Dataset Information

Morphometric network-based abnormalities correlate with psychiatric comorbidities and gene expression in PCDH19-related developmental and epileptic encephalopathy.

ABSTRACT: Protocadherin-19 (PCDH19) developmental and epileptic encephalopathy causes an early-onset epilepsy syndrome with limbic seizures, typically occurring in clusters and variably associated with intellectual disability and a range of psychiatric disorders including hyperactive, obsessive-compulsive and autistic features. Previous quantitative neuroimaging studies revealed abnormal cortical areas in the limbic formation (parahippocampal and fusiform gyri) and underlying white-matter fibers. In this study, we adopted morphometric, network-based and multivariate statistical methods to examine the cortex and substructure of the hippocampus and amygdala in a cohort of 20 PCDH19-mutated patients and evaluated the relation between structural patterns and clinical variables at individual level. We also correlated morphometric alterations with known patterns of PCDH19 expression levels. We found patients to exhibit high-significant reductions of cortical surface area at a whole-brain level (left/right p_value = 0.045/0.084), and particularly in the regions of the limbic network (left/right parahippocampal gyri p_value = 0.230/0.016; left/right entorhinal gyri p_value = 0.002/0.327), and bilateral atrophy of several subunits of the amygdala and hippocampus, particularly in the CA regions (head of the left CA3 p_value = 0.002; body of the right CA3 p_value = 0.004), and differences in the shape of hippocampal structures. More severe psychiatric comorbidities correlated with more significant altered patterns, with the entorhinal gyrus (p_value = 0.013) and body of hippocampus (p_value = 0.048) being more severely affected. Morphometric alterations correlated significantly with the known expression patterns of PCDH19 (r_value = -0.26, p_spin = 0.092). PCDH19 encephalopathy represents a model of genetically determined neural network based neuropsychiatric disease in which quantitative MRI-based findings correlate with the severity of clinical manifestations and had have a potential predictive value if analyzed early.

SUBMITTER: Lenge M

PROVIDER: S-EPMC10796344 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Morphometric network-based abnormalities correlate with psychiatric comorbidities and gene expression in PCDH19-related developmental and epileptic encephalopathy.

Lenge Matteo M Balestrini Simona S Napolitano Antonio A Mei Davide D Conti Valerio V Baldassarri Giulia G Trivisano Marina M Pellacani Simona S Macconi Letizia L Longo Daniela D Rossi Espagnet Maria Camilla MC Cappelletti Simona S D'Incerti Ludovico L Barba Carmen C Specchio Nicola N Guerrini Renzo R

Translational psychiatry 20240118 1

Protocadherin-19 (PCDH19) developmental and epileptic encephalopathy causes an early-onset epilepsy syndrome with limbic seizures, typically occurring in clusters and variably associated with intellectual disability and a range of psychiatric disorders including hyperactive, obsessive-compulsive and autistic features. Previous quantitative neuroimaging studies revealed abnormal cortical areas in the limbic formation (parahippocampal and fusiform gyri) and underlying white-matter fibers. In this ...[more]

PMID: 38238304

Similar Datasets

Project description:BackgroundDevelopmental and epileptic encephalopathies (DEEs) signify a group of heterogeneous neurodevelopmental disorder associated with early-onset seizures accompanied by developmental delay, hypotonia, mild to severe intellectual disability, and developmental regression. Variants in the DNM1 gene have been associated with autosomal dominant DEE type 31A and autosomal recessive DEE type 31B.MethodsIn the current study, a consanguineous Pakistani family consisting of a proband (IV-2) was clinically evaluated and genetically analyzed manifesting in severe neurodevelopmental phenotypes. WES followed by Sanger sequencing was performed to identify the disease-causing variant. Furthermore, 3D protein modeling and dynamic simulation of wild-type and mutant proteins along with reverse transcriptase (RT)-based mRNA expression were checked using standard methods.ResultsData analysis of WES revealed a novel homozygous non-sense variant (c.1402G>T; p. Glu468*) in exon 11 of the DNM1 gene that was predicted as pathogenic class I. Variants in the DNM1 gene have been associated with DEE types 31A and B. Different bioinformatics prediction tools and American College of Medical Genetics guidelines were used to verify the identified variant. Sanger sequencing was used to validate the disease-causing variant. Our approach validated the pathogenesis of the variant as a cause of heterogeneous neurodevelopmental disorders. In addition, 3D protein modeling showed that the mutant protein would lose most of the amino acids and might not perform the proper function if the surveillance non-sense-mediated decay mechanism was skipped. Molecular dynamics analysis showed varied trajectories of wild-type and mutant DNM1 proteins in terms of root mean square deviation, root mean square fluctuation and radius of gyration. Similarly, RT-qPCR revealed a substantial reduction of the DNM1 gene in the index patient.ConclusionOur finding further confirms the association of homozygous, loss-of-function variants in DNM1 associated with DEE type 31B. The study expands the genotypic and phenotypic spectrum of pathogenic DNM1 variants related to DNM1-associated pathogenesis.

Dataset Information

Morphometric network-based abnormalities correlate with psychiatric comorbidities and gene expression in PCDH19-related developmental and epileptic encephalopathy.

Publications

Morphometric network-based abnormalities correlate with psychiatric comorbidities and gene expression in PCDH19-related developmental and epileptic encephalopathy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets