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Epileptic Disorders : International... Apr 2024PACS2 pathogenic variants are associated with an autosomal dominant syndrome (OMIM DEE66), associating developmental and epileptic encephalopathy, facial dysmorphism,...
PACS2 pathogenic variants are associated with an autosomal dominant syndrome (OMIM DEE66), associating developmental and epileptic encephalopathy, facial dysmorphism, and cerebellar dysgenesis. However, no malformation of cortical development has been reported yet. We report here a seven-year-old child with a history of infantile epileptic spasm syndrome and a right insular polymicrogyria and pachygyria due to de novo PACS2 recurrent mutation c.625G>A (p.Glu209Lys). Our observation raises the question of the role of PACS2 in the cortical development. It also reminds the importance of cerebellar anomalies in the recognition of PACS-related DEE.
Topics: Child; Humans; Epilepsy; Epilepsy, Generalized; Mutation; Phenotype; Polymicrogyria; Syndrome; Vesicular Transport Proteins
PubMed: 38031819
DOI: 10.1002/epd2.20184 -
Seizure Mar 2024The DYNC1H1 variants are associated with abnormal brain morphology and neuromuscular disorders that are accompanied by epilepsy. This study aimed to explore the...
OBJECTIVES
The DYNC1H1 variants are associated with abnormal brain morphology and neuromuscular disorders that are accompanied by epilepsy. This study aimed to explore the relationship between DYNC1H1 variants and epilepsy.
MATERIALS AND METHODS
Trios-based whole-exome sequencing was performed on patients with epilepsy. Previously reported epilepsy-related DYNC1H1 variants were systematically reviewed to analyse genotype-phenotype correlation.
RESULTS
The DYNC1H1 variants were identified in four unrelated cases of infant-onset epilepsy, including two de novo and two biallelic variants. Two patients harbouring de novo missense variants located in the stem and stalk domains presented with refractory epilepsies, whereas two patients harbouring biallelic variants located in the regions between functional domains had mild epilepsy with infrequent focal seizures and favourable outcomes. One patient presented with pachygyria and neurodevelopmental abnormalities, and the other three patients presented with normal development. These variants have no or low frequencies in the Genome Aggregation Database. All the missense variants were predicted to be damaging using silico tools. Previously reported epilepsy-related variants were monoallelic variants, mainly de novo missense variants, and all the patients presented with severe epileptic phenotypes or developmental delay and malformations of cortical development. Epilepsy-related variants were clustered in the dimerization and stalk domains, and generalized epilepsy-associated variants were distributed in the stem domain.
CONCLUSION
This study suggested that DYNC1H1 variants are potentially associated with infant-onset epilepsy without neurodevelopmental disorders, expanding the phenotypic spectrum of DYNC1H1. The genotype-phenotype correlation helps to understand the underlying mechanisms of phenotypic variation.
Topics: Infant; Humans; Mutation; Epilepsy; Neurodevelopmental Disorders; Epilepsy, Generalized; Mutation, Missense; Phenotype; Cytoplasmic Dyneins
PubMed: 37903666
DOI: 10.1016/j.seizure.2023.10.010 -
Movement Disorders : Official Journal... Oct 2023
Topics: Humans; Magnetic Resonance Imaging; Classical Lissencephalies and Subcortical Band Heterotopias; Iron; Brain
PubMed: 37885407
DOI: 10.1002/mds.29592 -
Biomedizinische Technik. Biomedical... Apr 2024Second-generation headless compression screws (HCSs) are commonly used for the fixation of small bones and articular fractures. However, there is a lack of biomechanical...
Second-generation headless compression screws (HCSs) are commonly used for the fixation of small bones and articular fractures. However, there is a lack of biomechanical data regarding the application of such screws to radial head fractures. This study evaluated the mechanical properties of the fixation of radial head fractures using a single oblique HCS compared with those obtained using a standard locking radial head plate (LRHP) construct and a double cortical screw (DCS) construct. Radial synbone models were used for biomechanical tests of HCS, LRHP, and DCS constructs. All specimens were first cyclically loaded and then loaded to failure. The stiffness for the LRHP group was significantly higher than that for the other two groups, and that for the HCS group was significantly higher than that for the DCS group. The LRHP group had the greatest strength, followed by the HCS group and then the DCS group. The HCS construct demonstrated greater fixation strength than that of the commonly used cortical screws, although the plate group was the most stable. The present study revealed the feasibility of using a single oblique HCS, which has the advantages of being buried, requiring limited wound exposure, and having relatively easy operation, for treating simple radial head fractures.
Topics: Humans; Fracture Fixation, Internal; Bone Screws; Radial Head and Neck Fractures; Radius Fractures; Bone Plates; Biomechanical Phenomena; Classical Lissencephalies and Subcortical Band Heterotopias
PubMed: 37883038
DOI: 10.1515/bmt-2023-0107 -
European Journal of Human Genetics :... Jan 2024Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one...
Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1, have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2, another subunit of PIDDosome complex. Seven patients from five independent families presenting with a neurodevelopmental phenotype were identified through GeneMatcher-facilitated international collaborations. Exome sequencing analysis was carried out and revealed two distinct novel homozygous (NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25), and c.1174 C > T (p.Gln392Ter)) and compound heterozygous variants (c.[130 C > T];[876 + 1 G > T] p.[Arg44Ter];[?]) in CASP2 segregating within the families in a manner compatible with an autosomal recessive pattern. RNA studies of the c.876 + 1 G > T variant indicated usage of two cryptic splice donor sites, each introducing a premature stop codon. All patients from whom brain MRIs were available had a typical fronto-temporal LIS and pachygyria, remarkably resembling the CRADD and PIDD1-related neuroimaging findings. Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. In summary, we present patients with CASP2-related ID, anterior-predominant LIS, and pachygyria similar to previously reported patients with CRADD and PIDD1-related disorders, expanding the genetic spectrum of LIS and lending support that each component of the PIDDosome complex is critical for normal development of the human cerebral cortex and brain function.
Topics: Humans; Caspase 2; Lissencephaly; Alleles; Neurodevelopmental Disorders; Codon, Nonsense; Phenotype; Cysteine Endopeptidases
PubMed: 37880421
DOI: 10.1038/s41431-023-01461-2 -
Journal of Medical Genetics Jan 2024The Aristaless-related homeobox () gene is located on the X chromosome and encodes a transcription factor that is essential for brain development. While the clinical... (Review)
Review
The Aristaless-related homeobox () gene is located on the X chromosome and encodes a transcription factor that is essential for brain development. While the clinical spectrum of -related disorders is well described in males, from X linked lissencephaly with abnormal genitalia syndrome to syndromic and non-syndromic intellectual disability (ID), its phenotypic delineation in females is incomplete. Carrier females in families are usually asymptomatic, but ID has been reported in some of them, as well as in others with de novo variants. In this study, we collected the clinical and molecular data of 10 unpublished female patients with de novo pathogenic variants and reviewed the data of 63 females from the literature with either de novo variants (n=10), inherited variants (n=33) or variants of unknown inheritance (n=20). Altogether, the clinical spectrum of females with heterozygous pathogenic variants is broad: 42.5% are asymptomatic, 16.4% have isolated agenesis of the corpus callosum (ACC) or mild symptoms (learning disabilities, autism spectrum disorder, drug-responsive epilepsy) without ID, whereas 41% present with a severe phenotype (ie, ID or developmental and epileptic encephalopathy (DEE)). The ID/DEE phenotype was significantly more prevalent in females carrying de novo variants (75%, n=15/20) versus in those carrying inherited variants (27.3%, n=9/33). ACC was observed in 66.7% (n=24/36) of females who underwent a brain MRI. By refining the clinical spectrum of females carrying pathogenic variants, we show that ID is a frequent sign in females with this X linked condition.
Topics: Male; Humans; Female; Genes, Homeobox; Homeodomain Proteins; Autism Spectrum Disorder; Mutation; Transcription Factors; Intellectual Disability; Phenotype; Agenesis of Corpus Callosum
PubMed: 37879892
DOI: 10.1136/jmg-2023-109203 -
Pediatric Neurology Dec 2023Lissencephaly with cerebellar hypoplasia (LCH) is a rare variant form of lissencephaly, its distinctive neuroradiological phenotype being an important investigation clue...
Lissencephaly with cerebellar hypoplasia (LCH) is a rare variant form of lissencephaly, its distinctive neuroradiological phenotype being an important investigation clue regarding the potential involved genes, including variants in RELN gene. We report on a case of LCH whose clinical and neuroradiological features led to the identification of a homozygous pathogenic variant in RELN gene that has not been previously reported in the scientific literature.
Topics: Humans; Nervous System Malformations; Lissencephaly; Homozygote; Mutation
PubMed: 37879138
DOI: 10.1016/j.pediatrneurol.2023.09.012 -
Science Translational Medicine Oct 2023Zika virus (ZIKV) is a mosquito-borne flavivirus that can vertically transmit from mother to fetus, potentially causing congenital defects, including microcephaly. It is...
Zika virus (ZIKV) is a mosquito-borne flavivirus that can vertically transmit from mother to fetus, potentially causing congenital defects, including microcephaly. It is not fully understood why some fetuses experience severe complications after in utero exposure to ZIKV, whereas others do not. Given the antigenic similarity between ZIKV and the closely related virus dengue (DENV) and the potential of DENV-specific antibodies to enhance ZIKV disease severity in mice, we questioned whether maternal DENV immunity could influence fetal outcomes in a nonhuman primate model of ZIKV vertical transmission. We found significantly increased severity of congenital Zika syndrome (CZS) in fetuses of DENV-immune cynomolgus macaques infected with ZIKV in early pregnancy compared with naïve controls, which occurred despite no effect on maternal ZIKV infection or antibody responses. Ultrasound measurements of head circumference and biparietal diameter measurements taken sequentially throughout pregnancy demonstrated CZS in fetuses of DENV-immune pregnant macaques. Furthermore, severe CZS enhanced by DENV immunity was typified by reduced cortical thickness and increased frequency of neuronal death, hemorrhaging, cellular infiltrations, calcifications, and lissencephaly in fetal brains. This study shows that maternal immunity to DENV can worsen ZIKV neurological outcomes in fetal primates, and it provides an animal model of vertical transmission closely approximating human developmental timelines that could be used to investigate severe ZIKV disease outcomes and interventions in fetuses.
Topics: Pregnancy; Humans; Female; Animals; Mice; Zika Virus; Zika Virus Infection; Microcephaly; Fetus; Dengue; Macaca; Antibodies, Viral
PubMed: 37878671
DOI: 10.1126/scitranslmed.add2420 -
Brain : a Journal of Neurology Jan 2024Pathogenic variants in the MFN2 gene are commonly associated with autosomal dominant (CMT2A2A) or recessive (CMT2A2B) Charcot-Marie-Tooth disease, with possible...
Pathogenic variants in the MFN2 gene are commonly associated with autosomal dominant (CMT2A2A) or recessive (CMT2A2B) Charcot-Marie-Tooth disease, with possible involvement of the CNS. Here, we present a case of severe antenatal encephalopathy with lissencephaly, polymicrogyria and cerebellar atrophy. Whole genome analysis revealed a homozygous deletion c.1717-274_1734 del (NM_014874.4) in the MFN2 gene, leading to exon 16 skipping and in-frame loss of 50 amino acids (p.Gln574_Val624del), removing the proline-rich domain and the transmembrane domain 1 (TM1). MFN2 is a transmembrane GTPase located on the mitochondrial outer membrane that contributes to mitochondrial fusion, shaping large mitochondrial networks within cells. In silico modelling showed that the loss of the TM1 domain resulted in a drastically altered topological insertion of the protein in the mitochondrial outer membrane. Fetus fibroblasts, investigated by fluorescent cell imaging, electron microscopy and time-lapse recording, showed a sharp alteration of the mitochondrial network, with clumped mitochondria and clusters of tethered mitochondria unable to fuse. Multiple deficiencies of respiratory chain complexes with severe impairment of complex I were also evidenced in patient fibroblasts, without involvement of mitochondrial DNA instability. This is the first reported case of a severe developmental defect due to MFN2 deficiency with clumped mitochondria.
Topics: Pregnancy; Humans; Female; Homozygote; Mutation; Mitochondrial Proteins; Sequence Deletion; Mitochondria; Brain Diseases; Charcot-Marie-Tooth Disease; GTP Phosphohydrolases
PubMed: 37804319
DOI: 10.1093/brain/awad347 -
Neuropathology and Applied Neurobiology Oct 2023
Topics: Humans; Cobblestone Lissencephaly; Brain; Lissencephaly
PubMed: 37766395
DOI: 10.1111/nan.12939