-
Italian Journal of Pediatrics Apr 2024Hypoxic-ischemic encephalopathy (HIE) appears in neurological conditions where some brain areas are likely to be injured, such as deep grey matter, basal ganglia area,...
BACKGROUND
Hypoxic-ischemic encephalopathy (HIE) appears in neurological conditions where some brain areas are likely to be injured, such as deep grey matter, basal ganglia area, and white matter subcortical periventricular áreas. Moreover, modeling these brain areas in a newborn is challenging due to significant variability in the intensities associated with HIE conditions. This paper aims to evaluate functional measurements and 3D machine learning models of a given HIE case by correlating the affected brain areas with the pathophysiology and clinical neurodevelopmental.
CASE PRESENTATION
A comprehensive analysis of a term infant with perinatal asphyxia using longitudinal 3D brain information from Machine Learning Models is presented. The clinical analysis revealed the perinatal asphyxia diagnosis with APGAR <5 at 5 and 10 minutes, umbilical arterial pH of 7.0 BE of -21.2 mmol / L), neonatal seizures, and invasive ventilation mechanics. Therapeutic interventions: physical, occupational, and language neurodevelopmental therapies. Epilepsy treatment: vagus nerve stimulation, levetiracetam, and phenobarbital. Furthermore, the 3D analysis showed how the volume decreases due to age, exhibiting an increasing asymmetry between hemispheres. The results of the basal ganglia area showed that thalamus asymmetry, caudate, and putamen increase over time while globus pallidus decreases.
CLINICAL OUTCOMES
spastic cerebral palsy, microcephaly, treatment-refractory epilepsy.
CONCLUSIONS
Slight changes in the basal ganglia and cerebellum require 3D volumetry for detection, as standard MRI examinations cannot fully reveal their complex shape variations. Quantifying these subtle neurodevelopmental changes helps in understanding their clinical implications. Besides, neurophysiological evaluations can boost neuroplasticity in children with neurological sequelae by stimulating new neuronal connections.
Topics: Infant, Newborn; Infant; Pregnancy; Female; Child; Humans; Asphyxia; Brain; Hypoxia-Ischemia, Brain; Asphyxia Neonatorum; Seizures; Epilepsy
PubMed: 38594715
DOI: 10.1186/s13052-024-01633-w -
Frontiers in Pediatrics 2024Joubert syndrome (JS) is a rare autosomal recessive neurodevelopmental condition characterized by congenital mid-hindbrain abnormalities and a variety of clinical...
Joubert syndrome (JS) is a rare autosomal recessive neurodevelopmental condition characterized by congenital mid-hindbrain abnormalities and a variety of clinical manifestations. This article describes a case of Joubert syndrome type 21 with microcephaly, seizures, developmental delay and language regression, caused by a gene variant and examines the contributing variables. This paper advances the understanding of JS by summarizing the literature and offering detection patterns for practitioners with clinical suspicions of JS.
PubMed: 38586154
DOI: 10.3389/fped.2024.1305754 -
Korean Journal of Ophthalmology : KJO Jun 2024
Topics: Humans; Microcephaly; Retinal Diseases; Kinesins; Male; Female; Tomography, Optical Coherence; Mutation; Retina
PubMed: 38584445
DOI: 10.3341/kjo.2023.0144 -
The Journal of Biological Chemistry May 2024Selenoprotein I (SELENOI) catalyzes the final reaction of the CDP-ethanolamine branch of the Kennedy pathway, generating the phospholipids phosphatidylethanolamine (PE)...
Selenoprotein I (SELENOI) catalyzes the final reaction of the CDP-ethanolamine branch of the Kennedy pathway, generating the phospholipids phosphatidylethanolamine (PE) and plasmenyl-PE. Plasmenyl-PE is a key component of myelin and is characterized by a vinyl ether bond that preferentially reacts with oxidants, thus serves as a sacrificial antioxidant. In humans, multiple loss-of-function mutations in genes affecting plasmenyl-PE metabolism have been implicated in hereditary spastic paraplegia, including SELENOI. Herein, we developed a mouse model of nervous system-restricted SELENOI deficiency that circumvents embryonic lethality caused by constitutive deletion and recapitulates phenotypic features of hereditary spastic paraplegia. Resulting mice exhibited pronounced alterations in brain lipid composition, which coincided with motor deficits and neuropathology including hypomyelination, elevated reactive gliosis, and microcephaly. Further studies revealed increased lipid peroxidation in oligodendrocyte lineage cells and disrupted oligodendrocyte maturation both in vivo and in vitro. Altogether, these findings detail a critical role for SELENOI-derived plasmenyl-PE in myelination that is of paramount importance for neurodevelopment.
Topics: Animals; Humans; Mice; Brain; Homeostasis; Lipid Metabolism; Lipid Peroxidation; Mice, Knockout; Myelin Sheath; Oligodendroglia; Phosphatidylethanolamines; Phospholipid Ethers; Plasmalogens; Selenoproteins; Spastic Paraplegia, Hereditary
PubMed: 38582453
DOI: 10.1016/j.jbc.2024.107259 -
Frontiers in Neurology 2024Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized primarily by congenital microcephaly and intellectual disability but...
BACKGROUND
Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized primarily by congenital microcephaly and intellectual disability but without extra-central nervous system malformations. This investigation aimed to elucidate the genetic underpinnings of microcephaly in a patient from a Chinese consanguineous family.
METHODS
A comprehensive clinical assessment, including brain magnetic resonance imaging (MRI), electroencephalogram (EEG), and genetic analyses, was conducted to evaluate the patient's condition. Whole-exome sequencing (WES) was employed to identify the causative gene, followed by Sanger sequencing, to confirm the mutation and its segregation within the family. Reverse transcript polymerase chain reaction (RT-PCR) was utilized to detect changes in splicing. Western blot was employed to reveal the difference of protein expression level between the wild-type and mutant WDR62 in vitro.
RESULTS
The patient exhibited classic MCPH symptoms, including microcephaly, recurrent epilepsy, delayed psychomotor development, and intellectual disability. Additionally, asymmetrical limb length was noted as a prominent feature. MRI findings indicated reduced brain volume with cortical malformations, while EEG demonstrated heightened sharp wave activity. A molecular analysis uncovered a novel homozygous variant c.4154-6 C > G in the intron, and a functional analysis confirmed the pathogenicity of this mutation, resulting in the formation of an abnormal transcript with premature termination codons.
CONCLUSION
This study enhances our understanding of the genetic heterogeneity associated with MCPH and highlights the pivotal role of genetic testing in the diagnosing and managing of rare neurodevelopmental disorders. Furthermore, it highlights the potential of emerging genetic therapies in treating conditions such as MCPH2.
PubMed: 38576530
DOI: 10.3389/fneur.2024.1341864 -
Cureus Apr 2024Autosomal Dominant Mental Retardation Type 7 is a disorder caused by pathogenic variants in the gene. Clinical features associated with this gene mutation include focal...
Autosomal Dominant Mental Retardation Type 7 is a disorder caused by pathogenic variants in the gene. Clinical features associated with this gene mutation include focal dysmorphism, developmental delay, and epilepsy. In this report, we present a case of an 8-year-old boy with a gene mutation, whose clinical manifestations underscore the rarity and clinical challenges of this genetic condition. The patient is a known case of global developmental delay with intractable epilepsy on multiple anti-epileptic medications. Upon examination, the patient showed delayed developmental milestones, hypotonia with brisk deep tendon reflexes, as well as dysmorphic features in the form of microcephaly, deep-set eyes, prominent ears, and a short nose. MRI was done, and findings were suggestive of a gene mutation. The diagnosis was later confirmed by Whole Exome Sequencing (WES). Our report aims to contribute to the growing knowledge about mutations, facilitating a better understanding of the associated clinical features and implications for patient care.
PubMed: 38566780
DOI: 10.7759/cureus.57460 -
Disease Models & Mechanisms Apr 2024The addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to proteins (referred to as O-GlcNAcylation) is a modification that is crucial for vertebrate development....
The addition of O-linked β-N-acetylglucosamine (O-GlcNAc) to proteins (referred to as O-GlcNAcylation) is a modification that is crucial for vertebrate development. O-GlcNAcylation is catalyzed by O-GlcNAc transferase (OGT) and reversed by O-GlcNAcase (OGA). Missense variants of OGT have recently been shown to segregate with an X-linked syndromic form of intellectual disability, OGT-linked congenital disorder of glycosylation (OGT-CDG). Although the existence of OGT-CDG suggests that O-GlcNAcylation is crucial for neurodevelopment and/or cognitive function, the underlying pathophysiologic mechanisms remain unknown. Here we report a mouse line that carries a catalytically impaired OGT-CDG variant. These mice show altered O-GlcNAc homeostasis with decreased global O-GlcNAcylation and reduced levels of OGT and OGA in the brain. Phenotypic characterization of the mice revealed lower body weight associated with reduced body fat mass, short stature and microcephaly. This mouse model will serve as an important tool to study genotype-phenotype correlations in OGT-CDG in vivo and for the development of possible treatment avenues for this disorder.
Topics: Animals; N-Acetylglucosaminyltransferases; Intellectual Disability; Disease Models, Animal; Brain; Phenotype; Mice; Neurodevelopmental Disorders; beta-N-Acetylhexosaminidases; Glycosylation; Body Weight
PubMed: 38566589
DOI: 10.1242/dmm.050671 -
Molecular Genetics & Genomic Medicine Apr 2024Mandibulofacial dysostosis with microcephaly (MFDM, OMIM# 610536) is a rare monogenic disease that is caused by a mutation in the elongation factor Tu GTP binding domain...
BACKGROUND
Mandibulofacial dysostosis with microcephaly (MFDM, OMIM# 610536) is a rare monogenic disease that is caused by a mutation in the elongation factor Tu GTP binding domain containing 2 gene (EFTUD2, OMIM* 603892). It is characterized by mandibulofacial dysplasia, microcephaly, malformed ears, cleft palate, growth and intellectual disability. MFDM can be easily misdiagnosed due to its phenotypic overlap with other craniofacial dysostosis syndromes. The clinical presentation of MFDM is highly variable among patients.
METHODS
A patient with craniofacial anomalies was enrolled and evaluated by a multidisciplinary team. To make a definitive diagnosis, whole-exome sequencing was performed, followed by validation by Sanger sequencing.
RESULTS
The patient presented with extensive facial bone dysostosis, upward slanting palpebral fissures, outer and middle ear malformation, a previously unreported orbit anomaly, and spina bifida occulta. A novel, pathogenic insertion mutation (c.215_216insT: p.Tyr73Valfs*4) in EFTUD2 was identified as the likely cause of the disease.
CONCLUSIONS
We diagnosed this atypical case of MFDM by the detection of a novel pathogenetic mutation in EFTUD2. We also observed previously unreported features. These findings enrich both the genotypic and phenotypic spectrum of MFDM.
Topics: Humans; Microcephaly; Mandibulofacial Dysostosis; Phenotype; Mutation; Intellectual Disability; Peptide Elongation Factors; Ribonucleoprotein, U5 Small Nuclear
PubMed: 38562046
DOI: 10.1002/mgg3.2426 -
Molecular Medicine Reports May 2024Recurrent miscarriage is used to refer to more than three pregnancy failures before 20 weeks of gestation. Defective trophoblast cell growth and invasion are frequently...
Recurrent miscarriage is used to refer to more than three pregnancy failures before 20 weeks of gestation. Defective trophoblast cell growth and invasion are frequently observed in recurrent miscarriage. Several microRNAs (miRs), including miR‑155‑5p, are aberrantly upregulated in recurrent miscarriage; however, the underlying molecular mechanisms remain unclear. The centrosome orchestrates microtubule networks and coordinates cell cycle progression. In addition, it is a base for primary cilia, which are antenna‑like organelles that coordinate signaling during development and growth. Thus, deficiencies in centrosomal functions can lead to several disease, such as breast cancer and microcephaly. In the present study, the signaling cascades were analyzed by western blotting, and the centrosome and primary cilia were observed and analyzed by immunofluorescence staining. The results showed that overexpression of miR‑155‑5p induced centrosome amplification and blocked primary cilia formation in trophoblast cells. Notably, centrosome amplification inhibited trophoblast cell growth by upregulating apoptotic cleaved‑caspase 3 and cleaved‑poly (ADP‑ribose) polymerase in miR‑155‑5p‑overexpressing trophoblast cells. In addition, overexpression of miR‑155‑5p inhibited primary cilia formation, thereby inhibiting epithelial‑mesenchymal transition and trophoblast cell invasion. All phenotypes could be rescued when cells were co‑transfected with the miR‑155‑5p inhibitor, thus supporting the role of miR‑155‑5p in centrosomal functions. It was also found that miR‑155‑5p activated autophagy, whereas disruption of autophagy via the depletion of autophagy‑related 16‑like 1 alleviated miR‑155‑5p‑induced apoptosis and restored trophoblast cell invasion. In conclusion, the present study indicated a novel role of miR‑55‑5p in mediating centrosomal function in recurrent miscarriage.
Topics: Pregnancy; Female; Humans; MicroRNAs; Trophoblasts; Cell Proliferation; Centrosome; Cell Movement; Abortion, Habitual
PubMed: 38551159
DOI: 10.3892/mmr.2024.13209 -
Clinical Case Reports Apr 2024Fanconi anemia with Mitomycin C sensitivity is a rare, complex hematological condition. Our case study emphasizes the significance of early diagnosis, appropriate...
KEY CLINICAL MESSAGE
Fanconi anemia with Mitomycin C sensitivity is a rare, complex hematological condition. Our case study emphasizes the significance of early diagnosis, appropriate genetic testing, and cautious use of chemotherapeutic agents.
ABSTRACT
Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, congenital anomalies, and predisposition to cancer. Here, we present the case of a 6-year-old boy with a known diagnosis of Fanconi anemia who exhibited sensitivity to Mitomycin C. The patient had a history of recurrent blood transfusions due to anemia and was referred to our institution following worsening symptoms, including pallor, swelling in limbs, and respiratory distress. Physical examination revealed characteristic features of FA such as mesomelia, low-set ears, hyperpigmented macules, microcephaly, micropthalmos, and thumb hypoplasia. Imaging studies demonstrated bilateral radial hypoplasia and congenital agenesis of the left kidney. Laboratory investigations revealed pancytopenia, aberrant liver function tests, and elevated inflammatory markers. Importantly, the patient exhibited sensitivity to Mitomycin C, highlighting the necessity for caution in selecting chemotherapeutic agents in FA patients. This case underscores the importance of early recognition, comprehensive evaluation, and tailored management strategies of patients with Fanconi anemia to optimize outcomes and minimize complications.
PubMed: 38550724
DOI: 10.1002/ccr3.8711