scholarly journals Natural History of Retinal Degeneration in Ovine Models of CLN5 and CLN6 Neuronal Ceroid Lipofuscinoses

2021 ◽  
Author(s):  
Samantha J Murray ◽  
Nadia L Mitchell
Keyword(s):  
Time Course ◽  
Vision Loss ◽  
Ganglion Cells ◽  
Batten Disease ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Optimal Timing ◽  
Lysosomal Storage ◽  
Retinal Layers ◽  
Differential Vulnerability ◽  
History Of

Abstract Neuronal ceroid lipofuscinoses (NCL; Batten disease) are a group of inherited neurodegenerative diseases with a common set of symptoms including cognitive and motor decline and vision loss. Naturally occurring sheep models of CLN5 and CLN6 disease display the key clinical features of NCL, including a progressive loss of vision. We assessed retinal histology, inflammation, and lysosomal storage accumulation in CLN5 affected (CLN5−/−) and CLN6 affected (CLN6−/−) sheep eyes and age-matched controls at 3, 6, 12, and 18 months of age to determine the onset and progression of retinal pathology in NCL sheep. The retina of CLN5−/− sheep shows progressive atrophy of the outer retinal layers, widespread inflammation, and accumulation of lysosomal storage in retinal ganglion cells late in disease. In contrast, CLN6−/− retina shows significant atrophy of all retinal layers, progressive inflammation, and earlier accumulation of lysosomal storage. This study has highlighted the differential vulnerability of retinal layers and the time course of retinal atrophy in two distinct models of NCL disease. This data will be valuable in determining potential targets for ocular therapies and the optimal timing of these therapies for protection from retinal dysfunction and degeneration in NCL.

scholarly journals Aggregation chimeras provide evidence of in vivo intercellular correction in ovine CLN6 neuronal ceroid lipofuscinosis (Batten disease)

2021 ◽  
Author(s):  
Lucy A. Barry ◽  
Graham W. Kay ◽  
Nadia L. Mitchell ◽  
Samantha J. Murray ◽  
Nigel P. Jay ◽  
...  
Keyword(s):  
Vision Loss ◽  
Inflammatory Responses ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Batten Disease ◽  
Brain Regions ◽  
Glial Activation ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Lysosomal Storage ◽  
Storage Body

AbstractThe neuronal ceroid lipofuscinoses (NCLs; Batten disease) are fatal, mainly childhood, inherited neurodegenerative lysosomal storage diseases. Sheep affected with a CLN6 form display progressive regionally defined glial activation and subsequent neurodegeneration, indicating that neuroinflammation may be causative of pathogenesis. In this study, aggregation chimeras were generated from homozygous unaffected normal and CLN6 affected sheep embryos, resulting in seven chimeric animals with varied proportions of normal to affected cells. These sheep were classified as affected-like, recovering-like or normal-like, based on their cell-genotype ratios and their clinical and neuropathological profiles.Neuropathological examination of the affected-like animals revealed intense glial activation, prominent storage body accumulation and severe neurodegeneration within all cortical brain regions, along with vision loss and decreasing intracranial volumes and cortical thicknesses consistent with ovine CLN6 disease. In contrast, intercellular communication affecting pathology was evident at both the gross and histological level in the normal-like and recovering-like chimeras, resulting in a lack of glial activation and rare storage body accumulation in only a few cells. Initial intracranial volumes of the recovering-like chimeras were below normal but progressively recovered to about normal by two years of age. All had normal cortical thicknesses, and none went blind. Extended neurogenesis was evident in the brains of all the chimeras.This study indicates that although CLN6 is a membrane bound protein, the consequent defect is not cell intrinsic. The lack of glial activation and inflammatory responses in the normal-like and recovering-like chimeras indicate that newly generated cells are borne into a microenvironment conducive to maturation and survival.

Sudden Onset of Diplopia and a Skeletal Muscle Antibody

2021 ◽  
pp. 160-162
Author(s):  
John R. Mills
Keyword(s):  
Computed Tomography ◽  
Myasthenia Gravis ◽  
Patent Foramen Ovale ◽  
Time Course ◽  
Vision Loss ◽  
Sudden Onset ◽  
Foramen Ovale ◽  
Clinical Disorder ◽  
History Of ◽  
The Right

A 62-year-old man with a history of migraine came to the emergency department with sudden onset of horizontal diplopia and, subsequently, bilateral ptosis. He noted feeling unsteady when walking. He reported that the diplopia worsened throughout the day. He had a history of hepatitis C infection. He had some vision loss in his left eye, which was thought to relate to a retinopathy. He disclosed that he had a history of cold feet and had notably high arches. He had a pacemaker because of syncope attributed to sick sinus syndrome. Computed tomography angiography of the head and neck were ruled negative for intracranial stenosis, occlusions, or aneurysms. Computed tomography of the head indicated a tiny lacunar infarct in the right caudate head. Magnetic resonance imaging of the brain identified a tiny, periaqueductal, enhancing abnormality in the right midbrain that was thought to be likely ischemic, but there was some concern for a demyelinating or inflammatory lesion. Cerebrospinal fluid evaluation indicated an increased protein concentration. Serologic evaluation for myasthenia gravis striational antibodies were positive at a titer of 1:240. Serum protein studies indicated the presence of polyclonal hypergammaglobulinemia. Myasthenia gravis was effectively ruled out. Given the hyperacute time course, the patient’s clinical disorder was most probably explained by an ischemic stroke that affected the oculomotor nuclei regions causing ptosis and ophthalmoparesis. On follow-up, the patient was discovered to have a patent foramen ovale. Whether the patent foramen ovale was a contributing factor to the stroke is uncertain. The recurrence rate in this setting is thought to be low relative to other causes of stroke. Ultimately it was decided to not close the patent foramen ovale and to maintain the patient on clopidogrel and adult low-dose aspirin. The onset of diplopia is typically sudden, but this occurs exclusively with vascular pathologic processes. Diplopia that appears intermittently with diurnal variation suggests the possibility of a neuromuscular junction disease such as myasthenia gravis.

scholarly journals Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease

2019 ◽  
Vol 28 (23) ◽  
pp. 3867-3879 ◽  
Author(s):  
Sophia-Martha kleine Holthaus ◽  
Saul Herranz-Martin ◽  
Giulia Massaro ◽  
Mikel Aristorena ◽  
Justin Hoke ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Motor Coordination ◽  
Transmembrane Protein ◽  
Batten Disease ◽  
Premature Death ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Therapeutic Effects ◽  
Lysosomal Storage ◽  
Enzyme Replacement

Abstract The neuronal ceroid lipofuscinoses (NCLs), more commonly referred to as Batten disease, are a group of inherited lysosomal storage disorders that present with neurodegeneration, loss of vision and premature death. There are at least 13 genetically distinct forms of NCL. Enzyme replacement therapies and pre-clinical studies on gene supplementation have shown promising results for NCLs caused by lysosomal enzyme deficiencies. The development of gene therapies targeting the brain for NCLs caused by defects in transmembrane proteins has been more challenging and only limited therapeutic effects in animal models have been achieved so far. Here, we describe the development of an adeno-associated virus (AAV)-mediated gene therapy to treat the neurodegeneration in a mouse model of CLN6 disease, a form of NCL with a deficiency in the membrane-bound protein CLN6. We show that neonatal bilateral intracerebroventricular injections with AAV9 carrying CLN6 increase lifespan by more than 90%, maintain motor skills and motor coordination and reduce neuropathological hallmarks of Cln6-deficient mice up to 23 months post vector administration. These data demonstrate that brain-directed gene therapy is a valid strategy to treat the neurodegeneration of CLN6 disease and may be applied to other forms of NCL caused by transmembrane protein deficiencies in the future.

scholarly journals Altered protein secretion in Batten disease

2021 ◽  
Vol 14 (12) ◽  
Author(s):  
Robert J. Huber
Keyword(s):  
Protein Secretion ◽  
Vision Loss ◽  
Clinical Symptoms ◽  
Neurological Diseases ◽  
Batten Disease ◽  
Premature Death ◽  
Model Organisms ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Altered Protein ◽  
The Impact

ABSTRACT The neuronal ceroid lipofuscinoses (NCLs), collectively known as Batten disease, are a group of neurological diseases that affect all ages and ethnicities worldwide. There are 13 different subtypes of NCL, each caused by a mutation in a distinct gene. The NCLs are characterized by the accumulation of undigestible lipids and proteins in various cell types. This leads to progressive neurodegeneration and clinical symptoms including vision loss, progressive motor and cognitive decline, seizures, and premature death. These diseases have commonly been characterized by lysosomal defects leading to the accumulation of undigestible material but further research on the NCLs suggests that altered protein secretion may also play an important role. This has been strengthened by recent work in biomedical model organisms, including Dictyostelium discoideum, mice, and sheep. Research in D. discoideum has reported the extracellular localization of some NCL-related proteins and the effects of NCL-related gene loss on protein secretion during unicellular growth and multicellular development. Aberrant protein secretion has also been observed in mammalian models of NCL, which has allowed examination of patient-derived cerebrospinal fluid and urine for potential diagnostic and prognostic biomarkers. Accumulated evidence links seven of the 13 known NCL-related genes to protein secretion, suggesting that altered secretion is a common hallmark of multiple NCL subtypes. This Review highlights the impact of altered protein secretion in the NCLs, identifies potential biomarkers of interest and suggests that future work in this area can provide new therapeutic insight.

scholarly journals Patient-Derived Induced Pluripotent Stem Cell Models for Phenotypic Screening in the Neuronal Ceroid Lipofuscinoses

Molecules ◽  
2021 ◽  
Vol 26 (20) ◽  
pp. 6235
Author(s):  
Ahmed Morsy ◽  
Angelica V. Carmona ◽  
Paul C. Trippier
Keyword(s):  
Neuronal Ceroid Lipofuscinosis ◽  
Batten Disease ◽  
Induced Pluripotent Stem Cell ◽  
Epileptic Seizures ◽  
Premature Death ◽  
Model Systems ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Phenotypic Screening ◽  
Lysosomal Storage ◽  
Induced Pluripotent

Batten disease or neuronal ceroid lipofuscinosis (NCL) is a group of rare, fatal, inherited neurodegenerative lysosomal storage disorders. Numerous genes (CLN1–CLN8, CLN10–CLN14) were identified in which mutations can lead to NCL; however, the underlying pathophysiology remains elusive. Despite this, the NCLs share some of the same features and symptoms but vary in respect to severity and onset of symptoms by age. Some common symptoms include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and in the rare adult-onset, dementia. Currently, all forms of NCL are fatal, and no curative treatments are available. Induced pluripotent stem cells (iPSCs) can differentiate into any cell type of the human body. Cells reprogrammed from a patient have the advantage of acquiring disease pathogenesis along with recapitulation of disease-associated phenotypes. They serve as practical model systems to shed new light on disease mechanisms and provide a phenotypic screening platform to enable drug discovery. Herein, we provide an overview of available iPSC models for a number of different NCLs. More specifically, we highlight findings in these models that may spur target identification and drug development.

scholarly journals Neonatal brain-directed gene therapy rescues a mouse model of neurodegenerative CLN6 Batten disease

2019 ◽  
Author(s):  
Sophia-Martha kleine Holthaus ◽  
Saul Martin-Herranz ◽  
Giulia Massaro ◽  
Mikel Aristorena ◽  
Justin Hoke ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Motor Coordination ◽  
Transmembrane Protein ◽  
Batten Disease ◽  
Premature Death ◽  
Neuronal Ceroid Lipofuscinoses ◽  
Therapeutic Effects ◽  
Lysosomal Storage ◽  
Enzyme Replacement

The neuronal ceroid lipofuscinoses (NCLs), more commonly referred to as Batten disease, are a group of inherited lysosomal storage disorders that present with neurodegeneration, loss of vision and premature death. There are at least 13 genetically distinct forms of NCL. Enzyme replacement therapies and preclinical studies on gene supplementation have shown promising results for NCLs caused by lysosomal enzyme deficiencies. The development of gene therapies targeting the brain for NCLs caused by defects in transmembrane proteins has been more challenging and only limited therapeutic effects in animal models have been achieved so far. Here, we describe the development of an adeno-associated virus (AAV)-mediated gene therapy to treat the neurodegeneration in a mouse model of CLN6 disease, a form of NCL with a deficiency in the membrane-bound protein CLN6. We show that neonatal bilateral intracerebroventricular injections with AAV9 carrying CLN6 increase lifespan by more than 90%, maintain motor skills and motor coordination and reduce neuropathological hallmarks of Cln6-deficient mice up to 23 months post vector administration. These data demonstrate that brain-directed gene therapy is a valid strategy to treat the neurodegeneration of CLN6 disease and may be applied to other forms of NCL caused by transmembrane protein deficiencies in the future.

scholarly journals Changes in physiological properties of rat ganglion cells during retinal degeneration

2011 ◽  
Vol 105 (5) ◽  
pp. 2560-2571 ◽  
Author(s):  
Chris Sekirnjak ◽  
Lauren H. Jepson ◽  
Pawel Hottowy ◽  
Alexander Sher ◽  
Wladyslaw Dabrowski ◽  
...  
Keyword(s):  
Retinal Degeneration ◽  
Time Course ◽  
Vision Loss ◽  
Ganglion Cells ◽  
Receptive Fields ◽  
Similar Rate ◽  
Visual Signals ◽  
Light Responses ◽  
Functional Changes ◽  
Physiological Properties

Retinitis pigmentosa (RP) is a leading cause of degenerative vision loss, yet its progressive effects on visual signals transmitted from the retina to the brain are not well understood. The transgenic P23H rat is a valuable model of human autosomal dominant RP, exhibiting extensive similarities to the human disease pathology, time course, and electrophysiology. In this study, we examined the physiological effects of degeneration in retinal ganglion cells (RGCs) of P23H rats aged between P37 and P752, and compared them with data from wild-type control animals. The strength and the size of visual receptive fields of RGCs decreased rapidly with age in P23H retinas. Light responses mediated by rod photoreceptors declined earlier (∼P300) than cone-mediated light responses (∼P600). Responses of ON and OFF RGCs diminished at a similar rate. However, OFF cells exhibited hyperactivity during degeneration, whereas ON cells showed a decrease in firing rate. The application of synaptic blockers abolished about half of the elevated firing in OFF RGCs, indicating that the remodeled circuitry was not the only source of degeneration-induced hyperactivity. These results advance our understanding of the functional changes associated with retinal degeneration.

scholarly journals Acute Stroke Care during the COVID-19 Pandemic: Reduction in the Number of Admissions of Elderly Patients and Increase in Prehospital Delays

2021 ◽  
pp. 1-7
Author(s):  
Gabriel Velilla-Alonso ◽  
Andrés García-Pastor ◽  
Ángela Rodríguez-López ◽  
Ana Gómez-Roldós ◽  
Antonio Sánchez-Soblechero ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Acute Stroke ◽  
Time Course ◽  
Intravenous Thrombolysis ◽  
Stroke Care ◽  
Acute Stroke Care ◽  
Group Data ◽  
Radiological Data ◽  
History Of ◽  
Prehospital Delays

Introduction: We analyzed whether the coronavirus disease 2019 (COVID-19) crisis affected acute stroke care in our center during the first 2 months of lockdown in Spain. Methods: This is a single-center, retrospective study. We collected demographic, clinical, and radiological data; time course; and treatment of patients meeting the stroke unit admission criteria from March 14 to May 14, 2020 (COVID-19 period group). Data were compared with the same period in 2019 (pre-COVID-19 period group). Results: 195 patients were analyzed; 83 in the COVID-19 period group, resulting in a 26% decline of acute strokes and transient ischemic attacks (TIAs) admitted to our center compared with the previous year (p = 0.038). Ten patients (12%) tested positive for PCR SARS-CoV-2. The proportion of patients aged 65 years and over was lower in the COVID-19 period group (53 vs. 68.8%, p = 0.025). During the pandemic period, analyzed patients were more frequently smokers (27.7 vs. 10.7%, p = 0.002) and had less frequently history of prior stroke (13.3 vs. 25%, p = 0.043) or atrial fibrillation (9.6 vs. 25%, p = 0.006). ASPECTS score was lower (9 [7–10] vs. 10 [8–10], p = 0.032), NIHSS score was slightly higher (5 [2–14] vs. 4 [2–8], p = 0.122), onset-to-door time was higher (304 [93–760] vs. 197 [91.25–645] min, p = 0.104), and a lower proportion arrived within 4.5 h from onset of symptoms (43.4 vs. 58%, p = 0.043) during the CO­VID-19 period. There were no differences between proportion of patients receiving recanalization treatment (intravenous thrombolysis and/or mechanical thrombectomy) and in-hospital delays. Conclusion: We observed a reduction in the number of acute strokes and TIAs admitted during the COVID-19 period. This drop affected especially elderly patients, and despite a delay in their arrival to the emergency department, the proportion of patients treated with recanalization therapies was preserved.

scholarly journals In-depth transcriptomic analysis of human retina reveals molecular mechanisms underlying diabetic retinopathy

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kolja Becker ◽  
Holger Klein ◽  
Eric Simon ◽  
Coralie Viollet ◽  
Christian Haslinger ◽  
...  
Keyword(s):  
Diabetic Retinopathy ◽  
Rna Sequencing ◽  
Molecular Mechanisms ◽  
Vision Loss ◽  
Ganglion Cells ◽  
Expression Profiles ◽  
Cell Types ◽  
Sequencing Data ◽  
Disease Stages ◽  
Post Transcriptional Regulation

AbstractDiabetic Retinopathy (DR) is among the major global causes for vision loss. With the rise in diabetes prevalence, an increase in DR incidence is expected. Current understanding of both the molecular etiology and pathways involved in the initiation and progression of DR is limited. Via RNA-Sequencing, we analyzed mRNA and miRNA expression profiles of 80 human post-mortem retinal samples from 43 patients diagnosed with various stages of DR. We found differentially expressed transcripts to be predominantly associated with late stage DR and pathways such as hippo and gap junction signaling. A multivariate regression model identified transcripts with progressive changes throughout disease stages, which in turn displayed significant overlap with sphingolipid and cGMP–PKG signaling. Combined analysis of miRNA and mRNA expression further uncovered disease-relevant miRNA/mRNA associations as potential mechanisms of post-transcriptional regulation. Finally, integrating human retinal single cell RNA-Sequencing data revealed a continuous loss of retinal ganglion cells, and Müller cell mediated changes in histidine and β-alanine signaling. While previously considered primarily a vascular disease, attention in DR has shifted to additional mechanisms and cell-types. Our findings offer an unprecedented and unbiased insight into molecular pathways and cell-specific changes in the development of DR, and provide potential avenues for future therapeutic intervention.

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