Review
Genetics of the neuronal ceroid lipofuscinoses

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Abstract

The neuronal ceroid lipofuscinoses (NCLs) are an intriguing group of inherited neurodegenerative disorders characterized by blindness, progressive psychomotor deterioration and death of neocortical neurons. Clinically, four major NCL groups have been identified: infantile, late infantile, juvenile and adult. In recent years, our understanding of the molecular basis of different NCLs has advanced significantly. The accumulation of autofluorescent material in patients’ tissues has been shown to be caused by defects in either lysosomal enzymes or in novel membrane proteins of unknown function. Although the accumulated material is biochemically well defined and some of the causative mutations are known, a unifying hypothesis for the molecular basis of the NCLs remains elusive. Further work will be required to characterize the interactiving molecules and metabolic pathways involved in the pathogenesis of NCLs.

Introduction

The neuronal ceroid lipofuscinoses (NCLs) are a group of progressive neurodegenerative diseases, distinguished from other neurodegenerative disorders by the accumulation of autofluorescent material in multiple tissues of patients. The NCLs were known eponymously as Batten disease until the discovery of genetic loci in the 1990s and for the juvenile form this is still the best-known name. The autofluorescent storage material was shown to resemble ceroid and lipofuscin on histopathological stainings and the name neuronal ceroid lipofuscinosis was introduced by Zeman and Dyken [1]. This name is rather unsatisfactory because the accumulated material does not exactly correspond to ceroid or lipofuscin and the storage bodies are also observed in extra-neuronal tissues.

The NCLs are the most common neurodegenerative disorders of childhood. The incidence shows wide regional differences, being ∼1:10,000 in Northern Europe and the United States, and the estimated carrier frequency is 1% 2, 3. The diagnostic hallmark symptoms for NCLs are impaired vision as well as mental and motor deterioration, often accompanied by ataxia, myoclonus and epilepsy. Histopathological findings are characterized by accumulation of lipopigment in several tissues and various degrees of brain atrophy: depletion of cortical neurons and cortical astrocytogliosis 2, 4. The rate of progression varies and provides the basis for the diagnostic classification of different NCL-subtypes. None of the phenotypic features is diagnostic alone but the pattern of clinical symptoms, as well as histological and neurophysiological findings define the NCL-subtype 2, 4, 5.

Traditionally, three different autosomal recessive childhood main types are recognized: infantile (INCL), late infantile (LINCL) and juvenile (JNCL). Adult (ANCL) forms have also been described, with both dominant and recessive pattern of inheritance.

In addition to these main types, several variant NCL subtypes have been clinically defined, especially within LINCL. It is now clear that a considerable degree of locus and allelic heterogeneity underlies this spectrum of clinical phenotypes [6]. The aim of our review is to summarize current knowledge of the molecular and cell biological background of this intriguing group of severe brain disorders.

Section snippets

Storage material in NCL provided no clue to the molecular defect

The description of the accumulated autofluorescent material in NCL patients’ cells as ceroid and lipofuscin is somewhat non-specific because ceroid is found in several pathological conditions and lipofuscin often in aging tissues 2, 7. Thus it was not surprising that careful biochemical analyses of the storage material failed to reveal the primary cause of the disease. Accumulation occurs in the majority of tissues and starts in the prenatal period, as early as the first semester in the case of

Gene defects in different NCL subtypes

By linkage analyses in clinically well-defined families, chromosomal assignment has been established for all major NCL forms: 1p32 for INCL (gene locus CLN1) [18], 11p15 for LINCL (CLN2) [19] and 16p12 for JNCL (CLN3) [20]. In addition, three distinct LINCL-subtypes have been identified with separate genetic loci. These are the Finnish variant LINCL (CLN5) [21], variant LINCL (CLN6) [19] and the Turkish variant LINCL (CLN7) [22]. Recently a form of progressive epilepsy with mental retardation

Molecular genetics of atypical NCL forms

vLINCL (Finnish variant late infantile NCL CLN5) was described by Santavuori and colleagues in 1982. Age at death varies between 13 and 35 years and the degree of brain atrophy is between INCL and JNCL. By the genome-wide scan, the CLN5-locus was assigned to 13q22 in Finnish families and the gene was positionally cloned 21, 44••. The gene encodes a transmembrane protein of 407 amino acids, with an unknown function. The CLN5 sequence analysis of vLINCL patients revealed that 95% of Finnish

Animal models of NCL diseases

There are several natural animal models sharing clinical and histopathological features of NCL. As the correlation between different animal and human NCL types is largely unsolved, however, this restricts the optimal use of NCL animal models in the monitoring of tissue pathology or in the evaluation of biology-based therapies. To date, a knockout mouse phenotype has only been reported for the JNCL subtype 48, 49, 50.

Probably because of extensive inbreeding, several canine breeds — the miniature

Prenatal and carrier diagnostics in NCLs

The genetic information accumulated in NCL diseases during the past 10 years has not had a major impact on diagnosis of NCL disorders. Before the DNA era, prenatal diagnostics was based solely on demonstration of inclusion bodies in a chorionic villus sample (CVS) or free floating amniotic cells, obtained by transcervical or transabdominal biopsy 59, 60. After establishment of the chromosomal location or identification of the mutated gene, the diagnosis can be simultaneously done by DNA

Conclusions

Identification of molecular defects in the NCLs has revealed that they form a new group of lysosomal disorders that are distributed worldwide and represent the most common group of hereditary progressive neurodegenerative disorders of children.

Data have emerged to indicate that the mutation type correlates with the clinical phenotype of the patients and this information may in future improve the accuracy of genetic counseling and also guide the strategies aiming to identify functional domains

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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