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Journal of Medical Genetics Oct 2023was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of...
PURPOSE
was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of -related neurodevelopmental disorder.
METHODS
We collected detailed phenotypes of an international cohort of individuals (n=17) with variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated.
RESULTS
De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder.
CONCLUSION
We confirm the role of in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration.
Topics: Humans; Brain; Genotype; Intellectual Disability; Microcephaly; Periventricular Nodular Heterotopia; Phenotype; Seizures
PubMed: 37185208
DOI: 10.1136/jmg-2022-108803 -
Obstetrics & Gynecology Science Nov 2023Cytomegalovirus (CMV) infection during pregnancy is a global silent problem. Additionally, it is the leading cause of congenital infections, non-genetic sensorineural...
Cytomegalovirus (CMV) infection during pregnancy is a global silent problem. Additionally, it is the leading cause of congenital infections, non-genetic sensorineural hearing loss, and neurodevelopmental delays in infants. However, this has barely been recognized globally. This condition lacks adequate attention, which is further emphasized by the lack of awareness among healthcare workers and the general population. The impact of CMV infection is often overlooked because of the asymptomatic nature of its presentation in infected pregnant women and newborns, difficulty in diagnosis, and the perception that infants born to women with pre-existing antibodies against CMV have normal neonatal outcomes. This article highlights the latest information on the epidemiology, transmission, clinical manifestations, and development of CMV infection and its management. We reviewed the pathophysiology and clinical manifestations of CMV infection in pregnant women, diagnostic methods, including screening and prognostic markers, and updates in treatment modalities. Current advancements in research on vaccination and hyperimmunoglobulins with worldwide treatment protocols are highlighted.
PubMed: 37537975
DOI: 10.5468/ogs.23117 -
American Journal of Medical Genetics.... Jan 2024DYRK1A Syndrome (OMIM #614104) is caused by pathogenic variations in the DYRK1A gene located on 21q22. Haploinsufficiency of DYRK1A causes a syndrome with global...
DYRK1A Syndrome (OMIM #614104) is caused by pathogenic variations in the DYRK1A gene located on 21q22. Haploinsufficiency of DYRK1A causes a syndrome with global psychomotor delay and intellectual disability. Low birth weight, growth restriction with feeding difficulties, stature insufficiency, and microcephaly are frequently reported. This study aims to create specific growth charts for individuals with DYRK1A Syndrome and identify parameters for size prognosis. Growth parameters were obtained for 92 individuals with DYRK1A Syndrome (49 males vs. 43 females). The data were obtained from pediatric records, parent reporting, and scientific literature. Growth charts for height, weight, body mass index (BMI), and occipitofrontal circumference (OFC) were generated using generalized additive models through R package gamlss. The growth curves include height, weight, and OFC measurements for patients aged 0-5 years. In accordance with the literature, the charts show that individuals are more likely to present intrauterine growth restriction with low birth weight and microcephaly. The growth is then characterized by severe microcephaly, low weight, and short stature. This study proposes growth charts for widespread use in the management of patients with DYRK1A syndrome.
Topics: Male; Female; Child; Humans; Microcephaly; Growth Charts; Intellectual Disability; Syndrome; Body Mass Index; Body Height
PubMed: 37740550
DOI: 10.1002/ajmg.a.63412 -
Biomolecules Aug 2023The STIM family of proteins plays a crucial role in a plethora of cellular functions through the regulation of store-operated Ca entry (SOCE) and, thus, intracellular... (Review)
Review
The STIM family of proteins plays a crucial role in a plethora of cellular functions through the regulation of store-operated Ca entry (SOCE) and, thus, intracellular calcium homeostasis. The two members of the mammalian STIM family, STIM1 and STIM2, are transmembrane proteins that act as Ca sensors in the endoplasmic reticulum (ER) and, upon Ca store discharge, interact with and activate the Orai/CRACs in the plasma membrane. Dysregulation of Ca signaling leads to the pathogenesis of a variety of human diseases, including neurodegenerative disorders, cardiovascular diseases, cancer, and immune disorders. Therefore, understanding the mechanisms underlying Ca signaling pathways is crucial for developing therapeutic strategies targeting these diseases. This review focuses on several rare conditions associated with STIM1 mutations that lead to either gain- or loss-of-function, characterized by myopathy, hematological and immunological disorders, among others, and due to abnormal activation of CRACs. In addition, we summarize the current evidence concerning STIM2 allele duplication and deletion associated with language, intellectual, and developmental delay, recurrent pulmonary infections, microcephaly, facial dimorphism, limb anomalies, hypogonadism, and congenital heart defects.
Topics: Animals; Humans; Alleles; Body Fluids; Cardiovascular Diseases; Cell Membrane; Endoplasmic Reticulum; Mammals
PubMed: 37759684
DOI: 10.3390/biom13091284 -
Journal of Medical Ultrasound 2024Fetal microcephaly is a small head with various losses of cerebral cortical volume. The affected cases may suffer from a wide range in severity of impaired cerebral... (Review)
Review
Fetal microcephaly is a small head with various losses of cerebral cortical volume. The affected cases may suffer from a wide range in severity of impaired cerebral development from slight to severe mental retardation. It can be an isolated finding or with other anomalies depending on the heterogeneous causes including genetic mutations, chromosomal abnormalities, congenital infectious diseases, maternal alcohol consumption, and metabolic disorders during pregnancy. It is often a lifelong and incurable condition. Thus, early detection of fetal microcephaly and identification of the underlying causes are important for clinical staff to provide appropriate genetic counseling to the parents and accurate management.
PubMed: 38665355
DOI: 10.4103/jmu.jmu_18_23 -
Frontiers in Molecular Neuroscience 2023Recent studies promote new interest in the intersectionality between autism spectrum disorder (ASD) and Alzheimer's Disease. We have reported high levels of Amyloid-β... (Review)
Review
Recent studies promote new interest in the intersectionality between autism spectrum disorder (ASD) and Alzheimer's Disease. We have reported high levels of Amyloid-β Precursor Protein (APP) and secreted APP-alpha (sAPP) and low levels of amyloid-beta (Aβ) peptides 1-40 and 1-42 (Aβ40, Aβ42) in plasma and brain tissue from children with ASD. A higher incidence of microcephaly (head circumference less than the 3 percentile) associates with ASD compared to head size in individuals with typical development. The role of Aβ peptides as contributors to acquired microcephaly in ASD is proposed. Aβ may lead to microcephaly via disruption of neurogenesis, elongation of the G1/S cell cycle, and arrested cell cycle promoting apoptosis. As the APP gene exists on Chromosome 21, excess Aβ peptides occur in Trisomy 21-T21 (Down's Syndrome). Microcephaly and some forms of ASD associate with T21, and therefore potential mechanisms underlying these associations will be examined in this review. Aβ peptides' role in other neurodevelopmental disorders that feature ASD and acquired microcephaly are reviewed, including dup 15q11.2-q13, Angelman and Rett syndrome.
PubMed: 37808474
DOI: 10.3389/fnmol.2023.1201723 -
Pathogens and Disease Feb 2024Zika virus (ZIKV), which belongs to the Flavivirus family, is mainly transmitted via the bite of Aedes mosquitoes. In newborns, ZIKV infection can cause severe symptoms... (Review)
Review
Zika virus (ZIKV), which belongs to the Flavivirus family, is mainly transmitted via the bite of Aedes mosquitoes. In newborns, ZIKV infection can cause severe symptoms such as microcephaly, while in adults, it can lead to Guillain‒Barré syndrome (GBS). Due to the lack of specific therapeutic methods against ZIKV, the development of a safe and effective vaccine is extremely important. Several potential ZIKV vaccines, such as live attenuated, inactivated, nucleic acid, viral vector, and recombinant subunit vaccines, have demonstrated promising outcomes in clinical trials involving human participants. Therefore, in this review, the recent developmental progress, advantages and disadvantages of these five vaccine types are examined, and practical recommendations for future development are provided.
Topics: Infant, Newborn; Animals; Adult; Humans; Zika Virus; Zika Virus Infection; Mosquito Vectors; Vaccines
PubMed: 38192053
DOI: 10.1093/femspd/ftad036 -
Biochemical and Biophysical Research... Oct 2023Vaccinia-related kinase 1 (VRK1) is a serine/threonine kinase, for which mutations have been reported cause to neurodegenerative diseases, including spinal muscular...
Vaccinia-related kinase 1 (VRK1) is a serine/threonine kinase, for which mutations have been reported cause to neurodegenerative diseases, including spinal muscular atrophy, characterized by microcephaly, motor dysfunction, and impaired cognitive function, in humans. Partial Vrk1 knockdown in mice has been associated with microcephaly and impaired motor function. However, the pathophysiological relationship between VRK1 and neurodegenerative disorders and the precise mechanism of VRK1-related microcephaly and motor function deficits have not been fully investigated. To address this, in this study, we established vrk1-deficient (vrk1) zebrafish and found that they show mild microcephaly and impaired motor function with a low brain dopamine content. Furthermore, vrk1 zebrafish exhibited decreased cell proliferation, defects in nuclear envelope formation, and heterochromatin formation in the brain. To our knowledge, this is the first report demonstrating the important role of VRK1 in microcephaly and motor dysfunction in vivo using vrk1 zebrafish. These findings contribute to elucidating the pathophysiological mechanisms underlying VRK1-mediated neurodegenerative diseases associated with microcephaly.
Topics: Animals; Intracellular Signaling Peptides and Proteins; Microcephaly; Protein Serine-Threonine Kinases; Zebrafish; Zebrafish Proteins
PubMed: 37429068
DOI: 10.1016/j.bbrc.2023.07.005 -
Life (Basel, Switzerland) Dec 2023The progressive reappearance of Zika virus (ZIKV) infections since October 2013 and its circulation in >70 countries and territories (from French Polynesia to Brazil and... (Review)
Review
The progressive reappearance of Zika virus (ZIKV) infections since October 2013 and its circulation in >70 countries and territories (from French Polynesia to Brazil and other countries in the Americas, with sporadic spread in Europe and the East) has long been reported as a global public health emergency. ZIKV is a virus transmitted by arthropods (arboviruses), mainly by Aedes mosquitoes. ZIKV can also be transmitted to humans through mechanisms other than vector infection such as sexual intercourse, blood transfusions, and mother-to-child transmission. The latter mode of transmission can give rise to a severe clinical form called congenital Zika syndrome (CZS), which can result in spontaneous abortion or serious pathological alterations in the fetus such as microcephaly or neurological and orofacial anomalies. In this study, beside a succinct overview of the etiological, microbiological, and epidemiological aspects and modes of transmission of Zika virus infections, we have focused our attention on the pathogenetic and histopathological aspects in pregnancy and the pathogenetic and molecular mechanisms that can determine microcephaly, and consequently the clinical alterations, typical of the fetus and newborns, in a subject affected by CZS.
PubMed: 38255670
DOI: 10.3390/life14010055