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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, mental regression, behavioral changes, movement disorders, and the accumulation of autofluorescent storage material in the brain and tissues. Although at least 12 different genes have been identified, the NCLs have traditionally been categorized based on age of symptom onset: infantile, late-infantile, juvenile, and adult. Infantile and late-infantile NCL are caused primarily by defects in PPT1 and TPP1, respectively. Tissue damage is selective for the nervous system and many patients die in the first decade of life due to central nervous system degeneration. There is an overall incidence in the United States estimated at 1 in 12,500.
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 of 2. 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 (GRODs) in most cell types. PPT1 is thought to play an active role in various cell processes including apoptosis, endocytosis, and lipid metabolism. Infantile NCL has an incidence of 1 in 20,000 in Finland and is rare elsewhere.
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. In addition, molecular genetic testing of PPT1 or TPP1 may allow for identification of the disease causing mutations.
Evaluation of patients with clinical presentations suggestive of neuronal ceroid lipofuscinoses (NCL)
An aid in the differential diagnosis of infantile and late infantile NCL when fibroblasts are available
NCL testing in fibroblast specimens
Tripeptidyl peptidase 1 (TPP1) and palmitoyl-protein thioesterase 1 (PPT1) enzyme activity below 5 nmol/h/mg of protein are highly suggestive of late infantile and infantile neuronal ceroid lipofuscinoses (NCL), respectively.
This assay does not detect carrier status of neuronal ceroid lipofuscinoses (NCL).
Some variants with age of onset occurring in older individuals have been noted.
TRIPEPTIDYL PEPTIDASE 1
69-934 nmol/h/mg protein
PALMITOYL-PROTEIN THIOESTERASE 1
30-194 nmol/h/mg protein
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