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Update From the International Registry for Niemann-Pick Disease Type C (NP-C) in Clinical Practice
Abstracts / Molecular Genetics and Metabolism 105 (2012) S15–S69
Niemann–Pick disease, type C (NPC) is a pan-ethnic, autosomal recessive lysosomal storage disease with an incidence in France of 1/ 120,000. The public health burden of this devastating disease is disproportionate to its incidence and prevalence, and is further magnified by diagnostic delays, which are typically in the order of five years. Most patients experience a progressive dementia accompanied by vertical supranuclear gaze palsy ataxia, dysarthria, dysphagia, dystonia and in some cases, epilepsy and cataplexy. Several potential human therapeutic agents have been studied in vitro, in animal models of NPC, and in three human trials. Trial design and assignment of outcome measures in the human trials was hindered by the paucity of robust longitudinal natural history data. Before further human therapeutic trials are pursued, it is essential to refine understanding of the clinical course of NPC, and to identify clinical, neuropsychological and laboratory markers of disease burden and progression. The purpose of this study is to test the hypothesis that patients with NPC will demonstrate a specific pattern of neurocognitive deficits that will be present prior to the development of overt findings on formal neurological examination, and that will correlate with disease progression. 70 potential participants have been identified at the two network sites – the NIH Clinical Center and Mayo Clinic, and will be examined using a standardized set of instruments on an annual basis for the five years of the longitudinal study. doi:10.1016/j.ymgme.2011.11.128
Update From the International Registry for Niemann-Pick Disease Type C (NP-C) in Clinical Practice Marc Patterson a, Mercé Pineda b, Eugen Mengel c, Frits Wijburg d, Marie Vanier e, Barbara Schwierin f, Audrey Muller f, Jonathan Alsop g, Ed Wraith h, aMayo Clinic, Rochester, MN, USA, bHospital Sant Joan de Déu, Barcelona, Spain, cVilla Metabolica, University of Mainz, Germany, d Academic Medical Centre, University of Amsterdam, The Netherlands, e INSERM Unit 820, Lyon, France, fActelion Pharmaceuticals Ltd, Allschwil, Switzerland, gNumerus Ltd., Sandhurst, UK, hManchester Academic Health Science Centre, St Mary's Hospital, UK As of 19th August 2011, 121 patients (median (range) age 16.9 (0.9 56.6) years) have been enrolled in the Registry. Data presented are from all patients with available data. The median (range) age at onset of neurological manifestations among 100 patients was 8.2 (0.0 48.0) years, and the median (range) age at diagnosis among 110 patients was 11.8 (0.1 53.9) years. A history of neonatal jaundice was recorded in 4/4 (100%) patients with early-infantile onset of neurological manifestations (at age <1 to <2 years), 6/21 (29%) with late-infantile onset (at 2 to <6 years), 6/21 (29%) with juvenile onset (at 6 to < 15 years), and 3/20 (15%) with adolescent/adult onset (at ≥15 years). Eighty-eight of 121 (73%) patients were confirmed as receiving miglustat at enrolment; mean (SD) exposure among 86 patients was 1.69 (1.85) years. Psychiatric manifestations were present in 28/76 (37%) patients, and were most frequent in patients with adolescent/adult onset (n = 12; 46%). Seventy-one of 84 (85%) patients had neurological manifestations: ataxia (71%), vertical gaze palsy (68%), dysarthria (62%), cognitive impairment (60%), dysphagia (45%) and/or dystonia (45%). Median (range) composite disability scores (0 = normal; 1 = worst) were: 0.0 (0.0–0.94) in early infantile-onset (n = 7), 0.29 (0.0–1.0) in late infantile- onset (n = 28), 0.41 (0.15–0.88) in juvenile-onset (n = 28), and 0.29 (0.06–0.81) in adolescent/adult-onset patients (n = 26). Low numbers of patients had normal language (16/110; 15%), manipulation (21/109; 19%), ambulation (23/110; 21%), and/or swallowing (38/110; 35%). These data are in line with previous findings indicating
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different clinical manifestations according to age at onset of neurological disease. doi:10.1016/j.ymgme.2011.11.129
Glutamate Receptors: A Therapeutic Target in Batten Disease David Pearce, Sanford Research, Sioux Falls, SD, USA Currently there is no treatment for juvenile Batten disease, a fatal childhood neurodegenerative disorder caused by mutations in the CLN3 gene. The Cln3-knockout (Cln3Δex1-6) mouse model of the disease recapitulates several features of the human disorder including a deficit in motor coordination. Our previous studies demonstrated that acute attenuation of alpha-amino-3-hydroxy-5-methyl4-isoxazolepropionate (AMPA)-type glutamate receptor activity by the non-competitive AMPA antagonist, EGIS-8332, in both 1- and 6-7month-old Cln3Δex1-6 mice results in a significant improvement in motor coordination. Here we show that while the competitive AMPA receptor antagonist, NVP- AMP397 (1 mg/kg), caused a similar improvement in one-month-old Cln3Δex1-6 mice, acute inhibition of N-methyl-D-aspartate (NMDA)-type glutamate receptors by memantine (1 and 5 mg/kg i.p.) had no effect on the motor coordination at this early stage of the disease. In 6-7-month-old Cln3Δex1-6 mice, however, memantine induced a delayed but extended improvement of motor skills similarly to that observed previously with EGIS-8332 treatment. The age-dependent therapeutic effect of memantine implies that the pathomechanism in juvenile Batten disease changes during disease progression. In contrast to the acute treatment, repeated administration of memantine or EGIS-8332 (1 mg/kg, once a week for 4 weeks) to 6-month-old Cln3Δex1-6 mice did not have a beneficial effect on motor coordination. Histological analysis revealed that the repeated treatments did not have any impact upon microglial activation or the survival of vulnerable neuron populations. Memantine did not affect astrocytosis in the cortex. EGIS-8332, however, decreased astrocytic activation in the somatosensory barrelfield cortex. Our results show that acute inhibition of NMDA receptors can induce a prolonged therapeutic effect, identifying NMDA receptors as a new therapeutic target for juvenile Batten disease. doi:10.1016/j.ymgme.2011.11.130
Lysosome-Associated Protein 1 (LAMP-1) and Lysosome-Associated Protein 2 (LAMP-2) in Fabry Disease Ester Pereira, Adalberto Socorro da Silva, Semiramis Jamil Hadad do Monte, Universidade Federal do Piauí, Teresina, Piauí, Brasil The purpose of this study was to quantify the levels of lysosomeassociated protein 1 (LAMP-1) and lysosome-associated protein 2 (LAMP-2) in leukocyte cells from patients suffering from Fabry disease and to investigate a possible relationship between the levels of the LAMPs and the response to enzyme replacement therapy (ERT). In addition, we investigated the correlation of levels of the LAMPs with time of treatment and also compared the levels of the LAMPs between diseased and healthy individuals. The levels of the LAMPs were assessed by flow cytometry in both, blood samples from 17 Fabry disease patients through nine-month ERT administration and blood samples from 101 healthy individuals. We found that both LAMP-1 and LAMP-2 are higher expressed in phagocytic cells of patients compared to that ones of controls. Furthermore, such LAMP1 and LAMP-2 levels in phagocytes of FD carriers were found be
Niemann–Pick disease, type C (NPC) is a pan-ethnic, autosomal recessive lysosomal storage disease with an incidence in France of 1/ 120,000. The public health burden of this devastating disease is disproportionate to its incidence and prevalence, and is further magnified by diagnostic delays, which are typically in the order of five years. Most patients experience a progressive dementia accompanied by vertical supranuclear gaze palsy ataxia, dysarthria, dysphagia, dystonia and in some cases, epilepsy and cataplexy. Several potential human therapeutic agents have been studied in vitro, in animal models of NPC, and in three human trials. Trial design and assignment of outcome measures in the human trials was hindered by the paucity of robust longitudinal natural history data. Before further human therapeutic trials are pursued, it is essential to refine understanding of the clinical course of NPC, and to identify clinical, neuropsychological and laboratory markers of disease burden and progression. The purpose of this study is to test the hypothesis that patients with NPC will demonstrate a specific pattern of neurocognitive deficits that will be present prior to the development of overt findings on formal neurological examination, and that will correlate with disease progression. 70 potential participants have been identified at the two network sites – the NIH Clinical Center and Mayo Clinic, and will be examined using a standardized set of instruments on an annual basis for the five years of the longitudinal study. doi:10.1016/j.ymgme.2011.11.128
Update From the International Registry for Niemann-Pick Disease Type C (NP-C) in Clinical Practice Marc Patterson a, Mercé Pineda b, Eugen Mengel c, Frits Wijburg d, Marie Vanier e, Barbara Schwierin f, Audrey Muller f, Jonathan Alsop g, Ed Wraith h, aMayo Clinic, Rochester, MN, USA, bHospital Sant Joan de Déu, Barcelona, Spain, cVilla Metabolica, University of Mainz, Germany, d Academic Medical Centre, University of Amsterdam, The Netherlands, e INSERM Unit 820, Lyon, France, fActelion Pharmaceuticals Ltd, Allschwil, Switzerland, gNumerus Ltd., Sandhurst, UK, hManchester Academic Health Science Centre, St Mary's Hospital, UK As of 19th August 2011, 121 patients (median (range) age 16.9 (0.9 56.6) years) have been enrolled in the Registry. Data presented are from all patients with available data. The median (range) age at onset of neurological manifestations among 100 patients was 8.2 (0.0 48.0) years, and the median (range) age at diagnosis among 110 patients was 11.8 (0.1 53.9) years. A history of neonatal jaundice was recorded in 4/4 (100%) patients with early-infantile onset of neurological manifestations (at age <1 to <2 years), 6/21 (29%) with late-infantile onset (at 2 to <6 years), 6/21 (29%) with juvenile onset (at 6 to < 15 years), and 3/20 (15%) with adolescent/adult onset (at ≥15 years). Eighty-eight of 121 (73%) patients were confirmed as receiving miglustat at enrolment; mean (SD) exposure among 86 patients was 1.69 (1.85) years. Psychiatric manifestations were present in 28/76 (37%) patients, and were most frequent in patients with adolescent/adult onset (n = 12; 46%). Seventy-one of 84 (85%) patients had neurological manifestations: ataxia (71%), vertical gaze palsy (68%), dysarthria (62%), cognitive impairment (60%), dysphagia (45%) and/or dystonia (45%). Median (range) composite disability scores (0 = normal; 1 = worst) were: 0.0 (0.0–0.94) in early infantile-onset (n = 7), 0.29 (0.0–1.0) in late infantile- onset (n = 28), 0.41 (0.15–0.88) in juvenile-onset (n = 28), and 0.29 (0.06–0.81) in adolescent/adult-onset patients (n = 26). Low numbers of patients had normal language (16/110; 15%), manipulation (21/109; 19%), ambulation (23/110; 21%), and/or swallowing (38/110; 35%). These data are in line with previous findings indicating
S51
different clinical manifestations according to age at onset of neurological disease. doi:10.1016/j.ymgme.2011.11.129
Glutamate Receptors: A Therapeutic Target in Batten Disease David Pearce, Sanford Research, Sioux Falls, SD, USA Currently there is no treatment for juvenile Batten disease, a fatal childhood neurodegenerative disorder caused by mutations in the CLN3 gene. The Cln3-knockout (Cln3Δex1-6) mouse model of the disease recapitulates several features of the human disorder including a deficit in motor coordination. Our previous studies demonstrated that acute attenuation of alpha-amino-3-hydroxy-5-methyl4-isoxazolepropionate (AMPA)-type glutamate receptor activity by the non-competitive AMPA antagonist, EGIS-8332, in both 1- and 6-7month-old Cln3Δex1-6 mice results in a significant improvement in motor coordination. Here we show that while the competitive AMPA receptor antagonist, NVP- AMP397 (1 mg/kg), caused a similar improvement in one-month-old Cln3Δex1-6 mice, acute inhibition of N-methyl-D-aspartate (NMDA)-type glutamate receptors by memantine (1 and 5 mg/kg i.p.) had no effect on the motor coordination at this early stage of the disease. In 6-7-month-old Cln3Δex1-6 mice, however, memantine induced a delayed but extended improvement of motor skills similarly to that observed previously with EGIS-8332 treatment. The age-dependent therapeutic effect of memantine implies that the pathomechanism in juvenile Batten disease changes during disease progression. In contrast to the acute treatment, repeated administration of memantine or EGIS-8332 (1 mg/kg, once a week for 4 weeks) to 6-month-old Cln3Δex1-6 mice did not have a beneficial effect on motor coordination. Histological analysis revealed that the repeated treatments did not have any impact upon microglial activation or the survival of vulnerable neuron populations. Memantine did not affect astrocytosis in the cortex. EGIS-8332, however, decreased astrocytic activation in the somatosensory barrelfield cortex. Our results show that acute inhibition of NMDA receptors can induce a prolonged therapeutic effect, identifying NMDA receptors as a new therapeutic target for juvenile Batten disease. doi:10.1016/j.ymgme.2011.11.130
Lysosome-Associated Protein 1 (LAMP-1) and Lysosome-Associated Protein 2 (LAMP-2) in Fabry Disease Ester Pereira, Adalberto Socorro da Silva, Semiramis Jamil Hadad do Monte, Universidade Federal do Piauí, Teresina, Piauí, Brasil The purpose of this study was to quantify the levels of lysosomeassociated protein 1 (LAMP-1) and lysosome-associated protein 2 (LAMP-2) in leukocyte cells from patients suffering from Fabry disease and to investigate a possible relationship between the levels of the LAMPs and the response to enzyme replacement therapy (ERT). In addition, we investigated the correlation of levels of the LAMPs with time of treatment and also compared the levels of the LAMPs between diseased and healthy individuals. The levels of the LAMPs were assessed by flow cytometry in both, blood samples from 17 Fabry disease patients through nine-month ERT administration and blood samples from 101 healthy individuals. We found that both LAMP-1 and LAMP-2 are higher expressed in phagocytic cells of patients compared to that ones of controls. Furthermore, such LAMP1 and LAMP-2 levels in phagocytes of FD carriers were found be