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BACKGROUND: Pontocerebellar hypoplasia (PCH) may present with supratentorial phenotypes and is often accompanied by microcephaly. Damaging mutations in the X-linked gene CASK produce self-limiting microcephaly with PCH in females but are often lethal in males. CASK deficiency leads to early degeneration of cerebellar granule cells but its role in other regions of the brain remains uncertain. METHOD: We generated a conditional Cask knockout mice and deleted Cask ubiquitously after birth at different times. We examined the clinical features in several subjects with damaging mutations clustered in the central part of the CASK protein. We have performed phylogenetic analysis and RT-PCR to assess the splicing pattern within the same protein region and performed in silico structural analysis to examine the effect of splicing on the CASK's structure. RESULT: We demonstrate that deletion of murine Cask after adulthood does not affect survival but leads to cerebellar degeneration and ataxia over time. Intriguingly, damaging hemizygous CASK mutations in boys who display microcephaly and cerebral dysfunction but without PCH are known. These mutations are present in two vertebrate-specific CASK exons. These exons are subject to alternative splicing both in forebrain and hindbrain. Inclusion of these exons differentially affects the molecular structure and hence possibly the function/s of the CASK C-terminus. CONCLUSION: Loss of CASK function disproportionately affects the cerebellum. Clinical data, however, suggest that CASK may have additional vertebrate-specific function/s that play a role in the mammalian forebrain. Thus, CASK has an ancient function shared between invertebrates and vertebrates as well as novel vertebrate-specific function/s.
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Guanilato Quinases , Camundongos Knockout , Animais , Guanilato Quinases/genética , Guanilato Quinases/química , Camundongos , Masculino , Humanos , Feminino , Microcefalia/genética , Microcefalia/patologia , Mutação , Éxons/genética , Processamento Alternativo/genética , Filogenia , Cerebelo/metabolismo , Cerebelo/anormalidades , Cerebelo/patologiaRESUMO
Metachromatic leukodystrophy (MLD) is a fatal, progressive neurodegenerative disorder caused by biallelic pathogenic mutations in the ARSA (Arylsulfatase A) gene. With the advent of presymptomatic diagnosis and the availability of therapies with a narrow window for intervention, it is critical to define a standardized approach to diagnosis, presymptomatic monitoring, and clinical care. To meet the needs of the MLD community, a panel of MLD experts was established to develop disease-specific guidelines based on healthcare resources in the United States. This group developed a consensus opinion for best-practice recommendations, as follows: (i) Diagnosis should include both genetic and biochemical testing; (ii) Early diagnosis and treatment for MLD is associated with improved clinical outcomes; (iii) The panel supported the development of newborn screening to accelerate the time to diagnosis and treatment; (iv) Clinical management of MLD should include specialists familiar with the disease who are able to follow patients longitudinally; (v) In early onset MLD, including late infantile and early juvenile subtypes, ex vivo gene therapy should be considered for presymptomatic patients where available; (vi) In late-onset MLD, including late juvenile and adult subtypes, hematopoietic cell transplant (HCT) should be considered for patients with no or minimal disease involvement. This document summarizes current guidance on the presymptomatic monitoring of children affected by MLD as well as the clinical management of symptomatic patients. Future data-driven evidence and evolution of these recommendations will be important to stratify clinical treatment options and improve clinical care.
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Leucodistrofia Metacromática , Humanos , Recém-Nascido , Cerebrosídeo Sulfatase/genética , Consenso , Terapia Genética/métodos , Leucodistrofia Metacromática/terapia , Leucodistrofia Metacromática/diagnóstico , Leucodistrofia Metacromática/genética , Triagem Neonatal/métodos , Estados UnidosRESUMO
GEMIN5 exerts key biological functions regulating pre-mRNAs intron removal to generate mature mRNAs. A series of patients were reported harboring mutations in GEMIN5. No treatments are currently available for this disease. We treated two of these patients with oral Coenzyme Q10 (CoQ10), which resulted in neurological improvements, although MRI abnormalities remained. Whole Exome Sequencing demonstrated compound heterozygosity at the GEMIN5 gene in both cases: Case one: p.Lys742* and p.Arg1016Cys; Case two: p.Arg1016Cys and p.Ser411Hisfs*6. Functional studies in fibroblasts revealed a decrease in CoQ10 biosynthesis compared to controls. Supplementation with exogenous CoQ10 restored it to control intracellular CoQ10 levels. Mitochondrial function was compromised, as indicated by the decrease in oxygen consumption, restored by CoQ10 supplementation. Transcriptomic analysis of GEMIN5 patients compared with controls showed general repression of genes involved in CoQ10 biosynthesis. In the rigor mortis defective flies, CoQ10 levels were decreased, and CoQ10 supplementation led to an improvement in the adult climbing assay performance, a reduction in the number of motionless flies, and partial restoration of survival. Overall, we report the association between GEMIN5 dysfunction and CoQ10 deficiency for the first time. This association opens the possibility of oral CoQ10 therapy, which is safe and has no observed side effects after long-term therapy.
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Ataxia , Doenças Mitocondriais , Debilidade Muscular , Ubiquinona , Ubiquinona/deficiência , Adulto , Humanos , Ubiquinona/genética , Ubiquinona/uso terapêutico , Ubiquinona/metabolismo , Seguimentos , Doenças Mitocondriais/tratamento farmacológico , Doenças Mitocondriais/genética , Mutação , Proteínas do Complexo SMN/genéticaRESUMO
BACKGROUND AND OBJECTIVES: Heterozygous variants in RAR-related orphan receptor B (RORB) have recently been associated with susceptibility to idiopathic generalized epilepsy. However, few reports have been published so far describing pathogenic variants of this gene in patients with epilepsy and intellectual disability (ID). In this study, we aimed to delineate the epilepsy phenotype associated with RORB pathogenic variants and to provide arguments in favor of the pathogenicity of variants. METHODS: Through an international collaboration, we analyzed seizure characteristics, EEG data, and genotypes of a cohort of patients with heterozygous variants in RORB. To gain insight into disease mechanisms, we performed ex vivo cortical electroporation in mouse embryos of 5 selected variants, 2 truncating and 3 missense, and evaluated on expression and quantified changes in axonal morphology. RESULTS: We identified 35 patients (17 male, median age 10 years, range 2.5-23 years) carrying 32 different heterozygous variants in RORB, including 28 single-nucleotide variants or small insertions/deletions (12 missense, 12 frameshift or nonsense, 2 splice-site variants, and 2 in-frame deletions), and 4 microdeletions; de novo in 18 patients and inherited in 10. Seizures were reported in 31/35 (89%) patients, with a median age at onset of 3 years (range 4 months-12 years). Absence seizures occurred in 25 patients with epilepsy (81%). Nineteen patients experienced a single seizure type: absences, myoclonic absences, or absences with eyelid myoclonia and focal seizures. Nine patients had absence seizures combined with other generalized seizure types. One patient had presented with absences associated with photosensitive occipital seizures. Three other patients had generalized tonic-clonic seizures without absences. ID of variable degree was observed in 85% of the patients. Expression studies in cultured neurons showed shorter axons for the 5 tested variants, both truncating and missense variants, supporting an impaired protein function. DISCUSSION: In most patients, the phenotype of the RORB-related disorder associates absence seizures with mild-to-moderate ID. In silico and in vitro evaluation of the variants in our cohort, including axonal morphogenetic experiments in cultured neurons, supports their pathogenicity, showing a hypomorphic effect.
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Epilepsia Tipo Ausência , Epilepsia Generalizada , Deficiência Intelectual , Humanos , Masculino , Animais , Camundongos , Pré-Escolar , Criança , Adolescente , Adulto Jovem , Adulto , Lactente , Convulsões , Fenótipo , Epilepsia Tipo Ausência/genética , Epilepsia Generalizada/genética , Genótipo , Membro 2 do Grupo F da Subfamília 1 de Receptores NuclearesRESUMO
GEMIN5 is essential for core assembly of small nuclear Ribonucleoproteins (snRNPs), the building blocks of spliceosome formation. Loss-of-function mutations in GEMIN5 lead to a neurodevelopmental syndrome among patients presenting with developmental delay, motor dysfunction, and cerebellar atrophy by perturbing SMN complex protein expression and assembly. Currently, molecular determinants of GEMIN5-mediated disease have yet to be explored. Here, we identified SMN as a genetic suppressor of GEMIN5-mediated neurodegeneration in vivo. We discovered that an increase in SMN expression by either SMN gene therapy replacement or the antisense oligonucleotide (ASO), Nusinersen, significantly upregulated the endogenous levels of GEMIN5 in mammalian cells and mutant GEMIN5-derived iPSC neurons. Further, we identified a strong functional association between the expression patterns of SMN and GEMIN5 in patient Spinal Muscular Atrophy (SMA)-derived motor neurons harboring loss-of-function mutations in the SMN gene. Interestingly, SMN binds to the C-terminus of GEMIN5 and requires the Tudor domain for GEMIN5 binding and expression regulation. Finally, we show that SMN upregulation ameliorates defective snRNP biogenesis and alternative splicing defects caused by loss of GEMIN5 in iPSC neurons and in vivo. Collectively, these studies indicate that SMN acts as a regulator of GEMIN5 expression and neuropathologies.
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Atrofia Muscular Espinal , Proteínas de Ligação a RNA , Humanos , Neurônios Motores/metabolismo , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Ribonucleoproteínas Nucleares Pequenas/genética , Ribonucleoproteínas Nucleares Pequenas/química , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas do Complexo SMN/genética , Domínio TudorRESUMO
Learning is usually associated with a complex nervous system, but there is increasing evidence that life at all levels, down to single cells, can display intelligent behaviors. In both natural and artificial systems, learning is the adaptive updating of system parameters based on new information, and intelligence is a measure of the computational process that facilitates learning. Stentor coeruleus is a unicellular pond-dwelling organism that exhibits habituation, a form of learning in which a behavioral response decreases following a repeated stimulus. Stentor contracts in response to mechanical stimulation, which is an apparent escape response from aquatic predators. However, repeated low-force perturbations induce habituation, demonstrated by a progressive reduction in contraction probability. Here, we introduce a method for quantifying Stentor habituation using a microcontroller board-linked apparatus that can deliver mechanical pulses at a specified force and frequency, including methods for building the apparatus and setting up the experiment in a way that minimizes external perturbations. In contrast to the previously described approaches for mechanically stimulating Stentor, this device allows the force of stimulation to be varied under computer control during the course of a single experiment, thus greatly increasing the variety of input sequences that can be applied. Understanding habituation at the level of a single cell will help characterize learning paradigms that are independent of complex circuitry.
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Cilióforos , Habituação Psicofisiológica , Habituação Psicofisiológica/fisiologia , ProbabilidadeRESUMO
Although learning is often viewed as a unique feature of organisms with complex nervous systems, single-celled organisms also demonstrate basic forms of learning. The giant ciliate Stentor coeruleus responds to mechanical stimuli by contracting into a compact shape, presumably as a defense mechanism. When a Stentor cell is repeatedly stimulated at a constant level of force, it will learn to ignore that stimulus but will still respond to stronger stimuli. Prior studies of habituation in Stentor reported a graded response, suggesting that cells transition through a continuous range of response probabilities. By analyzing single cells using an automated apparatus to deliver calibrated stimuli, we find that habituation occurs via a single step-like switch in contraction probability within each cell, with the graded response in a population arising from the random distribution of switching times in individual cells. This step-like response allows Stentor behavior to be represented by a simple two-state model whose parameters can be estimated from experimental measurements. We find that transition rates depend on stimulus force and also on the time between stimuli. The ability to measure the behavior of the same cell to the same stimulus allowed us to quantify the functional heterogeneity among single cells. Together, our results suggest that the behavior of Stentor is governed by a two-state stochastic machine whose transition rates are sensitive to the time series properties of the input stimuli.
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Cilióforos , Habituação Psicofisiológica , Análise de Célula Única , Cilióforos/fisiologia , Fatores de TempoRESUMO
Pediatric encephalitis has significant morbidity and mortality, yet 50% of cases are unexplained. Host genetics plays a role in encephalitis' development; however, the contributing variants are poorly understood. One child with anti-NMDA receptor encephalitis and ten with unexplained encephalitis underwent whole genome sequencing to identify rare candidate variants in genes known to cause monogenic immunologic and neurologic disorders, and polymorphisms associated with increased disease risk. Using the professional Human Genetic Mutation Database (Qiagen), we divided the candidate variants into three categories: monogenic deleterious or potentially deleterious variants (1) in a disease-consistent inheritance pattern; (2) in carrier states; and (3) disease-related polymorphisms. Six patients (55%) had a deleterious or potentially deleterious variant in a disease-consistent inheritance pattern, five (45%) were heterozygous carriers for an autosomal recessive condition, and six (55%) carried a disease-related polymorphism. Finally, seven (64%) had more than one variant, suggesting possible polygenetic risk. Among variants identified were those implicated in atypical hemolytic uremic syndrome, common variable immunodeficiency, hemophagocytic lymphohistiocytosis, and systemic lupus erythematosus. This preliminary study shows genetic variation related to inborn errors of immunity in acute pediatric encephalitis. Future research is needed to determine if these variants play a functional role in the development of unexplained encephalitis.
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Encefalite , Linfo-Histiocitose Hemofagocítica , Humanos , Criança , Mutação , Heterozigoto , Polimorfismo Genético , Encefalite/genética , Variação GenéticaRESUMO
Pathogenic variants in GEMIN4 have recently been linked to an inherited autosomal recessive neurodevelopmental disorder characterized with microcephaly, cataracts, and renal abnormalities (NEDMCR syndrome). This report provides a retrospective review of 16 patients from 11 unrelated Saudi consanguineous families with GEMIN4 mutations. The cohort comprises 11 new and unpublished clinical details from five previously described patients. Only two missense, homozygous, pathogenic variants were found in all affected patients, suggesting a founder effect. All patients shared global developmental delay with variable ophthalmological, renal, and skeletal manifestations. In addition, we knocked down endogenous Drosophila GEMIN4 in neurons to further investigate the mechanism of the functional defects in affected patients. Our fly model findings demonstrated developmental defects and motor dysfunction suggesting that loss of GEMIN4 function is detrimental in vivo; likely similar to human patients. To date, this study presents the largest cohort of patients affected with GEMIN4 mutations. Considering that identifying GEMIN4 defects in patients presenting with neurodevelopmental delay and congenital cataract will help in early diagnosis, appropriate management and prevention plans that can be made for affected families.
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Anormalidades Múltiplas , Catarata , Microcefalia , Transtornos do Neurodesenvolvimento , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/genética , Catarata/patologia , Homozigoto , Humanos , Rim/anormalidades , Microcefalia/diagnóstico , Microcefalia/genética , Microcefalia/patologia , Antígenos de Histocompatibilidade Menor , Transtornos do Neurodesenvolvimento/genética , Linhagem , Ribonucleoproteínas Nucleares Pequenas/genética , Síndrome , Anormalidades UrogenitaisRESUMO
Lysosomal storage disorders (LSD) are multisystemic progressive disorders caused by genetic mutations involving lysosomal function. While LSDs are individually considered rare diseases, the overall true prevalence of these disorders is likely higher than our current estimates. More than two third of the LSDs have associated neurodegeneration and the neurological phenotype often defines the course of the disease and treatment outcomes. Addressing the neurological involvement in LSDs has posed a significant challenge in the rapidly evolving field of therapies for these diseases. In this review, we summarize current approaches and clinical trials available for patients with neuronopathic lysosomal storage disorders, exploring the opportunities and challenges that have emerged with each of these.
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Doenças por Armazenamento dos Lisossomos , Humanos , Terapia Genética , Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/terapia , Lisossomos , MutaçãoRESUMO
Dysfunction of RNA-binding proteins is often linked to a wide range of human disease, particularly with neurological conditions. Gemin5 is a member of the survival of the motor neurons (SMN) complex, a ribosome-binding protein and a translation reprogramming factor. Recently, pathogenic mutations in Gemin5 have been reported, but the functional consequences of these variants remain elusive. Here, we report functional and structural deficiencies associated with compound heterozygosity variants within the Gemin5 gene found in patients with neurodevelopmental disorders. These clinical variants are located in key domains of Gemin5, the tetratricopeptide repeat (TPR)-like dimerization module and the noncanonical RNA-binding site 1 (RBS1). We show that the TPR-like variants disrupt protein dimerization, whereas the RBS1 variant confers protein instability. All mutants are defective in the interaction with protein networks involved in translation and RNA-driven pathways. Importantly, the TPR-like variants fail to associate with native ribosomes, hampering its involvement in translation control and establishing a functional difference with the wild-type protein. Our study provides insights into the molecular basis of disease associated with malfunction of the Gemin5 protein.
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Doenças do Sistema Nervoso , Proteínas de Ligação a RNA , Ribossomos , Humanos , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , RNA/genética , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Ribossomos/genética , Ribossomos/metabolismo , Proteínas do Complexo SMN/genética , Proteínas do Complexo SMN/metabolismoRESUMO
The hereditary ataxias are a heterogenous group of disorders with an increasing number of causative genes being described. Due to the clinical and genetic heterogeneity seen in these conditions, the majority of such individuals endure a diagnostic odyssey or remain undiagnosed. Defining the molecular etiology can bring insights into the responsible molecular pathways and eventually the identification of therapeutic targets. Here, we describe the identification of biallelic variants in the GEMIN5 gene among seven unrelated families with nine affected individuals presenting with spastic ataxia and cerebellar atrophy. GEMIN5, an RNA-binding protein, has been shown to regulate transcription and translation machinery. GEMIN5 is a component of small nuclear ribonucleoprotein (snRNP) complexes and helps in the assembly of the spliceosome complexes. We found that biallelic GEMIN5 variants cause structural abnormalities in the encoded protein and reduce expression of snRNP complex proteins in patient cells compared with unaffected controls. Finally, knocking out endogenous Gemin5 in mice caused early embryonic lethality, suggesting that Gemin5 expression is crucial for normal development. Our work further expands on the phenotypic spectrum associated with GEMIN5-related disease and implicates the role of GEMIN5 among patients with spastic ataxia, cerebellar atrophy, and motor predominant developmental delay.
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INTRODUCTION: The Covid pandemic and social distancing has adversely impacted the conventional apprenticeship method of postgraduate training in laparoscopic surgery. Social media may be a useful adjunct for laparoscopic training, but its utility in developing countries like India has not been studied carefully. This paper describes an observational, cross-sectional study on the educational utility of Facebook groups based in India and which focus on laparoscopic gynecologic surgery. METHODS: The most popular Facebook groups involving Indians and focusing on laparoscopic gynecology were identified using appropriate search terms as well as inclusion and exclusion criteria. Demographic data related to the groups, the authors of posts as well as descriptive statistics of all the posts during the study period were collected and appropriate statistical analysis was performed. RESULTS: All the groups in this study were large and growing steadily. Posts related to laparoscopy were more likely to be videos, dealing with operative techniques and having educational value for postgraduate residents (p value < 0.001) compared to posts unrelated to laparoscopic surgery. The majority of posts (88.2%) presented original content created by group members rather than material shared from other sources. Members preferred to share laparoscopic content using links to their personal YouTube channels rather than using institutional YouTube channels, dedicated websites for laparoscopic surgery or direct posts on Facebook. Group members liked educational content and laparoscopic surgery-related content significantly more than other content. Only 16.7% of the laparoscopic surgeons could be identified to be working in academic institutes. CONCLUSION: Social media for medical education has inherent advantages and disadvantages. This article provides objective data regarding its utilisation in a developing country in the midst of the Covid pandemic, and provides a guide for further research and development of innovative teaching methods.
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GEMIN5, an RNA-binding protein is essential for assembly of the survival motor neuron (SMN) protein complex and facilitates the formation of small nuclear ribonucleoproteins (snRNPs), the building blocks of spliceosomes. Here, we have identified 30 affected individuals from 22 unrelated families presenting with developmental delay, hypotonia, and cerebellar ataxia harboring biallelic variants in the GEMIN5 gene. Mutations in GEMIN5 perturb the subcellular distribution, stability, and expression of GEMIN5 protein and its interacting partners in patient iPSC-derived neurons, suggesting a potential loss-of-function mechanism. GEMIN5 mutations result in disruption of snRNP complex assembly formation in patient iPSC neurons. Furthermore, knock down of rigor mortis, the fly homolog of human GEMIN5, leads to developmental defects, motor dysfunction, and a reduced lifespan. Interestingly, we observed that GEMIN5 variants disrupt a distinct set of transcripts and pathways as compared to SMA patient neurons, suggesting different molecular pathomechanisms. These findings collectively provide evidence that pathogenic variants in GEMIN5 perturb physiological functions and result in a neurodevelopmental delay and ataxia syndrome.
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Regulação da Expressão Gênica no Desenvolvimento/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Neurônios/metabolismo , Ribonucleoproteínas Nucleares Pequenas/metabolismo , Proteínas do Complexo SMN/genética , Alelos , Sequência de Aminoácidos , Animais , Pré-Escolar , Deficiências do Desenvolvimento/genética , Drosophila/genética , Drosophila/crescimento & desenvolvimento , Feminino , Técnicas de Silenciamento de Genes , Ontologia Genética , Células HEK293 , Humanos , Mutação com Perda de Função , Masculino , Hipotonia Muscular/genética , Dissinergia Cerebelar Mioclônica/genética , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Linhagem , Polimorfismo de Nucleotídeo Único , RNA-Seq , Ribonucleoproteínas Nucleares Pequenas/genética , Rigor Mortis/genética , Proteínas do Complexo SMN/metabolismoRESUMO
Cerebral palsy (CP) neurologic care and research efforts typically focus on children. However, most people with CP are adults. Adults with CP are at increased risk of new neurologic conditions, such as stroke and myelopathy, that require ongoing neurologic surveillance to distinguish them from baseline motor impairments. Neurologic factors could also contribute to the motor function decline, chronic pain, and chronic fatigue that are commonly experienced by adults with CP. Based on a systematic literature review, we suggest (1) guidelines for neurologic surveillance and neurologist referral and (2) clinical research questions regarding the evolving neurologic risks for adults with CP. ANN NEUROL 2021;89:860-871.
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Paralisia Cerebral/terapia , Neurologia , Assistência ao Paciente , Adulto , Criança , Humanos , Doenças do Sistema Nervoso/complicações , Doenças do Sistema Nervoso/terapiaRESUMO
BACKGROUND: CASK is an X-linked gene in mammals and its deletion in males is incompatible with life. CASK heterozygous mutations in female patients associate with intellectual disability, microcephaly, pontocerebellar hypoplasia, and optic nerve hypoplasia, whereas CASK hemizygous mutations in males manifest as early infantile epileptic encephalopathy with a grim prognosis. Here, we report a rare case of survival of a male patient harboring a CASK null mutation to adolescent age. METHODS: Trio whole exome sequencing analysis was performed from blood genomic DNA. Magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and electroencephalogram (EEG) analyses were performed to determine anomalies in brain development, metabolite concentrations, and electrical activity, respectively. RESULTS: Trio-WES analysis identified a de novo c.79C>T (p.Arginine27Ter) mutation in CASK causing a premature translation termination at the very N-terminus of the protein. The 17-years, and 11-month-old male patient displayed profound intellectual disability, microcephaly, dysmorphism, ponto-cerebellar hypoplasia, and intractable epilepsy. His systemic symptoms included overall reduced somatic growth, dysautonomia, ventilator and G tube dependence, and severe osteopenia. Brain MRI revealed a severe cerebellar and brain stem hypoplasia with progressive cerebral atrophy. EEG spectral analysis revealed a global functional defect with generalized background slowing and delta waves dominating even in the awake state. CONCLUSION: This case study is the first to report survival of a male patient carrying a CASK loss-of-function mutation to adolescence and highlights that improved palliative care could extend survival. Moreover, the genomic position encoding Arg27 in CASK may possess an increased susceptibility to mutations.
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Anormalidades Múltiplas/genética , Epilepsia/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Guanilato Quinases/genética , Deficiência Intelectual/genética , Mutação com Perda de Função , Anormalidades Múltiplas/patologia , Adolescente , Epilepsia/patologia , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Deficiência Intelectual/patologia , MasculinoRESUMO
PURPOSE OF STUDY: Advanced uterovaginal prolapse can significantly affect the quality of life in women and usually requires surgical management. McCall's culdoplasty (M) or sacrospinous fixation (SSF) are done at the time of vaginal hysterectomy with pelvic floor repair (VHPFR) to reduce recurrence, but recurrence rates of 15% and 33% have been reported with these procedures respectively. We hypothesize that combining VH-PFR with both McCall's culdoplasty and sacrospinous fixation (VH-PFR-M-SSF) may decrease recurrence rates compared to VH-PFR-M without significantly affecting other perioperative outcomes. METHODS: All patients with advanced uterovaginal prolapse and willing for VH-PFR at our institute from January 2015 to March 2018 were included after informed consent, except for medically unfit women and those preferring alternative management. We conducted a case control study comparing VH-PFR-M and VH-PFR-M-SSF with a follow-up period of 24 months. Qualitative and quantitative data were statistically analysed and Odds ratio and 95% Confidence interval was calculated. Kaplan Meier Curve was drawn and Log Rank test was used to compare recurrence. RESULTS: Out of 174 patients who underwent surgery in the study period, 131 patients (75.28%) underwent VH-PFR-M and 43 patients (24.71%) underwent VH-PFR-M-SSF. Both groups were comparable for age, body mass index, parity, postmenopausal status, comorbidities and aggravating factors. Patients with higher stage of prolapse were more in group 2 (p < 0.001). There were no intraoperative complications or postoperative surgical interventions in either group. The duration of surgery was not significantly different. Change in haematocrit was more in group 2 but no patient required blood transfusion. There was no statistically significant difference in recurrence rates between the 2 groups. CONCLUSION: The procedure (VH PFR M-SSF) is safe and affordable with good results in Stage 3 with advanced bulge and stage 4 prolapse.
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We describe association of olfactory bulb and olfactory tract abnormalities in a child with acrocallosal syndrome caused by kinesin family membrane 7 (KIF7) mutation in sonic hedgehog pathway. The child also had fontanellar bone in the anterior fontanelle, short sagittal suture, sagittal synostosis, hippocampal malrotation and Joubert malformation. Fontanellar bone has been described in GLI3 mutation and mutant mice models but has not been reported in KIF7 mutation. We briefly review the role of sonic hedgehog pathway and its components KIF7 and GLI3 in forebrain and olfactory system development and also describe olfactory system abnormality in a child with GLI3 mutation.
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Síndrome Acrocalosal/complicações , Acrocefalossindactilia/complicações , Bulbo Olfatório/anormalidades , Anormalidades Múltiplas/diagnóstico por imagem , Síndrome Acrocalosal/diagnóstico por imagem , Acrocefalossindactilia/diagnóstico por imagem , Encéfalo/anormalidades , Encéfalo/diagnóstico por imagem , Pré-Escolar , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Bulbo Olfatório/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: Recent reports have described single individuals with neurodevelopmental disability (NDD) harboring heterozygous KCNQ3 de novo variants (DNVs). We sought to assess whether pathogenic variants in KCNQ3 cause NDD and to elucidate the associated phenotype and molecular mechanisms. METHODS: Patients with NDD and KCNQ3 DNVs were identified through an international collaboration. Phenotypes were characterized by clinical assessment, review of charts, electroencephalographic (EEG) recordings, and parental interview. Functional consequences of variants were analyzed in vitro by patch-clamp recording. RESULTS: Eleven patients were assessed. They had recurrent heterozygous DNVs in KCNQ3 affecting residues R230 (R230C, R230H, R230S) and R227 (R227Q). All patients exhibited global developmental delay within the first 2 years of life. Most (8/11, 73%) were nonverbal or had a few words only. All patients had autistic features, and autism spectrum disorder (ASD) was diagnosed in 5 of 11 (45%). EEGs performed before 10 years of age revealed frequent sleep-activated multifocal epileptiform discharges in 8 of 11 (73%). For 6 of 9 (67%) recorded between 1.5 and 6 years of age, spikes became near-continuous during sleep. Interestingly, most patients (9/11, 82%) did not have seizures, and no patient had seizures in the neonatal period. Voltage-clamp recordings of the mutant KCNQ3 channels revealed gain-of-function (GoF) effects. INTERPRETATION: Specific GoF variants in KCNQ3 cause NDD, ASD, and abundant sleep-activated spikes. This new phenotype contrasts both with self-limited neonatal epilepsy due to KCNQ3 partial loss of function, and with the neonatal or infantile onset epileptic encephalopathies due to KCNQ2 GoF. ANN NEUROL 2019;86:181-192.