scholarly journals Poland Syndrome with Atypical Malformations Associated to a de novo 1.5 Mb Xp22.31 Duplication

2020 ◽  
Vol 51 (05) ◽  
pp. 359-363 ◽  
Author(s):  
Carmela R. Massimino ◽  
Pierluigi Smilari ◽  
Filippo Greco ◽  
Silvia Marino ◽  
Davide Vecchio ◽  
...  
Keyword(s):  
Central Nervous System ◽  
De Novo ◽  
Subcutaneous Tissue ◽  
Poland Syndrome ◽  
Pectoralis Muscle ◽  
Neurodevelopmental Delay ◽  
Hand Anomalies ◽  
Ectopic Neurohypophysis ◽  
Congenital Syndrome ◽  
Central Nervous System Malformation

AbstractPoland's syndrome (PS; OMIM 173800) is a rare congenital syndrome which consists of absence or hypoplasia of the pectoralis muscle. Other features can be variably associated, including rib defects. On the affected side other features (such as of breast and nipple anomalies, lack of subcutaneous tissue and skin annexes, hand anomalies, visceral, and vertebral malformation) have been variably documented. To date, association of PS with central nervous system malformation has been rarely reported remaining poorly understood and characterized. We report a left-sided PS patient carrying a de novo 1.5 Mb Xp22.31 duplication diagnosed in addiction to strabismus, optic nerves and chiasm hypoplasia, corpus callosum abnormalities, ectopic neurohypophysis, pyelic ectasia, and neurodevelopmental delay. Since, to our knowledge, this features' association has not been previously reported, we argue that this case may contribute to further widening of the variability of PS phenotype.

scholarly journals Novel Dominant KCNQ2 Exon 7 Partial In-Frame Duplication in a Complex Epileptic and Neurodevelopmental Delay Syndrome

2020 ◽  
Vol 21 (12) ◽  
pp. 4447
Author(s):  
Pedro A. Lazo ◽  
Juan L. García ◽  
Paulino Gómez-Puertas ◽  
Íñigo Marcos-Alcalde ◽  
Cesar Arjona ◽  
...  
Keyword(s):  
Protein Function ◽  
De Novo ◽  
3D Structure ◽  
Unknown Origin ◽  
Unknown Etiology ◽  
Neurodevelopmental Delay ◽  
Calmodulin Binding ◽  
Whole Exome ◽  
Dynamics Simulations ◽  
Frame Duplication

Complex neurodevelopmental syndromes frequently have an unknown etiology, in which genetic factors play a pathogenic role. This study utilizes whole-exome sequencing (WES) to examine four members of a family with a son presenting, since birth, with epileptic-like crises, combined with cerebral palsy, severe neuromotor and developmental delay, dystonic tetraparexia, axonal motor affectation, and hyper-excitability of unknown origin. The WES study detected within the patient a de novo heterozygous in-frame duplication of thirty-six nucleotides within exon 7 of the human KCNQ2 gene. This insertion duplicates the first twelve amino acids of the calmodulin binding site I. Molecular dynamics simulations of this KCNQ2 peptide duplication, modelled on the 3D structure of the KCNQ2 protein, suggest that the duplication may lead to the dysregulation of calcium inhibition of this protein function.

scholarly journals The biosynthetic origin of psychoactive kavalactones in kava

2018 ◽  
Author(s):  
Tomáš Pluskal ◽  
Michael P. Torrens-Spence ◽  
Timothy R. Fallon ◽  
Andrea De Abreu ◽  
Cindy H. Shi ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Biosynthetic Pathway ◽  
Chalcone Synthase ◽  
De Novo ◽  
Piper Methysticum ◽  
Heterologous Production ◽  
Traditional Use ◽  
Plant Biochemistry ◽  
Tailoring Enzymes

AbstractFor millennia, humans have used plants for medicinal purposes. However, our limited understanding of plant biochemistry hinders the translation of such ancient wisdom into modern pharmaceuticals1. Kava (Piper methysticum) is a medicinal plant native to the Polynesian islands with anxiolytic and analgesic properties supported by over 3,000 years of traditional use as well as numerous recent clinical trials2–5. The main psychoactive principles of kava, kavalactones, are a unique class of polyketide natural products known to interact with central nervous system through mechanisms distinct from those of the prescription psychiatric drugs benzodiazepines and opioids6,7. Here we reportde novoelucidation of the biosynthetic pathway of kavalactones, consisting of seven specialized metabolic enzymes. Based on phylogenetic and crystallographic analyses, we highlight the emergence of two paralogous styrylpyrone synthases, both of which have neofunctionalized from an ancestral chalcone synthase to catalyze the formation of the kavalactone scaffold. Structurally diverse kavalactones are then biosynthesized by subsequent regio- and stereo-specific tailoring enzymes. We demonstrate the feasibility of engineering heterologous production of kavalactones and their derivatives in bacterial, yeast, and plant hosts, thus opening an avenue towards the development of new psychiatric therapeutics for anxiety disorders, which affect over 260 million people globally8.

scholarly journals Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size

Brain ◽  
2019 ◽  
Vol 142 (9) ◽  
pp. 2617-2630 ◽  
Author(s):  
Diana Le Duc ◽  
Cecilia Giulivi ◽  
Susan M Hiatt ◽  
Eleonora Napoli ◽  
Alexios Panoutsopoulos ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Wnt Pathway ◽  
De Novo ◽  
Autism Spectrum ◽  
Neural Progenitors ◽  
Scaffolding Protein ◽  
Published Data ◽  
Ph Domain ◽  
Human Phenotype ◽  
Neurodevelopmental Delay

Abstract The underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and genome sequencing as well as array analysis of 13 individuals that point to pathogenic, heterozygous, mostly de novo variants in WDFY3 (significant de novo enrichment P = 0.003) as a monogenic cause of mild and non-specific neurodevelopmental delay. Nine variants were protein-truncating and four missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders (autism spectrum disorders/attention deficit hyperactivity disorder). One proband presented with an opposing phenotype of microcephaly and the only missense-variant located in the PH-domain of WDFY3. Findings of this case are supported by previously published data, demonstrating that pathogenic PH-domain variants can lead to microcephaly via canonical Wnt-pathway upregulation. In a separate study, we reported that the autophagy scaffolding protein WDFY3 is required for cerebral cortical size regulation in mice, by controlling proper division of neural progenitors. Here, we show that proliferating cortical neural progenitors of human embryonic brains highly express WDFY3, further supporting a role for this molecule in the regulation of prenatal neurogenesis. We present data on Wnt-pathway dysregulation in Wdfy3-haploinsufficient mice, which display macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. Consequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway. In summary, we present WDFY3 as a novel gene linked to mild to moderate neurodevelopmental delay and intellectual disability and conclude that variants putatively causing haploinsufficiency lead to macrocephaly, while an opposing pathomechanism due to variants in the PH-domain of WDFY3 leads to microcephaly.

scholarly journals De Novo Variants in CNOT1, a Central Component of the CCR4-NOT Complex Involved in Gene Expression and RNA and Protein Stability, Cause Neurodevelopmental Delay

2020 ◽  
Vol 107 (1) ◽  
pp. 164-172 ◽  
Author(s):  
Lisenka E.L.M. Vissers ◽  
Sreehari Kalvakuri ◽  
Elke de Boer ◽  
Sinje Geuer ◽  
Machteld Oud ◽  
...  
Keyword(s):  
Gene Expression ◽  
Protein Stability ◽  
De Novo ◽  
Central Component ◽  
Neurodevelopmental Delay

scholarly journals Identification of an Identical de Novo SCAMP5 Missense Variant in Four Unrelated Patients With Seizures and Severe Neurodevelopmental Delay

2020 ◽  
Vol 11 ◽  
Author(s):  
Xianru Jiao ◽  
Manuela Morleo ◽  
Vincenzo Nigro ◽  
Annalaura Torella ◽  
Stefano D’Arrigo ◽  
...  
Keyword(s):  
Language Development ◽  
Developmental Disorders ◽  
De Novo ◽  
Brain Mri ◽  
Brain Magnetic Resonance Imaging ◽  
Autism Spectrum ◽  
Neurodevelopmental Delay ◽  
Dysmorphic Features ◽  
Severe Intellectual Disability ◽  
Neurological Exam

Objective: To establish and broaden the phenotypic spectrum of secretory carrier membrane protein (SCAMP5) associated with epilepsy and neurodevelopmental delay.Methods: A Chinese patient was identified at the First Hospital of Peking University, and the three unrelated patients were recruited from two different countries (Italy and United States) through GeneMatcher. SCAMP5 pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed.Result: The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk. All four unrelated patients were found to have the same heterozygous pathogenic SCAMP5 de novo variant (p. Gly180Trp).Conclusion: Epilepsy, severe developmental delay, abnormal neurological exam findings, with or without ASD or variably dysmorphic features and were common in patients with SCAMP5 variant. The onset time and type of seizure varied greatly. The EEG and brain MRI findings were not consistent, but diverse and nonspecific. The motor ability of patients with heterozygous SCAMP5 variant might have a regressive course; language development was more severely affected.

Malformation of the Brain, Skull, and Spine

2021 ◽  
pp. 1057-1070
Author(s):  
Lily C. Wong-Kisiel
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Developmental Delay ◽  
Abnormal Development ◽  
Gene Expressions ◽  
Common Cause ◽  
Genetic Causes ◽  
The Central Nervous System ◽  
The Brain ◽  
Central Nervous System Malformation

Abnormal development of the central nervous system is a common cause of developmental delay and epilepsy. An understanding of central nervous system malformation begins with an overview of normal embryology. Genetic advances in embryogenesis have unfolded a complex orchestration of gene expressions in place of the traditional developmental epochs (induction, neurulation, proliferation, migration, organization, synaptogenesis, and myelination). Causes of malformation of the central nervous system are multifactorial. Genetic causes, vitamin excess or deficiency, infections, or teratogens any time during pregnancy may disturb the preprogrammed mechanisms.

scholarly journals De Novo Central Nervous System Processing of Myelin Antigen Is Required for the Initiation of Experimental Autoimmune Encephalomyelitis

2002 ◽  
Vol 168 (8) ◽  
pp. 4173-4183 ◽  
Author(s):  
Stephen Mark Tompkins ◽  
Josette Padilla ◽  
Mauro C. Dal Canto ◽  
Jenny P.-Y. Ting ◽  
Luc Van Kaer ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Experimental Autoimmune Encephalomyelitis ◽  
De Novo ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune
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