Neuronal ceroid lipofuscinoses (NCL) comprise the most common group of childhood encephalopathies caused by mutations in eight genetic loci, CLN1-CLN8.
Neuronal ceroid lipofuscinoses type I and type II (NCL1 and NCL2) also known as Batten disease are the commonly observed neurodegenerative lysosomal storage disorder caused by mutations in the PPT1 and TPP1 genes respectively.
Neuronal ceroid lipofuscinosis (NCL) type 1 (CLN1) is a neurodegenerative storage disorder caused by mutations in the gene encoding the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1).
A preliminary expression study of two of these mutant enzymes supports the conclusion that juvenile-onset NCL (JNCL with GROD) is caused by missense mutations in the PPT gene that result in mutated enzymes with residual PPT enzyme activity.
Additionally, compound heterozygous pathogenic variants of PPT1 gene were detected in a girl, who initially displayed typical RTT features, but progressed into neuronal ceroid lipofuscinoses (NCL) afterwards.
Although functions are defined for some of the soluble proteins that are defective in NCL (cathepsin D, PPT1, and TPP1), the primary function of the other proteins defective in NCLs (CLN3, CLN5, CLN6, CLN7, and CLN8) remain poorly defined.
Cases of ceroid lipofuscinosis with cytoplasmic storage of granular osmiophilic deposits are associated with reduced activity of palmitoyl-protein thioesterase-1 (PPT-1) and mutations in CLN1, and occur from infancy to adulthood.
CLN1 disease (OMIM #256730) is an early childhood ceroid-lipofuscinosis associated with mutated <i>CLN1</i>, whose product Palmitoyl-Protein Thioesterase 1 (PPT1) is a lysosomal enzyme involved in the removal of palmitate residues from S-acylated proteins.
Considering that inclusions of lipofuscin-like substances are observed in retinal pigmentary cells of patients with Stargardt's disease on the one hand, and that the early symptoms of neuronal ceroid lipofuscinosis (CLN3) are suggestive of Stargardt's disease on the other hand (age of loss of visual acuity, appearance of the fundus), we decided to test allelism of Stargardt's disease with the infantile (CLN1) and juvenile forms of neuronal ceroid lipofuscinosis (CLN3), which map to chromosomes 1p32 and 16p12-p11 respectively.
In conclusion, the PPT1 expression pattern differed from the two other lysosomal enzymes implicated in NCL diseases, thus suggesting a distinctive role for PPT1 in brain development.