scholarly journals Case Report: CNNM2 Mutations Cause Damaged Brain Development and Intractable Epilepsy in a Patient Without Hypomagnesemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiucui Li ◽  
Shijia Bao ◽  
Wei Wang ◽  
Xulai Shi ◽  
Ying Hu ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Brain Development ◽  
De Novo ◽  
Basolateral Membrane ◽  
Intractable Epilepsy ◽  
Chinese Patient ◽  
Renal Tubules ◽  
Variable Degree ◽  
Mild Intellectual Disability ◽  
Severity Of The Disease

A series of neurological manifestations such as intellectual disability and epilepsy are closely related to hypomagnesemia. Cyclin M2 (CNNM2) proteins, as a member of magnesium (Mg2+) transporters, were found along the basolateral membrane of distal renal tubules and involved in the reabsorption of Mg2+. Homozygous and heterozygous variants in CNNM2 reported so far were responsible for a variable degree of hypomagnesemia, several of which also showed varying degrees of neurological phenotypes such as intellectual disability and epilepsy. Here, we report a de novo heterozygous CNNM2 variant (c.2228C > T, p.Ser743Phe) in a Chinese patient, which is the variant located in the cyclic nucleotide monophosphate-binding homology (CNBH) domain of CNNM2 proteins. The patient presented with mild intellectual disability and refractory epilepsy but without hypomagnesemia. Thus, we reviewed the literature and analyzed the phenotypes related to CNNM2 variants, and then concluded that the number of variant alleles and the changed protein domains correlates with the severity of the disease, and speculated that the CNBH domain of CNNM2 possibly plays a limited role in Mg2+ transport but a significant role in brain development. Furthermore, it can be speculated that neurological phenotypes such as intellectual disability and seizures can be purely caused by CNNM2 variants.

scholarly journals Clonazepam as an Effective Treatment for Epilepsy in a Female Patient with NEXMIF Mutation: Case Report

2020 ◽  
Vol 11 (4) ◽  
pp. 232-238 ◽  
Author(s):  
Masashi Ogasawara ◽  
Eiji Nakagawa ◽  
Eri Takeshita ◽  
Kohei Hamanaka ◽  
Satoko Miyatake ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Female Patient ◽  
De Novo ◽  
Intractable Epilepsy ◽  
Good Choice ◽  
De Novo Mutation ◽  
Facial Dysmorphism ◽  
Mild Intellectual Disability ◽  
Female Patients ◽  
Male Patients

The <i>NEXMIF</i> (<i>KIAA2022</i>) gene is located in the X chromosome, and hemizygous mutations in <i>NEXMIF</i> cause X-linked intellectual disability in male patients. Female patients with heterozygous mutations in <i>NEXMIF</i> also show similar, but milder, intellectual disability. Most female patients demonstrate intractable epilepsy compared with male patients, and the treatment strategy for epilepsy is still uncertain. Thus far, 24 female patients with <i>NEXMIF</i> mutations have been reported. Of these 24 patients, 20 also have epilepsy. Until now, epilepsy has been controlled in only 2 of these female patients. We report a female patient with a heterozygous de novo mutation, NM_001008537.2:c.1123del (p.Glu375Argfs*21), in <i>NEXMIF</i>. The patient showed mild intellectual disability, facial dysmorphism, obesity, generalized tonic-clonic seizures, and nonconvulsive status epilepticus. Sodium valproate was effective but caused secondary amenorrhea. We successfully treated her epilepsy with clonazepam without side effects, indicating that clonazepam might be a good choice to treat epilepsy in patients with <i>NEXMIF</i> mutations.

scholarly journals Focal segmental glomerulosclerosis and mild intellectual disability in a patient with a novel de novo truncating TRIM8 mutation

2020 ◽  
Vol 63 (9) ◽  
pp. 103972
Author(s):  
Martin A. McClatchey ◽  
Zachary D. du Toit ◽  
Rhys Vaughan ◽  
Sharon D. Whatley ◽  
Sara Martins ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Focal Segmental Glomerulosclerosis ◽  
De Novo ◽  
Mild Intellectual Disability ◽  
Segmental Glomerulosclerosis

A novel de novo heterozygous deletion at 13q14.2-q21.1 in two siblings with mild intellectual disability

Gene Reports ◽  
2018 ◽  
Vol 12 ◽  
pp. 201-207
Author(s):  
Kirti Mittal ◽  
Laxmi Kirola ◽  
Sridevi Hegde ◽  
Mitesh Shetty ◽  
Madhulika Kabra ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Heterozygous Deletion ◽  
Mild Intellectual Disability

scholarly journals A 9-year-old-girl with Phelan McDermid Syndrome, who had been diagnosed with an autism spectrum disorder

2016 ◽  
Vol 19 (2) ◽  
pp. 85-90 ◽  
Author(s):  
I Görker ◽  
H Gürkan ◽  
S Demir Ulusal ◽  
E Atlı ◽  
E Ikbal Atlı
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
De Novo ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Comparative Genomic ◽  
Parental Origin ◽  
Mild Intellectual Disability ◽  
First Case

AbstractPhelan McDermid Syndrome (PHMDS) (OMIM #606232), is a contiguous gene disorder resulting from deletion of the distal long arm of chromosome 22. The 22q13.3 deletions and mutations that lead to a loss of a functional copy of SHANK3 (OMIM *606230) cause the syndrome, characterized by moderate to profound intellectual disability, severely delayed or absent speech, hypotonia, and autism spectrum disorder (ASD) or ASD traits. In this study, we present the case of a 9-year-old girl who had earlier been diagnosed with an ASD. Our findings were a clinically mild intellectual disability, rounded face, pointed chin but no autistic findings. We learned that her neuromotor development was delayed and she had neonatal hypotonia in her history. A heterozygous deletion of MLC1, SBF1, MAPK8IP2, ARSA, SHANK3 and ACR genes, located on 22q13.33, was defined by multiplex ligation-dependent probe amplification (MLPA). Deletion of 22q13.3 (ARSA) region was confirmed by a fluorescent in situ hybridization (FISH) technique. The 22q13.3 deletion was found to be de novo in our patient, and she was diagnosed with PHMDS. We confirmed the 22q13.3 deletion and also determined a gain of 8p23.3-23.2 by array comparative genomic hybridization (aCGH). Fluorescent in situ hybridization was performed to determine whether the deletion was of parental origin and to identify regions of chromosomes where the extra 8p may have been located. The parents were found to be normal. The extra copy of 8p was observed on 22q in the patient. She is the first case reported in association with the 22q deletion of 8p duplications in the literature.

Genes influenced by MEF2C contribute to neurodevelopmental disease via gene expression changes that affect multiple types of cortical excitatory neurons

2019 ◽  
Author(s):  
Donna Cosgrove ◽  
Laura Whitton ◽  
Laura Fahey ◽  
Pilib Ó Broin ◽  
Gary Donohoe ◽  
...  
Keyword(s):  
Gene Expression ◽  
Intellectual Disability ◽  
Cognitive Function ◽  
Brain Development ◽  
Differentially Expressed Genes ◽  
De Novo ◽  
Cell Types ◽  
Differentially Expressed ◽  
Glutamatergic Neurons ◽  
Excitatory Neurons

AbstractMyocyte enhancer factor 2 C (MEF2C) is an important transcription factor during neurodevelopment. Mutation or deletion of MEF2C causes intellectual disability (ID) and common variants within MEF2C are associated with cognitive function and schizophrenia risk. We investigated if genes influenced by MEF2C during neurodevelopment are enriched for genes associated with neurodevelopmental phenotypes, and if this can be leveraged to identify biological mechanisms and individual brain cell types affected. We used a set of 1,052 genes that were differentially expressed in the adult mouse brain following early embryonic deletion of Mef2c in excitatory cortical neurons. Using GWAS data, we found these differentially expressed genes (DEGs) to be enriched for genes associated with schizophrenia, intelligence and educational attainment but not autism spectrum disorder (ASD). Using sequencing data from trios studies, we found these DEGs to be enriched for genes containing de novo mutations reported in ASD and ID, but not schizophrenia. Using single cell RNA-seq data, we identified that a number of different excitatory glutamatergic neurons in the cortex were enriched for these DEGs including deep layer pyramidal cells and cells in the retrosplenial cortex, entorhinal cortex and subiculum. These data indicate that genes influenced by MEF2C during neurodevelopment contribute to cognitive function and risk of neurodevelopmental disorders. Within excitatory neurons, common SNPs in these genes contribute to cognition and SZ risk via an effect on synaptic function based on gene ontology analysis. In contrast, rare mutations contribute to earlier onset ASD and ID via an effect on cell morphogenesis.Author SummarySchizophrenia is a complex disorder caused by many genes. Current drugs for schizophrenia are only partially effective and do not treat cognitive deficits, which are key factors for explaining disability. Here we take an individual gene identified in genetic studies of schizophrenia and cognition called MEF2C, which on its own is a very important regulator of brain development. We use data from a mouse study where MEF2C has been stopped from functioning or knocked out during brain development. The effect of that knock out has been measured when the mice reach adulthood, in the form of a set of differentially expressed genes (DEGs) from the somatosensory cortex. We found that this set of DEGs contains more genes than expected by chance that are associated with schizophrenia and cognition or contain rare new (de novo) mutations reported in autism and intellectual disability. Using gene expression data from single brain cells, we identified that a number of specific excitatory glutamatergic neurons in the cortex were enriched for these DEGs. This study provides evidence that the molecular mechanisms that underpin schizophrenia and cognitive function include disruption of cell types influenced by MEF2C.

scholarly journals A de novo frameshift pathogenic variant in TBR1 identified in autism without intellectual disability

2020 ◽  
Vol 14 (1) ◽  
Author(s):  
Laurie-Anne Sapey-Triomphe ◽  
Julie Reversat ◽  
Gaëtan Lesca ◽  
Nicolas Chatron ◽  
Marina Bussa ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Magnetic Resonance ◽  
Brain Development ◽  
Language Impairment ◽  
De Novo ◽  
Genetic Alterations ◽  
Autism Spectrum ◽  
Pathogenic Variant ◽  
Pathogenic Variants ◽  
Patient Reported

Abstract Background In order to be able to provide accurate genetic counseling to patients with Autism Spectrum Disorder (ASD), it is crucial to identify correlations between heterogeneous phenotypes and genetic alterations. Among the hundreds of de novo pathogenic variants reported in ASD, single-nucleotide variations and small insertions/deletions were reported in TBR1. This gene encodes a transcription factor that plays a key role in brain development. Pathogenic variants in TBR1 are often associated with severe forms of ASD, including intellectual disability and language impairment. Methods Adults diagnosed with ASD but without intellectual disability (diagnosis of Asperger syndrome, according to the DSM-IV) took part in a genetic consultation encompassing metabolic assessments, a molecular karyotype and the screening of a panel of 268 genes involved in intellectual disability, ASD and epilepsy. In addition, the patient reported here went through a neuropsychological assessment, structural magnetic resonance imaging and magnetic resonance spectroscopy measurements. Results Here, we report the case of a young adult male who presents with a typical form of ASD. Importantly, this patient presents with no intellectual disability or language impairment, despite a de novo heterozygous frameshift pathogenic variant in TBR1, leading to an early premature termination codon (c.26del, p.(Pro9Leufs*12)). Conclusion Based on this case report, we discuss the role of TBR1 in general brain development, language development, intellectual disability and other symptoms of ASD. Providing a detailed clinical description of the individuals with such pathogenic variants should help to understand the genotype-phenotype relationships in ASD.

A de novo 3.57 Mb microdeletion in 8q12.3q13.2 in a patient with mild intellectual disability and epilepsy

2012 ◽  
Vol 55 (5) ◽  
pp. 358-361 ◽  
Author(s):  
Willem M.A. Verhoeven ◽  
Jos I.M. Egger ◽  
Ilse Feenstra ◽  
Nicole de Leeuw
Keyword(s):  
Intellectual Disability ◽  
De Novo ◽  
Mild Intellectual Disability

scholarly journals Modeling Somatic Mutations Associated With Neurodevelopmental Disorders in Human Brain Organoids

2022 ◽  
Vol 14 ◽  
Author(s):  
Bipan K. Deb ◽  
Helen S. Bateup
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Neurodevelopmental Disorders ◽  
Somatic Mutations ◽  
De Novo ◽  
Intractable Epilepsy ◽  
Model Systems ◽  
Loss Of Function ◽  
And Function ◽  
The Impact

Neurodevelopmental disorders (NDDs) are a collection of diseases with early life onset that often present with developmental delay, cognitive deficits, and behavioral conditions. In some cases, severe outcomes such as brain malformations and intractable epilepsy can occur. The mutations underlying NDDs may be inherited or de novo, can be gain- or loss-of-function, and can affect one or more genes. Recent evidence indicates that brain somatic mutations contribute to several NDDs, in particular malformations of cortical development. While advances in sequencing technologies have enabled the detection of these somatic mutations, the mechanisms by which they alter brain development and function are not well understood due to limited model systems that recapitulate these events. Human brain organoids have emerged as powerful models to study the early developmental events of the human brain. Brain organoids capture the developmental progression of the human brain and contain human-enriched progenitor cell types. Advances in human stem cell and genome engineering provide an opportunity to model NDD-associated somatic mutations in brain organoids. These organoids can be tracked throughout development to understand the impact of somatic mutations on early human brain development and function. In this review, we discuss recent evidence that somatic mutations occur in the developing human brain, that they can lead to NDDs, and discuss how they could be modeled using human brain organoids.

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