Chapter 154

## Abstract

Abstract

1. 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.

2. The clinical manifestations of the NCLs are distinctive and vary by age of onset. INCL is characterized by normal development to the age of 6 to 12 months, followed by mental retardation, arrest of cognitive and motor development, microcephaly, myoclonus, and visual deterioration. The EEG is isoelectric by about age 3. Classical LINCL presents between 2 and 4 years of age with severe myoclonic seizures and a slow progression to blindness. Distinctive “giant” visual and somatosensory evoked potentials are seen. Several variant forms of LINCL have clinical presentations intermediate between the classical late infantile and juvenile forms. Juvenile NCL (the most common form of NCL) presents as progressive visual failure between the ages of 4 to 9 years. Cognitive decline and motor deterioration follow inexorably, leading to death in the third or fourth decades. Seizures are a variable feature. Adult NCL (Kufs disease) is distinguished from the other NCL types by the absence of visual failure and an onset at around 30 years of age. A mild progressive myoclonic epilepsy in Finland (“Northern epilepsy”) with a nearly normal life span is now also recognized as an NCL disease.

3. 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.

4. 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.

5. 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 late infantile NCL, have also been identified. The protein defective in JNCL (battenin) is a lysosomal membrane protein, as is most probably the protein defective in Finnish variant LINCL. The function of these novel proteins is unknown.

6. With the possible exception of some adult-onset NCL families, the inheritance of the NCLs is autosomal recessive. At least eight genes are involved, and genetic linkage analysis has led to the identification of six confirmed genetic NCL loci. Four of these genes (CLN1, CLN2, CLN3, and CLN5) have been identified and characterized. Over 20 different mutations in the CLN1 and CLN3 genes have been reported, and phenotype-genotype correlations are beginning to emerge. The molecular genetics have also shown that previous clinical phenotypes do not always correlate with the molecular defect. For example, some JNCL cases (“GROD” variants) are caused by subtle mutations in the CLN1 gene.

7. The laboratory diagnosis of NCL depends primarily on the recognition of storage material by electron microscopic examination of peripheral blood leukocytes or other accessible tissue. Diagnostic enzymatic assays are available for the infantile and classical late infantile forms. DNA-based diagnostic tests are available for the infantile, late infantile (classical and Finnish variant), and juvenile forms. Prenatal diagnosis is now available for most of the major forms.

8. No specific treatment is available for any of the NCL disorders beyond best supportive care. Refractory seizures are a distressing symptom for many patients and require the skilled use of anticonvulsant medications, usually in combination. As infantile and classical late infantile NCL are caused by deficiencies in soluble lysosomal enzymes, strategies designed to replace the defective lysosomal enzymes are appropriately applied to these disorders.

9. Naturally occurring NCL disorders have been described in the sheep, dog, and mouse. Syntenic relationships of chromosomal loci suggest that the New Zealand Southhampshire sheep and the nclf mouse are models for CLN6. Transgenic mouse models for the major forms of NCL are under development. The use of appropriate animal models will greatly facilitate the development of new therapies for the NCL disorders.

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