Ultrastructure of the Retina in Adult Neuronal Ceroid Lipofuscinosis

Goebel, Hans H.; Schochet, Sydney S.; Jaynes, Margaret; Gutmann, Ludwig

doi:10.1159/000046477

Cited by 8 publications

(4 citation statements)

References 15 publications

(15 reference statements)

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“…CLN5 defects normally cause a variant form of LINCL with onset at around 4 -7 years of age and survival into the second or third decade of life (18), although variants with slightly later onset (ϳ9 years of age) have been reported (26,27). For the ANCL case analyzed here, onset of disease was at 20 years of age, and the patient survived until 33 years old (17). Neither of the CLN5 mutations (C126Y and Y374C) 2 have been identified previously.…”

Section: Discussionmentioning

confidence: 86%

Mass Spectrometry-based Protein Profiling to Determine the Cause of Lysosomal Storage Diseases of Unknown Etiology

Sleat¹,

Ding

Wang

et al. 2009

Molecular & Cellular Proteomics

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Diagnosis of lysosomal storage diseases (LSDs) can be problematic in atypical cases where clinical phenotype may overlap with other genetically distinct disorders. In addition, LSDs may result from mutations in genes not yet implicated in disease. Thus, there are individuals that are diagnosed with apparent LSD based upon clinical criteria where the gene defect remains elusive. The objective of this study was to determine whether comparative proteomics approaches could provide useful insights into such cases. Most LSDs arise from mutations in genes encoding lysosomal proteins that contain mannose 6-phosphate, a carbohydrate modification that acts as a signal for intracellular targeting to the lysosome. We purified mannose 6-phosphorylated proteins by affinity chromatography and estimated relative abundance of individual proteins in the mixture by spectral counting of peptides detected by tandem mass spectrometry. Our rationale was that proteins that are decreased or absent in patients compared with controls could represent candidates for the primary defect, directing biochemical or genetics studies. On a survey of brain autopsy specimens from 23 patients with either confirmed or possible lysosomal disease, this approach identified or validated the genetic basis for disease in eight cases. These results indicate that this protein expression approach is useful for identifying defects in cases of undiagnosed lysosomal disease, and we demonstrated that it can be used with more accessible patient samples, e.g. cultured cells. Furthermore this approach was instrumental in the identification or validation of mutations in two lysosomal proteins, CLN5 and sulfamidase, in the adult form of neuronal ceroid lipofuscinosis.

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Section: Discussionmentioning

confidence: 86%

Mass Spectrometry-based Protein Profiling to Determine the Cause of Lysosomal Storage Diseases of Unknown Etiology

Sleat¹,

Ding

Wang

et al. 2009

Molecular & Cellular Proteomics

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“…Electrophysiological and neuroradiological studies are non-specific. Ophthalmologic studies are normal in contrast to studies in childhood forms of NCL, with preservation of photoreceptors and other retinal neurons, but accumulation of NCL-specific lipopigments occurs (9). us, demonstration of lysosomal storage material, which is usually composed of mixed inclusions (FP, Cv, GROD), in biopsy material, eg, skin, conjunctiva, muscle, rectal, and if necessary, brain, is mandatory for definitive diagnosis.…”

Section: Cln4-adult Ncl (Ancl)mentioning

confidence: 97%

“…ese morphological criteria may serve to distinguish ANCL neurons from other lipofuscin-containing nerve cell bodies (Figure 2). e retina contains SCMAS in lipopigments, but shows preservation of photoreceptors (9). Moreover, in the sporadic and autosomal-recessive forms, extracerebral formation of diseasespecific lipopigments has been noted in mural cells of vessels and in eccrine sweat glands of skin tissue (1).…”

Section: Diagnosis and Phenotype-genotype Correlationmentioning

confidence: 99%

Current State of Clinical and Morphological Features in Human NCL

2004

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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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“…In patient A (from Poland), a mutation in exon 17 changed Val-580 to a Met in helix R. In patient B (described in ref. 21), a mutation in exon 18 changed Thr-628 to Arg in the first cytoplasmic cystathionine ␤-synthase (CBS) domain (Fig. 12, which is published as supporting information on the PNAS web site).…”

Section: Mutational Analysis Of Patients With Late-onset Ncl the Nclmentioning

confidence: 99%

Lysosomal storage disease upon disruption of the neuronal chloride transport protein ClC-6

Poët

Kornak

Schweizer

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

170

221

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Mammalian CLC proteins function as Cl ؊ channels or as electrogenic Cl ؊ ͞H ؉ exchangers and are present in the plasma membrane and intracellular vesicles. We now show that the ClC-6 protein is almost exclusively expressed in neurons of the central and peripheral nervous systems, with a particularly high expression in dorsal root ganglia. ClC-6 colocalized with markers for late endosomes in neuronal cell bodies. The disruption of ClC-6 in mice reduced their pain sensitivity and caused moderate behavioral abnormalities. Neuronal tissues showed autofluorescence at initial axon segments. At these sites, electron microscopy revealed electron-dense storage material that caused a pathological enlargement of proximal axons. These deposits were positive for several lysosomal proteins and other marker proteins typical for neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. However, the lysosomal pH of Clcn6 ؊/؊ neurons appeared normal. CLCN6 is a candidate gene for mild forms of human NCL. Analysis of 75 NCL patients identified ClC-6 amino acid exchanges in two patients but failed to prove a causative role of CLCN6 in that disease.acidification ͉ anion transport ͉ Batten disease ͉ channelopathy ͉ Kufs' disease

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Ultrastructure of the Retina in Adult Neuronal Ceroid Lipofuscinosis

Cited by 8 publications

References 15 publications

Mass Spectrometry-based Protein Profiling to Determine the Cause of Lysosomal Storage Diseases of Unknown Etiology

Mass Spectrometry-based Protein Profiling to Determine the Cause of Lysosomal Storage Diseases of Unknown Etiology

Current State of Clinical and Morphological Features in Human NCL

Lysosomal storage disease upon disruption of the neuronal chloride transport protein ClC-6

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