CLN3 – Neuronal Ceroid Lipofuscinosis

Juvenile neuronal ceroid lipofuscinosis (JNCL) is an autosomal recessive lysosomal storage disorder characterized by early visual failure, seizures, cognitive and motor decline, and premature death. The CLN3 gene encodes a multi‐pass lysosomal membrane protein, battenin, essential for lysosomal homeostasis and neuronal survival. Pathogenic variants in CLN3 disrupt endosomal–lysosomal trafficking and lead to accumulation of autofluorescent lipopigments in neurons and peripheral tissues (PMID:35628533).

Clinical genetic studies have identified CLN3 variants in over 77 unrelated probands diagnosed with JNCL, with consistent autosomal recessive inheritance and segregation in consanguineous families (PMID:11142754). In one large Pakistani kindred, a novel homozygous in‐frame deletion c.181_183del (p.Asp61del) segregated with disease in four affected relatives (PMID:30892110). Case reports expand the variant spectrum beyond the common 1.02‐kb deletion, including c.1135_1138del (p.Leu379MetfsTer11) in an unrelated patient causing a frameshift and premature stop (PMID:23877479).

Affected individuals typically present between 4 and 10 years with bull’s‐eye maculopathy, night blindness, photophobia, visual loss (HP:0000572), seizures (HP:0001250), and developmental regression (HP:0002376). Neuroimaging reveals cerebral and cerebellar atrophy, periventricular white matter changes, and thin corpus callosum. Peripheral blood films often show vacuolated lymphocytes, aiding early diagnosis.

Functional assays demonstrate that the prevalent 461–677 deletion mutant is retained in the endoplasmic reticulum and fails to reach lysosomes, whereas the rare E295K missense mutant traffics normally but lacks activity in yeast complementation assays, indicating distinct molecular defects (PMID:10332042). Mouse Cln3 knockout models recapitulate human histopathology, including subunit‐c accumulation, retinal degeneration, and neurobehavioral deficits, supporting haploinsufficiency as a mechanism.

Integration of genetic and experimental data yields a Definitive gene–disease relationship: over 77 probands, multi‐family segregation, and concordant functional models. ClinGen genetic evidence is Strong (32 pathogenic variants in 77 probands, AR inheritance, segregation in consanguineous families [PMID:11142754]), and functional evidence is Moderate (ER retention of deletion mutant, lysosomal mislocalization and rescue assays in yeast and mouse [PMID:10332042]).

Key Take‐Home: CLN3 testing is essential for children with early visual decline and neurodegeneration, guiding genetic counseling, carrier screening, and potential enrollment in emerging therapies.

References

• Genetic Testing • 2000 • Molecular diagnosis of and carrier screening for the neuronal ceroid lipofuscinoses. PMID:11142754
• The International Journal of Neuroscience • 2019 • A novel in-frame mutation in CLN3 leads to Juvenile neuronal ceroid lipofuscinosis in a large Pakistani family. PMID:30892110
• Journal of Child Neurology • 2013 • A novel c.1135_1138delCTGT mutation in CLN3 leads to juvenile neuronal ceroid lipofuscinosis. PMID:23877479
• Human Molecular Genetics • 1999 • Defective intracellular transport of CLN3 is the molecular basis of Batten disease (JNCL). PMID:10332042
• International Journal of Molecular Sciences • 2022 • Recent Insight into the Genetic Basis, Clinical Features, and Diagnostic Methods for Neuronal Ceroid Lipofuscinoses. PMID:35628533

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