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Gary S Johnson - One of the best experts on this subject based on the ideXlab platform.
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a rare homozygous mfsd8 single base pair deletion and frameshift in the whole genome sequence of a chinese crested dog with neuronal ceroid Lipofuscinosis
BMC Veterinary Research, 2015Co-Authors: Dennis P Obrien, Martin L. Katz, Tendai Mhlangamutangadura, Robert D. Schnabel, Jeremy F. Taylor, Natasha J. Olby, Gary S JohnsonAbstract:Background The neuronal ceroid lipofuscinoses are heritable lysosomal storage diseases characterized by progressive neurological impairment and the accumulation of autofluorescent storage granules in neurons and other cell types. Various forms of human neuronal ceroid Lipofuscinosis have been attributed to mutations in at least 13 different genes. So far, mutations in the canine orthologs of 7 of these genes have been identified in DNA from dogs with neuronal ceroid Lipofuscinosis. The identification of new causal mutations could lead to the establishment of canine models to investigate the pathogenesis of the corresponding human neuronal ceroid lipofuscinoses and to evaluate and optimize therapeutic interventions for these fatal human diseases.
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A rare homozygous MFSD8 single-base-pair deletion and frameshift in the whole genome sequence of a Chinese Crested dog with neuronal ceroid Lipofuscinosis
BMC Veterinary Research, 2015Co-Authors: Juyuan Guo, Martin L. Katz, Robert D. Schnabel, Jeremy F. Taylor, Natasha J. Olby, Dennis P O’brien, Tendai Mhlanga-mutangadura, Gary S JohnsonAbstract:Background The neuronal ceroid lipofuscinoses are heritable lysosomal storage diseases characterized by progressive neurological impairment and the accumulation of autofluorescent storage granules in neurons and other cell types. Various forms of human neuronal ceroid Lipofuscinosis have been attributed to mutations in at least 13 different genes. So far, mutations in the canine orthologs of 7 of these genes have been identified in DNA from dogs with neuronal ceroid Lipofuscinosis. The identification of new causal mutations could lead to the establishment of canine models to investigate the pathogenesis of the corresponding human neuronal ceroid lipofuscinoses and to evaluate and optimize therapeutic interventions for these fatal human diseases. Case presentation We obtained blood and formalin-fixed paraffin-embedded brain sections from a rescue dog that was reported to be a young adult Chinese Crested. The dog was euthanized at approximately 19 months of age as a consequence of progressive neurological decline that included blindness, anxiety, and cognitive impairment. A diagnosis of neuronal ceroid Lipofuscinosis was made based on neurological signs, magnetic resonance imaging of the brain, and fluorescence microscopic and electron microscopic examination of brain sections. We isolated DNA from the blood and used it to generate a whole genome sequence with 33-fold average coverage. Among the 7.2 million potential sequence variants revealed by aligning the sequence reads to the canine genome reference sequence was a homozygous single base pair deletion in the canine ortholog of one of 13 known human NCL genes: MFSD8:c.843delT. MFSD8:c.843delT is predicted to cause a frame shift and premature stop codon resulting in a truncated protein, MFSD8:p.F282Lfs13* , missing its 239 C-terminal amino acids. The MFSD8:c.843delT allele is absent from the whole genome sequences of 101 healthy canids or dogs with other diseases. The genotyping of archived DNA from 1478 Chinese Cresteds did not identify any additional MFSD8:c.843delT homozygotes and found only one heterozygote. Conclusion We conclude that the neurodegenerative disease of the Chinese Crested rescue dog was neuronal ceroid Lipofuscinosis and that homozygosity for the MFSD8:c.843delT sequence variant was very likely to be the molecular-genetic cause of the disease.
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Assessment of retinal function and characterization of lysosomal storage body accumulation in the retinas and brains of Tibetan Terriers with ceroid-Lipofuscinosis.
American journal of veterinary research, 2005Co-Authors: Martin L. Katz, Gary S Johnson, Kristina Narfström, Dennis P. O'brienAbstract:OBJECTIVE To characterize lysosomal storage body accumulation in the retina and brain of Tibetan Terriers with ceroid-Lipofuscinosis and determine whether the disease in these dogs is accompanied by impaired retinal function and retinal degeneration. ANIMALS Three 7- to 10-year-old Tibetan Terriers with ceroid-Lipofuscinosis and 1 healthy 5-year-old Tibetan Terrier. PROCEDURE Owners completed a questionnaire to identify behavioral and physical signs indicative of ceroid-Lipofuscinosis. Neurologic, behavioral, and ophthalmologic evaluations, including full-field electroretinograms, were performed on each dog. Fluorescence, light, and electron microscopy were performed on specimens of retina, cerebral cortex, and cerebellum of all dogs postmortem. RESULTS Behavioral assessments of the affected dogs revealed moderate visual impairment in low-light conditions but good vision in bright light. On funduscopic evaluation of these dogs, abnormalities detected ranged from none to signs of moderately advanced retinal degeneration. Compared with findings in the control dog, electroretinography revealed depressed rod cell function with some impairment of cone cell function in the affected dogs. Morphologically, disease-specific storage bodies were detected in retinal Muller cells and neurons, particularly in ganglion cells, and in cells of the cerebral cortex and cerebellum in affected dogs. Substantial photoreceptor cell loss and disruption of photoreceptor outer segment morphology appeared to develop late in the disease. IMPLICATIONS FOR HUMAN MEDICINE: The similarities between ceroid-Lipofuscinosis in Tibetan Terriers and some forms of ceroid-Lipofuscinosis in humans suggest that the canine disease may have a genetic and biochemical basis similar to that of one of the ceroid-Lipofuscinosis disorders in humans.
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A mouse gene knockout model for juvenile ceroid-Lipofuscinosis (batten disease)
Journal of Neuroscience Research, 1999Co-Authors: Martin L. Katz, Hisashi Shibuya, Satbir Kaur, Chun-lan Gao, Gary S JohnsonAbstract:The human hereditary ceroid-lipofuscinoses are a group of autosomal recessively inherited diseases characterized by massive accumulations of autofluorescent lysosomal storage bodies in the cells of many tissues and by neuronal degeneration throughout the central nervous system. There are a number of clinically and genetically distinct forms of ceroid-Lipofuscinosis, the most common of which is the juvenile type, also known as Batten disease and CLN3. To study the mechanisms that lead to pathology in CLN3 and to evaluate potential therapies, a mouse model has been generated by targeted disruption of the mouse ortholog of the CLN3 gene (Cln3). As in affected humans, mice homozygous for the disrupted Cln3 allele show accumulation of autofluorescent storage material in neurons and other cell types. The storage material consists of membrane-bounded intracellular inclusions with ultrastructural features typical of the ceroid-lipofuscinoses. The accumulation of this storage material validates the Cln3 knockout mice as a model for the human disorder. J. Neurosci. Res. 57:551–556, 1999. © 1999 Wiley-Liss, Inc.
Martin L. Katz - One of the best experts on this subject based on the ideXlab platform.
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a rare homozygous mfsd8 single base pair deletion and frameshift in the whole genome sequence of a chinese crested dog with neuronal ceroid Lipofuscinosis
BMC Veterinary Research, 2015Co-Authors: Dennis P Obrien, Martin L. Katz, Tendai Mhlangamutangadura, Robert D. Schnabel, Jeremy F. Taylor, Natasha J. Olby, Gary S JohnsonAbstract:Background The neuronal ceroid lipofuscinoses are heritable lysosomal storage diseases characterized by progressive neurological impairment and the accumulation of autofluorescent storage granules in neurons and other cell types. Various forms of human neuronal ceroid Lipofuscinosis have been attributed to mutations in at least 13 different genes. So far, mutations in the canine orthologs of 7 of these genes have been identified in DNA from dogs with neuronal ceroid Lipofuscinosis. The identification of new causal mutations could lead to the establishment of canine models to investigate the pathogenesis of the corresponding human neuronal ceroid lipofuscinoses and to evaluate and optimize therapeutic interventions for these fatal human diseases.
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A rare homozygous MFSD8 single-base-pair deletion and frameshift in the whole genome sequence of a Chinese Crested dog with neuronal ceroid Lipofuscinosis
BMC Veterinary Research, 2015Co-Authors: Juyuan Guo, Martin L. Katz, Robert D. Schnabel, Jeremy F. Taylor, Natasha J. Olby, Dennis P O’brien, Tendai Mhlanga-mutangadura, Gary S JohnsonAbstract:Background The neuronal ceroid lipofuscinoses are heritable lysosomal storage diseases characterized by progressive neurological impairment and the accumulation of autofluorescent storage granules in neurons and other cell types. Various forms of human neuronal ceroid Lipofuscinosis have been attributed to mutations in at least 13 different genes. So far, mutations in the canine orthologs of 7 of these genes have been identified in DNA from dogs with neuronal ceroid Lipofuscinosis. The identification of new causal mutations could lead to the establishment of canine models to investigate the pathogenesis of the corresponding human neuronal ceroid lipofuscinoses and to evaluate and optimize therapeutic interventions for these fatal human diseases. Case presentation We obtained blood and formalin-fixed paraffin-embedded brain sections from a rescue dog that was reported to be a young adult Chinese Crested. The dog was euthanized at approximately 19 months of age as a consequence of progressive neurological decline that included blindness, anxiety, and cognitive impairment. A diagnosis of neuronal ceroid Lipofuscinosis was made based on neurological signs, magnetic resonance imaging of the brain, and fluorescence microscopic and electron microscopic examination of brain sections. We isolated DNA from the blood and used it to generate a whole genome sequence with 33-fold average coverage. Among the 7.2 million potential sequence variants revealed by aligning the sequence reads to the canine genome reference sequence was a homozygous single base pair deletion in the canine ortholog of one of 13 known human NCL genes: MFSD8:c.843delT. MFSD8:c.843delT is predicted to cause a frame shift and premature stop codon resulting in a truncated protein, MFSD8:p.F282Lfs13* , missing its 239 C-terminal amino acids. The MFSD8:c.843delT allele is absent from the whole genome sequences of 101 healthy canids or dogs with other diseases. The genotyping of archived DNA from 1478 Chinese Cresteds did not identify any additional MFSD8:c.843delT homozygotes and found only one heterozygote. Conclusion We conclude that the neurodegenerative disease of the Chinese Crested rescue dog was neuronal ceroid Lipofuscinosis and that homozygosity for the MFSD8:c.843delT sequence variant was very likely to be the molecular-genetic cause of the disease.
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Assessment of retinal function and characterization of lysosomal storage body accumulation in the retinas and brains of Tibetan Terriers with ceroid-Lipofuscinosis.
American journal of veterinary research, 2005Co-Authors: Martin L. Katz, Gary S Johnson, Kristina Narfström, Dennis P. O'brienAbstract:OBJECTIVE To characterize lysosomal storage body accumulation in the retina and brain of Tibetan Terriers with ceroid-Lipofuscinosis and determine whether the disease in these dogs is accompanied by impaired retinal function and retinal degeneration. ANIMALS Three 7- to 10-year-old Tibetan Terriers with ceroid-Lipofuscinosis and 1 healthy 5-year-old Tibetan Terrier. PROCEDURE Owners completed a questionnaire to identify behavioral and physical signs indicative of ceroid-Lipofuscinosis. Neurologic, behavioral, and ophthalmologic evaluations, including full-field electroretinograms, were performed on each dog. Fluorescence, light, and electron microscopy were performed on specimens of retina, cerebral cortex, and cerebellum of all dogs postmortem. RESULTS Behavioral assessments of the affected dogs revealed moderate visual impairment in low-light conditions but good vision in bright light. On funduscopic evaluation of these dogs, abnormalities detected ranged from none to signs of moderately advanced retinal degeneration. Compared with findings in the control dog, electroretinography revealed depressed rod cell function with some impairment of cone cell function in the affected dogs. Morphologically, disease-specific storage bodies were detected in retinal Muller cells and neurons, particularly in ganglion cells, and in cells of the cerebral cortex and cerebellum in affected dogs. Substantial photoreceptor cell loss and disruption of photoreceptor outer segment morphology appeared to develop late in the disease. IMPLICATIONS FOR HUMAN MEDICINE: The similarities between ceroid-Lipofuscinosis in Tibetan Terriers and some forms of ceroid-Lipofuscinosis in humans suggest that the canine disease may have a genetic and biochemical basis similar to that of one of the ceroid-Lipofuscinosis disorders in humans.
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A mouse gene knockout model for juvenile ceroid-Lipofuscinosis (batten disease)
Journal of Neuroscience Research, 1999Co-Authors: Martin L. Katz, Hisashi Shibuya, Satbir Kaur, Chun-lan Gao, Gary S JohnsonAbstract:The human hereditary ceroid-lipofuscinoses are a group of autosomal recessively inherited diseases characterized by massive accumulations of autofluorescent lysosomal storage bodies in the cells of many tissues and by neuronal degeneration throughout the central nervous system. There are a number of clinically and genetically distinct forms of ceroid-Lipofuscinosis, the most common of which is the juvenile type, also known as Batten disease and CLN3. To study the mechanisms that lead to pathology in CLN3 and to evaluate potential therapies, a mouse model has been generated by targeted disruption of the mouse ortholog of the CLN3 gene (Cln3). As in affected humans, mice homozygous for the disrupted Cln3 allele show accumulation of autofluorescent storage material in neurons and other cell types. The storage material consists of membrane-bounded intracellular inclusions with ultrastructural features typical of the ceroid-lipofuscinoses. The accumulation of this storage material validates the Cln3 knockout mice as a model for the human disorder. J. Neurosci. Res. 57:551–556, 1999. © 1999 Wiley-Liss, Inc.
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Methylated lysine in storage body protein of sheep with hereditary ceroid-Lipofuscinosis.
Biochimica et biophysica acta, 1992Co-Authors: Martin L. Katz, Klaus O. GerhardtAbstract:Abstract Juvenile ceroid-Lipofuscinosis (Batten disease) is a hereditary storage disease with an autosomal-recessive mode of transmission. This disorder has been identified in humans, dogs and sheep. It is characterized by massive accumulations of autofluorescent storage bodies in many tissues. This storage body accumulation is accompanied by functional decline and degeneration of the affected tissues, and ultimatelyresults in premature death. The primary defect responsible for juvenile ceroid-Lipofuscinosis has not been identified. Previous studies have indicated that the storage material is primarily protein. Why this protein accumulates in storage bodies remains to he determined. In affected humans, the storage body protein appears to be abnormally rich in a methylated derivative of lysine ( ϵ - N -trimethyllysine). Studies were undertaken to determine whether the storage bodies from sheep with hereditary ceroid-Lipofuscinosis were also characterized by the presence of this modified amino acid. Chromatographic and mass spectral analyses of hydrolysates of the storage body protein indicated significant fraction of the lysine residues in this protein were present as the ϵ - N -trimethyl derivative. This modified amino acid was not detected in hydrolysates of protein from normal sheep tissues or from tissues of sheep with GM 1 gangliosidosis, nor did it appear to be present in the storage body protein from a human subject with the late infantile form of ceroid-Lipofuscinosis. Thus, it is apparently specific to the storage body protein that accumulates in the juvenile type of this disease. The abnormal presence of ϵ - N -trimethyllysine in proteins could interfere with their sorting or degradation within cells and thus cause them to accumulate in the storage bodies characteristic of the human juvenile and ovine ceroid-lipofuscinoses.
Samia Pichard - One of the best experts on this subject based on the ideXlab platform.
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paediatric onset neuronal ceroid Lipofuscinosis first symptoms and presentation at diagnosis
Developmental Medicine & Child Neurology, 2020Co-Authors: Blandine Dozierespuyravel, Elisa Lopez Hernandez, Jeanphilippe Puech, Hala Nasser, Monique Elmalehberges, Adina Ilea, Catherine Delanoe, A. Gelot, Catherine Caillaud, Samia PichardAbstract:Neuronal ceroid lipofuscinoses (NCLs) are rare, progressive disorders. Through this series of 20 patients with NCL, we illustrate differences between subtypes in their presenting symptoms and clinical, imaging, and electrophysiological results to raise awareness of symptom diversity. Data were available on presenting symptoms, genetics, magnetic resonance imaging (MRI), electroencephalography (including with low-frequency intermittent photic stimulation), visual responses, and electron microscopy. Causal mutations were identified in 10 patients. Eleven patients had neuronal ceroid Lipofuscinosis type 2 (CLN2) disease and their most common presenting symptom was seizures, although motor and language defects were also reported. Five patients with CLN2 disease showed abnormalities at initial MRI, but only three showed a photic response with low-frequency stimulation. Seizures were not as common a presenting symptom in other NCL subtypes. Patients with NCLs present with diverse symptoms, which may not be characteristic in early disease stages. These signs and symptoms should lead to rapid diagnostic confirmatory testing for NCLs. WHAT THIS PAPER ADDS: Disease presentation is not uniform for neuronal ceroid lipofuscinoses. Characteristic clinical test results may not be identified in early disease stages.
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paediatric onset neuronal ceroid Lipofuscinosis first symptoms and presentation at diagnosis
Developmental Medicine & Child Neurology, 2020Co-Authors: Blandine Dozierespuyravel, Elisa Lopez Hernandez, Jeanphilippe Puech, Hala Nasser, Monique Elmalehberges, Adina Ilea, Catherine Delanoe, A. Gelot, Catherine Caillaud, Samia PichardAbstract:Neuronal ceroid lipofuscinoses (NCLs) are rare, progressive disorders. Through this series of 20 patients with NCL, we illustrate differences between subtypes in their presenting symptoms and clinical, imaging, and electrophysiological results to raise awareness of symptom diversity. Data were available on presenting symptoms, genetics, magnetic resonance imaging (MRI), electroencephalography (including with low-frequency intermittent photic stimulation), visual responses, and electron microscopy. Causal mutations were identified in 10 patients. Eleven patients had neuronal ceroid Lipofuscinosis type 2 (CLN2) disease and their most common presenting symptom was seizures, although motor and language defects were also reported. Five patients with CLN2 disease showed abnormalities at initial MRI, but only three showed a photic response with low-frequency stimulation. Seizures were not as common a presenting symptom in other NCL subtypes. Patients with NCLs present with diverse symptoms, which may not be characteristic in early disease stages. These signs and symptoms should lead to rapid diagnostic confirmatory testing for NCLs. WHAT THIS PAPER ADDS: Disease presentation is not uniform for neuronal ceroid lipofuscinoses. Characteristic clinical test results may not be identified in early disease stages.
Robert D. Jolly - One of the best experts on this subject based on the ideXlab platform.
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Chapter 11 The Neuronal Ceroid-lipofuscinoses (Batten Disease)
Advances in Cell Aging and Gerontology, 1999Co-Authors: Robert D. Jolly, Alfried Kohlschütter, David N Palmer, Steven U. WalkleyAbstract:Publisher Summary This chapter discusses the clinical, genetic, and biochemical aspects of the neuronal ceroid-lipofuscinoses. These are a group of inherited neurodegenerative diseases also characterized by accumulation of a fluorescent lipopigment in neurons and many other cell types. Infantile ceroid-Lipofuscinosis (CLN 1) is associated with a deficiency of palmitoyl–protein thioesterase, but the relationship between this and the main storage material, sphingolipid activating proteins A and D, is also obscure. The theoretical enzyme substrates are energy rich thioesters. It is possible that they become distributed beyond the lysosomal compartment and are toxic either to membrane systems or induce excitotoxicity of neurons with consequent catastrophic neurodegeneration early in the course of the disease. A full understanding of the pathogeneses of these diseases is necessary to allow specific therapeutic strategies to be developed. The animal models will remain critical to this even after the biochemical and molecular lesions are determined for each form of the disease.
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Hematopoietic cell transplantation in fetal lambs with ceroid-Lipofuscinosis
American Journal of Medical Genetics, 1995Co-Authors: V. J. Westlake, Boyd R. Jones, Roslyn Machon, Robert D. Jolly, Esmail D. Zanjani, David Mellor, William KrivitAbstract:Hematopoietic cells from the liver of normal 45-48-day-old fetal lambs (Hb type AA) were transplanted intraperitoneally into 58-60-day-old recipient fetuses (Hb type BB). The recipient fetuses resulted from mating homozygous ceroid-Lipofuscinosis affected males with heterozygous, phenotypically normal, females. The sex of the donor fetus was also recorded. At age 21/2 months the recipient lambs with ceroid-Lipofuscinosis were diagnosed by histopathology of brain biopsies. Monitoring of blood and bone marrow cells showed that an average of 9% of blood cells in ceroid-Lipofuscinosis affected recipients were of donor origin. No differences were evident in the clinical course of disease, brain weight, or histopathology of organs between transplanted and non-transplanted lambs with ceroid-Lipofuscinosis. Under the conditions of this experiment, transplantation of fetal hematopoietic cells was not beneficial. © 1995 Wiley-Liss, Inc.
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Characterization of the expressed genes for subunit c of mitochondrial ATP synthase in sheep with ceroid Lipofuscinosis.
Biochemical Journal, 1993Co-Authors: S. M. Medd, John E Walker, Robert D. JollyAbstract:The human and bovine genomes each contain two expressed nuclear genes, called P1 and P2, for subunit c, a hydrophobic subunit of the membrane sector, Fo, of mitochondrial ATP synthase. Both P1 and P2 encode the same mature protein, but the associated mitochondrial import sequences are different. In sheep with the neurodegenerative disease ceroid Lipofuscinosis, and also in humans with Batten's disease, unmodified subunit c accumulates in lysosome-derived organelles in a variety of tissues. However, the sequences of cDNAs for P1 and P2 from sheep with ceroid Lipofuscinosis were identical to those in healthy control animals. Therefore, since there was no mutation in either of the mitochondrial import sequences of subunit c in the diseased animals, ceroid Lipofuscinosis does not arise from changes in an import sequence causing mis-targeting of the c subunit to lysosomes. The levels of expression of P1 and P2 genes were approximately the same in diseased and healthy animals, and so the protein is unlikely to accumulate because of excessive transcription of either gene. Transcription of a spliced pseudogene related to P2 was detected in both a control animal and a sheep with ceroid Lipofuscinosis. The transcripts encode amino acids 1-31 of the P2 mitochondrial targeting sequence. In the diseased animal, an arginine replaced a glutamine in the control sequence. However, restriction fragment analysis of genomic DNA from a further 12 sheep established that the sequence differences were not linked to ceroid Lipofuscinosis.
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Round-table discussion of animal models of ceroid-Lipofuscinosis (Batten Disease)
Journal of inherited metabolic disease, 1993Co-Authors: Robert D. JollyAbstract:The panel was of the opinion that collection, breeding, description and full characterization of animal forms of ceroid-Lipofuscinosis were to be encouraged. Whereas there was advantage in relating each entity to a human form, this should not be overemphasized as each disease reflects a unique mutation and expression of disease may be modified by the degree of residual enzyme activity and species-related factors. The study of animal forms of ceroid-Lipofuscinosis will help define (1) the range of entities classified as ceroid-Lipofuscinosis in both general and particular senses, and (2) the characteristics that define the syndrome of ceroid-Lipofuscinosis. It allows genetic breeding, manipulative and terminal experiments not possible in human patients. The list of animal models (see Table 1) is limited to those that are bred for study or sporadic cases presently being studied and compared by research workers in the field of Batten disease research.
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Bovine ceroid-Lipofuscinosis (Batten's disease): The major component stored is the DCCD-reactive proteolipid, subunit c, of mitochondrial ATP synthase
Veterinary Research Communications, 1991Co-Authors: R. D. Martinus, S. L. Bayliss, G G Midwinter, G. J. Shaw, Robert D. Jolly, P A W Harper, D. N. PalmerAbstract:The ceroid-lipofuscinoses (Batten's disease) are a group of recessively inherited lysosomal storage diseases of children and animals in which there is intracellular accumulation of a fluorescent lipopigment in a wide variety of cells. Lipopigment bodies isolated from pancreas, liver, kidney and brain tissue from a heifer affected with ceroid-Lipofuscinosis contained between 55 and 62% protein. A dominant component comigrated on LDS-PAGE with the major low molecular weight protein stored in ovine ceroid-Lipofuscinosis. It was identified by amino acid sequence and mass spectroscopy as the full subunit c of mitochondrial ATP synthase, normally found only in the inner mitochondrial membrane, where it is estimated to account for 2–4% of the membrane protein. In pancreatic lipopigment it accounted for at least 40% of the total lipopigment mass and this storage was considered specific to the disease. No other mitochondrial proteins were found in storage bodies. These results are similar to those found in studies on the ovine and the late infantile and juvenile human forms of the disease. It is concluded that bovine ceroid-Lipofuscinosis is also a proteolipid proteinosis in which subunit c of mitochondrial ATP synthase is specifically stored in lysosome derived organelles.
Blandine Dozierespuyravel - One of the best experts on this subject based on the ideXlab platform.
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paediatric onset neuronal ceroid Lipofuscinosis first symptoms and presentation at diagnosis
Developmental Medicine & Child Neurology, 2020Co-Authors: Blandine Dozierespuyravel, Elisa Lopez Hernandez, Jeanphilippe Puech, Hala Nasser, Monique Elmalehberges, Adina Ilea, Catherine Delanoe, A. Gelot, Catherine Caillaud, Samia PichardAbstract:Neuronal ceroid lipofuscinoses (NCLs) are rare, progressive disorders. Through this series of 20 patients with NCL, we illustrate differences between subtypes in their presenting symptoms and clinical, imaging, and electrophysiological results to raise awareness of symptom diversity. Data were available on presenting symptoms, genetics, magnetic resonance imaging (MRI), electroencephalography (including with low-frequency intermittent photic stimulation), visual responses, and electron microscopy. Causal mutations were identified in 10 patients. Eleven patients had neuronal ceroid Lipofuscinosis type 2 (CLN2) disease and their most common presenting symptom was seizures, although motor and language defects were also reported. Five patients with CLN2 disease showed abnormalities at initial MRI, but only three showed a photic response with low-frequency stimulation. Seizures were not as common a presenting symptom in other NCL subtypes. Patients with NCLs present with diverse symptoms, which may not be characteristic in early disease stages. These signs and symptoms should lead to rapid diagnostic confirmatory testing for NCLs. WHAT THIS PAPER ADDS: Disease presentation is not uniform for neuronal ceroid lipofuscinoses. Characteristic clinical test results may not be identified in early disease stages.
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paediatric onset neuronal ceroid Lipofuscinosis first symptoms and presentation at diagnosis
Developmental Medicine & Child Neurology, 2020Co-Authors: Blandine Dozierespuyravel, Elisa Lopez Hernandez, Jeanphilippe Puech, Hala Nasser, Monique Elmalehberges, Adina Ilea, Catherine Delanoe, A. Gelot, Catherine Caillaud, Samia PichardAbstract:Neuronal ceroid lipofuscinoses (NCLs) are rare, progressive disorders. Through this series of 20 patients with NCL, we illustrate differences between subtypes in their presenting symptoms and clinical, imaging, and electrophysiological results to raise awareness of symptom diversity. Data were available on presenting symptoms, genetics, magnetic resonance imaging (MRI), electroencephalography (including with low-frequency intermittent photic stimulation), visual responses, and electron microscopy. Causal mutations were identified in 10 patients. Eleven patients had neuronal ceroid Lipofuscinosis type 2 (CLN2) disease and their most common presenting symptom was seizures, although motor and language defects were also reported. Five patients with CLN2 disease showed abnormalities at initial MRI, but only three showed a photic response with low-frequency stimulation. Seizures were not as common a presenting symptom in other NCL subtypes. Patients with NCLs present with diverse symptoms, which may not be characteristic in early disease stages. These signs and symptoms should lead to rapid diagnostic confirmatory testing for NCLs. WHAT THIS PAPER ADDS: Disease presentation is not uniform for neuronal ceroid lipofuscinoses. Characteristic clinical test results may not be identified in early disease stages.