BBADIS-64223; No. of pages: 5; 4C: 2 Biochimica et Biophysica Acta xxx (2015) xxx–xxx
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Biochimica et Biophysica Acta
Review
2Q1
Human NCL Neuropathology☆
3Q2
Josefine Radke a,1, Werner Stenzel a,2, Hans H. Goebel a,b,⁎
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Article history: Received 10 March 2015 Received in revised form 7 May 2015 Accepted 11 May 2015 Available online xxxx
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Keywords: Neuronal ceroid lipofuscinoses CLN Lipopigments Fingerprint profiles Lysosome SCMAS GROD Ultrastructure
Department of Neuropathology, Charité - Universitätsmedizin Berlin, Charitéplatz 1 | Virchowweg 15, D-10117 Berlin, Germany Department of Neuropathology, University Medicine of the Johannes Gutenberg University, Mainz, Germany
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The neuronal ceroid lipofuscinoses (NCL) currently encompass fourteen genetically different forms, CLN1 to CLN14, but are all morphologically marked by loss of nerve cells, particularly in the cerebral and cerebellar cortices, and the cerebral and extracerebral formation of lipopigments. These lipopigments show distinct ultrastructural patterns, i.e., granular, curvilinear/rectilinear and fingerprint profiles. They contain − although to a different degree among the different CLN forms − subunit C of ATP synthase, saposins A and D, and beta-amyloid proteins. Extracerebral pathology, apart from lipopigment formation, which provides diagnostic information, is scant or non-existent. The retina undergoes atrophy in all childhood forms. While many new data and findings have been obtained by immunohistochemistry in mouse and other animal models, similar findings in human NCL are largely missing, thus recommending respective studies of archived brain tissues. The newly described NCL forms, i.e., CLN 10 to CLN 14, also require further studies to provide complete neuropathology. This article is part of a Special Issue entitled: “Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease),” edited by Romina Kohan, Susan L. Cotman and Sara E. Mole. © 2015 Published by Elsevier B.V.
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1. Introduction
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The neuronal ceroid lipofuscinoses (NCL) are diagnosed by mutations, but defined by morphological features − though diagnosed by morphology when genetics are not available. The morphological criteria entail loss of neurons, especially in the cerebral and cerebellar cortices and accumulation of lipopigments within cells. The former may, at least partially, give rise to clinical symptoms and the latter to diagnosis. The relationship between these two features, i.e., loss of neurons and accretion of lipopigments (Figs. 1 and 2), is still insufficiently known. Distribution and severity of cellular loss will best be appreciated by autopsy which, however, will hardly inform about the dynamics of the disease. As lipopigments accrue in almost every cell type and organ, i.e., the central and peripheral nervous systems and extracerebral tissues, the biopsy of easily accessible organs, e.g., blood lymphocytes, skin, conjunctiva, and rectum, have readily been employed in the diagnostic armamentarium. The main diagnostic tool for biopsies is the electron microscope. Complete description of an NCL and its full
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☆ This article is part of a Special Issue entitled: “Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease),” edited by Romina Kohan, Susan L. Cotman and Sara E. Mole. ⁎ Corresponding author at: Department of Neuropathology, Charité - Universitätsmedizin Berlin, Charitéplatz 1 | Virchowweg 15, D-10117 Berlin, Germany. Tel.: +49 30 450 536073; fax: +49 30 450 536940. E-mail addresses: josefi[email protected] (J. Radke), [email protected] (W. Stenzel), [email protected] (H.H. Goebel). 1 Tel.: +49 30 450 536004; fax: +49 30 450 536940. 2 Tel.: +49 30 450 536073; fax: +49 30 450 536940.
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nosological ascertainment may be based on both biopsy and autopsy in an individual patient and individual form of NCL, of which so far 14 genetically identified forms exist, CLN1 to CLN14. As the morphologies of autopsy and biopsy are overlapping, the complete pathology is best illustrated by discussing the various levels of visual recognition, from the naked eye to the light and electron microscopes.
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2. Gross pathology
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Macroscopic pathology is confined to the central nervous system, largely to the cerebrum and the cerebellum, whereas brainstem and spinal cord appear rather unremarkable. Long-term loss of nerve cells and their processes results in atrophy (Fig. 1A), especially of the cerebral cortex and the cerebellum, together with widening of the ventricles and the subarachnoid space. Looking at the mantle of the brain, the gyri are reduced in thickness, the sulci are gaping and the leptomeninges appear thickened, more severely in the occipital lobes than the frontal ones. The smooth glistening surface of the sectioned cerebral and cerebellar cortices may be replaced by a gritty, occasionally spongy appearance, due to excessive loss of nerve cells. The earlier neuronal death sets in, the more severe is atrophy, being farthest advanced in the infantile type and least in the adult type. Reduced brain weights in the individual CLN forms are given in Table 1. However, a protracted course, for instance in CLN3, may further advance the atrophy. In addition, by longstanding good care, with the vital organs longer intact and the body in less severe decay, the brain continues to shrink to further atrophy. Massive loss of neurons in the
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http://dx.doi.org/10.1016/j.bbadis.2015.05.007 0925-4439/© 2015 Published by Elsevier B.V.
Please cite this article as: J. Radke, et al., Human NCL Neuropathology, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbadis.2015.05.007
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Table 1 Brain weight (grams) in CLN forms [34]. NCL type
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Histological abnormalities are variegated, sometimes contradicting and often incomplete. Three different aspects prevail in the tissues, of which the relationship to each other is not always clear: Firstly, the loss of nerve cells, largely identified by loss of nerve cell bodies rather than processes, is concomitant with subsequent reaction of microglia and astrocytes as well as, secondly, loss of myelin due to axonal degeneration and, thirdly, accumulation of lipopigments. Only the latter phenomenon is assessable in extracerebral organs while any additional convincing histopathology in visceral and other organs, such as skin or skeletal muscle, is largely absent. While with increasing age and survival, especially of patients with juvenile NCL, cardiac symptoms, frequently conduction defects, have become apparent, the few cardiopathological reports emphasize the often heavy formation of NCL lipopigments, with vacuolation and lipopigment formation of fingerprint and curvilinear profiles therein [1], particularly in the conduction system [2,3] and degenerative myocardial pathology, fatty substitution and fibrosis [3,4]. In view of the wealth of modern techniques applicable to the tissues in NCL, the knowledge of lesions within the central nervous system in NCL is still incomplete. As gross pathology and histopathology of the central nervous system are largely based on autopsies − brain biopsies were usually only studied for the diagnostic accumulation of lipopigments and their ultrastructure, rather than structural pathology by light microscopy − major and more complete autopsy reports date back from the premolecular era and even from times when NCL was part of the nosological group of “amaurotic familial idiocy,” and such often comprehensive, long, old-time reports are still perfectly valid when retroactively associated with molecular data as provided for the original neuropathological report on classical CLN2, the late infantile form of Jansky–Bielschowsky [5–7]. Since that past history, NCL has been distinguished from other lysosomal diseases affecting the central nervous system by showing autofluorescence of enlarged nerve cells and has also been subclassified in various forms, earlier called infantile, late infantile, juvenile, and adult forms, but now enhanced by recent additional molecular results from CLN1 to CLN14. On the other hand, availability of autopsy tissues and the opportunity to study postmortem CNS by histopathology have been diminished and severely hampered by the dwindling numbers of autopsies. Hence, assessment of precise and complete pathological changes across the entire neuraxis is still patchy. At autopsy, the cortices of the cerebrum and the cerebellum may variably be depleted of neurons. This emphasizes the fact that autopsy studies usually pertain to the end stage of the disease which is most advanced in the early-childhood forms, although in earlier times NCL patients often died of infectious diseases, e.g., tuberculosis in particular, thereby preventing progression of the NCL to reach its end stage. Loss of neurons is evaluated by recording density and layering of neuronal perikarya. Only a rare neuronal perikaryon may be present in the depleted cortex in CLN1 or infantile NCL. Loss of cortical layers and cytoarchitecture and its most severe form of tissue rarefaction, sponginess of cortical areas, may be encountered [7]. Preferential loss of neurons may only be recognized in NCL forms that, even at autopsy, do not show near-complete neuronal depletion, e.g., in juvenile and adult forms. Also, neuronal depletion and subsequent cortical atrophy
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cerebral cortex and cerebellum also means reduced volume of hemispherical white matter, corpus callosum and long tracts, especially the pyramidal tracts which can be observed at the medullary and spinal cord levels. In CLN3, the substantia nigra may appear pale, perhaps owing to impaired formation or loss of neuromelanin in respective neuronal cell bodies. Juvenile and adult NCL brains may display a light brownish or deep yellow hue of grey matter because of excessive formation of lipopigments in nerve cells before their depletion.
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Fig. 1. A: Atrophic cerebral cortex in infantile NCL. B: Atrophic retina with only remnants of photoreceptor inner segments and severe loss of neurons, CLN2, hematoxylin–eosin (original magnification: 16×). C: Normal retina, hematoxylin-eosin (original magnification: 20×). D: Numerous nerve cells, replete with SCMAS-containing lipopigements, CLN5 (original magnification: 16×). E: Autofluorescence of lipopigments in the cerebral cortex, infantile NCL (original magnification: 40×). F: Lipopigments in muscle fibers display enhanced histochemical activity of acid phosphatase (original magnification: 20×).
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Compact GROD in a lymphocyte, infantile NCL (original magnification: 11000×). B: Curvilinear profiles, classic late infantile NCL (original magnification: 21600×). C: Fingerprint profiles in a lysosomal vacuole of a lymphocyte, juvenile NCL (original magnification 21600×); Inset: Fingerprint profiles at high magnification. D: GROD in vitamin E deficiency (original magnification, 21600×).
Please cite this article as: J. Radke, et al., Human NCL Neuropathology, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbadis.2015.05.007
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NCL-specific lipopigments are divided into GROD (granular osmiophilic deposits) and non-GROD ultrastructural patterns, the former correlating well with accumulation of the SAP proteins, the latter with the accumulation of the SCMAS, confirmed by immunoelectron microscopy [20]. GROD (Fig. 2A) is seen in CLN1, CLN4, CLN10 and sometimes with non-GROD features in adult CLN6, CLN8 and CLN14 [21]. Non-GROD patterns are those of curvilinear profiles (Fig. 2B), of which rectilinear profiles are probably a subtype, and fingerprint profiles (Fig. 2C), both of them appearing either separate
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The retina is involved in the pathological process of NCL in all childhood forms (Fig. 1B, C), although in the different CLN forms visual problems and final blindness not always appear in the forefront among clinical symptoms. Postmortem studies on retina in NCL are scant, and their pathology may or may not represent end-stage pathology. Thus, the dynamics of retinal degeneration in NCL may only be recognized by comparing postmortem retinal specimens of different CLN types. In the end stage, the once ten-layered retina may appear transformed into a broad glial scar devoid of any neuronal elements, but containing pigment-carrying macrophages and pigment epithelium. Apparently, retinal degeneration starts at the outer segments of the photoreceptors, proceeding inward during the course of the disease. Loss of photoreceptors is more prominent in central regions. Sometime during the degenerative process, when the outer limiting membrane may have become discontinued, proliferating retinal epithelial cells may migrate into the atrophic retina and may scatter around intraretinal vessels, the fundoscopic equivalent of the so-called “bone spicules.” NCL-specific lipopigments may be seen in residual glial cells and macrophages, as well as in immigrant retinal pigment epithelial cells, then mixed with melanin granules. Loss of ganglion cells results in disappearance of axons and, subsequently, their myelin sheaths, i.e., optic atrophy associated with gliosis. Retinal atrophy is most pronounced in CLN1 and CLN3, less so in CLN2 (Fig. 1C). In CLN5, less severe pathology has briefly been described [16]. Here, the inner ganglion cell layer appeared most profoundly affected with even photoreceptors preserved while lipopigments accrued in the remaining ganglion cells and pigment epithelial cells, together with melanin granules in the latter, but less in bipolar and photoreceptor neurons. Gliosis was emphasized by immunohistochemical evidence of glial fibrillary acidic protein (GFAP). Reports on autopsied retinas in adult NCL are even rarer. As visual failure or blindness are frequently, but not always, absent in adult NCL [17] and fundoscopic and electroretinographic findings also often are unremarkable, absence of pathology from the retina may be inferred. A postmortem study [18] on a 33-year-old woman who had late adolescence onset of molecularly proven CLN5 [19] revealed preservation of all retinal layers including those of the photoreceptors, but lipopigment formation was encountered in each neuronal cell type suggesting that retinal degeneration and lipopigment formation may not be closely associated.
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4. Retinal pathology
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However, lipopigment deposition is not confined to neurons but may also be encountered in macrophages and astrocytes as well as mural cells of vessels. Furthermore, owing to the widespread extracerebral formation of NCL-specific lipopigments, these may also be demonstrated in extracerebral ganglion cells of spinal and autonomic ganglia, including those of the rectum – a target of biopsies in former times – and in visceral organs at autopsy, and by biopsy, in more easily accessible organs, such as skin, blood lymphocytes, skeletal muscle, conjunctiva, and rectum because lipopigment deposits may be minuscule and, thus, not all light microscopic techniques may be successful in demonstrating the lipopigments. Hence electron microscopy is essential for diagnosis by biopsy
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are not uniform across the brain – they increase from frontal lobes to occipital ones. According to earlier studies of rather thick tissue sections, small neurons of layer II are preferentially affected [8,9]. Neurons of layer III are also severely and early marked by loss. Neuronal depletion in subcortical areas, i.e., the basal ganglia, the brainstem, cerebellar nuclei and spinal cord, has fragmentarily been reported, for instance in relation to the individual genetic forms of CLN1 to CLN14. Neuronal loss in subcortical grey matter is variable in degree, also dependent on the age of the diseased patient. The thalamus and dentate nucleus may show depletion of neurons. True quantitative studies, as well as those distinguishing different nerve cell classes within a grey-matter complex, have not yet been procured. A preferential excessive formation of lipopigments has been observed in small spiny neurons of the striatum while the aspiny neurons are less affected [10]. Histological abnormalities, however, probably start earlier, outside the neuronal perikarya because Golgi studies reveal dearth of dendritic spines in apical dendrites, although lipopigments are not deposited here [7]. This early degeneration may elicit a microglial response and impart criteria of neuroinflammation. The activated microglia may have a proinflammatory influence on the tissue and may further damage the neuronal population. Together with microglial activation, macrophages phagocytose cellular debris and lipopigments. Loss of neurons and their axons causes breakdown of myelin and, thus, demyelination, although largely of secondary nature. Finally, first cellular astrocytosis and later fibrillar astrocytosis ensue and, hence, transform areas of preceding primary nerve cell loss into scarred regions. While immunohistochemistry focuses on the presence and type of lipopigments − to be discussed later in this article − almost nothing is known about immunohistochemical demonstration of CLN-specific proteins and their mutant forms. Of the four enzyme proteins, i.e., PPT1 (CLN1), TPP1 (CLN2), cathepsin-D (CLN10), and cathepsin-F (CLN13), apparently an antibody against TPP1 may demonstrate the absence of the TPP1 protein in brain tissue. Cathepsin-D, deficient in CLN10, was immunohistochemically found absent in brain tissue in congenital NCL [11]. Although antibodies against murine cln proteins have been generated and employed, no such cln or CLN antibodies have been applied to human tissue. Occasionally, immunohistochemical evidence of apoptosis has been provided [12]. A clear reaction, both of micoglia and astrocytes, however, has immunohistochemically been corroborated (own unpublished observation), demonstrating early microglial reaction in grey-matter areas with little neuronal loss indicating additional and, most likely, preceding damage to neuronal processes. All in all, in view of the diagnostic significance of immunohistochemistry, very little new information has been procured by NCL brains, apart from the lipopigment composition. Lipopigment formation, the hallmark of NCL among lysosomal diseases, can be recognized by the presence of yellowish granules in hematoxylin-eosin-stained sections of cerebral neurons, further corroborated by PAS and lipid stains, such as Sudan black, autofluorescence (Fig. 1E) and, using frozen unfixed tissue, enhanced enzyme histochemical activity of lysosomal acid phosphatase (Fig. 1F). Components of the lipopigments can immunohistochemically be ascertained with antibodies against the subunit C of mitochondrial ATP synthase (SCMAS, Fig. 1D) and/or sphingolipid activator proteins (SAP) A and D. Although SCMAS prevails in certain CLN forms, i.e., CLN2, CLN3, and CLN5 to CLN8, SAP-A and -D predominate in others, i.e., CLN1 and CLN10. The presence of both proteins, although not in equal amounts, may be encountered in careful studies [13]. In several instances, the beta-A4 amyloid and the amyloid precursor protein have been identified in lipopigments [14,15]. Both, autofluorescence and immunohistochemistry of SCMAS and SAP not only outline the enlarged perikarya but also emphasize lipopigment location in proximal axonal segments or axon spindles, here – and in other respective neuronal lysosomal diseases – called meganeurites whilst dendrites, except those of Purkinje cells, are devoid of lipopigment storage.
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Please cite this article as: J. Radke, et al., Human NCL Neuropathology, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbadis.2015.05.007
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CLN1 CLN2 CLN3 CLN4 CLN5 CLN6 CLN7 CLN8 CLN9 CLN10 CLN11 CLN12 CLN13 CLN14
GRODs CL FP (CL, RL) GRODs RL, CL, FP RL,CL, FP RL, FP CL-like, FP, granular GRODs, CL, FP GRODs FP FP FP RL, FP
SAPs SCMAS SCMAS SAPs SCMAS SCMAS SCMAS SCMAS SCMAS SAPs Not known Not known Not known SCMAS
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Autopsy studies have been performed on each of the childhood forms of NCL, some of them rather recently, and are available in a semi-detailed fashion [34] as well as molecularly undefined adult NCL [34], CLN4 [35–37], and CLN13 [38]. They emphasize the almost complete to rather mild loss of neurons in cerebral and cerebellar cortices, according to age of onset and CLN type. Subcortical pathology has been described in varying detail while electron microscopy of the NCL-specific lipopigments is well known in cerebral and extracerebral tissues. Postmortem studies on cerebral and non-cerebral tissues of patients affected by CLN11 to CLN14, however, are incomplete (Table 3), awaiting future confirmatory and expanding investigations. Proceeding microglial activation has introduced the concept of neuroinflammation, particularly in murine and other animal models. Modern immunohistochemical techniques have, however, been only scantily applied to human brain tissues of which biopsied and autopsied samples are certainly available from numerous archives. Hence, retroactive studies on such archival tissues are highly needed to compare their results with those of spontaneous animal and genetically engineered mouse models to assess their significance in human NCL brain and extracerebral pathology. Such archival morphological investigations can and ought to be supplemented and molecularly confirmed by, for instance, Sanger sequencing or other molecular techniques of isolated DNA from archival tissue blocks. Future studies filling gaps in neuropathological knowledge of recently described human NCL forms are also essential to evaluate to which extent newly described CLN forms fit within the nosological framework of NCL.
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Table 2 MORPHOLOGICAL Characteristics of Human Neuronal Ceroid-Lipofuscinoses (NCLs) (based on references [23] and [25]).
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mucopolysaccharidoses, especially type III A [29,30]. The ultrastructure of these “associated” lipopigments appeared atypical or NCL nonclassical [28–30]. NCL-typical ultrastructural pattern, e.g., fingerprint profiles, have also been seen in blood lymphocytes in mucopolysaccharidoses [31]. Another ultrastructural differential diagnosis is the occurrence of intralysosomal curvilinear profiles in chloroquine intoxication affecting the skeletal muscle, the retina, and other tissues. In vitamin E deficiency, autofluorescent, unltrastructurally finely granular lipopigments accrue in neurons (Fig. 2D) and extracerebral tissues [32,33].
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or in combination, namely, in CLN2, CLN3, CLN5 to CLN8, and CLN11–14. These intralysosomal curvilinear or fingerprint profiles form, electron microscopically, conspicuous curvilinear bodies or fingerprint bodies, or mixed bodies. A topographical survey in different cerebral grey matter areas of these various ultrastructural patterns have been given for classic late infantile type Jansky–Bielschowsky and classic juvenile type Spielmeyer–Sjögren [22]. In skeletal muscle, however, muscle fibers only carry curvilinear/ rectilinear inclusions, no fingerprint profiles [23], the latter may be encountered in mural cells of skeletal muscle vessels. In CLN3, multiple vacuoles may be seen in blood lymphocytes [23], some of which contain fingerprint profiles. Vacuoles may also be encountered in secretory cells of eccrine sweat glands in CLN3. Occasionally, peculiar “myoclonus bodies” or spheroids are encountered in subcortical grey matter which; however, lack NCL-specific ultrastructural patterns, have apparently lost immunohistochemical reactivity to SCMAS antibodies, and can be observed in CLN1, CLN3, CLN6, and especially in CLN2 [24]. In complex-structured extracerebral tissues, formation of NCLspecific lipopigments may not be ubiquitous. For instance, in skin only secretory not ductal cells of eccrine sweat glands carry NCL-specific lipopigments, while apocrine sweat glands lack NCL-specific lipopigment deposits. A comprehensive survey of NCL lipopigment ultrastructure outside of the brain has recently been provided [23,25] (Table 2). A picture of other visceral organs, such as pancreas, adrenals, and kidney is not yet completely known. Among circulating blood cells, only lymphocytes and monocytes show NCL-specific lipopigment formation, but not granulocytes or thrombocytes. Morphological prenatal investigation aims at amniotic fluid cells, fetal tissues, such as skin or blood lymphocytes, and often chorionic villi. In the latter, only endothelial cells may show CLN-specific lipopigments while cytotrophoblasts, syntrophoblasts and fibroblasts are spared [25,26]. The lipopigments in villous endothelial cells may contain GROD in CLN1, curvilinear profiles in CLN2, 5, and 6, and lamellar fingerprint-like ultrastructure in CLN3 and variants [26]. Time may be an important factor in prenatal morphological investigation as at 11 weeks no lipopigments were detected in villous endothelial cells in molecularly proven CLN5, but at 14 weeks (end of pregnancy), they were of curvilinear and lamellar ultrastructure [27]. Likewise, lipopigments were not detected in fetal tissues at 14 weeks of gestation [27]. Lipopigments resembling those seen in NCL have also been observed in other lysosomal diseases, both at the immunohistochemical level – by demonstrating accumulation of SCMAS, a component of the lipopigments in NCL [13] – as well as at the ultrastructural level in other lysosomal diseases, such as GM1-gangliosidosis [28] or
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Abbreviations: CL = curvilinear profiles; FP = fingerprint profiles; RL = rectilinear profiles; GRODs = granular osmiophilic deposits; SAPs = sphingolipid activator proteins; SCMAS = subunit C of mitochondrial adenosine triphosphate synthase.
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Table 3 t3:1 Ultrastructure and location of extracerebral lipopigments in recently identified forms of t3:2 Neuronal Ceroid Lipofuscinoses, reported so far. t3:3 NCL type gene CLN4 DNAJC5
Location
Rectal neurons Lymphocytes Eccrine sweat glands CLN10 Skeletal muscle CTSD Schwann cells CLN11 Lymphocytes GRN Secretory eccrine sweat gland cells CLN12 Skeletal muscle: satellite cells, not myofibers ATP13A2 Fibroblasts, peripheral nerve, endothelial cells, pericytes perineurial cells, Schwann cells CLN13 Dermal fibroblasts CTSF CLN14 Skin, fibroblasts, KCTD7 Secretory eccrine sweat gland cells
EM pattern
Reference
t3:4
GROD GROD/CP GROD GROD GROD FP FP lamellar
[39] [40] [36,37] [41] [42] [43] [38] [44,45]
t3:5 t3:6
GROD, FP [46,47] GROD, FP [48]
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Contents lists available at ScienceDirect
Biochimica et Biophysica Acta
Review
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Human NCL Neuropathology☆
3Q2
Josefine Radke a,1, Werner Stenzel a,2, Hans H. Goebel a,b,⁎
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Article history: Received 10 March 2015 Received in revised form 7 May 2015 Accepted 11 May 2015 Available online xxxx
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Keywords: Neuronal ceroid lipofuscinoses CLN Lipopigments Fingerprint profiles Lysosome SCMAS GROD Ultrastructure
Department of Neuropathology, Charité - Universitätsmedizin Berlin, Charitéplatz 1 | Virchowweg 15, D-10117 Berlin, Germany Department of Neuropathology, University Medicine of the Johannes Gutenberg University, Mainz, Germany
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The neuronal ceroid lipofuscinoses (NCL) currently encompass fourteen genetically different forms, CLN1 to CLN14, but are all morphologically marked by loss of nerve cells, particularly in the cerebral and cerebellar cortices, and the cerebral and extracerebral formation of lipopigments. These lipopigments show distinct ultrastructural patterns, i.e., granular, curvilinear/rectilinear and fingerprint profiles. They contain − although to a different degree among the different CLN forms − subunit C of ATP synthase, saposins A and D, and beta-amyloid proteins. Extracerebral pathology, apart from lipopigment formation, which provides diagnostic information, is scant or non-existent. The retina undergoes atrophy in all childhood forms. While many new data and findings have been obtained by immunohistochemistry in mouse and other animal models, similar findings in human NCL are largely missing, thus recommending respective studies of archived brain tissues. The newly described NCL forms, i.e., CLN 10 to CLN 14, also require further studies to provide complete neuropathology. This article is part of a Special Issue entitled: “Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease),” edited by Romina Kohan, Susan L. Cotman and Sara E. Mole. © 2015 Published by Elsevier B.V.
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1. Introduction
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The neuronal ceroid lipofuscinoses (NCL) are diagnosed by mutations, but defined by morphological features − though diagnosed by morphology when genetics are not available. The morphological criteria entail loss of neurons, especially in the cerebral and cerebellar cortices and accumulation of lipopigments within cells. The former may, at least partially, give rise to clinical symptoms and the latter to diagnosis. The relationship between these two features, i.e., loss of neurons and accretion of lipopigments (Figs. 1 and 2), is still insufficiently known. Distribution and severity of cellular loss will best be appreciated by autopsy which, however, will hardly inform about the dynamics of the disease. As lipopigments accrue in almost every cell type and organ, i.e., the central and peripheral nervous systems and extracerebral tissues, the biopsy of easily accessible organs, e.g., blood lymphocytes, skin, conjunctiva, and rectum, have readily been employed in the diagnostic armamentarium. The main diagnostic tool for biopsies is the electron microscope. Complete description of an NCL and its full
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☆ This article is part of a Special Issue entitled: “Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease),” edited by Romina Kohan, Susan L. Cotman and Sara E. Mole. ⁎ Corresponding author at: Department of Neuropathology, Charité - Universitätsmedizin Berlin, Charitéplatz 1 | Virchowweg 15, D-10117 Berlin, Germany. Tel.: +49 30 450 536073; fax: +49 30 450 536940. E-mail addresses: josefi[email protected] (J. Radke), [email protected] (W. Stenzel), [email protected] (H.H. Goebel). 1 Tel.: +49 30 450 536004; fax: +49 30 450 536940. 2 Tel.: +49 30 450 536073; fax: +49 30 450 536940.
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nosological ascertainment may be based on both biopsy and autopsy in an individual patient and individual form of NCL, of which so far 14 genetically identified forms exist, CLN1 to CLN14. As the morphologies of autopsy and biopsy are overlapping, the complete pathology is best illustrated by discussing the various levels of visual recognition, from the naked eye to the light and electron microscopes.
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2. Gross pathology
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Macroscopic pathology is confined to the central nervous system, largely to the cerebrum and the cerebellum, whereas brainstem and spinal cord appear rather unremarkable. Long-term loss of nerve cells and their processes results in atrophy (Fig. 1A), especially of the cerebral cortex and the cerebellum, together with widening of the ventricles and the subarachnoid space. Looking at the mantle of the brain, the gyri are reduced in thickness, the sulci are gaping and the leptomeninges appear thickened, more severely in the occipital lobes than the frontal ones. The smooth glistening surface of the sectioned cerebral and cerebellar cortices may be replaced by a gritty, occasionally spongy appearance, due to excessive loss of nerve cells. The earlier neuronal death sets in, the more severe is atrophy, being farthest advanced in the infantile type and least in the adult type. Reduced brain weights in the individual CLN forms are given in Table 1. However, a protracted course, for instance in CLN3, may further advance the atrophy. In addition, by longstanding good care, with the vital organs longer intact and the body in less severe decay, the brain continues to shrink to further atrophy. Massive loss of neurons in the
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Please cite this article as: J. Radke, et al., Human NCL Neuropathology, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbadis.2015.05.007
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Table 1 Brain weight (grams) in CLN forms [34]. NCL type
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t1:4 t1:5 t1:6 t1:7 t1:8 t1:9 t1:10
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Histological abnormalities are variegated, sometimes contradicting and often incomplete. Three different aspects prevail in the tissues, of which the relationship to each other is not always clear: Firstly, the loss of nerve cells, largely identified by loss of nerve cell bodies rather than processes, is concomitant with subsequent reaction of microglia and astrocytes as well as, secondly, loss of myelin due to axonal degeneration and, thirdly, accumulation of lipopigments. Only the latter phenomenon is assessable in extracerebral organs while any additional convincing histopathology in visceral and other organs, such as skin or skeletal muscle, is largely absent. While with increasing age and survival, especially of patients with juvenile NCL, cardiac symptoms, frequently conduction defects, have become apparent, the few cardiopathological reports emphasize the often heavy formation of NCL lipopigments, with vacuolation and lipopigment formation of fingerprint and curvilinear profiles therein [1], particularly in the conduction system [2,3] and degenerative myocardial pathology, fatty substitution and fibrosis [3,4]. In view of the wealth of modern techniques applicable to the tissues in NCL, the knowledge of lesions within the central nervous system in NCL is still incomplete. As gross pathology and histopathology of the central nervous system are largely based on autopsies − brain biopsies were usually only studied for the diagnostic accumulation of lipopigments and their ultrastructure, rather than structural pathology by light microscopy − major and more complete autopsy reports date back from the premolecular era and even from times when NCL was part of the nosological group of “amaurotic familial idiocy,” and such often comprehensive, long, old-time reports are still perfectly valid when retroactively associated with molecular data as provided for the original neuropathological report on classical CLN2, the late infantile form of Jansky–Bielschowsky [5–7]. Since that past history, NCL has been distinguished from other lysosomal diseases affecting the central nervous system by showing autofluorescence of enlarged nerve cells and has also been subclassified in various forms, earlier called infantile, late infantile, juvenile, and adult forms, but now enhanced by recent additional molecular results from CLN1 to CLN14. On the other hand, availability of autopsy tissues and the opportunity to study postmortem CNS by histopathology have been diminished and severely hampered by the dwindling numbers of autopsies. Hence, assessment of precise and complete pathological changes across the entire neuraxis is still patchy. At autopsy, the cortices of the cerebrum and the cerebellum may variably be depleted of neurons. This emphasizes the fact that autopsy studies usually pertain to the end stage of the disease which is most advanced in the early-childhood forms, although in earlier times NCL patients often died of infectious diseases, e.g., tuberculosis in particular, thereby preventing progression of the NCL to reach its end stage. Loss of neurons is evaluated by recording density and layering of neuronal perikarya. Only a rare neuronal perikaryon may be present in the depleted cortex in CLN1 or infantile NCL. Loss of cortical layers and cytoarchitecture and its most severe form of tissue rarefaction, sponginess of cortical areas, may be encountered [7]. Preferential loss of neurons may only be recognized in NCL forms that, even at autopsy, do not show near-complete neuronal depletion, e.g., in juvenile and adult forms. Also, neuronal depletion and subsequent cortical atrophy
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cerebral cortex and cerebellum also means reduced volume of hemispherical white matter, corpus callosum and long tracts, especially the pyramidal tracts which can be observed at the medullary and spinal cord levels. In CLN3, the substantia nigra may appear pale, perhaps owing to impaired formation or loss of neuromelanin in respective neuronal cell bodies. Juvenile and adult NCL brains may display a light brownish or deep yellow hue of grey matter because of excessive formation of lipopigments in nerve cells before their depletion.
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Fig. 1. A: Atrophic cerebral cortex in infantile NCL. B: Atrophic retina with only remnants of photoreceptor inner segments and severe loss of neurons, CLN2, hematoxylin–eosin (original magnification: 16×). C: Normal retina, hematoxylin-eosin (original magnification: 20×). D: Numerous nerve cells, replete with SCMAS-containing lipopigements, CLN5 (original magnification: 16×). E: Autofluorescence of lipopigments in the cerebral cortex, infantile NCL (original magnification: 40×). F: Lipopigments in muscle fibers display enhanced histochemical activity of acid phosphatase (original magnification: 20×).
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Compact GROD in a lymphocyte, infantile NCL (original magnification: 11000×). B: Curvilinear profiles, classic late infantile NCL (original magnification: 21600×). C: Fingerprint profiles in a lysosomal vacuole of a lymphocyte, juvenile NCL (original magnification 21600×); Inset: Fingerprint profiles at high magnification. D: GROD in vitamin E deficiency (original magnification, 21600×).
Please cite this article as: J. Radke, et al., Human NCL Neuropathology, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbadis.2015.05.007
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NCL-specific lipopigments are divided into GROD (granular osmiophilic deposits) and non-GROD ultrastructural patterns, the former correlating well with accumulation of the SAP proteins, the latter with the accumulation of the SCMAS, confirmed by immunoelectron microscopy [20]. GROD (Fig. 2A) is seen in CLN1, CLN4, CLN10 and sometimes with non-GROD features in adult CLN6, CLN8 and CLN14 [21]. Non-GROD patterns are those of curvilinear profiles (Fig. 2B), of which rectilinear profiles are probably a subtype, and fingerprint profiles (Fig. 2C), both of them appearing either separate
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The retina is involved in the pathological process of NCL in all childhood forms (Fig. 1B, C), although in the different CLN forms visual problems and final blindness not always appear in the forefront among clinical symptoms. Postmortem studies on retina in NCL are scant, and their pathology may or may not represent end-stage pathology. Thus, the dynamics of retinal degeneration in NCL may only be recognized by comparing postmortem retinal specimens of different CLN types. In the end stage, the once ten-layered retina may appear transformed into a broad glial scar devoid of any neuronal elements, but containing pigment-carrying macrophages and pigment epithelium. Apparently, retinal degeneration starts at the outer segments of the photoreceptors, proceeding inward during the course of the disease. Loss of photoreceptors is more prominent in central regions. Sometime during the degenerative process, when the outer limiting membrane may have become discontinued, proliferating retinal epithelial cells may migrate into the atrophic retina and may scatter around intraretinal vessels, the fundoscopic equivalent of the so-called “bone spicules.” NCL-specific lipopigments may be seen in residual glial cells and macrophages, as well as in immigrant retinal pigment epithelial cells, then mixed with melanin granules. Loss of ganglion cells results in disappearance of axons and, subsequently, their myelin sheaths, i.e., optic atrophy associated with gliosis. Retinal atrophy is most pronounced in CLN1 and CLN3, less so in CLN2 (Fig. 1C). In CLN5, less severe pathology has briefly been described [16]. Here, the inner ganglion cell layer appeared most profoundly affected with even photoreceptors preserved while lipopigments accrued in the remaining ganglion cells and pigment epithelial cells, together with melanin granules in the latter, but less in bipolar and photoreceptor neurons. Gliosis was emphasized by immunohistochemical evidence of glial fibrillary acidic protein (GFAP). Reports on autopsied retinas in adult NCL are even rarer. As visual failure or blindness are frequently, but not always, absent in adult NCL [17] and fundoscopic and electroretinographic findings also often are unremarkable, absence of pathology from the retina may be inferred. A postmortem study [18] on a 33-year-old woman who had late adolescence onset of molecularly proven CLN5 [19] revealed preservation of all retinal layers including those of the photoreceptors, but lipopigment formation was encountered in each neuronal cell type suggesting that retinal degeneration and lipopigment formation may not be closely associated.
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However, lipopigment deposition is not confined to neurons but may also be encountered in macrophages and astrocytes as well as mural cells of vessels. Furthermore, owing to the widespread extracerebral formation of NCL-specific lipopigments, these may also be demonstrated in extracerebral ganglion cells of spinal and autonomic ganglia, including those of the rectum – a target of biopsies in former times – and in visceral organs at autopsy, and by biopsy, in more easily accessible organs, such as skin, blood lymphocytes, skeletal muscle, conjunctiva, and rectum because lipopigment deposits may be minuscule and, thus, not all light microscopic techniques may be successful in demonstrating the lipopigments. Hence electron microscopy is essential for diagnosis by biopsy
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are not uniform across the brain – they increase from frontal lobes to occipital ones. According to earlier studies of rather thick tissue sections, small neurons of layer II are preferentially affected [8,9]. Neurons of layer III are also severely and early marked by loss. Neuronal depletion in subcortical areas, i.e., the basal ganglia, the brainstem, cerebellar nuclei and spinal cord, has fragmentarily been reported, for instance in relation to the individual genetic forms of CLN1 to CLN14. Neuronal loss in subcortical grey matter is variable in degree, also dependent on the age of the diseased patient. The thalamus and dentate nucleus may show depletion of neurons. True quantitative studies, as well as those distinguishing different nerve cell classes within a grey-matter complex, have not yet been procured. A preferential excessive formation of lipopigments has been observed in small spiny neurons of the striatum while the aspiny neurons are less affected [10]. Histological abnormalities, however, probably start earlier, outside the neuronal perikarya because Golgi studies reveal dearth of dendritic spines in apical dendrites, although lipopigments are not deposited here [7]. This early degeneration may elicit a microglial response and impart criteria of neuroinflammation. The activated microglia may have a proinflammatory influence on the tissue and may further damage the neuronal population. Together with microglial activation, macrophages phagocytose cellular debris and lipopigments. Loss of neurons and their axons causes breakdown of myelin and, thus, demyelination, although largely of secondary nature. Finally, first cellular astrocytosis and later fibrillar astrocytosis ensue and, hence, transform areas of preceding primary nerve cell loss into scarred regions. While immunohistochemistry focuses on the presence and type of lipopigments − to be discussed later in this article − almost nothing is known about immunohistochemical demonstration of CLN-specific proteins and their mutant forms. Of the four enzyme proteins, i.e., PPT1 (CLN1), TPP1 (CLN2), cathepsin-D (CLN10), and cathepsin-F (CLN13), apparently an antibody against TPP1 may demonstrate the absence of the TPP1 protein in brain tissue. Cathepsin-D, deficient in CLN10, was immunohistochemically found absent in brain tissue in congenital NCL [11]. Although antibodies against murine cln proteins have been generated and employed, no such cln or CLN antibodies have been applied to human tissue. Occasionally, immunohistochemical evidence of apoptosis has been provided [12]. A clear reaction, both of micoglia and astrocytes, however, has immunohistochemically been corroborated (own unpublished observation), demonstrating early microglial reaction in grey-matter areas with little neuronal loss indicating additional and, most likely, preceding damage to neuronal processes. All in all, in view of the diagnostic significance of immunohistochemistry, very little new information has been procured by NCL brains, apart from the lipopigment composition. Lipopigment formation, the hallmark of NCL among lysosomal diseases, can be recognized by the presence of yellowish granules in hematoxylin-eosin-stained sections of cerebral neurons, further corroborated by PAS and lipid stains, such as Sudan black, autofluorescence (Fig. 1E) and, using frozen unfixed tissue, enhanced enzyme histochemical activity of lysosomal acid phosphatase (Fig. 1F). Components of the lipopigments can immunohistochemically be ascertained with antibodies against the subunit C of mitochondrial ATP synthase (SCMAS, Fig. 1D) and/or sphingolipid activator proteins (SAP) A and D. Although SCMAS prevails in certain CLN forms, i.e., CLN2, CLN3, and CLN5 to CLN8, SAP-A and -D predominate in others, i.e., CLN1 and CLN10. The presence of both proteins, although not in equal amounts, may be encountered in careful studies [13]. In several instances, the beta-A4 amyloid and the amyloid precursor protein have been identified in lipopigments [14,15]. Both, autofluorescence and immunohistochemistry of SCMAS and SAP not only outline the enlarged perikarya but also emphasize lipopigment location in proximal axonal segments or axon spindles, here – and in other respective neuronal lysosomal diseases – called meganeurites whilst dendrites, except those of Purkinje cells, are devoid of lipopigment storage.
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Please cite this article as: J. Radke, et al., Human NCL Neuropathology, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbadis.2015.05.007
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CLN1 CLN2 CLN3 CLN4 CLN5 CLN6 CLN7 CLN8 CLN9 CLN10 CLN11 CLN12 CLN13 CLN14
GRODs CL FP (CL, RL) GRODs RL, CL, FP RL,CL, FP RL, FP CL-like, FP, granular GRODs, CL, FP GRODs FP FP FP RL, FP
SAPs SCMAS SCMAS SAPs SCMAS SCMAS SCMAS SCMAS SCMAS SAPs Not known Not known Not known SCMAS
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Autopsy studies have been performed on each of the childhood forms of NCL, some of them rather recently, and are available in a semi-detailed fashion [34] as well as molecularly undefined adult NCL [34], CLN4 [35–37], and CLN13 [38]. They emphasize the almost complete to rather mild loss of neurons in cerebral and cerebellar cortices, according to age of onset and CLN type. Subcortical pathology has been described in varying detail while electron microscopy of the NCL-specific lipopigments is well known in cerebral and extracerebral tissues. Postmortem studies on cerebral and non-cerebral tissues of patients affected by CLN11 to CLN14, however, are incomplete (Table 3), awaiting future confirmatory and expanding investigations. Proceeding microglial activation has introduced the concept of neuroinflammation, particularly in murine and other animal models. Modern immunohistochemical techniques have, however, been only scantily applied to human brain tissues of which biopsied and autopsied samples are certainly available from numerous archives. Hence, retroactive studies on such archival tissues are highly needed to compare their results with those of spontaneous animal and genetically engineered mouse models to assess their significance in human NCL brain and extracerebral pathology. Such archival morphological investigations can and ought to be supplemented and molecularly confirmed by, for instance, Sanger sequencing or other molecular techniques of isolated DNA from archival tissue blocks. Future studies filling gaps in neuropathological knowledge of recently described human NCL forms are also essential to evaluate to which extent newly described CLN forms fit within the nosological framework of NCL.
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Table 2 MORPHOLOGICAL Characteristics of Human Neuronal Ceroid-Lipofuscinoses (NCLs) (based on references [23] and [25]).
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mucopolysaccharidoses, especially type III A [29,30]. The ultrastructure of these “associated” lipopigments appeared atypical or NCL nonclassical [28–30]. NCL-typical ultrastructural pattern, e.g., fingerprint profiles, have also been seen in blood lymphocytes in mucopolysaccharidoses [31]. Another ultrastructural differential diagnosis is the occurrence of intralysosomal curvilinear profiles in chloroquine intoxication affecting the skeletal muscle, the retina, and other tissues. In vitamin E deficiency, autofluorescent, unltrastructurally finely granular lipopigments accrue in neurons (Fig. 2D) and extracerebral tissues [32,33].
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or in combination, namely, in CLN2, CLN3, CLN5 to CLN8, and CLN11–14. These intralysosomal curvilinear or fingerprint profiles form, electron microscopically, conspicuous curvilinear bodies or fingerprint bodies, or mixed bodies. A topographical survey in different cerebral grey matter areas of these various ultrastructural patterns have been given for classic late infantile type Jansky–Bielschowsky and classic juvenile type Spielmeyer–Sjögren [22]. In skeletal muscle, however, muscle fibers only carry curvilinear/ rectilinear inclusions, no fingerprint profiles [23], the latter may be encountered in mural cells of skeletal muscle vessels. In CLN3, multiple vacuoles may be seen in blood lymphocytes [23], some of which contain fingerprint profiles. Vacuoles may also be encountered in secretory cells of eccrine sweat glands in CLN3. Occasionally, peculiar “myoclonus bodies” or spheroids are encountered in subcortical grey matter which; however, lack NCL-specific ultrastructural patterns, have apparently lost immunohistochemical reactivity to SCMAS antibodies, and can be observed in CLN1, CLN3, CLN6, and especially in CLN2 [24]. In complex-structured extracerebral tissues, formation of NCLspecific lipopigments may not be ubiquitous. For instance, in skin only secretory not ductal cells of eccrine sweat glands carry NCL-specific lipopigments, while apocrine sweat glands lack NCL-specific lipopigment deposits. A comprehensive survey of NCL lipopigment ultrastructure outside of the brain has recently been provided [23,25] (Table 2). A picture of other visceral organs, such as pancreas, adrenals, and kidney is not yet completely known. Among circulating blood cells, only lymphocytes and monocytes show NCL-specific lipopigment formation, but not granulocytes or thrombocytes. Morphological prenatal investigation aims at amniotic fluid cells, fetal tissues, such as skin or blood lymphocytes, and often chorionic villi. In the latter, only endothelial cells may show CLN-specific lipopigments while cytotrophoblasts, syntrophoblasts and fibroblasts are spared [25,26]. The lipopigments in villous endothelial cells may contain GROD in CLN1, curvilinear profiles in CLN2, 5, and 6, and lamellar fingerprint-like ultrastructure in CLN3 and variants [26]. Time may be an important factor in prenatal morphological investigation as at 11 weeks no lipopigments were detected in villous endothelial cells in molecularly proven CLN5, but at 14 weeks (end of pregnancy), they were of curvilinear and lamellar ultrastructure [27]. Likewise, lipopigments were not detected in fetal tissues at 14 weeks of gestation [27]. Lipopigments resembling those seen in NCL have also been observed in other lysosomal diseases, both at the immunohistochemical level – by demonstrating accumulation of SCMAS, a component of the lipopigments in NCL [13] – as well as at the ultrastructural level in other lysosomal diseases, such as GM1-gangliosidosis [28] or
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Abbreviations: CL = curvilinear profiles; FP = fingerprint profiles; RL = rectilinear profiles; GRODs = granular osmiophilic deposits; SAPs = sphingolipid activator proteins; SCMAS = subunit C of mitochondrial adenosine triphosphate synthase.
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Table 3 t3:1 Ultrastructure and location of extracerebral lipopigments in recently identified forms of t3:2 Neuronal Ceroid Lipofuscinoses, reported so far. t3:3 NCL type gene CLN4 DNAJC5
Location
Rectal neurons Lymphocytes Eccrine sweat glands CLN10 Skeletal muscle CTSD Schwann cells CLN11 Lymphocytes GRN Secretory eccrine sweat gland cells CLN12 Skeletal muscle: satellite cells, not myofibers ATP13A2 Fibroblasts, peripheral nerve, endothelial cells, pericytes perineurial cells, Schwann cells CLN13 Dermal fibroblasts CTSF CLN14 Skin, fibroblasts, KCTD7 Secretory eccrine sweat gland cells
EM pattern
Reference
t3:4
GROD GROD/CP GROD GROD GROD FP FP lamellar
[39] [40] [36,37] [41] [42] [43] [38] [44,45]
t3:5 t3:6
GROD, FP [46,47] GROD, FP [48]
Please cite this article as: J. Radke, et al., Human NCL Neuropathology, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbadis.2015.05.007
t3:7 t3:8 t3:9 t3:10 t3:11 t3:12 t3:13 t3:14 t3:15 t3:16
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The authors gratefully acknowledge excellent technical support by Petra Matylewski and Silvia Stefaniak. The authors do not have any conflict of interest.
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Please cite this article as: J. Radke, et al., Human NCL Neuropathology, Biochim. Biophys. Acta (2015), http://dx.doi.org/10.1016/ j.bbadis.2015.05.007
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