The Experts below are selected from a list of 219 Experts worldwide ranked by ideXlab platform
Sondra W Levin - One of the best experts on this subject based on the ideXlab platform.
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mri brain volume measurements in infantile neuronal Ceroid lipofuscinosis
American Journal of Neuroradiology, 2017Co-Authors: Eva H Baker, Sondra W Levin, Zhongjian Zhang, Anil B MukherjeeAbstract:BACKGROUND AND PURPOSE: Infantile neuronal Ceroid lipofuscinosis is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase 1 deficiency, which impairs degradation of palmitoylated proteins (constituents of Ceroid) by lysosomal hydrolases. Consequent lysosomal Ceroid accumulation leads to neuronal injury, resulting in rapid neurodegeneration and childhood death. As part of a project studying the treatment benefits of a combination of cysteamine bitartrate and N -acetyl cysteine, we made serial measurements of patients9 brain volumes with MR imaging. MATERIALS AND METHODS: Ten patients with infantile neuronal Ceroid lipofuscinosis participating in a treatment/follow-up study underwent brain MR imaging that included high-resolution T1-weighted images. After manual placement of a mask delineating the surface of the brain, a maximum-likelihood classifier was applied to determine total brain volume, further subdivided as cerebrum, cerebellum, brain stem, and thalamus. Patients9 brain volumes were compared with those of a healthy population. RESULTS: Major subdivisions of the brain followed similar trajectories with different timing. The cerebrum demonstrated early, rapid volume loss and may never have been normal postnatally. The thalamus dropped out of the normal range around 6 months of age; the cerebellum, around 2 years of age; and the brain stem, around 3 years of age. CONCLUSIONS: Rapid cerebral volume loss was expected on the basis of previous qualitative reports. Because our study did not include a nontreatment arm and because progression of brain volumes in infantile neuronal Ceroid lipofuscinosis has not been previously quantified, we could not determine whether our intervention had a beneficial effect on brain volumes. However, the level of quantitative detail in this study allows it to serve as a reference for evaluation of future therapeutic interventions.
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oral cysteamine bitartrate and n acetylcysteine for patients with infantile neuronal Ceroid lipofuscinosis a pilot study
Lancet Neurology, 2014Co-Authors: Eva H Baker, Sondra W Levin, Zhongjian Zhang, Wadih M Zein, Zenaide M N Quezado, Ning Miao, Andrea L Gropman, Kurt J GriffinAbstract:Summary Background Infantile neuronal Ceroid lipofuscinosis is a devastating neurodegenerative lysosomal storage disease caused by mutations in the gene ( CLN1 or PPT1 ) encoding palmitoyl-protein thioesterase-1 (PPT1). We have previously reported that phosphocysteamine and N-acetylcysteine mediate Ceroid depletion in cultured cells from patients with this disease. We aimed to assess whether combination of oral cysteamine bitartrate and N-acetylcysteine is beneficial for patients with neuronal Ceroid lipofuscinosis. Methods Children between 6 months and 3 years of age with infantile neuronal Ceroid lipofuscinosis with any two of the seven most lethal PPT1 mutations were eligible for inclusion in this pilot study. All patients were recruited from physician referrals. Patients received oral cysteamine bitartrate (60 mg/kg per day) and N-acetylcysteine (60 mg/kg per day) and were assessed every 6–12 months until they had an isoelectric electroencephalogram (EEG, attesting to a vegetative state) or were too ill to travel. Patients were also assessed by electroretinography, brain MRI and magnetic resonance spectroscopy (MRS), and electron microscopic analyses of leukocytes for granular osmiophilic deposits (GRODs). Children also underwent physical and neurodevelopmental assessments on the Denver scale. Outcomes were compared with the reported natural history of infantile neuronal Ceroid lipofuscinosis and that of affected older siblings. This trial is registered with ClinicalTrials.gov, number NCT00028262. Findings Between March 14, 2001, and June 30, 2012, we recruited ten children with infantile neuronal Ceroid lipofuscinosis; one child was lost to follow-up after the first visit and nine patients (five girls and four boys) were followed up for 8 to 75 months. MRI showed abnormalities similar to those in previous reports; brain volume and N-acetyl aspartic acid (NAA) decreased steadily, but no published quantitative MRI or MRS studies were available for comparison. None of the children acquired new developmental skills, and their retinal function decreased progressively. Average time to isoelectric EEG (52 months, SD 13) was longer than reported previously (36 months). At the first follow-up visit, peripheral leukocytes in all nine patients showed virtually complete depletion of GRODs. Parents and physicians reported less irritability, improved alertness, or both in seven patients. No treatment-related adverse events occurred apart from mild gastrointestinal discomfort in two patients, which disappeared when liquid cysteamine bitartrate was replaced with capsules. Interpretation Our findings suggest that combination therapy with cysteamine bitartrate and N-acetylcysteine is associated with delay of isoelectric EEG, depletion of GRODs, and subjective benefits as reported by parents and physicians. Our systematic and quantitative report of the natural history of patients with infantile neuronal Ceroid lipofuscinosis provides a guide for future assessment of experimental therapies. Funding National Institutes of Health.
Kurt J Griffin - One of the best experts on this subject based on the ideXlab platform.
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oral cysteamine bitartrate and n acetylcysteine for patients with infantile neuronal Ceroid lipofuscinosis a pilot study
Lancet Neurology, 2014Co-Authors: Eva H Baker, Sondra W Levin, Zhongjian Zhang, Wadih M Zein, Zenaide M N Quezado, Ning Miao, Andrea L Gropman, Kurt J GriffinAbstract:Summary Background Infantile neuronal Ceroid lipofuscinosis is a devastating neurodegenerative lysosomal storage disease caused by mutations in the gene ( CLN1 or PPT1 ) encoding palmitoyl-protein thioesterase-1 (PPT1). We have previously reported that phosphocysteamine and N-acetylcysteine mediate Ceroid depletion in cultured cells from patients with this disease. We aimed to assess whether combination of oral cysteamine bitartrate and N-acetylcysteine is beneficial for patients with neuronal Ceroid lipofuscinosis. Methods Children between 6 months and 3 years of age with infantile neuronal Ceroid lipofuscinosis with any two of the seven most lethal PPT1 mutations were eligible for inclusion in this pilot study. All patients were recruited from physician referrals. Patients received oral cysteamine bitartrate (60 mg/kg per day) and N-acetylcysteine (60 mg/kg per day) and were assessed every 6–12 months until they had an isoelectric electroencephalogram (EEG, attesting to a vegetative state) or were too ill to travel. Patients were also assessed by electroretinography, brain MRI and magnetic resonance spectroscopy (MRS), and electron microscopic analyses of leukocytes for granular osmiophilic deposits (GRODs). Children also underwent physical and neurodevelopmental assessments on the Denver scale. Outcomes were compared with the reported natural history of infantile neuronal Ceroid lipofuscinosis and that of affected older siblings. This trial is registered with ClinicalTrials.gov, number NCT00028262. Findings Between March 14, 2001, and June 30, 2012, we recruited ten children with infantile neuronal Ceroid lipofuscinosis; one child was lost to follow-up after the first visit and nine patients (five girls and four boys) were followed up for 8 to 75 months. MRI showed abnormalities similar to those in previous reports; brain volume and N-acetyl aspartic acid (NAA) decreased steadily, but no published quantitative MRI or MRS studies were available for comparison. None of the children acquired new developmental skills, and their retinal function decreased progressively. Average time to isoelectric EEG (52 months, SD 13) was longer than reported previously (36 months). At the first follow-up visit, peripheral leukocytes in all nine patients showed virtually complete depletion of GRODs. Parents and physicians reported less irritability, improved alertness, or both in seven patients. No treatment-related adverse events occurred apart from mild gastrointestinal discomfort in two patients, which disappeared when liquid cysteamine bitartrate was replaced with capsules. Interpretation Our findings suggest that combination therapy with cysteamine bitartrate and N-acetylcysteine is associated with delay of isoelectric EEG, depletion of GRODs, and subjective benefits as reported by parents and physicians. Our systematic and quantitative report of the natural history of patients with infantile neuronal Ceroid lipofuscinosis provides a guide for future assessment of experimental therapies. Funding National Institutes of Health.
Eva H Baker - One of the best experts on this subject based on the ideXlab platform.
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mri brain volume measurements in infantile neuronal Ceroid lipofuscinosis
American Journal of Neuroradiology, 2017Co-Authors: Eva H Baker, Sondra W Levin, Zhongjian Zhang, Anil B MukherjeeAbstract:BACKGROUND AND PURPOSE: Infantile neuronal Ceroid lipofuscinosis is a devastating neurodegenerative storage disease caused by palmitoyl-protein thioesterase 1 deficiency, which impairs degradation of palmitoylated proteins (constituents of Ceroid) by lysosomal hydrolases. Consequent lysosomal Ceroid accumulation leads to neuronal injury, resulting in rapid neurodegeneration and childhood death. As part of a project studying the treatment benefits of a combination of cysteamine bitartrate and N -acetyl cysteine, we made serial measurements of patients9 brain volumes with MR imaging. MATERIALS AND METHODS: Ten patients with infantile neuronal Ceroid lipofuscinosis participating in a treatment/follow-up study underwent brain MR imaging that included high-resolution T1-weighted images. After manual placement of a mask delineating the surface of the brain, a maximum-likelihood classifier was applied to determine total brain volume, further subdivided as cerebrum, cerebellum, brain stem, and thalamus. Patients9 brain volumes were compared with those of a healthy population. RESULTS: Major subdivisions of the brain followed similar trajectories with different timing. The cerebrum demonstrated early, rapid volume loss and may never have been normal postnatally. The thalamus dropped out of the normal range around 6 months of age; the cerebellum, around 2 years of age; and the brain stem, around 3 years of age. CONCLUSIONS: Rapid cerebral volume loss was expected on the basis of previous qualitative reports. Because our study did not include a nontreatment arm and because progression of brain volumes in infantile neuronal Ceroid lipofuscinosis has not been previously quantified, we could not determine whether our intervention had a beneficial effect on brain volumes. However, the level of quantitative detail in this study allows it to serve as a reference for evaluation of future therapeutic interventions.
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oral cysteamine bitartrate and n acetylcysteine for patients with infantile neuronal Ceroid lipofuscinosis a pilot study
Lancet Neurology, 2014Co-Authors: Eva H Baker, Sondra W Levin, Zhongjian Zhang, Wadih M Zein, Zenaide M N Quezado, Ning Miao, Andrea L Gropman, Kurt J GriffinAbstract:Summary Background Infantile neuronal Ceroid lipofuscinosis is a devastating neurodegenerative lysosomal storage disease caused by mutations in the gene ( CLN1 or PPT1 ) encoding palmitoyl-protein thioesterase-1 (PPT1). We have previously reported that phosphocysteamine and N-acetylcysteine mediate Ceroid depletion in cultured cells from patients with this disease. We aimed to assess whether combination of oral cysteamine bitartrate and N-acetylcysteine is beneficial for patients with neuronal Ceroid lipofuscinosis. Methods Children between 6 months and 3 years of age with infantile neuronal Ceroid lipofuscinosis with any two of the seven most lethal PPT1 mutations were eligible for inclusion in this pilot study. All patients were recruited from physician referrals. Patients received oral cysteamine bitartrate (60 mg/kg per day) and N-acetylcysteine (60 mg/kg per day) and were assessed every 6–12 months until they had an isoelectric electroencephalogram (EEG, attesting to a vegetative state) or were too ill to travel. Patients were also assessed by electroretinography, brain MRI and magnetic resonance spectroscopy (MRS), and electron microscopic analyses of leukocytes for granular osmiophilic deposits (GRODs). Children also underwent physical and neurodevelopmental assessments on the Denver scale. Outcomes were compared with the reported natural history of infantile neuronal Ceroid lipofuscinosis and that of affected older siblings. This trial is registered with ClinicalTrials.gov, number NCT00028262. Findings Between March 14, 2001, and June 30, 2012, we recruited ten children with infantile neuronal Ceroid lipofuscinosis; one child was lost to follow-up after the first visit and nine patients (five girls and four boys) were followed up for 8 to 75 months. MRI showed abnormalities similar to those in previous reports; brain volume and N-acetyl aspartic acid (NAA) decreased steadily, but no published quantitative MRI or MRS studies were available for comparison. None of the children acquired new developmental skills, and their retinal function decreased progressively. Average time to isoelectric EEG (52 months, SD 13) was longer than reported previously (36 months). At the first follow-up visit, peripheral leukocytes in all nine patients showed virtually complete depletion of GRODs. Parents and physicians reported less irritability, improved alertness, or both in seven patients. No treatment-related adverse events occurred apart from mild gastrointestinal discomfort in two patients, which disappeared when liquid cysteamine bitartrate was replaced with capsules. Interpretation Our findings suggest that combination therapy with cysteamine bitartrate and N-acetylcysteine is associated with delay of isoelectric EEG, depletion of GRODs, and subjective benefits as reported by parents and physicians. Our systematic and quantitative report of the natural history of patients with infantile neuronal Ceroid lipofuscinosis provides a guide for future assessment of experimental therapies. Funding National Institutes of Health.
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, Catherine Caillaud, Hala Nasser, Monique Elmalehberges, Elisa Lopez Hernandez, Antoinette Gelot, Adina Ilea, Catherine Delanoe, Jeanphilippe Puech, 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.
Leena Peltonen - One of the best experts on this subject based on the ideXlab platform.
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cln5 a novel gene encoding a putative transmembrane protein mutated in finnish variant late infantile neuronal Ceroid lipofuscinosis
Nature Genetics, 1998Co-Authors: Minna Savukoski, Tuomas Klockars, Ville Holmberg, Pirkko Santavuori, Eric S Lander, Leena PeltonenAbstract:CLN5 , a novel gene encoding a putative transmembrane protein mutated in Finnish variant late infantile neuronal Ceroid lipofuscinosis
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Molecular genetics of neuronal Ceroid lipofuscinoses
Pediatric Research, 1992Co-Authors: Irma Järvelä, Pirkko Santavuori, Jouni Vesa, Elina Hellsten, Leena PeltonenAbstract:This overview describes recent advances in molecular biology of neuronal Ceroid lipofuscinoses (CLN). Despite intensive research during last 20 years, the basic defects of these autosomal recessive-progressive encepha- lopathies of childhood remain unknown. Consequently, no specific cure is available. Methods of positional cloning (reverse genetics) starting from random linkage approach have been applied to search for gene defects in the infantile and juvenile forms of the disease. The results of this random search for disease loci have for the first time revealed molecular heterogeneity of CLN diseases. The gene defect causing the infantile form has been assigned to lp32 in the Finnish family material, whereas the disease locus of the juvenile form has been localized to 16p12 in European and Canadian families. Finally, the gene defect causing the late infantile form has been excluded from both lp32 and 16p12 chromosomal regions, referring to a third, still unknown locus causing CLN disease. Consequently, reliable prenatal and carrier diagnostics have now become possible in families with the infantile and juvenile forms of the disease, and DNA-based prenatal diagnostics have been successfully applied in the infantile form. Most im- portantly, the assignment of gene loci has brought these fatal brain diseases within the reach of molecular cloning strategies that eventually will result in revealing both the infantile and juvenile CLN genes and in identifying corre- sponding gene products. (Pediatr Res 32: 645-648, 1992) Abbreviations CLN, Ceroid lipofuscinosis, neuronal CLN1, infantile neuronal Ceroid lipofuscinosis CLN2, late infantile neuronal Ceroid lipofuscinosis CLN3, juvenile neuronal Ceroid lipofuscinosis MRI, magnetic resonance imaging stance common to the different forms of CLN resembles lipopig- ment, showing autofluorescence and acid phosphatase activity and intense staining with the Sudan black B and periodic acid Schiff methods. These properties are similar to those of lipofuscin and Ceroid. Lipofuscin is a compound known to accumulate in most cell types with age. It is caused by nonspecific peroxidation of polyunsaturated fatty acids present in complex lipids of differ- ent membranes. Ceroid is also a compound with some charac- teristics of lipofuscin, but it is formed mainly in certain experi- mental and pathologic conditions (4). These morphologic find- ings are highly nonspecific in nature, and, consequently, numerous theories (5-8) are put forward to explain the pathology of CLN diseases. However, no fruitful clues to elucidate the metabolic basis of these brain diseases have been suggested. CLASSIFICATION CLN in childhood are divided into three principal clinical groups: infantile (INCL, Santavuori disease, CLNI, McKusick 256730), late infantile (LINCL, Jansky-Bielschowsky disease, early-onset Batten's disease, CLN2, McKusick 204500), and juvenile (JNCL, late-onset Batten's disease, Spielmeyer-sjogren- Vogt disease, CLN3, McKusick 204200) (2, 9). A fourth type, adult CLN (Kufs' disease, CLN4, McKusick 204300), is typically a rare form in adults and will not be considered further here. The classification of CLN is based on the age of onset, clinical course of the disease, neurologic, ophthalmologic, neurophysio- logic, and ultrastructural findings (Table 1) (2). All childhood forms are inherited as an autosomal recessive trait. About 10% of all CLN patients represent variant or atypical forms, which are dificult to classify into the three main childhood groups (10- 14). Repeated clinical examinations of the patients and sufficient follow-up times provide diagnostic accuracy in uncertain cases. These patients usually have features common to both the late infantile and juvenile forms and are classified as the late infantile group, which, consequently, can actually represent several disease entities.