Table I.
Identifying Features of Neuronal Ceroid Lipofuscinoses (NCL) 1
| Neuronal ceroid lipofuscinoses type | Gene/protein (disease variant) | Age of onset | Symptoms | Protein localization2 | Protein function/activity3 | Abnormal lipid/protein composition |
|---|---|---|---|---|---|---|
| CLN1 | PPT1 (INCL) | 5 months to 2 years (infantile) | Decreased head growth, blindness, seizures, hyperexcitability, slowed motor and mental development | Lysosomal matrix, extralysosomal vesicles, extracellular | Palmitoylthioesterase | Phospholipids (lipofuscin)/SAPs |
| CLN2 | TPP1 (LINCL) | 2–4 years (late infantile) | Progressive dementia, motor dysfunction, seizures, myoclonus, ataxia, loss of vision | Lysosomal matrix | Serine protease | Unknown lipids/SCMAS |
| CLN3 | CLN3 (JNCL) | 4–10 years (juvenile) | Visual failure from retinal degeneration, progressive cognitive decline, motor dysfunction, seizures, and behavior problems | Late endosomal / lysosomal membrane, presynaptic vesicles | Modulation of vesicular trafficking/fusion, pH regulation and osmoregulation284, resistance to endoplasmic reticulum stress56; regulation of ganglioside levels285 | BMP, phospholipids, galactosyl-ceramide/SCMAS |
| CLN4 | DNAJC5, CSPα, (Parry NCL) | ~30 years (adult) | Slow progressing, death 10–20 years after onset | Cytosolic, associated-vesicular membranes | Hsc70 co-chaperone (exo/endocytosis) | Unknown lipids/SAPs |
| CLN5 | CLN5 (Finnish variant) | 4.5–6 years (late infantile, juvenile) | Slight motor clumsiness, seizures, ataxia, myoclonus | Lysosomal matrix | Modulation of vesicular trafficking/fusion | Sphingolipids/SCMAS |
| CLN6 | CLN6 | 2–4 years (late infantile); and adult onset | Resembles LINCL in clinical characteristics | ER-lysosomal membrane | Likely involved with degradation of post-translationally modified proteins in lysosomes286 | Phospho- and glycosphingo-lipids, cholesterol/SCMAS |
| CLN7 | MFSD8 | 2–4 years (late infantile) | Seizures, poor mobility, visual impairment | Lysosomal membrane | Transmembrane transporter function predicted, regulation of soluble lysosomal proteins287 | Unknown lipids/SCMAS |
| CLN8 | CLN8 (EPMR) | 5–10 years (juvenile) | Increasing seizures until puberty, then decreasing frequency through adulthood | ER/ERGIC membrane | Regulation in lipid metabolism predicted, regulates lysosome biogenesis72, Endoplasmic reticulum-export recycling receptor71 | Ceramides, phospholipids, sphingolipids, sulfatides/SCMAS |
| CLN9 | Unknown | Unknown | unknown | unknown | UNK, role in ceramide synthesis postulated | Ceramides, sphingomyelin, sphingolipids, globosides/protein n.d. |
| CLN10 | CTSD/Cathepsin D (congenital) | Congenital, neonatal, and late infantile variants288 | Epilepsy, extreme brain atrophy, with death in a few days from cardiac failure | Lysosomal matrix, extracellular | Aspartyl endopeptidase | BMP, cholesterol, phospho- and sphingo-lipids/SAPs |
| CLN11 | GRN/Progranulin | 22–23 years (adult) | Seizures, visual deterioration, myoclonus | Extracellular | UNK, roles in inflammation, embryogenesis, cell motility and tumorigenesis postulated, non-enzyme | lipids/protein n.d. |
| CLN12 | ATPase 13A2, | 13–16 years (adult) | Poor mobility, myoclonus, deteriorated speech | Lysosomal membrane, multivesicular bodies | UNK, regulation of ion homeostasis postulated, secretion of exosomes and α-synuclein86, non-enzyme | lipids/protein n.d. |
| CLN13 | CTSF/Cathepsin F (Adult Kufs type B) | 20–32 years (adult) | Dementia, personality changes | Lysosomal matrix | Cysteine protease | lipids/protein n.d. |
| CLN14 | K+ channel protein (KCTD7) | 8–24 months (infantile) | Seizures, visual and verbal deterioration, brain atrophy | Cytostolic, associated to membrane | Transmembrane protein voltage-gate potasium channel complex, potassium and glutamine transport92, autophagy93 | lipids/protein n.d. |
1
Abbreviations: NCL (neuronal ceroid lipofuscinoses), CLN (ceroid lipofuscinosis neuronal), INCL (infantile NCL), LINCL (late infantile NCL), JNCL (juvenile NCL), PPT1 (palmitoyl protein thioesterase1), TTP1 (tripeptidyl peptidase1), MFSD8 (major facilitator superfamily domain‐containing protein 8), EPMR (progressive epilepsy with mental retardation), KCTD7 (potassium channel tetramerization domain containing protein 7), SCMAS (subunit c of mitochondrial ATP synthase), SAPs (sphingolipid activator proteins), BMP (bis(monoacylglycerol)phosphate), and n.d. (not determined).
2
Soluble proteins (CLN1, CLN2, CLN5, CLN10, CLN13); transmembrane proteins (CLN3, CLN6, CLN7, CLN8, CLN12, CLN14).
3
Functions are unknown (UNK) for most of the CLNs; however, investigations have determined possible function/activity.