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International Journal of Molecular... May 2022Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of vacuolating leukodystrophy (white matter disorder), which is mainly caused by defects... (Review)
Review
Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a rare type of vacuolating leukodystrophy (white matter disorder), which is mainly caused by defects in MLC1 or glial cell adhesion molecule (GlialCAM) proteins. In addition, autoantibodies to GlialCAM are involved in the pathology of multiple sclerosis. and genes encode for membrane proteins of unknown function, which has been linked to the regulation of different ion channels and transporters, such as the chloride channel VRAC (volume regulated anion channel), ClC-2 (chloride channel 2), and connexin 43 or the Na/K-ATPase pump. However, the mechanisms by which MLC proteins regulate these ion channels and transporters, as well as the exact function of MLC proteins remain obscure. It has been suggested that MLC proteins might regulate signalling pathways, but the mechanisms involved are, at present, unknown. With the aim of answering these questions, we have recently described the brain GlialCAM interactome. Within the identified proteins, we could validate the interaction with several G protein-coupled receptors (GPCRs), including the orphan GPRC5B and the proposed prosaposin receptors GPR37L1 and GPR37. In this review, we summarize new aspects of the pathophysiology of MLC disease and key aspects of the interaction between GPR37 receptors and MLC proteins.
Topics: Astrocytes; Chloride Channels; Cysts; Hereditary Central Nervous System Demyelinating Diseases; Humans; Megalencephaly; Membrane Proteins; Nervous System Malformations; Receptors, G-Protein-Coupled
PubMed: 35628339
DOI: 10.3390/ijms23105528 -
Molecular Genetics & Genomic Medicine Aug 2021Phosphatase and tensin homolog (PTEN) germline mutations are associated with cancer syndromes (PTEN hamartoma tumor syndrome; PHTS) and in pediatric patients with autism...
BACKGROUND
Phosphatase and tensin homolog (PTEN) germline mutations are associated with cancer syndromes (PTEN hamartoma tumor syndrome; PHTS) and in pediatric patients with autism spectrum disorder (ASD) and macrocephaly. The exact prevalence of PTEN mutations in patients with ASD and macrocephaly is uncertain; with prevalence rates ranging from 1% to 17%. Most studies are retrospective and contain more adult than pediatric patients, there is a need for more prospective pediatric studies.
METHODS
We recruited 131 patients (108 males, 23 females) with ASD and macrocephaly between the ages of 3 and 18 from five child and adolescent psychiatry clinics in Turkey from July 2018 to December 2019. We defined macrocephaly as occipito-frontal HC size at or greater than 2 standard deviations (SD) above the mean for age and sex on standard growth charts. PTEN gene sequence analysis was performed using a MiSeq next generation sequencing (NGS) platform, (Illumina).
CONCLUSION
PTEN gene sequence analyses identified three pathogenic/likely pathogenic mutations [NM_000314.6; p.(Pro204Leu), (p.Arg233*) and novel (p.Tyr176Cys*8)] and two variants of uncertain significance (VUS) [NM_000314.6; p.(Ala79Thr) and c.*10del]. We also report that patient with (p.Tyr176Cys*8) mutation has Grade 1 hepatosteatosis, a phenotype not previously described. This is the first PTEN prevalence study of patients with ASD and macrocephaly in Turkey and South Eastern Europe region with a largest homogenous cohort. The prevalence of PTEN mutations was found 3.8% (VUS included) or 2.29% (VUS omitted). We recommend testing for PTEN mutations in all patients with ASD and macrocephaly.
Topics: Adolescent; Autism Spectrum Disorder; Child; Child, Preschool; Female; Gene Frequency; Humans; Male; Megalencephaly; Mutation; PTEN Phosphohydrolase; Turkey
PubMed: 34268892
DOI: 10.1002/mgg3.1739 -
European Journal of Medical Genetics Dec 2022Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and...
BACKGROUND
Pathogenic PTEN germline variants cause PTEN Hamartoma Tumor Syndrome (PHTS), a rare disease with a variable genotype and phenotype. Knowledge about these spectra and genotype-phenotype associations could help diagnostics and potentially lead to personalized care. Therefore, we assessed the PHTS genotype and phenotype spectrum in a large cohort study.
METHODS
Information was collected of 510 index patients with pathogenic or likely pathogenic (LP/P) PTEN variants (n = 467) or variants of uncertain significance. Genotype-phenotype associations were assessed using logistic regression analyses adjusted for sex and age.
RESULTS
At time of genetic testing, the majority of children (n = 229) had macrocephaly (81%) or developmental delay (DD, 61%), and about half of the adults (n = 238) had cancer (51%), macrocephaly (61%), or cutaneous pathology (49%). Across PTEN, 268 LP/P variants were identified, with exon 5 as hotspot. Missense variants (n = 161) were mainly located in the phosphatase domain (PD, 90%) and truncating variants (n = 306) across all domains. A trend towards 2 times more often truncating variants was observed in adults (OR = 2.3, 95%CI = 1.5-3.4) and patients with cutaneous pathology (OR = 1.6, 95%CI = 1.1-2.5) or benign thyroid pathology (OR = 2.0, 95%CI = 1.1-3.5), with trends up to 2-4 times more variants in PD. Whereas patients with DD (OR = 0.5, 95%CI = 0.3-0.9) or macrocephaly (OR = 0.6, 95%CI = 0.4-0.9) had about 2 times less often truncating variants compared to missense variants. In DD patients these missense variants were often located in domain C2.
CONCLUSION
The PHTS phenotypic diversity may partly be explained by the PTEN variant coding effect and the combination of coding effect and domain. PHTS patients with early-onset disease often had missense variants, and those with later-onset disease often truncating variants.
Topics: Humans; Hamartoma Syndrome, Multiple; Cohort Studies; Genetic Association Studies; PTEN Phosphohydrolase; Megalencephaly; Phenotype
PubMed: 36270489
DOI: 10.1016/j.ejmg.2022.104632 -
Annual Review of Pathology Jan 2019Malformations of cortical development encompass heterogeneous groups of structural brain anomalies associated with complex neurodevelopmental disorders and diverse... (Review)
Review
Malformations of cortical development encompass heterogeneous groups of structural brain anomalies associated with complex neurodevelopmental disorders and diverse genetic and nongenetic etiologies. Recent progress in understanding the genetic basis of brain malformations has been driven by extraordinary advances in DNA sequencing technologies. For example, somatic mosaic mutations that activate mammalian target of rapamycin signaling in cortical progenitor cells during development are now recognized as the cause of hemimegalencephaly and some types of focal cortical dysplasia. In addition, research on brain development has begun to reveal the cellular and molecular bases of cortical gyrification and axon pathway formation, providing better understanding of disorders involving these processes. New neuroimaging techniques with improved resolution have enhanced our ability to characterize subtle malformations, such as those associated with intellectual disability and autism. In this review, we broadly discuss cortical malformations and focus on several for which genetic etiologies have elucidated pathogenesis.
Topics: Cerebral Cortex; Hemimegalencephaly; Humans; Intellectual Disability; Lissencephaly; Malformations of Cortical Development; Microcephaly; Mutation; Neurodevelopmental Disorders; Neuroimaging; Polymicrogyria
PubMed: 30677308
DOI: 10.1146/annurev-pathmechdis-012418-012927 -
International Journal of Molecular... May 2024Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians.... (Review)
Review
Macrocephaly, characterized by an abnormally large head circumference, often co-occurs with distinctive finger changes, presenting a diagnostic challenge for clinicians. This review aims to provide a current synthetic overview of the main acquired and genetic etiologies associated with macrocephaly and finger changes. The genetic cause encompasses several categories of diseases, including bone marrow expansion disorders, skeletal dysplasias, ciliopathies, inherited metabolic diseases, RASopathies, and overgrowth syndromes. Furthermore, autoimmune and autoinflammatory diseases are also explored for their potential involvement in macrocephaly and finger changes. The intricate genetic mechanisms involved in the formation of cranial bones and extremities are multifaceted. An excess in growth may stem from disruptions in the intricate interplays among the genetic, epigenetic, and hormonal factors that regulate human growth. Understanding the underlying cellular and molecular mechanisms is important for elucidating the developmental pathways and biological processes that contribute to the observed clinical phenotypes. The review provides a practical approach to delineate causes of macrocephaly and finger changes, facilitate differential diagnosis and guide for the appropriate etiological framework. Early recognition contributes to timely intervention and improved outcomes for affected individuals.
Topics: Humans; Megalencephaly; Fingers
PubMed: 38791606
DOI: 10.3390/ijms25105567 -
Dialogues in Clinical Neuroscience Dec 2018Expansion of the human brain, and specifically the neocortex, is among the most remarkable evolutionary processes that correlates with cognitive, emotional, and social... (Review)
Review
Expansion of the human brain, and specifically the neocortex, is among the most remarkable evolutionary processes that correlates with cognitive, emotional, and social abilities. Cortical expansion is determined through a tightly orchestrated process of neural stem cell proliferation, migration, and ongoing organization, synaptogenesis, and apoptosis. Perturbations of each of these intricate steps can lead to abnormalities of brain size in humans, whether small (microcephaly) or large (megalencephaly). Abnormalities of brain growth can be clinically isolated or occur as part of complex syndromes associated with other neurodevelopmental problems (eg, epilepsy, autism, intellectual disability), brain malformations, and body growth abnormalities. Thorough review of the genetic literature reveals that human microcephaly and megalencephaly are caused by mutations of a rapidly growing number of genes linked within critical cellular pathways that impact early brain development, with important pathomechanistic links to cancer, body growth, and epilepsy. Given the rapid rate of causal gene identification for microcephaly and megalencephaly understanding the roles and interplay of these important signaling pathways is crucial to further unravel the mechanisms underlying brain growth disorders and, more fundamentally, normal brain growth and development in humans. In this review, we will (a) overview the definitions of microcephaly and megalencephaly, highlighting their classifications in clinical practice; (b) overview the most common genes and pathways underlying microcephaly and megalencephaly based on the fundamental cellular processes that are perturbed during cortical development; and (c) outline general clinical molecular diagnostic workflows for children and adults presenting with microcephaly and megalencephaly.
Topics: Autistic Disorder; Brain; Humans; Megalencephaly; Microcephaly; Mutation; Organ Size
PubMed: 30936767
DOI: 10.31887/DCNS.2018.20.4/gmirzaa -
Biomedicines Jun 2022Sporadic vascular malformations (VMs) are a large group of disorders of the blood and lymphatic vessels caused by somatic mutations in several genes-mainly regulating...
Sporadic vascular malformations (VMs) are a large group of disorders of the blood and lymphatic vessels caused by somatic mutations in several genes-mainly regulating the RAS/MAPK/ERK and PI3K/AKT/mTOR pathways. We performed a cross-sectional study of 43 patients affected with sporadic VMs, who had received molecular diagnosis by high-depth targeted next-generation sequencing in our center. Clinical and imaging features were correlated with the sequence variants identified in lesional tissues. Six of nine patients with capillary malformation and overgrowth (CMO) carried the recurrent somatic mutation p.Arg183Gln, while two had mutations. Unexpectedly, 8 of 11 cases of diffuse CM with overgrowth (DCMO) carried known mutations, and the remaining 3 had pathogenic variants. Recurrent mutations were identified in the patients with megalencephaly-CM-polymicrogyria (MCAP), CLOVES, and Klippel-Trenaunay syndrome. Interestingly, somatic mutations were associated with hand/foot anomalies not only in MCAP and CLOVES, but also in CMO and DCMO. Two patients with blue rubber bleb nevus syndrome carried double somatic mutations, two of which were previously undescribed. In addition, a novel sporadic case of Parkes Weber syndrome (PWS) due to an mosaic pathogenic variant was described. Finally, a girl with a mild PWS and another diagnosed with CMO carried pathogenic somatic variants, showing the variability of phenotypic features associated with mutations. Overall, our findings expand the clinical and molecular spectrum of sporadic VMs, and show the relevance of genetic testing for accurate diagnosis and emerging targeted therapies.
PubMed: 35740480
DOI: 10.3390/biomedicines10061460 -
Frontiers in Neuroscience 2023Brain size is controlled by several factors during neuronal development, including neural progenitor proliferation, neuronal arborization, gliogenesis, cell death, and... (Review)
Review
Brain size is controlled by several factors during neuronal development, including neural progenitor proliferation, neuronal arborization, gliogenesis, cell death, and synaptogenesis. Multiple neurodevelopmental disorders have co-morbid brain size abnormalities, such as microcephaly and macrocephaly. Mutations in histone methyltransferases that modify histone H3 on Lysine 36 and Lysine 4 (H3K36 and H3K4) have been identified in neurodevelopmental disorders involving both microcephaly and macrocephaly. H3K36 and H3K4 methylation are both associated with transcriptional activation and are proposed to sterically hinder the repressive activity of the Polycomb Repressor Complex 2 (PRC2). During neuronal development, tri-methylation of H3K27 (H3K27me3) by PRC2 leads to genome wide transcriptional repression of genes that regulate cell fate transitions and neuronal arborization. Here we provide a review of neurodevelopmental processes and disorders associated with H3K36 and H3K4 histone methyltransferases, with emphasis on processes that contribute to brain size abnormalities. Additionally, we discuss how the counteracting activities of H3K36 and H3K4 modifying enzymes vs. PRC2 could contribute to brain size abnormalities which is an underexplored mechanism in relation to brain size control.
PubMed: 36845425
DOI: 10.3389/fnins.2023.989109 -
AJNR. American Journal of Neuroradiology Oct 2021Definitions of fetal microcephaly and macrocephaly are debatable. A better understanding of their long-term prognoses would help guide parental education and counseling....
BACKGROUND AND PURPOSE
Definitions of fetal microcephaly and macrocephaly are debatable. A better understanding of their long-term prognoses would help guide parental education and counseling. This study aimed to explore the correlation between 2D and 3D fetal brain MR imaging biometry results and the long-term neurodevelopmental outcomes.
MATERIALS AND METHODS
This analysis is a historical cohort study. Fetal brain biometry was measured on 2D and 3D MR imaging using a volumetric MR imaging semiautomated algorithm. We measured and assessed the following brain structures: the supratentorial brain volume and cerebellar volume and cerebellar volume/supratentorial brain volume ratio, in addition to commonly used 2D brain MR imaging biometric variables, including occipitofrontal diameter, biparietal diameter, and transcerebellar diameter. Microcephaly was defined as ≤ 3rd percentile; and macrocephaly, as ≥ 97th percentile, corresponding to -2 SDs and +2 SDs. The neurodevelopmental outcome of this study cohort was evaluated using the Vineland-II Adaptive Behavior Scales, and the measurements were correlated to the Vineland standard scores.
RESULTS
A total of 70 fetuses were included. No significant correlation was observed between the Vineland scores and either the supratentorial brain volume, cerebellar volume, or supratentorial brain volume/cerebellar volume ratio in 3D or 2D MR imaging measurements, after correction for multiple comparisons. No differences were found among fetuses with macrocephaly, normocephaly, or microcephaly regarding the median Vineland standard scores.
CONCLUSIONS
Provided there is normal brain structure on MR imaging, the developmental milestone achievements in early years are unrelated to 2D and 3D fetal brain MR imaging biometry, in the range of measurements depicted in this study.
Topics: Biometry; Brain; Cohort Studies; Female; Fetus; Gestational Age; Humans; Magnetic Resonance Imaging; Megalencephaly; Microcephaly; Pregnancy; Ultrasonography, Prenatal
PubMed: 34385141
DOI: 10.3174/ajnr.A7225 -
Neurosurgical Review Oct 2011Benign external hydrocephalus in infants, characterized by macrocephaly and typical neuroimaging findings, is considered as a self-limiting condition and is therefore... (Review)
Review
Benign external hydrocephalus in infants, characterized by macrocephaly and typical neuroimaging findings, is considered as a self-limiting condition and is therefore rarely treated. This review concerns all aspects of this condition: etiology, neuroimaging, symptoms and clinical findings, treatment, and outcome, with emphasis on management. The review is based on a systematic search in the Pubmed and Web of Science databases. The search covered various forms of hydrocephalus, extracerebral fluid, and macrocephaly. Studies reporting small children with idiopathic external hydrocephalus were included, mostly focusing on the studies reporting a long-term outcome. A total of 147 studies are included, the majority however with a limited methodological quality. Several theories regarding pathophysiology and various symptoms, signs, and clinical findings underscore the heterogeneity of the condition. Neuroimaging is important in the differentiation between external hydrocephalus and similar conditions. A transient delay of psychomotor development is commonly seen during childhood. A long-term outcome is scarcely reported, and the results are varying. Although most children with external hydrocephalus seem to do well both initially and in the long term, a substantial number of patients show temporary or permanent psychomotor delay. To verify that this truly is a benign condition, we suggest that future research on external hydrocephalus should focus on the long-term effects of surgical treatment as opposed to conservative management.
Topics: Cerebrospinal Fluid Shunts; Diagnosis, Differential; Electroencephalography; Fetal Diseases; Humans; Hydrocephalus; Infant; Infant, Newborn; Neuropsychological Tests; Treatment Outcome
PubMed: 21647596
DOI: 10.1007/s10143-011-0327-4