Clinical Information

The neuronal ceroid lipofuscinoses (NCL) comprise a group of recessively inherited neurodegenerative disorders involved in lysosomal protein catabolism. Clinically they are characterized by vision loss, seizures, developmental regression, behavioral changes, movement disorders, and distinguished from other neurodegenerative disorders by the accumulation of auto fluorescent storage material in the brain and tissues. Although at least 13 different genes have been identified, the NCL have traditionally been categorized based on the age of onset of symptoms: infantile, late-infantile, juvenile, and adult. Infantile (CLN1) and late-infantile NCL (CLN2) are caused by defects in palmitoyl-protein thioesterase 1 (PPT1) and tripeptidyl peptidase 1 (TPP1), respectively. Deficiency of tripeptidyl peptidase is also a cause of autosomal recessive spinocerebellar ataxia-7.

Children affected by infantile NCL (CLN1) typically have normal growth and development until about 6 to 12 months of age. Slowed head growth occurs at around 9 months followed by psychomotor degeneration, seizures, and progressive macular degeneration leading to blindness by the age 2 years. CLN1 is caused by a deficiency of the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1), which cleaves long-chain fatty acids (usually palmitate) from cysteine residues. Electron microscopy shows granular osmophilic deposits in most cell types. PPT1 is thought to play an active role in various cell processes including apoptosis, endocytosis, and lipid metabolism.

The late infantile form of NCL (CLN2) is primarily caused by deficiency of the lysosomal enzyme tripeptidyl peptidase 1 (TPP1), which cleaves tripeptides from the N-terminus of polypeptides. Tissue damage results from the defective degradation and consequent accumulation of storage material with a curvilinear profile by electron microscopy. There is widespread loss of neuronal tissue especially in the cerebellum and hippocampal region. Disease onset occurs at 2 to 4 years of age with seizures, ataxia, myoclonus, psychomotor retardation, vision loss, and speech impairment.

Diagnostic strategy depends on the age of onset of symptoms. In children presenting between the ages 0 to 4 years, enzyme assay of PPT1 and TPP1 is an appropriate first step. For other patients suspected of having an NCL, molecular genetic testing of CLN genes is available; see NCLGP / Neuronal Ceroid Lipofuscinosis (Batten Disease) Gene Panel, Varies.