The neuronal ceroid lipofuscinoses (NCL) are a group of progressive hereditary neurodegenerative disorders of children that are distinguished from other neurodegenerative diseases by the accumulation of autofluorescent material (“aging pigment”) in the brain and other tissues. The major clinical features include seizures, psychomotor deterioration, blindness, and premature death. Distinct subgroups of NCL have been recognized that differ in the age of onset of symptoms and the appearance of the storage material by electron microscopy. Three major groups—infantile (INCL), classical late infantile (LINCL), and juvenile (JNCL, also referred to as Batten disease)—are caused by autosomal recessive mutations in the CLN1, CLN2, and CLN3 genes, respectively. A small number of adult-onset NCL cases (tentatively designated CLN4), variant late-infantile forms (CLN5, CLN6, and tentatively, CLN7), and a progressive myoclonic epilepsy (CLN8) are also recognized as NCL disorders. The protein products of the CLN1 (palmitoyl-protein thioesterase) and CLN2 (pepinase) genes are soluble lysosomal enzymes, whereas the CLN3 protein (battenin) is a lysosomal membrane protein, as is (tentatively) the CLN5 protein. The identification of mutations in genes encoding lysosomal proteins in several forms of NCL has led to the recognition of the lipofuscinoses as true lysosomal storage disorders.
All of the NCLs show accumulation of autofluorescent storage material in multiple tissues by light microscopy. In the brain, ballooning of neurons by storage material, macrophage reaction, and cortical astrocytic gliosis may be striking. The cerebral cortex is disproportionately affected. The appearance of the storage material under the electron microscope is highly characteristic for each of the major NCL types: granular osmiophilic deposits (GROD) in INCL, curvilinear profiles in classical LINCL, and fingerprint profiles in juvenile neuronal ceroid lipofuscinosis (JNCL). Variant forms of LINCL usually show a mixture of curvilinear and fingerprint profiles. Adult onset (Kufs) disease shows fingerprint profiles in most cases, but GROD in others. Although the lysosomal storage is present in peripheral tissues, tissue destruction and cell loss are nearly entirely restricted to the central nervous system.
In contrast to other lysosomal storage disorders, classical biochemical characterization of NCL storage material has not provided insights sufficient to uncover the underlying biochemical defects. This is probably due to the heterogeneous nature of the storage material. Subunit c of mitochondrial ATP synthase is a major storage protein identified in late infantile, juvenile, and adult forms of NCL, and sphingolipid activator proteins accumulate to a striking degree in INCL. The relationship between the nature of the storage material and the identified molecular defect still remains unclear.
Infantile NCL is caused by a deficiency in a lysosomal thioesterase activity (palmitoyl-protein thioesterase [PPT]) that removes fatty acids attached in thioester linkage to cysteine residues in proteins. Accumulation of small fatty acyl-cysteine-containing compounds has been demonstrated in cultured cells from INCL patients by metabolic labeling studies. Classical LINCL is caused by deficiency of a lysosomal protease, pepinase. It is one of the rare lysosomal storage diseases caused by a deficiency of a lysosomal protease. Proteins defective in JNCL, and a Finnish variant ...