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Neuronal ceroid lipofuscinosis comprises a group of lysosomal diseases transmitted by autosomal recessive inheritance. Often unrecognized, this disease should be evoked in children or adolescents with blindness due to retinal pigmentation, dementia and myoclonal seizures. Retinal pigmentation is lacking in adults. The characteristic feature is an accumulation of fluorescent lipopigments deposited within cells, especially neurons. Histology examination gives the diagnosis based on the ultrastructure of skin biopsies and identification of the disease-specific lysosomal inclusions. The disease can also be identified in children by identification of mutations on genes CLN1, CLN3 and CLN5. The pathophysiology of these diseases remains unknown and treatment is limited to symptomatic care.
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PMID:[Neuronal ceroid lipofuscinosis. An unknown overload disease]. 869 64

The neuronal ceroid lipofuscinoses (NCL) are a relatively frequent group of progressive neurodegenerative disorders in children with similar, but not identical, clinical and morphological features, entailing different clinical groups, some of which have been found to represent different genetic entities, ie, infantile (INCL) or CLN1, late-infantile (LINCL) or CLN2, juvenile (JNCL) or CLN3, and a Finnish variant of LINCL or CLN5. Within the clinical pentad are included seizures, motor disturbances, visual impairment, dementia, and familial occurrence in an autosomal-recessive fashion. The ultrastructure of accruing lipopigments is diagnostically required to recognize an individual patient's NCL by showing granular lipopigments in INCL, curvilinear profiles (with or without fingerprint profiles) in LINCL and fingerprint profiles (with or without curvilinear profiles) in JNCL. Identification of genes for INCL and JNCL, together with electron microscopy in LINCL, allows safe prenatal diagnosis which is still impossible by biochemical techniques, unlike other lysosomal disorders. However, both cause and pathogenesis of the individual forms of NCL are still unknown, and therapy is gravely insufficient.
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PMID:The neuronal ceroid-lipofuscinoses. 896 9

The neuronal ceroid lipofuscinoses (NCL) are neurodegenerative disorders with psychomotor deterioration, seizures, visual failure and premature death, all associated with abnormal storage of lipoproteins within lysosomes. The most common forms of NCL are an infantile form (INCL, CLN1), a late infantile form (LINCL, CLN2) and a juvenile onset form (JNCL, CLN3). The electroretinogram (ERG) is abnormal early in all three of these forms and eventually is totally ablated. The purpose of this report is to describe the ERG in INCL, LINCL and JNCL. The ERGs of 7 patients who were examined by the author over the past 15 years were reviewed. Ganzfeld ERG responses were recorded using the ISCEV standard protocol and an intensity response series over a 3.7 log unit range. The earliest ERG manifestation of INCL is a marked loss of the scotopic and photopic b-wave with relative preservation of the a-wave; this defect, which was evident for both rods and cones, suggests preservation of photoreceptor outer segment function with severe disturbance of transmission of the signal to the second-order neuron, the bipolar cells. For LINCL, the rod responses were mildly abnormal but more preserved than in INCL or JNCL. The cone b-wave amplitudes in patients with early LINCL were severely subnormal with prolonged implicit times. Patients with JNCL invariably showed severe to profound ERG abnormalities when first tested, with essentially no rod-mediated activity and marked loss of a-wave amplitudes with even greater loss of b-wave amplitudes, creating electronegative configuration waveforms. Differences in the ERG responses were thus found that provide further clues to the earliest site of pathology within the retina.
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PMID:The dystrophic retina in multisystem disorders: the electroretinogram in neuronal ceroid lipofuscinoses. 977 20

The neuronal ceroid-lipofuscinoses (Batten disease) are a group of severe neurodegenerative disorders characterized clinically by visual loss, seizures and psychomotor degeneration, and pathologically by loss of neurons and lysosomal accumulation of autofluorescent storage material resembling ageing pigment. To date, eight genetic loci have been identified (CLN1-8). Four CLN genes have been isolated (CLN1, CLN2, CLN3 and CLN5) and their gene products have been characterized. CLN1 is a lysosomal palmitoyl-protein thioesterase (PPT) and CLN2 is a lysosomal pepstatin-insensitive peptidase. CLN3 and CLN5 are proteins with multiple membrane-spanning regions and have no homologies to other proteins that would suggest their function. The CLN3 protein is associated with lysosomal membranes and the intracellular location of the CLN5 protein is unknown. Therefore, there is ample evidence that the neuronal ceroid-lipofuscinoses represent a new class of lysosomal storage disorders.
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PMID:The neuronal ceroid-lipofuscinoses (Batten disease): a new class of lysosomal storage diseases. 1040 85

The neuronal ceroid lipofuscinoses (NCL) are a large group of autosomal recessive lysosomal storage disorders with both enzymatic deficiency and structural protein dysfunction. Previously, diagnosis of NCL was based on age at onset and clinicopathologic (C-P) findings, classified as 1) infantile (INCL), 2) late infantile (LINCL), 3) juvenile (JNCL), and 4) adult (ANCL). Most patients with NCL have progressive ocular and cerebral dysfunction, including cognitive/motor dysfunction and uncontrolled seizures. After reviewing 319 patients with NCL, the authors found that 64 (20%) did not fit into this classification of NCL. With research progress, four additional forms have been recognized: 5) Finnish, 6) Gypsy/Indian, and 7) Turkish variants of LINCL and 8) northern epilepsy, also known as progressive epilepsy with mental retardation. These eight NCL forms resulted from 100 different mutations on genes CLN1to CLN8 causing different phenotypes (http://www.ucl.ac.uk/ncl). The genes CLN1 and CLN2 encode lysosomal palmitoyl protein thioesterase and tripeptidyl peptidase 1. The function of CLN3, CLN5, and CLN8 gene-encoded products is unknown, although their predicted amino acid sequences suggest they have a transmembrane topology. The diagnosis of NCL is based on C-P findings, enzymatic assay, and molecular genetic testing. Before biochemical and genetic tests are conducted, ultrastructural studies (i.e., blood [buffy coat] or punch biopsies [skin, conjunctiva]) must be performed to confirm the presence and nature of lysosomal storage material (fingerprint or curvilinear profiles or granular osmiophilic deposits). The recognition of variable onset from infancy to middle age supersedes the traditional emphasis on age-related NCL forms.
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PMID:Pheno/genotypic correlations of neuronal ceroid lipofuscinoses. 1154 35

A 5-year-old boy presented with frequent absences. Speech began to regress. He became ataxic, barely able to walk. Studies with Xe-133 and hexamethylpropylene amine oxime single-photon emission computed tomography revealed sharply decreased cerebral blood flow, especially in the occipital area. Landau-Kleffner syndrome was suspected but a sleep electroencephalogram showed few abnormalities. He was started on clorazepate and diltiazem. A skin biopsy to rule out possible CLN2 revealed, instead of the predicted curvilinear profiles, granular osmiophilic deposits, consistent with infantile neuronal ceroid lipofuscinosis (CLN1). The family reported increased seizure frequency and consulted with a colleague, who advised them to resume valproate and discontinue diltiazem. The boy died shortly thereafter. Decreased cerebral blood flow is a new finding in CLN1 with delayed onset. Calcium-channel blockers improve cerebral blood flow and perhaps delay clinical regression.
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PMID:Impaired temporo-occipital blood flow in an atypical CLN1 case with late infantile onset and granular osmiophilic deposits. 1158 94

The neuronal ceroid-lipofuscinoses (NCL) are the most common group of progressive neurodegenerative diseases in children, with an incidence as high as one in 12,500 live births. The main features of this disease are failure of psychomotor development, impaired vision, seizures, and premature death. Many biochemical and physiological studies have been initiated to determine the cellular defect underlying the disease, although only a few traits have been truly associated with the disorders. One of the paradox's of the NCL-diseases is the characteristic accumulation of autofluorescent hydrophobic material in the lysosomes of neurons and other cell types. However, the accumulation of this lysosomal storage material, which no doubt contributes to the neurologic disease, does not apparently lead to disease outside the CNS, and how these cellular alterations relate to the neurodegeneration in NCLs is unknown. Mutations have been identified in six distinct genes/proteins, namely CLN1, which encodes PPT1, a protein thiolesterase; CLN2, which encodes TPP1, a serine protease; and CLN3, CLN5, CLN6, and CLN8, which encode novel transmembrane proteins. Mutation in any one of these CLN-proteins results in a distinct type of NCL-disease. However, there are many shared similarities in the pathology of these diseases. The most obvious connection between PPT1, TPP1, CLN3, CLN5, CLN6, and CLN8 is their subcellular localization. To date, three of the four proteins whose subcellular localization has been confirmed, namely PPT1, TPP1, and CLN3, reside in the lysosome. We review the function of the CLN-proteins and discuss the possibility that a disruption in a common biological process leads to an NCL-disease.
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PMID:The neuronal ceroid lipofuscinoses: mutations in different proteins result in similar disease. 1202 57

The neuronal ceroid lipofuscinoses (NCL) are a large group of autosomal recessive lysosomal storage disorders with both enzymatic deficiency and structural protein dysfunction. Previously, diagnosis of NCL was based on age at onset and clinicopathological (C-P) findings described 4 forms, classified as infantile (INCL) (2), late-infantile (LINCL) (5), juvenile (JNCL) (6), and adult (ANCL) (12). Most patients with NCL have progressive ocular and cerebral dysfunction, including cognitive/motor dysfunction and uncontrolled seizures. After reviewing 520 patients with NCL, we found that about 104 (20%) did not fit this classification of NCL. With further research, 4 additional forms have been recognized: Finnish (13), Gypsy/Indian (14), Turkish (15)--variants of LINCL, and Northern epilepsy (16), also known as progressive epilepsy with mental retardation. These eight NCL forms resulted from 151 different mutations in genes CLN1 to CLN8 causing different phenotypes (http://www.ucl.ac.uk/ncl). The genes CLN1 and CLN2 encode lysosomal palmitoyl protein thioesterase and tripeptidyl peptidase 1. The diagnosis of NCL is based on clinicopathological (C-P) findings, enzymatic assay, and molecular genetic testing. Ultrastructural studies must be performed to confirm the presence and nature of lysosomal storage material (fingerprint or curvilinear profiles, or granular osmiophilic deposits) before doing biochemical testing. Pheno/genotypic correlation studies are discussed.
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PMID:Current state of clinical and morphological features in human NCL. 1499 38

The neuronal ceroid lipofuscinoses (NCL), also known as Batten disease, are a group of inherited severe neurodegenerative disorders primarily affecting children. They are characterised by the accumulation of autofluorescent storage material in many cells. Children suffer from visual failure, seizures, progressive physical and mental decline and premature death, associated with the loss of cortical neurones. Six genes have been identified that cause human NCL (CLN1, CLN2, CLN3, CLN5, CLN6, CLN8), and approximately 150 mutations have been described. The majority of mutations result in a characteristic disease course for each gene. However, mutations associated with later disease onset or a more protracted disease course have also been described. At least seven common mutations exist, either with a world-wide distribution or associated with families from specific countries. All mutations are described in the NCL Mutation Database (http://www.uc.ac.uk/ncl).
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PMID:The genetic spectrum of human neuronal ceroid-lipofuscinoses. 1499 39

The neuronal ceroid-lipofuscinoses (NCLs) are recessively inherited lysosomal storage diseases, currently classified into 8 forms (CLN1-CLN8). Collectively, the NCLs constitute the most common group of progressive encephalopathies of childhood, and present with visual impairment, psychomotor deterioration and severe seizures. Despite recent identification of the underlying disease genes, the mechanisms leading to neurodegeneration and epilepsy in the NCLs remain poorly understood. To investigate these events, we examined the patterns of storage deposition, neurodegeneration, and glial activation in the hippocampus of patients with CLN1, CLN2, CLN3, CLN5 and CLN8 using histochemistry and immunohistochemistry. These different forms of NCL shared distinct patterns of neuronal degeneration in the hippocampus, with heavy involvement of sectors CA2-CA4 but relative sparing of CA1. This selective pattern of degeneration was also observed in immunohistochemically identified interneurons, which exhibited a graded severity of loss according to phenotype, with calretinin-positive interneurons relatively spared. Furthermore, glial activation was also regionally specific, with microglial activation most pronounced in areas of greatest neuronal loss, and astrocyte activation prominent in areas where neuronal loss was less evident. In conclusion, the NCLs share a common pattern of selective hippocampal pathology, distinct from that seen in the majority of temporal lobe epilepsies.
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PMID:Hippocampal pathology in the human neuronal ceroid-lipofuscinoses: distinct patterns of storage deposition, neurodegeneration and glial activation. 1560 81


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