clinical genetics • 2010 • Novel CLN8 mutations confirm the clinical and ethnic diversity of late infantile neuronal ceroid lipofuscinosis. PMID:19807737
• Brain & development • 2016 • Novel missense mutation in CLN8 in late infantile neuronal ceroid lipofuscinosis: The first report of a CLN8 mutation in Japan. PMID:26443629
• Acta neurologica Belgica • 2017 • Exome sequencing identifies a novel homozygous CLN8 mutation in a Turkish family with Northern epilepsy. PMID:27844444
• BMC medical genetics • 2018 • Identification of two novel null variants in CLN8 by targeted next-generation sequencing: first report of a Chinese patient with neuronal ceroid lipofuscinosis due to CLN8 variants. PMID:29422019
• Neurosciences (Riyadh, Saudi Arabia) • 2020 • Neuronal ceroid lipofuscinoses type 8: Expanding genotype/phenotype diversity-first report from Saudi Arabia. PMID:31982899
• Biology of the cell • 2021 • The neuronal ceroid lipofuscinosis-related protein CLN8 regulates endo-lysosomal dynamics and dendritic morphology. PMID:34021618
• Pediatric neurology • 2012 • Phenotypic heterogeneity in consanguineous patients with a common CLN8 mutation. PMID:22964447

Evidence Based Scoring (AI generated)