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Keigo Takahashi, Nicholas R Rensing, Elizabeth M Eultgen, Sophie H Wang, Hemanth R Nelvagal, Steven Q Le, Marie S Roberts, Balraj Doray, Edward B Han, Patricia I Dickson, Michael Wong, Mark S Sands, Jonathan D Cooper
GABAergic interneuron deficits have been implicated in the epileptogenesis of multiple neurological diseases. While epileptic seizures are a key clinical hallmark of CLN2 disease, a childhood-onset neurodegenerative lysosomal storage disorder caused by a deficiency of tripeptidyl peptidase 1 (TPP1), the etiology of these seizures remains elusive. Given that Cln2 R207X/R207X mice display fatal spontaneous seizures and an early loss of several cortical interneuron populations, we hypothesized that those two events might be causally related...
March 30, 2024: bioRxiv
#2
JOURNAL ARTICLE
Nour El Hoda Mustaphi, Fatima Ezzahra Aboutofil, Lamyae El Houssni, Eiad Saif, Joel T Mague, Karim Chkirate, El Mokhtar Essassi
The quinoxaline moiety in the title mol-ecule, C13 H13 ClN2 O3 , is almost planar (r.m.s. deviation of the fitted atoms = 0.033 Å). In the crystal, C-H⋯O hydrogen bonds plus slipped π-stacking and C-H⋯π(ring) inter-actions generate chains of mol-ecules extending along the b -axis direction. The chains are connected by additional C-H⋯O hydrogen bonds. Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H⋯H (37...
March 1, 2024: Acta Crystallographica. Section E, Crystallographic Communications
#3
JOURNAL ARTICLE
Norberto Guelbert, Oscar Mauricio Espitia Segura, Carolina Amoretti, Angélica Arteaga Arteaga, Nora Graciela Atanacio, Sabrina Bazan Natacha, Ellaine Doris Fernandes Carvalho, Maria Denise Fernandes Carvalho de Andrade, Inés María Denzler, Consuelo Durand, Erlane Ribeiro, Juan Carlos Giugni, Gabriel González, Dolores González Moron, Guillermo Guelbert, Zulma Janneth Hernández Rodriguez, Katiane Embiruçu Emilia, Marcelo Andrés Kauffman, Nury Isabel Mancilla, Laureano Marcon, Alessandra Marques Pereira, Carolina Fischinger Moura de Souza, Victor Adrián Muñoz, Ricardo Andrés Naranjo Flórez, André Luiz Pessoa, María Victoria Ruiz, Martha Luz Solano Villareal, Norma Spécola, Lina Marcela Tavera, Javiera Tello, Mónica Troncoso Schifferli, Sonia Ugrina, María Magdalena Vaccarezza, Diane Vergara, María Mercedes Villanueva
INTRODUCTION: Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), is a neurodegenerative autosomal recessive disease caused by TPP1 gene variants , with a spectrum of classic and atypical phenotypes. The aim of treatment is to slow functional decline as early as possible in an attempt to improve quality of life and survival. This study describes the clinical characteristics as well as the response to treatment with cerliponase alfa. MATERIALS AND METHODS: A retrospective study was conducted in five Latin-American countries, using clinical records from patients with CLN2...
March 2024: Molecular Genetics and Metabolism Reports
#4
JOURNAL ARTICLE
Riham Sghyar, Abdeslem Bentama, Amal Haoudi, Ahmed Mazzah, Joel T Mague, Tuncer Hökelek, El Mestafa El Hadrami, Nada Kheira Sebbar
The title mol-ecule, [Fe2 (C5 H5 )2 (C23 H17 ClN2 )]·C3 H7 NO, is twisted end to end and the central N/C/N unit is disordered. In the crystal, several C-H⋯π(ring) inter-actions lead to the formation of layers, which are connected by further C-H⋯π(ring) inter-actions. A Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H⋯H (60.2%) and H⋯C/C⋯H (27.0%) inter-actions. Hydrogen bonding, C-H⋯π(ring) inter-actions and van der Waals inter-actions dominate the crystal packing...
March 1, 2024: Acta Crystallographica. Section E, Crystallographic Communications
#5
David L Rogers, Emily De Los Reyes, Thomas A Mendel, Brian Caprul, Sarah Podlasiak, Catherine O Jordan
Classically, peripheral vascular changes in the retina in patients with neuronal ceroid lipofuscinosis type 2 (CLN2) are described as vascular attenuation seen in the late stages of disease on the Weill Connell Ophthalmic Severity Score (WCOSS) staging system. We describe isolated, mild, peripheral vasculitis with peripheral arteriolar dropout identified by fluorescein angiography in patients with a WCOSS grade of stage 2. We believe this vasculitis represents an early vasodegenerative phase of disease that leads to the vascular attenuation seen in later stages of the disease...
February 8, 2024: Journal of AAPOS: the Official Publication of the American Association for Pediatric Ophthalmology and Strabismus
#6
JOURNAL ARTICLE
Farid N Naghiyev, Victor N Khrustalev, Mehmet Akkurt, Evgeny A Dukhnovsky, Ajaya Bhattarai, Ali N Khalilov, İbrahim G Mamedov
In the crystal of the title compound, C6 H9 ClN2 O, mol-ecular pairs form dimers with an R 2 2 (8) motif through N-H⋯O hydrogen bonds. These dimers are connect into ribbons parallel to the (100) plane with R 4 4 (10) motifs by N-H⋯O hydrogen bonds along the c- axis direction. In addition, π-π [centroid-to-centroid distance = 3.4635 (9) Å] and C-Cl⋯π inter-actions between the ribbons form layers parallel to the (100) plane. The three-dimensional consolidation of the crystal structure is also ensured by Cl⋯H and Cl⋯Cl inter-actions between these layers...
February 1, 2024: Acta Crystallographica. Section E, Crystallographic Communications
#7
JOURNAL ARTICLE
Rachel Bican, Virginia Goddard, Nicolas Abreu, Danielle Peifer, Andrea Basinger, Michelle Sveda, Kelly Tanner, Emily C de Los Reyes
BACKGROUND: Batten disease is a rare, progressive neurogenetic disorder composed of 13 genotypes that often presents in childhood. Children present with seizures, vision loss, and developmental regression. Neurorehabilitation services (i.e., physical therapy, occupational therapy, and speech-language therapy) can help improve the quality of life for children and their families. Owing to the rarity of Batten disease, there are no standardized clinical recommendations or outcome assessments...
March 2024: Pediatric Neurology
#8
JOURNAL ARTICLE
Amanda Brambila, Beth E Prichard, Jerry T DeWitt, Douglas R Kellogg
Entry into the cell cycle in late G1 phase occurs only when sufficient growth has occurred. In budding yeast, a cyclin called Cln3 is thought to link cell cycle entry to cell growth. Cln3 accumulates during growth in early G1 phase and eventually helps trigger expression of late G1 phase cyclins that drive cell cycle entry. All current models for cell cycle entry assume that expression of late G1 phase cyclins is initiated at the transcriptional level. Current models also assume that the sole function of Cln3 in cell cycle entry is to promote transcription of late G1 phase cyclins, and that Cln3 works solely in G1 phase...
January 17, 2024: Molecular Biology of the Cell
#9
JOURNAL ARTICLE
Priyanka K, Priya N Madhana, Rajalakshmanan Eswaramoorthy, Magesh Ramasamy
Neuronal ceroid-lipofuscinosis (NCLs) are a group of severe neurodegenerative conditions, most likely present in infantile, late infantile, juvenile, and adult-onset forms. Their phenotypic characteristics comprise eyesight damage, reduced motor activity and cognitive function, and sometimes tend to die in the initial stage. In recent studies, NCLs have been categorized into at least 14 genetic collections (CLN1-14). CLN2 gene encodes Tripeptidyl peptidase 1 (TPP1), which affects late infantile-onset form. In this study, we retrieved a mutational dataset screening for TPP1 protein from various databases (ClinVar, UniProt, HGMD)...
January 8, 2024: Metabolic Brain Disease
#10
JOURNAL ARTICLE
Ana Catalina Rodriguez-Martinez, James Wawrzynski, Robert H Henderson
PURPOSE OF REVIEW: This paper provides an update on intravitreal (IVT) enzyme replacement therapy (ERT) in metabolic retinal diseases; particularly neuronal ceroid lipofuscinosis type 2 (CLN2) also known as Batten disease. RECENT FINDINGS: ERT is being explored in CLN2 related Batten disease, a fatal neurodegenerative condition associated with retinopathy and blindness that is caused by the deficiency of lysosomal enzyme TPP1. Cerliponase alfa, a recombinant human tripeptidyl-peptidase1 (rhTPP1) administered by intraventricular infusions has been demonstrated to slow the rate of neurodegenerative decline but not retinopathy...
December 27, 2023: Current Opinion in Ophthalmology
#11
JOURNAL ARTICLE
Angela Schulz, Nicola Specchio, Emily de Los Reyes, Paul Gissen, Miriam Nickel, Marina Trivisano, Shawn C Aylward, Anupam Chakrapani, Christoph Schwering, Eva Wibbeler, Lena Marie Westermann, Douglas J Ballon, Jonathan P Dyke, Anu Cherukuri, Shailesh Bondade, Peter Slasor, Jessica Cohen Pfeffer
BACKGROUND: Cerliponase alfa is a recombinant human tripeptidyl peptidase 1 (TPP1) enzyme replacement therapy for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2 disease), which is caused by mutations in the TPP1 gene. We aimed to determine the long-term safety and efficacy of intracerebroventricular cerliponase alfa in children with CLN2 disease. METHODS: This analysis includes cumulative data from a primary 48-week, single-arm, open-label, multicentre, dose-escalation study (NCT01907087) and the 240-week open-label extension with 6-month safety follow-up, conducted at five hospitals in Germany, Italy, the UK, and the USA...
January 2024: Lancet Neurology
#12
JOURNAL ARTICLE
James Wawrzynski, Ana Rodriguez Martinez, Dorothy Ann Thompson, Dipak Ram, Richard Bowman, Rebecca Whiteley, Chin Gan, Louise Harding, Amanda Mortensen, Philippa Mills, Paul Gissen, Robert H Henderson
BACKGROUND/OBJECTIVES: CLN2 Batten Disease is a fatal neurodegenerative condition of childhood associated with retinal dystrophy and blindness. Intracerebroventricular infusion of rhTPP1 greatly slows the rate of neurodegenerative decline but not retinopathy. Intravitreal rhTPP1 is known to slow retinal degeneration in a canine model of CLN2. We report a first-in-man controlled clinical trial of intravitreal rhTPP1 for CLN2 associated retinal dystrophy. SUBJECTS/METHODS: 8 children aged 5-9 with CLN2 Batten Disease were prospectively enroled...
December 4, 2023: Eye
#13
Jordan Xiao, Jonathan J Turner, Mardo Kõivomägi, Jan M Skotheim
Progression through the cell cycle depends on the phosphorylation of key substrates by cyclin-dependent kinases. In budding yeast, these substrates include the transcriptional inhibitor Whi5 that regulates the G1/S transition. In early G1 phase, Whi5 is hypo-phosphorylated and inhibits the SBF complex that promotes transcription of the cyclins CLN1 and CLN2 . In late-G1, Whi5 is rapidly hyper-phosphorylated by Cln1,2 in complex with the cyclin-dependent kinase Cdk1. This hyper-phosphorylation inactivates Whi5 and excludes it from the nucleus...
November 4, 2023: bioRxiv
#14
JOURNAL ARTICLE
Guimiao Tian, Sihui Long
In the crystal structure of the title compound, C13 H11 ClN2 O2 , the mol-ecules form a three-dimensional network based on two types of hydrogen bonds between NH groups and the carbonyl oxygen atoms and amides. The mol-ecule is highly twisted, as evidenced by the dihedral angle between the 6-oxo-1,6-di-hydro-pyridine and benzene rings [88.1 (2)°].
July 2023: IUCrData
#15
JOURNAL ARTICLE
Attila D Kovács, Jose L Gonzalez Hernandez, David A Pearce
Batten disease is a group of mostly pediatric neurodegenerative lysosomal storage disorders caused by mutations in the CLN1-14 genes. We have recently shown that acidified drinking water attenuated neuropathological changes and improved motor function in the Cln1R151X and Cln3-/- mouse models of infantile CLN1 and juvenile CLN3 diseases. Here we tested if acidified drinking water has beneficial effects in Cln2R207X mice, a nonsense mutant model of late infantile CLN2 disease. Cln2R207X mice have motor deficits, muscle weakness, develop tremors, and die prematurely between 4 and 6 months of age...
November 6, 2023: Scientific Reports
#16
JOURNAL ARTICLE
Saki Nakashima, Masashi Hamada, Tomohiko Kimura, Shuichi Tanifuji, Akiko Takahashi, Daiki Yashita, Yu Kakimoto, Takashi Matsukawa, Hiroyuki Ishiura, Tatsushi Toda
Neuronal ceroid lipofuscinosis type 2 (CLN2) is an autosomal recessive lysosomal disease caused by decreased activity of the enzyme tripeptidyl peptidase 1 (TPP1) due to pathogenic variants in the TPP1 gene. Cerliponase alfa, a recombinant proenzyme form of TPP1, has shown efficacy in preventing motor and language function decline in early-stage CLN2. However, the safety and effects of this therapy in advanced-stage CLN2 are unclear. We herein report a case of intraventricular cerliponase alfa treatment for over a year in a patient with advanced-stage CLN2...
November 6, 2023: Internal Medicine
#17
JOURNAL ARTICLE
Connolly Steigerwald, Jill Borsuk, John Pappas, Miranda Galey, Anna Scott, Joseph M Devaney, Danny E Miller, Nicolas J Abreu
Neuronal ceroid lipofuscinosis type 2 (CLN2) is an autosomal recessive neurodegenerative disorder with enzyme replacement therapy available. We present two siblings with a clinical diagnosis of CLN2 disease, but no identifiable TPP1 variants after standard clinical testing. Long-read sequencing identified a homozygous deep intronic variant predicted to affect splicing, confirmed by clinical DNA and RNA sequencing. This case demonstrates how traditional laboratory assays can complement emerging molecular technologies to provide a precise molecular diagnosis...
December 2023: Molecular Genetics and Metabolism
#18
Hannah G Leppert, Joelle T Anderson, Kaylie J Timm, Cristina Davoli, Melissa A Pratt, Clarissa D Booth, Katherine A White, Mitchell J Rechtzigel, Brandon L Meyerink, Tyler B Johnson, Jon J Brudvig, Jill M Weimer
Lysosomal storage disorders (LSDs) are a genetically and clinically diverse group of diseases characterized by lysosomal dysfunction. Batten disease is a family of severe LSDs primarily impacting the central nervous system. Here we show that AF38469, a small molecule inhibitor of sortilin, improves lysosomal and glial pathology across multiple LSD models. Live-cell imaging and comparative transcriptomics demonstrates that the transcription factor EB (TFEB), an upstream regulator of lysosomal biogenesis, is activated upon treatment with AF38469...
September 22, 2023: bioRxiv
#19
JOURNAL ARTICLE
Bishnu P De, Jonathan B Rosenberg, Nithya Selvan, Isabelle Wilson, Nadir Yusufzai, Alessandria Greco, Stephen M Kaminsky, Linda A Heier, Rodolfo Ricart Arbona, Ileana Miranda, Sebastien Monette, Anju Nair, Richie Khanna, Ronald G Crystal, Dolan Sondhi
CLN2 disease is a fatal, childhood autosomal recessive disorder caused by mutations in CLN2 gene, encoding tripeptidyl peptidase 1 (TPP-1). Loss of TPP-1 activity leads to accumulation of storage material in lysosomes and resultant neuronal cell death with neurodegeneration. Genotype/phenotype comparisons suggest that the phenotype should be ameliorated with increase of TPP-1 levels to 5-10% of normal with wide central nervous system (CNS) distribution. Our previous clinical study showed that intraparenchymal administration of AAVrh...
August 25, 2023: Human Gene Therapy
#20
JOURNAL ARTICLE
Doreswamy Geetha, Channappa N Kavitha, Thayamma R Divakara, Yeriyur B Basavaraju, Hemmige S Yathirajan, Sean Parkin
The synthesis and crystal structure of a monoclinic polymorph of 2-amino-5-chloro-benzo-phenone oxime, C13 H11 ClN2 O, are presented. The mol-ecular conformation results from twisting of the phenyl and 2-amino-5-chloro benzene rings attached to the oxime group, which subtend a dihedral angle of 80.53 (4)°. In the crystal, centrosymmetric dimers are formed as a result of pairs of strong O-H⋯N hydrogen bonds. A comparison is made to a previously known triclinic polymorph, including differences in atom-atom contacts obtained via a Hirshfeld-surface analysis...
June 1, 2023: Acta Crystallographica. Section E, Crystallographic Communications
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