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Molecular Genetics & Genomic Medicine Jul 2023Neurodevelopmental disorders associated with periventricular nodular heterotopia (PVNH) are characterized by phenotypic and genetic heterogeneity. NEDD4L mutation can... (Review)
Review
BACKGROUND
Neurodevelopmental disorders associated with periventricular nodular heterotopia (PVNH) are characterized by phenotypic and genetic heterogeneity. NEDD4L mutation can lead to PVNH7. However, at present, only eight NEDD4L pathogenic variants have been identified across 15 cases of PVNH7 worldwide. Given this dearth of evidence, the precise correlations between genetic pathogenesis and phenotypes remain to be determined.
METHODS
This report discusses the case of a 19-month-old male child with cleft palate, seizures, psychomotor retardation, and hypotonia, for whom we verified the genetic etiology using Trio-whole-exome and Sanger sequencing to analyze the potential pathogenicity of the mutant protein structure. Mutant plasmids were constructed for in vitro analyses. After transfection into human 293 T cells, the mutant transcription process was analyzed using real-time PCR (RT-PCR), and levels of mutant protein expression were examined using western blotting (WB) and immunofluorescence (IF) experiments.
RESULTS
Genetic analyses revealed a novel missense mutation Gln900Arg, located in the homologous to E6-APC terminal (HECT) domain of NEDD4L and that the parents were wild-type, suggestive of a de novo mutation. The variant was predicted to be pathogenic by bioinformatics software, which also suggested alterations in the structural stability of the mutant protein. RT-PCR results indicated that the mutation did not affect mRNA expression, whereas WB and IF results indicated that the level of mutant protein was significantly reduced by 41.07%.
CONCLUSION
Functional experiments demonstrated that Gln900Arg probably did not lead to transcriptional abnormalities in this patient, instead leading to increased ubiquitination activity owing to the constitutive activation of the HECT domain, thereby promoting protein degradation. Extensive clinical reports should be generated for patients presenting with PVNH and/or polymicrogyria, developmental delay, syndactyly, and hypotonia to increase the pool of evidence related to NEDD4L.
Topics: Humans; Infant; Male; Muscle Hypotonia; Mutation; Mutation, Missense; Periventricular Nodular Heterotopia; Seizures
PubMed: 36934385
DOI: 10.1002/mgg3.2169 -
Child's Nervous System : ChNS :... May 2024Pathogenic variants in RAC3 cause a neurodevelopmental disorder with brain malformations and craniofacial dysmorphism, called NEDBAF. This gene encodes a small GTPase,...
Pathogenic variants in RAC3 cause a neurodevelopmental disorder with brain malformations and craniofacial dysmorphism, called NEDBAF. This gene encodes a small GTPase, which plays a critical role in neurogenesis and neuronal migration. We report a 31 weeks of gestation fetus with triventricular dilatation, and temporal and perisylvian polymicrogyria, without cerebellar, brainstem, or callosal anomalies. Trio whole exome sequencing identified a RAC3 (NM_005052.3, GRCh38) probably pathogenic de novo variant c.276 T>A p.(Asn92Lys). Eighteen patients harboring 13 different and essentially de novo missense RAC3 variants were previously reported. All the patients presented with corpus callosum malformations. Gyration disorders, ventriculomegaly (VM), and brainstem and cerebellar malformations have frequently been described. The only previous prenatal case associated with RAC3 variant presented with complex brain malformations, mainly consisting of midline and posterior fossa anomalies. We report the second prenatal case of NEDBAF presenting an undescribed pattern of cerebral anomalies, including VM and polymicrogyria, without callosal, cerebellar, or brainstem malformations. All neuroimaging data were reviewed to clarify the spectrum of cerebral malformations.
Topics: Pregnancy; Female; Humans; Polymicrogyria; Prenatal Diagnosis; Nervous System Malformations; Agenesis of Corpus Callosum; Mutation, Missense; Hydrocephalus; rac GTP-Binding Proteins
PubMed: 38214746
DOI: 10.1007/s00381-024-06285-z -
Cell Death & Disease May 2024CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly...
CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly expressed in the central nervous system (CNS) where emergent functions of the complement pathway modulate neural development and synaptic activity. While a genetic risk factor for neuropsychiatric disorders, the role of CSMD1 in neurodevelopmental disorders is unclear. Through international variant sharing, we identified inherited biallelic CSMD1 variants in eight individuals from six families of diverse ancestry who present with global developmental delay, intellectual disability, microcephaly, and polymicrogyria. We modeled CSMD1 loss-of-function (LOF) pathogenesis in early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs). We show that CSMD1 is necessary for neuroepithelial cytoarchitecture and synchronous differentiation. In summary, we identified a critical role for CSMD1 in brain development and biallelic CSMD1 variants as the molecular basis of a previously undefined neurodevelopmental disorder.
Topics: Humans; Intellectual Disability; Membrane Proteins; Female; Male; Neurodevelopmental Disorders; Alleles; Malformations of Cortical Development; Child; Child, Preschool; Cell Differentiation; Tumor Suppressor Proteins
PubMed: 38816421
DOI: 10.1038/s41419-024-06768-6 -
Cureus Apr 2024We report a case of developmental and epileptic encephalopathy with spike-and-wave activation during sleep with 22q11.2 deletion syndrome in a patient who had undergone...
We report a case of developmental and epileptic encephalopathy with spike-and-wave activation during sleep with 22q11.2 deletion syndrome in a patient who had undergone hemispherotomy and achieved developmental improvement. A four-year-old male child with paralysis on the left side of his body since birth had a mild developmental delay. An MRI of the brain revealed polymicrogyria diffusely throughout the right hemisphere. He was diagnosed with the 22q11.2 deletion syndrome at one year of age. Focal impaired awareness seizure in the right hemisphere origin and focal to bilateral tonic-clonic seizure appeared by two years of age. At three years of age, myoclonic seizures occurred, which induced frequent falls. Simultaneously, developmental and epileptic encephalopathy with spike-and-wave activation during sleep were observed. At four years and seven months of age, the patient underwent a right hemispherotomy. Epileptic seizures and spike-and-wave activation during sleep disappeared, and cognitive improvement was observed one year after surgery. In spite of chromosomal abnormalities being present, drug-resistant epilepsy with localized regions on MRI should be evaluated to determine surgical options to improve cognitive function and development.
PubMed: 38765340
DOI: 10.7759/cureus.58424 -
Metabolites Mar 2024Multi-omics approaches, which integrate genomics, transcriptomics, proteomics, and metabolomics, have emerged as powerful tools in the diagnosis of rare diseases. We...
Multi-omics approaches, which integrate genomics, transcriptomics, proteomics, and metabolomics, have emerged as powerful tools in the diagnosis of rare diseases. We used untargeted metabolomics and whole-genome sequencing (WGS) to gain a more comprehensive understanding of a rare disease with a complex presentation affecting female twins from a consanguineous family. The sisters presented with polymicrogyria, a Dandy-Walker malformation, respiratory distress, and multiorgan dysfunctions. Through WGS, we identified two rare homozygous variants in both subjects, a pathogenic variant in (p.Arg565Trp) and a novel variant in (p.Glu910Val). These genes have been previously associated with autosomal recessive polymicrogyria and hypomyelinating neuropathy with/without contractures, respectively. The twins exhibited symptoms that overlapped with both of these conditions. The results of the untargeted metabolomics analysis revealed significant metabolic perturbations relating to neurodevelopmental abnormalities, kidney dysfunction, and microbiome. The significant metabolites belong to essential pathways such as lipids and amino acid metabolism. The identification of variants in two genes, combined with the support of metabolic perturbation, demonstrates the rarity and complexity of this phenotype and provides valuable insights into its underlying mechanisms.
PubMed: 38535312
DOI: 10.3390/metabo14030152 -
Neurology. Genetics Jun 2024To report novel biallelic variants in a family presenting with pure hereditary spastic paraparesis.
OBJECTIVES
To report novel biallelic variants in a family presenting with pure hereditary spastic paraparesis.
METHODS
Two affected sisters presented with unsolved hereditary spastic paraparesis and underwent clinical and imaging assessments. This was followed by short-read next-generation sequencing.
RESULTS
Analysis of next-generation sequencing data uncovered compound heterozygous variants in (NM_058004.4: c.[3883C>A];[5785A>C]; p.[(His1295Asn);(Thr1929Pro)]. Using ACMG guidelines, both variants were classified as likely pathogenic.
DISCUSSION
Here, next-generation sequencing revealed 2 novel compound heterozygous variants in the phosphatidylinositol 4-kinase alpha gene () in 2 sisters presenting with progressive pure hereditary spastic paraparesis. Pathogenic variants in have previously been associated with a spectrum of disorders including autosomal recessive perisylvian polymicrogyria, with cerebellar hypoplasia, arthrogryposis, and pure spastic paraplegia. The cases presented in this study expand the phenotypic spectrum associated with variants and contribute new likely pathogenic variants for testing in patients with otherwise unsolved hereditary spastic paraparesis.
PubMed: 38685974
DOI: 10.1212/NXG.0000000000200152 -
Cortex; a Journal Devoted To the Study... Feb 2024The absence of speech is a clinical phenotype seen across neurodevelopmental syndromes, offering insights for neural language models. We present a case of bilateral...
The absence of speech is a clinical phenotype seen across neurodevelopmental syndromes, offering insights for neural language models. We present a case of bilateral perisylvian polymicrogyria (BPP) and complete absence of speech with considerable language comprehension and production difficulties. We extensively characterized the auditory speech perception and production circuitry by employing a multimodal neuroimaging approach. Results showed extensive cortical thickening in motor and auditory-language regions. The auditory cortex lacked sensitivity to speech stimuli despite relatively preserved thalamic projections yet had no intrinsic functional organization. Subcortical structures implicated in early stages of processing exhibited heightened sensitivity to speech. The arcuate fasciculus, a suggested marker of language in BPP, showed similar volume and integrity to a healthy control. The frontal aslant tract, linked to oromotor function, was partially reconstructed. These findings highlight the importance of assessing the auditory cortex beyond speech production structures to understand absent speech in BPP. Despite profound cortical alterations, the intrinsic motor network and motor-speech pathways remained largely intact. This case underscores the need for comprehensive phenotyping using multiple MRI modalities to uncover causes of severe disruption in language development.
Topics: Humans; Auditory Cortex; Speech; Polymicrogyria; Speech Perception; Magnetic Resonance Imaging; Phenotype; Abnormalities, Multiple; Intellectual Disability; Malformations of Cortical Development
PubMed: 38109835
DOI: 10.1016/j.cortex.2023.11.006