The neuronal ceroid-lipofuscinoses: From past to present

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1 Biochimica et Biophysica Acta 1762 (2006) Review The neuronal ceroid-lipofuscinoses: From past to present Matti Haltia Departments of Pathology, University of Helsinki and Helsinki University Central Hospital, PO Box 21, Helsinki, Finland Received 13 April 2006; accepted 28 June 2006 Available online 8 July 2006 Abstract The neuronal ceroid-lipofuscinoses (NCLs) are inherited lysosomal storage diseases and constitute the most common group of children's progressive encephalopathies. Most childhood forms of NCL are clinically characterized by progressive loss of vision as well as mental and motor deterioration, epileptic seizures, and premature death, while the rare adult forms are dominated by dementia. All forms of NCL share common pathomorphological features. Autofluorescent, periodic acid-schiff- and Sudan black B-positive granules, resistant to lipid solvents, accumulate in the cytoplasm of most nerve cells, and there is progressive and remarkably selective neuronal degeneration and loss. For a long time, the NCLs were grouped under the heading of the amaurotic family idiocies and conceived as lipidoses. However, in the late 1980ies and 1990ies the NCL storage cytosomes were shown to consist largely of two hydrophobic proteins: either subunit c of mitochondrial ATP synthase or sphingolipid activator proteins A and D. Since 1995 numerous mutations in at least seven different genes have been shown to underlie the multiple human and animal forms of NCL. This review discusses the historical evolution of the NCL concept and the impact of the recent biochemical and molecular genetic findings on our views on the classification and pathogenesis of these devastating brain disorders Elsevier B.V. All rights reserved. Keywords: Neuronal ceroid lipofuscinoses; Batten disease; Lysosomal storage; Molecular pathology; Classification 1. Introduction The neuronal ceroid-lipofuscinoses (NCLs, also referred to as Batten's disease) [90] are inherited lysosomal storage diseases and collectively constitute the most common group of children's progressive encephalopathies. Their overall incidence in the US has been estimated at 1: [49], and certain forms of NCL are relatively frequent in Northern European populations [74]. In addition to the human NCLs, a number of spontaneous animal forms of NCL have been described, discussed in detail elsewhere in this issue. The clinical and pathological features of the human NCLs have been thoroughly reviewed in recent years [18,20,82]. With one exception, the NCLs show an autosomal recessive mode of inheritance, and may have a congenital, infantile, late infantile, juvenile or adult onset. Most childhood forms are clinically characterized by progressive loss of vision as well as Tel.: address: matti.j.haltia@helsinki.fi. mental and motor deterioration, epileptic seizures and premature death, while the rare adult-onset forms are dominated by dementia. Despite the varying clinical features, all forms of NCL share unifying pathomorphological characteristics. Autofluorescent, periodic acid-schiff (PAS)- and Sudan black B- positive granules, resistant to lipid solvents, accumulate in the cytoplasm of most nerve cells (Fig. 1) and, to a lesser extent, of many other cell types. There is progressive and remarkably selective neuronal loss, coupled with astrocytic proliferation and hypertrophy as well as macrophage infiltration. In the most severe congenital and infantile NCLs the cortical and retinal neurons may be almost completely destroyed, resulting in extreme brain and retinal atrophy. The ultrastructure of the accumulating storage cytosomes varies between the different forms of NCL [13] (Fig. 2) and has long served as the basis of their classification, along with the age of clinical onset [18,20,82]. The biochemical nature of the materials accumulating within the pathological autofluorescent cytosomes first began to be understood in the late 1980ies [43,45,70], and the first genomic defects causing NCL were identified in 1995 [1,79]. Since then, /$ - see front matter 2006 Elsevier B.V. All rights reserved. doi: /j.bbadis

2 M. Haltia / Biochimica et Biophysica Acta 1762 (2006) Fig. 1. The intraneuronal storage material in all forms of neuronal ceroid-lipofuscinosis shows autofluorescence in ultraviolet light, seen here as moon-like crescents around the nuclei of cortical neurons (A). The storage granules stain positively with Luxol fast blue (B), periodic acid-schiff (C) and Sudan black B (D) methods. Paraffin sections from the cerebral cortex of a patient with CLN5 300 (A) and CLN (B D). Reproduced with permission from the Journal of Neuropathology and Experimental Neurology. altogether 7 different NCL genes have been isolated. The purpose of this paper is to review the historical development of the NCL concept and to discuss the impact of the recent molecular findings on our views on the classification and pathogenesis of these devastating brain disorders. 2. The first clinical description The credit for the first clinical description of any form of NCL is usually given to Dr. Otto Christian Stengel, physician at the Copper Mining Company of Røros, a small Norwegian town. His Account of a singular illness among four siblings in the vicinity of Røraas (Fig. 3) was published in the first volume of the first Norwegian medical Journal in 1826 [66] and coupled systematic clinical observation with scientific thinking. The four consecutive children, two boys and two girls, of apparently healthy parents did well until the age of 6 years when their sight began to deteriorate. Within years, the disease led to blindness, progressive mental deterioration and loss of speech, epileptic fits, and premature death (by the time of publication the two oldest siblings had died at the ages of 21 and 20 years). No autopsies were performed. Stengel's report, written in Norwegian, remained unnoticed until attention was brought to its significance by his countrymen more than a century later. 3. The amaurotic family idiocies The concept of amaurotic family idiocy [51] was created by the American neurologist Sachs, based on his observations in a set of siblings of rapidly progressive loss of vision, combined with severe mental retardation of infantile onset. The disease was morphologically characterized by accumulation of material of lipid nature within markedly ballooned nerve cells of the central nervous system. Between the years 1903 and 1914 a number of further patients with progressive loss of vision and psychomotor retardation but with a later onset were described in a familial setting. Patients with both late infantile and juvenile onset were reported by Batten [3,4] and Vogt [83 85], patients with a juvenile onset by Spielmeyer [63 65], and patients with late infantile onset by Janský [29] and Bielschowsky [6]. At neuropathological autopsy, all these further patients showed accumulation within nerve cells of granular material with lipid-like staining qualities. Inspired by the clinical similarities (familial occurrence, progressive loss of Fig. 2. The ultrastructural appearances of the intraneuronal storage deposits vary between the different forms of the neuronal ceroid-lipofuscinoses. Four basic types can be delineated: (A) granular osmiophilic deposits are characteristic of the infantile and other forms of CLN1, 10,000; (B) curvilinear profiles are typical of classic late infantile neuronal ceroid-lipofuscinosis CLN2, 20,000; (C) fingerprint patterns are the predominant type of intraneuronal inclusions in the juvenile form CLN3, 30,000; (D) many inclusions in the variant forms of late infantile neuronal ceroid-lipofuscinosis correspond to the rectilinear complex, 15,000. Reproduced with permission from the Journal of Neuropathology and Experimental Neurology.

3 852 M. Haltia / Biochimica et Biophysica Acta 1762 (2006) Fig. 3. The first page of Dr. Otto Christian Stengel's original clinical description of juvenile NCL in the first volume of the first Norwegian medical journal Eyr in vision and mental retardation) and the unifying pathological concept of intraneuronal thesaurismosis [59,60] or storage, all these familial cases were gradually lumped together and considered to represent variants of amaurotic family idiocies of either infantile (Tay Sachs), late-infantile (Janský Bielschowsky), or juvenile (Spielmeyer Sjögren) onset. In 1925 Kufs published his first report on familial adult onset intellectual deterioration with similar neuropathological features but without loss of vision [35]. Klenk's biochemical studies in 1939 [33] showed an increased cerebral ganglioside concentration in the infantile Tay Sachs form of amaurotic family idiocy, and in 1962 Svennerholm identified the major storage material in this disease as GM2-ganglioside [67]. However, he also confirmed Klenk's observation that there was no increase in the amount of gangliosides in the juvenile form of amaurotic family idiocy. 4. The neuronal ceroid-lipofuscinoses Klenk's and Svennerholm's studies already indicated that the group of the amaurotic family idiocies was biochemically heterogeneous. Furthermore, comparative histochemical and electron microscopic studies in the early 1960ies demonstrated that the intraneuronal storage cytosomes in the juvenile Spielmeyer Sjögren form of amaurotic family idiocy [88] radically differed from the membraneous cytoplasmic bodies found in the infantile Tay Sachs form [68] and were close to the autofluorescent lipopigments ceroid and lipofuscin [88,89].In contrast to the storage material in the infantile Tay Sachs type of amaurotic family idiocy, the storage cytosomes in the late infantile and juvenile cases were largely resistant to lipid solvents and showed a characteristic curvilinear (late infantile) or fingerprint (juvenile) pattern [88,89]. In order to clearly distinguish the late infantile and juvenile forms of the amaurotic family idiocy and the histochemically similar Kuf's adult onset disease from Tay Sachs disease and other gangliosidoses, Zeman and Dyken [90] proposed the new term neuronal ceroid-lipofuscinosis (NCL), based on the histochemical and electron microscopic characteristics of the storage material. After inclusion of a new infantile type of NCL, described by Haltia et al. [21,22] and Santavuori et al. [55] and characterized by storage cytosomes with a finely granular ultrastructure (granular osmiophilic deposits or GRODs), and the first animal form of NCL in English setters [34], a new classification of the NCLs was proposed [87], essentially based on the age of clinical onset and the ultrastructure of the storage cytosomes. Four different types of human NCL and a canine form were distinguished. The human forms of NCL included the infantile (Haltia Santavuori), late infantile (Janský Bielschowsky, juvenile (Spielmeyer Sjögren) and the adult (Kufs) types [87]. This classification did not pay attention to the occasional congenital cases reported earlier [11,41,53]. With time, a number of atypical or variant cases were reported, often with a late infantile/early juvenile onset [37,56,57,72,81], expanding the spectrum of human NCLs further. Surprisingly, even Northern epilepsy, an inherited childhood epilepsy syndrome with relatively mild and protracted mental retardation [26], turned out to be a novel form of NCL at neuropathological analysis [23,25]. New forms of spontaneous NCL were also discovered in many breeds of dogs [32], as well as in cats [7,19,39,77], sheep [12,30,31], goats [15], cattle [24,48], horses [73], and mice [9,10]. 5. Classification based on storage materials The ovine models turned out to be important in the further development of the NCL concept. Isolation and biochemical analysis of the storage cytosomes in New Hampshire sheep showed that they were largely composed of protein, not lipid [43]. The main component was identified as subunit c of the mitochondrial ATP synthase [14,45], soon found as the major stored protein also in most other animal and human types of NCL [44]. However, purification and protein chemical studies of the storage cytosomes in the human infantile type of NCL established sphingolipid activator proteins (saposins) A and D as their main protein components [70]. Subsequently, sphingolipid activator proteins were also discovered as the predominant protein component of the storage material in the miniature Schnauzer dog model [46], the congenital ovine model [71], and the congenital human NCL [61]. Consequently, the human and animal forms of NCL can now be classified into two main categories, based on the chemical identity of the predominant storage protein: those storing subunit c and those storing sphingolipid activator proteins A and D (Table 1). The principle stored compound seems to determine the ultrastructure of the storage cytosomes. Storage of sphingolipid activator proteins has invariably been associated with GRODs, while storage of subunit c has been associated with more variable electron microscopic appearances (curvilinear, rectilinear or fingerprint patterns). 6. Molecular genetic classification The first NCL gene, responsible for the infantile form of NCL, was identified by a positional candidate gene approach in

4 M. Haltia / Biochimica et Biophysica Acta 1762 (2006) Table 1 The human neuronal ceroid-lipofuscinoses (NCLs): molecular genetic classification Disease Eponyme OMIM number Clinical phenotype Ultrastruct. phenotype Chromos. Gene Gene product CLN1 Haltia - Santavuori [22,55] 256,730 INCL (LINCL, JNCL, ANCL) GROD 1p32 CLN1 [79] PPT1 SAPs CLN2 Janský-Bielschowsky [6,29] 204,500 LINCL CL 11p15 CLN2 [62] TPP1 SCMAS CLN3 Spielmeyer-Sjögren 204,200 JNCL FP (CL, RL) 16p12 CLN3 [1] CLN3 SCMAS [3,4,63 65,84] CLN4 Kufs [35] 204,300 ANCL FP, granular??? SCMAS CLN5 vlincl Finnish [56,57,72] 256,731 vlincl RL, CL, FP 13q22 CLN5 [58] CLN5 SCMAS CLN6 Lake-Cavanagh [37] 601,780 vlincl (early juvenile) RL, CL, FP 15q21 23 CLN6 [16,80] CLN6 SCMAS CLN7 vlincl Turkish [81] vlincl RL, FP??? SCMAS CLN8 Northern epilepsy [23,25,26] 600,143 EPMR, vlincl CL-like, granular 8p32 CLN8 [47] CLN8 SCMAS Congenital NCL Congenital NCL [11,41,53] Congenital NCL GROD 11p15.5 CTSD [61] Cathepsin D SAPs Parry disease Parry [8,40] 162,350 ANCL (autosomal dominant) GROD??? SAPs Abbreviations: INCL, LINCL, vlincl, JNCL and ANCL, infantile, late infantile, variant late infantile, juvenile and adult onset neuronal ceroid-lipofuscinosis; EPMR, epilepsy with progressive mental retardation; GROD, granular osmiophilic deposits; CL, curvilinear profiles; FP, fingerprint bodies; RL, rectilinear profiles; SCMAS, subunit c of mitochondrial ATP synthase; SAPs, sphingolipid activator proteins. Stored protein 1995 [79]. It encodes palmitoyl protein thioesterase 1 (PPT1), a soluble lysosomal enzyme. In the very same year, collaboration of five research groups also led to the isolation, by positional cloning, of the gene behind juvenile NCL, encoding a novel putative membrane protein [1]. Since 1995 five further genes [16,47,58,61,62,71,80] and an ever increasing number of mutations responsible for human and/or animal forms of NCL have been identified, now listed in a mutation database at www. ucl.ac.uk/ncl. As a consequence, the human NCLs are now classified into eight main genetic forms (CLN1 8) [18,20,27,69], based on the number of hitherto predicted genetic loci (Table 1). A few rare forms of NCL, including the congenital [2,17,28] and dominantly inherited adult onset NCL (Parry disease) [8,40], still remain without proper genetic assignment (Table 1). It is important to keep in mind that different mutations in a single gene may give rise to different clinical phenotypes, including different ages at onset, depending on the exact site and type of the mutation. Common mutations that predominate in a given form of NCL are usually associated with the classic clinical picture, while rare private mutations may result in a deviant phenotype. CLN1 may serve as an example in this respect. Although the storage cytosomes of all CLN1 patients so-far reported have shared the same ultrastructural pattern (granular osmiophilic bodies), the clinical onset of the disease has varied from infantile to late-infantile, juvenile [54] or even adult [76]. Mutations associated with the classic severe infantile phenotype are located close to the active site (Ser 155) of the gene product PPT1 and profoundly disturb the structure and function of the enzyme. In contrast, mutations resulting in late-onset forms of CLN1 are remote from the catalytic triad, leading only to limited changes in protein structure [5,52]. 7. Pathogenetic hypotheses For a long time the different forms of NCL were conceived as lipidoses, along with Tay Sachs disease, the prototype of the amaurotic family idiocies. Analyses of the storage material were believed to provide answers as to their exact etiopathogenesis. However, in contrast to Tay Sachs disease, no ganglioside accumulation could be demonstrated in brain tissue [33,67,88], and the NCLs finally had to be separated from the gangliosidoses [90]. The histochemical similarity of the NCL storage cytosomes to the lipopigments ceroid and lipofuscin [88,90] prompted the next main hypothesis. It was proposed that the basic defect was the formation of pathological lipopigments, possibly due to an increased rate of polyunsaturated fatty acid peroxidation [86]. However, despite numerous experimental and clinical studies, including treatment of patients with various antioxidants, no conclusive evidence could be presented in favor of this idea. The final blow to the lipidosis concept came by the demonstration of proteins, either subunit c of the mitochondrial ATP synthase [14,45] or sphingolipid activator proteins [70], as the major components of the purified NCL storage cytosomes. Molecular genetic linkage studies, based on families of NCL patients, carefully diagnosed by clinical and neuropathological methods, finally led to the identification of seven genes and over 150 different mutations behind the various forms of human NCL. Apart from cathepsin D, first identified as responsible for the congenital ovine model [71] and later for congenital human NCL [61], all the NCL genes so far isolated in animals have turned out to be homologues of previously established human NCL genes. The products of the CLN1 and CLN2 genes, PPT1 and tripeptidyl peptidase 1 (TPP1), are soluble lysosomal enzymes as is cathepsin D, an aspartyl proteinase, whereas the CLN 3, CLN6, CLN8 and, possibly, CLN5 are transmembrane proteins with still largely unknown functions (see [36]). The newly discovered genetic heterogeneity of the NCLs contrasts sharply with their remarkably uniform morphological phenotype, the very basis of the whole NCL concept. How can defects in these seven seemingly disparate genes lead to essentially the same end result: intraneuronal accumulation of certain hydrophobic proteins, coupled with highly selective neuronal degeneration and death? So far, the mechanisms of accumulation of subunit c of mitochondrial ATP synthase and sphingolipid activator proteins and their relation, if any, to the depletion of neurons remain unsolved. Likewise, although both apoptotic [38,50] and excitotoxic [75] mechanisms have been proposed, the deranged metabolic pathways leading to neuronal

5 854 M. Haltia / Biochimica et Biophysica Acta 1762 (2006) degeneration and death in NCL remain to be elucidated. The uniform neuropathological features of the NCLs suggest the existence of a common final pathogenetic pathway. Recent observations of physical interactions of the CLN5 protein with CLN2 and CLN3 [78] provide some experimental support in favor of this idea. The existence of both human and ovine congenital forms of NCL as well as recent experimental data from the New Hampshire sheep model [42] show that the pathogenic events may begin already at an early stage of fetal development. In conclusion, studies of the multiple human and animal forms of NCL have so far identified a set of seven largely novel genes whose defects result in selective degeneration and loss of central nervous system neurons. It is evident that the metabolic pathways involved are of vital importance for the survival of neurons and that their identification will deepen our understanding of aging, neurodegeneration and neurodegenerative disorders in general. Acknowledgements I would like to dedicate this article to the memory of Professor Pirkko Santavuori, M.D., Ph.D. ( ), a great clinician and my friend and collaborator in NCL research for more than 35 years. I am indebted to Docent Jaana Tyynelä, Ph.D., for valuable help in the preparation of this review. References [1] Isolation of a novel gene underlying Batten disease, CLN3. The International Batten Disease Consortium, Cell 82 (1995) [2] R. Barohn, D. Dowd, K. Kagan-Hallet, Congenital ceroid-lipofuscinosis, Pediatr. Neurol. 8 (1991) [3] F. Batten, Cerebral degeneration with symmetrical changes in the maculae in two members of a family, Trans. Ophthalmol. Soc. U. K. 23 (1903) [4] F. 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