CLN5 – Neuronal ceroid lipofuscinosis type 5

Neuronal ceroid lipofuscinosis type 5 (NCL5) is a rare autosomal recessive lysosomal storage disorder characterized by progressive developmental regression, seizures, visual failure, and motor decline leading to premature death. CLN5 was first described in the Finnish late-infantile variant but has since been identified across diverse populations. Genetic evidence from a multicentre cohort of 15 unrelated patients confirmed nine distinct CLN5 mutations, including six truncating alleles, with disease onset between 2 and 7 years (15 probands) ([PMID:28542837]).

A Chinese patient with developmental regression and grand mal epilepsy was found to harbour a novel frameshift mutation c.718_719delAT (p.Met240fs) and a de novo whole-gene deletion unmasking the sequence variant (1 proband) ([PMID:32393339]). In two consanguineous Pakistani families, WES identified homozygous CLN5 variants c.925_926del (p.Leu309AlafsTer4) and c.477T>C (p.Cys159Arg) segregating with disease in three affected children (3 probands) ([PMID:32302805]).

All reported CLN5 patients exhibit autosomal recessive inheritance with no reported affected carriers. Variants include missense (e.g., c.188G>A (p.Arg63His)), frameshift, nonsense, splice, and whole-gene deletions, with recurrent truncating alleles correlating with earlier onset and rapid decline.

Functional studies demonstrate that CLN5 polypeptides interact with CLN2 and CLN3 in lysosomes, and disease mutations disrupt the CLN5–CLN2 interaction, indicating loss of lysosomal function ([PMID:12134079]). Cellular assays reveal that pathogenic variants impair N-glycosylation, proteolytic processing, lysosomal trafficking, and stability of CLN5 protein ([PMID:20052765]).

Recent structural and enzymatic characterization uncovered a novel cysteine-based S-depalmitoylase activity for CLN5, with catalytic residues His166 and Cys280 essential for thioesterase function; patient-derived mutations abolish this activity and recapitulate lysosomal dysfunction in neuronal progenitors ([PMID:35427157]). Together, these concordant in vitro and patient-derived data support haploinsufficiency as the primary mechanism of pathogenesis.

No conflicting evidence has been reported that disputes the association of biallelic CLN5 variants with NCL5. Additional animal models and longitudinal natural history studies are in progress but exceed current ClinGen scoring.

Key Take-home: Strong genetic and diverse functional evidence establish CLN5 as a definitive cause of neuronal ceroid lipofuscinosis type 5, enabling accurate molecular diagnosis and informing future therapeutic strategies.

References

• Developmental medicine and child neurology • 2017 • Phenotype and natural history of variant late infantile ceroid-lipofuscinosis 5. PMID:28542837
• BMC medical genetics • 2020 • A novel pathogenic frameshift variant unmasked by a large de novo deletion at 13q21.33-q31.1 in a Chinese patient with neuronal ceroid lipofuscinosis type 5. PMID:32393339
• Journal of the neurological sciences • 2020 • Novel likely disease-causing CLN5 variants identified in Pakistani patients with neuronal ceroid lipofuscinosis. PMID:32302805
• Molecular biology of the cell • 2002 • Neuronal ceroid lipofuscinoses are connected at molecular level: interaction of CLN5 protein with CLN2 and CLN3. PMID:12134079
• Human mutation • 2010 • The neuronal ceroid lipofuscinosis protein CLN5: new insights into cellular maturation, transport, and consequences of mutations. PMID:20052765
• Science advances • 2022 • Cln5 represents a new type of cysteine-based S-depalmitoylase linked to neurodegeneration. PMID:35427157

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