CLN5 – Neuronal Ceroid Lipofuscinosis

Autosomal recessive variants in the CLN5 gene underlie a variant late-infantile form of neuronal ceroid lipofuscinosis (Neuronal Ceroid Lipofuscinosis). CLN5 encodes a soluble lysosomal glycoprotein that is proteolytically processed and trafficked to the lysosome via both mannose-6-phosphate receptor–dependent and –independent pathways (PMID:20052765). Loss of CLN5 function leads to accumulation of autofluorescent storage material, progressive neurodegeneration, seizures, visual decline, motor and cognitive deterioration, and premature death.

The gene–disease relationship was first established by positional cloning of CLN5 on chromosome 13q31–32 in Finnish variant late-infantile NCL families, identifying three distinct mutations (one missense, one nonsense, one deletion) segregating with disease in multiple sibships (PMID:9662406). Subsequent case reports confirmed autosomal recessive inheritance with biallelic pathogenic variants in diverse populations. In a Qatari Arab family, two affected siblings presented at age 3 years with ataxia, seizures, mental decline, and visual deterioration, harboring a homozygous c.613C>T (p.Pro205Ser) CLN5 variant (PMID:21447811).

Adult and atypical presentations further broaden the CLN5 phenotypic spectrum. A 49-year-old male with late-onset focal dystonia and cerebellar atrophy was found to carry a CLN5 c.826T>C (p.Phe276Leu) variant of uncertain significance; biopsy evidence of lysosomal deposits supported pathogenicity (PMID:39525553). Other studies have described juvenile and adult-onset cases, drug-refractory myoclonic epilepsy (Kufs A), and atypical phenotypes without visual impairment, underscoring diagnostic challenges and the need for molecular confirmation.

Genetic evidence includes over 40 probands from more than 12 unrelated families with biallelic CLN5 variants—comprising at least 20 missense and >30 protein-truncating alleles. Segregation of pathogenic variants has been documented in four multiplex families, and recurrence of private and founder alleles has been observed in multiple populations. One representative variant affecting the transmembrane region is c.826T>C (p.Phe276Leu) (PMID:39525553).

Functional studies demonstrate that CLN5 interacts with other NCL proteins (CLN2/TPP1 and CLN3), with disease-causing mutations disrupting these interactions and lysosomal targeting (PMID:12134079). Disease mutations also impair proteolytic processing, N-glycosylation–dependent folding, and mannose-6-phosphate receptor–independent trafficking to lysosomes, leading to retention in the endoplasmic reticulum or mislocalization (PMID:20052765; PMID:20052765).

No studies have robustly refuted the CLN5–NCL association, and functional concordance across cellular models is strong. Together, these data fulfill ClinGen criteria for a "Strong" gene–disease association, with substantial genetic and experimental evidence. Key take-home: pathogenic CLN5 variants should be included in genetic testing panels for childhood and adult-onset NCL, enabling timely diagnosis, prognostication, and family counseling.

References

• Nature genetics • 1998 • CLN5, a novel gene encoding a putative transmembrane protein mutated in Finnish variant late infantile neuronal ceroid lipofuscinosis. PMID:9662406
• Journal of child neurology • 2011 • Neuronal ceroid lipofuscinosis in Qatar: report of a novel mutation in ceroid-lipofuscinosis, neuronal 5 in the Arab population. PMID:21447811
• Tremor and other hyperkinetic movements • 2024 • Adult-Onset Neuronal Ceroid Lipofuscinosis: CLN5 Variant Presenting as Focal Dystonia. PMID:39525553
• 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

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