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Nature Reviews. Neurology Nov 2022The current understanding of neurological diseases is derived mostly from direct analysis of patients and from animal models of disease. However, most patient studies do... (Review)
Review
The current understanding of neurological diseases is derived mostly from direct analysis of patients and from animal models of disease. However, most patient studies do not capture the earliest stages of disease development and offer limited opportunities for experimental intervention, so rarely yield complete mechanistic insights. The use of animal models relies on evolutionary conservation of pathways involved in disease and is limited by an inability to recreate human-specific processes. In vitro models that are derived from human pluripotent stem cells cultured in 3D have emerged as a new model system that could bridge the gap between patient studies and animal models. In this Review, we summarize how such organoid models can complement classical approaches to accelerate neurological research. We describe our current understanding of neurodevelopment and how this process differs between humans and other animals, making human-derived models of disease essential. We discuss different methodologies for producing organoids and how organoids can be and have been used to model neurological disorders, including microcephaly, Zika virus infection, Alzheimer disease and other neurodegenerative disorders, and neurodevelopmental diseases, such as Timothy syndrome, Angelman syndrome and tuberous sclerosis. We also discuss the current limitations of organoid models and outline how organoids can be used to revolutionize research into the human brain and neurological diseases.
Topics: Animals; Humans; Organoids; Brain; Microcephaly; Neurodegenerative Diseases; Zika Virus Infection; Zika Virus; Neurology
PubMed: 36253568
DOI: 10.1038/s41582-022-00723-9 -
Science (New York, N.Y.) Sep 2023Inactivation of the ubiquitin ligase Ube3a causes the developmental disorder Angelman syndrome, whereas increased Ube3a dosage is associated with autism spectrum...
Inactivation of the ubiquitin ligase Ube3a causes the developmental disorder Angelman syndrome, whereas increased Ube3a dosage is associated with autism spectrum disorders. Despite the enriched localization of Ube3a in the axon terminals including presynapses, little is known about the presynaptic function of Ube3a and mechanisms underlying its presynaptic localization. We show that developmental synapse elimination requires presynaptic Ube3a activity in neurons. We further identified the domain of Ube3a that is required for its interaction with the kinesin motor. Angelman syndrome-associated missense mutations in the interaction domain attenuate presynaptic targeting of Ube3a and prevent synapse elimination. Conversely, increased Ube3a activity in presynapses leads to precocious synapse elimination and impairs synaptic transmission. Our findings reveal the physiological role of Ube3a and suggest potential pathogenic mechanisms associated with Ube3a dysregulation.
Topics: Animals; Angelman Syndrome; Autism Spectrum Disorder; Down-Regulation; Drosophila Proteins; Synaptic Transmission; Ubiquitin-Protein Ligases; Drosophila melanogaster; Synapses
PubMed: 37708280
DOI: 10.1126/science.ade8978 -
Science Translational Medicine Mar 2023Angelman syndrome is a devastating neurogenetic disorder for which there is currently no effective treatment. It is caused by mutations or epimutations affecting the...
Angelman syndrome is a devastating neurogenetic disorder for which there is currently no effective treatment. It is caused by mutations or epimutations affecting the expression or function of the maternally inherited allele of the ubiquitin-protein ligase E3A () gene. The paternal allele is imprinted in neurons of the central nervous system (CNS) by the antisense () transcript, which represents the distal end of the small nucleolar host gene 14 () transcription unit. Reactivating the expression of the paternal allele in the CNS has long been pursued as a therapeutic option for Angelman syndrome. Here, we described the development of an antisense oligonucleotide (ASO) therapy for Angelman syndrome that targets an evolutionarily conserved region demarcating the start of the transcript. We designed and chemically optimized gapmer ASOs targeting specific sequences at the start of the human transcript. We showed that ASOs targeting this region precisely and efficiently repress the transcription of , reactivating the expression of the paternal allele in neurotypical and Angelman syndrome induced pluripotent stem cell-derived neurons. We further showed that human-targeted ASOs administered to the CNS of cynomolgus macaques by lumbar intrathecal injection repress and reactivate the expression of the paternal allele throughout the CNS. These findings support the advancement of this investigational molecular therapy for Angelman syndrome into clinical development (ClinicalTrials.gov, NCT04259281).
Topics: Humans; Angelman Syndrome; Alleles; Ubiquitin-Protein Ligases
PubMed: 36947593
DOI: 10.1126/scitranslmed.abf4077 -
JCI Insight Aug 2021Angelman syndrome (AS) is a severe neurodevelopmental disorder for which only symptomatic treatment with limited benefits is available. AS is caused by mutations...
Angelman syndrome (AS) is a severe neurodevelopmental disorder for which only symptomatic treatment with limited benefits is available. AS is caused by mutations affecting the maternally inherited ubiquitin protein ligase E3A (UBE3A) gene. Previous studies showed that the silenced paternal Ube3a gene can be activated by targeting the antisense Ube3a-ATS transcript. We investigated antisense oligonucleotide-induced (ASO-induced) Ube3a-ATS degradation and its ability to induce UBE3A reinstatement and rescue of AS phenotypes in an established Ube3a mouse model. We found that a single intracerebroventricular injection of ASOs at postnatal day 1 (P1) or P21 in AS mice resulted in potent and specific UBE3A reinstatement in the brain, with levels up to 74% of WT levels in the cortex and a full rescue of sensitivity to audiogenic seizures. AS mice treated with ASO at P1 also showed rescue of established AS phenotypes, such as open field and forced swim test behaviors, and significant improvement on the reversed rotarod. Hippocampal plasticity of treated AS mice was comparable to WT but not significantly different from PBS-treated AS mice. No rescue was observed for the marble burying and nest building phenotypes. Our findings highlight the promise of ASO-mediated reactivation of UBE3A as a disease-modifying treatment for AS.
Topics: Angelman Syndrome; Animals; Biological Variation, Population; Disease Models, Animal; Gene Expression Profiling; Gene Silencing; Mice; Oligonucleotides, Antisense; Targeted Gene Repair; Treatment Outcome; Ubiquitin-Protein Ligases
PubMed: 34369389
DOI: 10.1172/jci.insight.145991 -
Neuroscience and Biobehavioral Reviews Feb 2023Neurotrophins (NTs) as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) play multiple roles in different settings including neuronal development,... (Review)
Review
Neurotrophins (NTs) as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) play multiple roles in different settings including neuronal development, function and survival in both the peripheral and the central nervous systems from early stages. This report aims to provide a summary and subsequent review of evidences on the role of NTs in rare and non-common pediatric human diseases associated with changes in neurodevelopment. A variety of diseases has been analyzed and many have been linked to NTs neurobiological effects, including chronic granulomatous disease, hereditary sensory and autonomic neuropathy, Duchenne muscular dystrophy, Bardet-Biedl syndrome, Angelman syndrome, fragile X syndrome, trisomy 16, Williams-Beuren syndrome, Prader-Willi syndrome, WAGR syndrome, fetal alcohol spectrum disorders, Down syndrome and Klinefelter Syndrome. NTs alterations have been associated with numerous pathologic manifestations including cognitive defects, behavioral abnormalities, epilepsy, obesity, tumorigenesis as well as muscle-skeletal, immunity, bowel, pain sensibility and cilia diseases. In this report, we discuss that further studies are needed to clear a possible therapeutic role of NTs in these still often uncurable diseases.
Topics: Child; Humans; Brain-Derived Neurotrophic Factor; Nerve Growth Factor; Obesity; Prader-Willi Syndrome; Syndrome
PubMed: 36563920
DOI: 10.1016/j.neubiorev.2022.105015 -
Brain : a Journal of Neurology Sep 2021A common observation in EEG research is that consciousness vanishes with the appearance of delta (1-4 Hz) waves, particularly when those waves are high amplitude. High... (Review)
Review
A common observation in EEG research is that consciousness vanishes with the appearance of delta (1-4 Hz) waves, particularly when those waves are high amplitude. High amplitude delta oscillations are frequently observed in states of diminished consciousness, including slow wave sleep, anaesthesia, generalized epileptic seizures, and disorders of consciousness, such as coma and the vegetative state. This strong correlation between loss of consciousness and high amplitude delta oscillations is thought to stem from the widespread cortical deactivation that occurs during the 'down states' or troughs of these slow oscillations. Recently, however, many studies have reported the presence of prominent delta activity during conscious states, which casts doubt on the hypothesis that high amplitude delta oscillations are an indicator of unconsciousness. These studies include work in Angelman syndrome, epilepsy, behavioural responsiveness during propofol anaesthesia, postoperative delirium, and states of dissociation from the environment such as dreaming and powerful psychedelic states. The foregoing studies complement an older, yet largely unacknowledged, body of literature that has documented awake, conscious patients with high amplitude delta oscillations in clinical reports from Rett syndrome, Lennox-Gastaut syndrome, schizophrenia, mitochondrial diseases, hepatic encephalopathy, and non-convulsive status epilepticus. At the same time, a largely parallel body of recent work has reported convincing evidence that the complexity or entropy of EEG and magnetoencephalographic signals strongly relates to an individual's level of consciousness. Having reviewed this literature, we discuss plausible mechanisms that would resolve the seeming contradiction between high amplitude delta oscillations and consciousness. We also consider implications concerning theories of consciousness, such as integrated information theory and the entropic brain hypothesis. Finally, we conclude that false inferences of unconscious states can be best avoided by examining measures of electrophysiological complexity in addition to spectral power.
Topics: Brain; Consciousness; Delta Rhythm; Electroencephalography; Epilepsy; Humans; Unconsciousness
PubMed: 33693596
DOI: 10.1093/brain/awab095 -
JAMA Neurology Dec 2022It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes.
IMPORTANCE
It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes.
OBJECTIVE
To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes.
DESIGN, SETTING, AND PARTICIPANTS
This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals.
EXPOSURES
Genetic test results.
MAIN OUTCOMES AND MEASURES
Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms.
RESULTS
Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595 (368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584 [365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%).
CONCLUSIONS AND RELEVANCE
Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.
Topics: Humans; Female; Infant, Newborn; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Middle Aged; Male; Retrospective Studies; Cross-Sectional Studies; Genetic Testing; Epilepsy; Seizures
PubMed: 36315135
DOI: 10.1001/jamaneurol.2022.3651 -
Neurology Apr 2023The genetic developmental and epileptic encephalopathies (DEEs) comprise a large group of severe epilepsy syndromes, with a wide phenotypic spectrum. Currently, the...
BACKGROUND AND OBJECTIVES
The genetic developmental and epileptic encephalopathies (DEEs) comprise a large group of severe epilepsy syndromes, with a wide phenotypic spectrum. Currently, the rates of convulsive status epilepticus (CSE), nonconvulsive status epilepticus (NCSE), and sudden unexplained death in epilepsy (SUDEP) in these diseases are not well understood. We aimed to describe the proportions of patients with frequently observed genetic DEEs who developed CSE, NCSE, mortality, and SUDEP. Understanding the risks of these serious presentations in each genetic DEE will enable earlier diagnosis and appropriate management.
METHODS
In this retrospective analysis of patients with a genetic DEE, we estimated the proportions with CSE, NCSE, and SUDEP and the overall and SUDEP-specific mortality rates for each genetic diagnosis. We included patients with a pathogenic variant in the genes , , , , , , , , , , and and with Angelman syndrome (AS).
RESULTS
The cohort comprised 510 individuals with a genetic DEE, in whom we observed CSE in 47% and NCSE in 19%. The highest proportion of CSE occurred in patients with -associated DEEs, including 181/203 (89%; 95% CI 84-93) patients with Dravet syndrome and 8/15 (53%; 95% CI 27-79) non-Dravet -DEEs. CSE was also notable in patients with pathogenic variants in (6/10; 60%; 95% CI 26-88) and (8/15; 53%; 95% CI 27-79). NCSE was common in patients with non-Dravet -DEEs (8/15; 53%; 95% CI 27-79) and was notable in patients with -DEEs (6/14; 43%; 95% CI 18-71) and AS (6/19; 32%; 95% CI 13-57). There were 42/510 (8%) deaths among the cohort, producing a mortality rate of 6.1 per 1,000 person-years (95% CI 4.4-8.3). Cases of SUDEP accounted for 19/42 (48%) deaths. Four genes were associated with SUDEP: , , , and The estimated SUDEP rate was 2.8 per 1,000 person-years (95% CI 1.6-4.3).
DISCUSSION
We showed that proportions of patients with CSE, NCSE, and SUDEP differ for commonly encountered genetic DEEs. The estimates for each genetic DEE studied will inform early diagnosis and management of status epilepticus and SUDEP and inform disease-specific counseling for patients and families in this high-risk group of conditions.
Topics: Humans; Retrospective Studies; Sudden Unexpected Death in Epilepsy; Status Epilepticus; Epilepsies, Myoclonic; Epileptic Syndromes; Angelman Syndrome; Death, Sudden; Protocadherins; Potassium Channels, Sodium-Activated; Nerve Tissue Proteins
PubMed: 36750385
DOI: 10.1212/WNL.0000000000207080