CLN6 – Ceroid Lipofuscinosis, Neuronal, Type 6A

CLN6-related ceroid lipofuscinosis (CLN6 disease; MONDO:0011144) is an autosomal recessive neurodegenerative lysosomal storage disorder characterized by progressive ataxia, seizures, motor and cognitive decline, and early visual impairment. Affected individuals harbor biallelic CLN6 (HGNC:2077) variants leading to loss of ER-resident CLN6 function.

Autosomal recessive inheritance is supported by multiple unrelated families. Eight probands harboring homozygous or compound heterozygous CLN6 variants have been described: one Thai child with c.794_796del (p.Ser265del) presenting with ataxia and Rett-like features (PMID:36137348), one Chinese boy with c.892G>A (p.Glu298Lys) and cerebellar atrophy (PMID:30285654), three Cypriot patients with c.407G>A (p.Arg136His) and p.Tyr295Cys in two families presenting juvenile onset without visual loss (PMID:34868216), and three Pakistani probands with homozygous c.768C>G (p.Asp256Glu), c.889C>A (p.Pro297Thr), or c.316dup (p.Arg106ProfsTer26) causing variable progressive myoclonic epilepsy (PMID:38382230).

Segregation analysis demonstrated co-segregation of CLN6 variants with disease in one large multiplex family (1 additional affected relative). The variant spectrum includes frameshift truncations (e.g., c.316dup (p.Arg106ProfsTer26)), in-frame deletions (p.Ser265del), and missense substitutions affecting transmembrane and luminal domains, consistent with a loss-of-function mechanism.

Functional studies establish that CLN6 is an ER-resident membrane protein essential for lysosomal enzyme trafficking and anti-aggregate activity. Transfection and immunofluorescence confirm ER localization and dimerization of wild-type CLN6, while patient-derived mutations impair degradation of endocytosed arylsulfatase A (PMID:15010453). Interaction with CRMP-2 is disrupted in nclf mouse models leading to impaired neurite maturation and interneuron loss (PMID:19235893). Mutant CLN6 proteins show accelerated proteasomal degradation, and murine Cln6(nclf) models recapitulate motor, visual, and pathological features of human disease (PMID:20020536; PMID:24223841).

Mechanistically, biallelic loss-of-function alleles in CLN6 lead to ER quality control–mediated degradation of mutant proteins, defective lysosomal enzyme processing, and accumulation of storage material. Concordant cellular, biochemical, and animal model data support a haploinsufficiency paradigm with no evidence of dominant-negative effects.

No studies have refuted the CLN6–CLN6 disease association. Together, genetic and functional evidence fulfill ClinGen criteria for a Strong gene-disease relationship. Clinical genetic testing for CLN6 should be considered in patients with unexplained early-onset ataxia, myoclonic epilepsy, or Rett-like regression when MECP2 is negative.

Key Take-home: CLN6 loss-of-function variants cause autosomal recessive variant late-infantile neuronal ceroid lipofuscinosis (Type 6A), with diagnosis facilitated by genomic sequencing and confirmed by supportive functional assays.

References

• Pediatric neurology • 2022 • Neuronal Ceroid Lipofuscinoses Presenting as Rett-like Phenotype: A Two-Case Report From Thailand PMID:36137348
• BMC medical genetics • 2018 • A first CLN6 variant case of late infantile neuronal ceroid lipofuscinosis caused by a homozygous mutation in a boy from China: a case report PMID:30285654
• Frontiers in genetics • 2021 • A Novel CLN6 Variant Associated With Juvenile Neuronal Ceroid Lipofuscinosis in Patients With Absence of Visual Loss as a Presenting Feature PMID:34868216
• Epilepsy research • 2024 • Whole exome sequencing identifies variable expressivity of CLN6 variants in Progressive myoclonic epilepsy affected families PMID:38382230
• The Journal of biological chemistry • 2004 • Defective endoplasmic reticulum-resident membrane protein CLN6 affects lysosomal degradation of endocytosed arylsulfatase A PMID:15010453
• Journal of neuroscience research • 2009 • Protein product of CLN6 gene responsible for variant late-onset infantile neuronal ceroid lipofuscinosis interacts with CRMP-2 PMID:19235893
• Human mutation • 2010 • Pathogenic mutations cause rapid degradation of lysosomal storage disease-related membrane protein CLN6 PMID:20020536
• PloS one • 2013 • A murine model of variant late infantile ceroid lipofuscinosis recapitulates behavioral and pathological phenotypes of human disease PMID:24223841

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