NCL nomenclature underwent a major change in 1969 (Zeman and Dyken, 1969) when the name ‘neuronal ceroid lipofuscinosis’ was used for the first time. This was proposed 25 years before the first NCL genes were identified. Since then the genes underlying most, but not all, human NCL disease have been identified, and it is clear that this group of diseases shows genetic heterogeneity (mutations in different genes may result in similar clinical disease phenotypes), allelic heterogeneity (different mutations within the same disease gene may result in very different clinical disease phenotypes), and can be phenotypically heterogeneous even within the same family (the same mutation in the same disease gene is linked with differing clinical symptoms and rates of disease progression). It is timely to review the current nomenclature, assess its accuracy and appropriateness, and, if necessary, revise it. Nomenclature is closely related to the classification of NCL diseases and has implications for NCL diagnosis.This chapter, and the following related Chapter 3, was initially drafted by the editors, who represent clinical, molecular genetic, biological, and morphological interests, and further revised by a panel of world experts in the NCLs.The overriding reason for classification of a disease is to provide a definition for subtypes that is universally understood. But first, a definition for the NCLs is required. A general definition of an NCL disorder is:A progressive degenerative disease of the brain and, in most cases, the retina, in association with intracellular storage of material that is morphologically characterized as ceroid lipofuscin or similar to it.

The Neuronal Ceroid Lipofuscinoses (NCLs) are lysosomal storage diseases (LSDs) affecting the central nervous system (CNS), with generally recessive inheritance. They are characterized by pathological lipofuscin-like material accumulating in cells. The clinical phenotypes at all onset ages show progressive loss of vision, decreasing cognitive and motor skills, epileptic seizures and premature death, with dementia without visual loss prominent in the rarer adult forms. Eight causal genes, CLN10/CTSD, CLN1/PPT1, CLN2/TPP1, CLN3, CLN5, CLN6, CLN7/MFSD8, CLN8, with more than 265 mutations and 38 polymorphisms (http://www.ucl.ac.uk/ncl) have been described. Other NCL genes are hypothesized, including CLN4 and CLN9; CLCN6, CLCN7 and possibly SGSH are under study. Some therapeutic strategies applied to other LSDs with significant systemic involvement would not be effective in NCLs due to the necessity of passing the blood brain barrier to prevent the neurodegeneration, repair or restore the CNS functionality. There are therapies for the NCLs currently at preclinical stages and under phase 1 trials to establish safety in affected children. These approaches involve enzyme replacement, gene therapy, neural stem cell replacement, immune therapy and other pharmacological approaches. In the next decade, progress in the understanding of the natural history and the biochemical and molecular cascade of events relevant to the pathogenesis of these diseases in humans and animal models will be required to achieve significant therapeutic advances.

Objective: Mutations in the CLN3 gene lead to juvenile neuronal ceroid lipofuscinosis, a pediatric neurodegenerative disorder characterized by visual loss, epilepsy and psychomotor deterioration. Although most CLN3 patients carry the same 1 kb deletion in the CLN3 gene, their disease phenotype is variable. The aims of this study were to identify (1) genes which are dysregulated in CLN3-disease regardless of the clinical course and could act as new biomarkers, and (2) modifier genes which may affect the progression of the disease delaying deterioration.

OBJECTIVES:To explore a potential expansion of the phenotypic and genotypic characteristics of Finnish variant late-infantile neuronal ceroid lipofuscinosis (NCL), we screened a collection of 47 patients with clinically diagnosed NCL in whom no molecular diagnosis had been made.METHODS:We used PCR amplification of genomic DNA, followed by fluorescent-labeled dideoxy-nucleotide chain termination sequencing and multiplex ligation-dependent probe amplification, to screen our cohort of patients for mutations in CLN5. We collected ethnic background, clinical, and pathologic information, as available, to clarify the breadth of CLN5 disease expression and to explore possible genotype-phenotype correlations.RESULTS:We identified 10 patients with pathogenic CLN5 mutations, including 11 mutations not previously described: 4 missense, 5 out-of-frame insertion/deletion mutations, and 2 large intragenic deletions. We also documented 3 previously reported CLN5 mutations. The age at disease onset in this cohort is predominantly juvenile rather than late infantile. Importantly, we have identified 2 adult-onset patients who share a common pathogenic allele. The majority of patients presented with motor and visual impairments and not seizures. In those patients with available longitudinal data, most had progressed to global neurodevelopmental and visual failure with seizures within 1 to 4 years.CONCLUSIONS:Our study suggests that CLN5 mutations 1) are more common in patients with neuronal ceroid lipofuscinosis (NCL) than previously reported, 2) are found in non-Finnish NCL patients of broad ethnic diversity, and 3) can be identified in NCL patients with disease onset in adult and juvenile epochs. CLN5 genetic testing is warranted in a wider population with clinical and pathologic features suggestive of an NCL disorder.

The neuronal ceroid lipofuscinoses (NCLs) are the most common group of neurodegenerative diseases in children. Mutations in the CLN1 gene, which encodes the enzyme palmitoyl protein thioesterase 1 (PPT1), usually cause infantile-onset NCL (INCL) (Santavouri-Haltia disease, MIM 256730).1 INCL has an age at onset of 8 to 18 months with rapid visual and psychomotor deterioration, ataxia, hypotonia, and seizures.2 Retinal pigment aggregation does not usually occur. In all cases, a granular pattern of storage material in cells is observed by electron microscopy. However, in one family, onset was as late as adulthood.3 We describe a second family with adult-onset NCL caused by a novel mutation in the CLN1/PPT1 gene. A 24-year-old woman with no significant family history was diagnosed with hypomanic episodes because of a 12- to 24-month history of “low self-esteem and mood, irritability, lack of interest, and bizarre behavior including a tendency to wander the streets” and thus treated with olanzapine and valproate. A few months later, she reported the inability to see properly. Ophthalmologic evaluation showed normal visual acuity, pupillary reaction, and normal optic discs and macular and retinal appearance in the presence of “extremely tubular” tunnel vision in both eyes when the automated visual field tests were performed but with inconsistent responses on Goldman’s fields assessment. She had a history of declining academic abilities after age 18 years. She was emotionally labile, but no other neurologic abnormalities were detected. Brain MRI showed marked generalized cerebral and cerebellar atrophy with no focal abnormalities (figure) (see also figure E-1 on the Neurology Web site at www.neurology.org). Hematologic, biochemical, and vasculitic screens and standard lysosomal enzymes assays were normal. Visual evoked responses were delayed bilaterally. Flash electroretinograms …

In the past decade there have been significant advances in our understanding of the molecular genetic basis of the neuronal ceroid lipofuscinoses, a clinically and genetically heterogeneous group of childhood neurodegenerative storage disorders. Recent research progress is reviewed here, to summarize new disease gene identification, diagnostics, treatment, protein functional studies and investigations into the underlying molecular pathogenesis of these devastating disorders.

Major advances in the molecular genetic analysis of the neuronal ceroid lipofuscinoses (NCL) have recently been made: the genes for two major types have been identified and the chromosomal location for a third defined.CLN1, the gene for infantile NCL (Santavuori-Haltia disease) encodes palmitoyl protein thioesterase (PPT). Most patients (75% of disease chromosomes) have the same point mutation. In contrast,CLN3, the gene for juvenile NCL (Batten or Spielmeyer-Vogt-Sjögren disease) is not a previously known gene, nor does its product display homology to any previously described proteins. The same 1 kb genomic deletion is present in the majority of patients (81% of disease chromosomes).CLN5, the gene for Finnish variant late infantile NCL, has been mapped to 13q and should be identified in the near future. The gene for late-infantile NCL (Jansky-Bielschowsky disease) has not yet been localized to a chromosome despite intensive research. It is likely that this type of NCL is caused by mutations in more than one gene each resulting in the same phenotype.

The neuronal ceroid lipofuscinoses comprise a group of inherited neurodegenerative disorders characterized by the accumulation of autoflourescent lipopigment in neurones and other cell types. Three main childhood sub-types occur: infantile (Haltia-Santavouri disease, locus CLN1), late-infantile (Jansky-Bielschowsky disease, locus CLN2) and juvenile (Spielmeyer-Sjogren-Vogt, Batten disease, locus CLN3). Inheritance is autosomal recessive. The basic biochemical defect remains unknown. The infantile disease Iocus (CLN1) has been mapped to human chromosome 1p32 and the juvenile disease Iocus (CLN3) to human chromosome 16p12 by linkage analysis. Marker loci in strong allelic association with the disease loci have been identified in each case and haplotype analysis suggests a founder mutation for CLN1 and CLN3. Classical late-infantile disease (CLN2) has been shown not to be an allelic variant of either CLN1 or CLN3. Identification of linked markers has provided a new method for pre-natal diagnosis. Work is in progress to clone CLN1 and CLN3 and to map CLN2. This will allow elucidation of the molecular genetic basis of the neuronal ceroid lipofuscinoses.