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lipofuscinosis

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https://www.readbyqxmd.com/read/28901431/isolated-chromosome-8p23-2%C3%A2-pter-deletion-novel-evidence-for-developmental-delay-intellectual-disability-microcephaly-and-neurobehavioral-disorders
#1
Shanshan Shi, Shaobin Lin, Baojiang Chen, Yi Zhou
The current study presents a patient carrying a de novo ~6 Mb deletion of the isolated chromosome 8p23.2‑pter that was identified with a single‑nucleotide polymorphism array. The patient was characterized by developmental delay (DD)/intellectual disability (ID), microcephaly, autism spectrum disorder, attention‑deficit/hyperactivity disorders and mildly dysmorphic features. The location, size and gene content of the deletion observed in this patient were compared with those in 7 patients with isolated 8p23...
September 7, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28890641/pharmaceutical-approval-update
#2
Michele B Kaufman
Sarilumab (Kevzara) for moderately to severely active rheumatoid arthritis; valbenazine (Ingrezza), the first approval for tardive dyskinesia; and cerliponase alpha (Brineura) for late infantile neuronal ceroid lipofuscinosis type-2 disease.
September 2017: P & T: a Peer-reviewed Journal for Formulary Management
https://www.readbyqxmd.com/read/28878621/the-networks-of-genes-encoding-palmitoylated-proteins-in-axonal-and-synaptic-compartments-are-affected-in-ppt1-overexpressing-neuronal-like-cells
#3
Francesco Pezzini, Marzia Bianchi, Salvatore Benfatto, Francesca Griggio, Stefano Doccini, Rosalba Carrozzo, Arvydas Dapkunas, Massimo Delledonne, Filippo M Santorelli, Maciej M Lalowski, Alessandro Simonati
CLN1 disease (OMIM #256730) is an early childhood ceroid-lipofuscinosis associated with mutated CLN1, whose product Palmitoyl-Protein Thioesterase 1 (PPT1) is a lysosomal enzyme involved in the removal of palmitate residues from S-acylated proteins. In neurons, PPT1 expression is also linked to synaptic compartments. The aim of this study was to unravel molecular signatures connected to CLN1. We utilized SH-SY5Y neuroblastoma cells overexpressing wild type CLN1 (SH-p.wtCLN1) and five selected CLN1 patients' mutations...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28833537/gm2-gangliosidosis-in-shiba-inu-dogs-with-an-in-frame-deletion-in-hexb
#4
A Kolicheski, G S Johnson, N A Villani, D P O'Brien, T Mhlanga-Mutangadura, D A Wenger, K Mikoloski, J S Eagleson, J F Taylor, R D Schnabel, M L Katz
Consistent with a tentative diagnosis of neuronal ceroid lipofuscinosis (NCL), autofluorescent cytoplasmic storage bodies were found in neurons from the brains of 2 related Shiba Inu dogs with a young-adult onset, progressive neurodegenerative disease. Unexpectedly, no potentially causal NCL-related variants were identified in a whole-genome sequence generated with DNA from 1 of the affected dogs. Instead, the whole-genome sequence contained a homozygous 3 base pair (bp) deletion in a coding region of HEXB...
September 2017: Journal of Veterinary Internal Medicine
https://www.readbyqxmd.com/read/28828399/intracellular-proteolysis-of-progranulin-generates-stable-lysosomal-granulins-that-are-haploinsufficient-in-patients-with-frontotemporal-dementia-caused-by-grn-mutations
#5
Christopher J Holler, Georgia Taylor, Qiudong Deng, Thomas Kukar
Homozygous or heterozygous mutations in the GRN gene, encoding progranulin (PGRN), cause neuronal ceroid lipofuscinosis (NCL) or frontotemporal dementia (FTD), respectively. NCL and FTD are characterized by lysosome dysfunction and neurodegeneration, indicating PGRN is important for lysosome homeostasis in the brain. PGRN is trafficked to the lysosome where its functional role is unknown. PGRN can be cleaved into seven 6-kDa proteins called granulins (GRNs); however, little is known about how GRNs are produced or if levels of GRNs are altered in FTD-GRN mutation carriers...
July 2017: ENeuro
https://www.readbyqxmd.com/read/28792770/proteomic-analysis-of-brain-and-cerebrospinal-fluid-from-the-three-major-forms-of-neuronal-ceroid-lipofuscinosis-reveals-potential-biomarkers
#6
David E Sleat, Abla Tannous, Istvan Sohar, Jennifer A Wiseman, Haiyan Zheng, Meiqian Qian, Caifeng Zhou, Winnie Xin, Rosemary Barone, Katherine B Sims, Dirk F Moore, Peter Lobel
Clinical trials have been conducted for the neuronal ceroid lipofuscinoses (NCLs), a group of neurodegenerative lysosomal diseases that primarily affect children. While clinical rating systems will evaluate long-term efficacy, biomarkers to measure short-term response to treatment would be extremely valuable. To identify candidate biomarkers, we analyzed autopsy brain and matching CSF samples from controls and three genetically distinct NCLs due to deficiencies in palmitoyl protein thioesterase 1 (CLN1 disease), tripeptidyl peptidase 1 (CLN2 disease) and CLN3 protein (CLN3 disease)...
August 9, 2017: Journal of Proteome Research
https://www.readbyqxmd.com/read/28743268/the-lysosomal-protein-cathepsin-l-is-a-progranulin-protease
#7
Chris W Lee, Jeannette N Stankowski, Jeannie Chew, Casey N Cook, Ying-Wai Lam, Sandra Almeida, Yari Carlomagno, Kwok-Fai Lau, Mercedes Prudencio, Fen-Biao Gao, Matthew Bogyo, Dennis W Dickson, Leonard Petrucelli
Haploinsufficiency of GRN, the gene encoding progranulin (PGRN), causes frontotemporal lobar degeneration (FTLD), the second most common cause of early-onset dementia. Receptor-mediated lysosomal targeting has been shown to regulate brain PGRN levels, and complete deficiency of PGRN is a direct cause of neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Here we show that the lysosomal cysteine protease cathepsin L (Cat L) can mediate the proteolytic cleavage of intracellular PGRN into poly-granulin and granulin fragments...
July 25, 2017: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/28740222/primary-fibroblasts-from-csp%C3%AE-mutation-carriers-recapitulate-hallmarks-of-the-adult-onset-neuronal-ceroid-lipofuscinosis
#8
Bruno A Benitez, Mark S Sands
Mutations in the co- chaperone protein, CSPα, cause an autosomal dominant, adult-neuronal ceroid lipofuscinosis (AD-ANCL). The current understanding of CSPα function exclusively at the synapse fails to explain the autophagy-lysosome pathway (ALP) dysfunction in cells from AD-ANCL patients. Here, we demonstrate unexpectedly that primary dermal fibroblasts from pre-symptomatic mutation carriers recapitulate in vitro features found in the brains of AD-ANCL patients including auto-fluorescent storage material (AFSM) accumulation, CSPα aggregates, increased levels of lysosomal proteins and lysosome enzyme activities...
July 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28673981/synergistic-effects-of-treating-the-spinal-cord-and-brain-in-cln1-disease
#9
Charles Shyng, Hemanth R Nelvagal, Joshua T Dearborn, Jaana Tyynelä, Robert E Schmidt, Mark S Sands, Jonathan D Cooper
Infantile neuronal ceroid lipofuscinosis (INCL, or CLN1 disease) is an inherited neurodegenerative storage disorder caused by a deficiency of the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). It was widely believed that the pathology associated with INCL was limited to the brain, but we have now found unexpectedly profound pathology in the human INCL spinal cord. Similar pathological changes also occur at every level of the spinal cord of PPT1-deficient (Ppt1(-/-) ) mice before the onset of neuropathology in the brain...
July 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28647554/conditional-loss-of-progranulin-in-neurons-is-not-sufficient-to-cause-neuronal-ceroid-lipofuscinosis-like-neuropathology-in-mice
#10
Terri L Petkau, Jake Blanco, Blair R Leavitt
Progranulin deficiency due to heterozygous null mutations in the GRN gene is a common cause of familial frontotemporal lobar degeneration (FTLD), while homozygous loss-of-function GRN mutations cause neuronal ceroid lipofuscinosis (NCL). Aged progranulin-knockout mice display highly exaggerated lipofuscinosis, microgliosis, and astrogliosis, as well as mild cell loss in specific brain regions. Progranulin is a secreted glycoprotein expressed in both neurons and microglia, but not astrocytes, in the brain. We generated conditional progranulin-knockout mice that lack progranulin in nestin-expressing cells (Nes-cKO mice), which include most neurons as well as astrocytes...
June 21, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28632327/photosensitivity-is-an-early-marker-of-neuronal-ceroid-lipofuscinosis-type-2-disease
#11
Nicola Specchio, Marcello Bellusci, Nicola Pietrafusa, Marina Trivisano, Luca de Palma, Federico Vigevano
OBJECTIVE: This study aimed to identify early clinical, magnetic resonance imaging (MRI), and electroencephalographic (EEG) characteristics of neuronal ceroid lipofuscinosis type 2 (CLN2) disease to enable early diagnosis, thus providing the key to early treatment, and optimized care and outcomes. METHODS: Retrospective clinical chart review of a series of patients diagnosed with CLN2 disease from 2005 to 2015 at a single center in Italy. Clinical, MRI, and EEG findings were reviewed...
August 2017: Epilepsia
https://www.readbyqxmd.com/read/28623936/safety-and-potential-efficacy-of-gemfibrozil-as-a-supportive-treatment-for-children-with-late-infantile-neuronal-ceroid-lipofuscinosis-and-other-lipid-storage-disorders
#12
REVIEW
Kyeongsoon Kim, Hynda K Kleinman, Hahn-Jun Lee, Kalipada Pahan
Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is a group of genetically distinct lysosomal disorders that mainly affect the central nervous system, resulting in progressive motor and cognitive decline primarily in children. Multiple distinct genes involved in the metabolism of lipids have been identified to date with various mutations in this family of diseases. There is no cure for these diseases but some new therapeutic approaches have been tested that offer more hope than the standard palliative care...
June 17, 2017: Orphanet Journal of Rare Diseases
https://www.readbyqxmd.com/read/28595912/the-effect-of-manganese-exposure-in-atp13a2-deficient-mice
#13
Sheila M Fleming, Nicholas A Santiago, Elizabeth J Mullin, Shanta Pamphile, Swagata Karkare, Andrew Lemkuhl, Osunde R Ekhator, Stephen C Linn, John G Holden, Diana S Aga, Jerome A Roth, Benjamin Liou, Ying Sun, Gary E Shull, Patrick J Schultheis
Loss of function mutations in the P5-ATPase ATP13A2 are associated with Kufor-Rakeb Syndrome and Neuronal Ceroid Lipofuscinosis. While the function of ATP13A2 is unclear, in vitro studies suggest it is a lysosomal protein that interacts with the metals manganese (Mn) and zinc and the presynaptic protein alpha-synuclein. Loss of ATP13A2 function in mice causes sensorimotor deficits, enhanced autofluorescent storage material, and accumulation of alpha-synuclein. The present study sought to determine the effect of Mn administration on these same outcomes in ATP13A2-deficient mice...
June 6, 2017: Neurotoxicology
https://www.readbyqxmd.com/read/28589525/cerliponase-alfa-first-global-approval
#14
REVIEW
Anthony Markham
Cerliponase alfa (Brineura™) is a recombinant human tripeptidyl peptidase-1 (TPP1) being developed by BioMarin Pharmaceutical Inc. for use in patients with neuronal ceroid lipofuscinosis type 2 (CLN2), a paediatric neurodegenerative disease caused by a deficiency in TPP1. CLN2 is characterised by progressive impairment of motor function, language deficiencies, seizures, ataxia, blindness and early death, and intracerebroventricular infusion of cerliponase alfa has been shown to reduce the progression of functional decline...
July 2017: Drugs
https://www.readbyqxmd.com/read/28587997/long-term-follow-up-of-two-siblings-with-adult-onset-neuronal-ceroid-lipofuscinosis-kufs-type-a
#15
Çiğdem Özkara, Ayşegül Gündüz, Tülin Coşkun, Bengi Gül Alpaslan, Burcu Zeydan, Şakir Delil, Mikko Muona, Anna-Elina Lehesjoki, Meral E Kızıltan
Reports on the clinical presentation of adult-onset neuronal ceroid lipofuscinoses (NCL) are scarce compared to infantile- and childhood-onset forms. Here, we aimed to present detailed temporal evolution of clinical and electrophysiological features of two siblings with adult-onset NCL and homozygous mutation in the CLN6 gene. We retrospectively analysed medical records and electrophysiological data in order to delineate evolution of clinical and electrophysiological findings. Electrophysiological studies included routine EEG and video-EEG, as well as polymyographic analysis of myoclonus and brainstem reflex studies...
June 6, 2017: Epileptic Disorders: International Epilepsy Journal with Videotape
https://www.readbyqxmd.com/read/28586915/specific-alleles-of-cln7-mfsd8-a-protein-that-localizes-to-photoreceptor-synaptic-terminals-cause-a-spectrum-of-nonsyndromic-retinal-dystrophy
#16
MULTICENTER STUDY
Kamron N Khan, Mohammed E El-Asrag, Cristy A Ku, Graham E Holder, Martin McKibbin, Gavin Arno, James A Poulter, Keren Carss, Tejaswi Bommireddy, Saghar Bagheri, Benjamin Bakall, Hendrik P Scholl, F Lucy Raymond, Carmel Toomes, Chris F Inglehearn, Mark E Pennesi, Anthony T Moore, Michel Michaelides, Andrew R Webster, Manir Ali
Purpose: Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study. Methods: Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology...
June 1, 2017: Investigative Ophthalmology & Visual Science
https://www.readbyqxmd.com/read/28579939/the-role-of-co-chaperones-in-synaptic-proteostasis-and-neurodegenerative-disease
#17
REVIEW
Erica L Gorenberg, Sreeganga S Chandra
Synapses must be preserved throughout an organism's lifespan to allow for normal brain function and behavior. Synapse maintenance is challenging given the long distances between the termini and the cell body, reliance on axonal transport for delivery of newly synthesized presynaptic proteins, and high rates of synaptic vesicle exo- and endocytosis. Hence, synapses rely on efficient proteostasis mechanisms to preserve their structure and function. To this end, the synaptic compartment has specific chaperones to support its functions...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28546289/a-tripeptidyl-peptidase-1-is-a-binding-partner-of-the-golgi-ph-regulator-gphr-in-dictyostelium
#18
Maria Stumpf, Rolf Müller, Berthold Gaßen, Regina Wehrstedt, Petra Fey, Malte A Karow, Ludwig Eichinger, Gernot Glöckner, Angelika A Noegel
Mutations in tripeptidyl peptidase 1 (TPP1) have been associated with late infantile neuronal ceroid lipofuscinosis (NCL), a neurodegenerative disorder. TPP1 is a lysosomal serine protease, which removes tripeptides from the N-terminus of proteins and is composed of an N-terminal prodomain and a catalytic domain. It is conserved in mammals, amphibians, fish and the amoeba Dictyostelium discoideum. D. discoideum harbors at least six genes encoding TPP1, tpp1A to tpp1F We identified TPP1F as binding partner of Dictyostelium GPHR (Golgi pH regulator), which is an evolutionarily highly conserved intracellular transmembrane protein...
July 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28542837/phenotype-and-natural-history-of-variant-late-infantile-ceroid-lipofuscinosis-5
#19
MULTICENTER STUDY
Alessandro Simonati, Ruth E Williams, Nardo Nardocci, Minna Laine, Roberta Battini, Angela Schulz, Barbara Garavaglia, Francesca Moro, Francesco Pezzini, Filippo M Santorelli
AIM: To characterize the phenotypic profile of a cohort of children affected with CLN5, a rare form of neuronal ceroid-lipofuscinosis (NCL), and to trace the features of the natural history of the disease. METHOD: Records of 15 children (nine males, six females) were obtained from the data sets of the DEM-CHILD International NCL Registry. Disease progression was measured by rating six functional domains at different time points along the disease course. All patients underwent mutation analysis of the CLN5 gene and ultrastructural investigations of peripheral tissues...
August 2017: Developmental Medicine and Child Neurology
https://www.readbyqxmd.com/read/28542676/detailed-clinical-phenotype-and-molecular-genetic-findings-in-cln3-associated-isolated-retinal-degeneration
#20
MULTICENTER STUDY
Cristy A Ku, Sarah Hull, Gavin Arno, Ajoy Vincent, Keren Carss, Robert Kayton, Douglas Weeks, Glenn W Anderson, Ryan Geraets, Camille Parker, David A Pearce, Michel Michaelides, Robert E MacLaren, Anthony G Robson, Graham E Holder, Elise Heon, F Lucy Raymond, Anthony T Moore, Andrew R Webster, Mark E Pennesi
Importance: Mutations in genes traditionally associated with syndromic retinal disease are increasingly found to cause nonsyndromic inherited retinal degenerations. Mutations in CLN3 are classically associated with juvenile neuronal ceroid lipofuscinosis, a rare neurodegenerative disease with early retinal degeneration and progressive neurologic deterioration, but have recently also been identified in patients with nonsyndromic inherited retinal degenerations. To our knowledge, detailed clinical characterization of such cases has yet to be reported...
July 1, 2017: JAMA Ophthalmology
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