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Frontiers in Pediatrics 2021Macrocephaly affects up to 5% of the pediatric population and is defined as an abnormally large head with an occipitofrontal circumference (OFC) >2 standard deviations... (Review)
Review
Macrocephaly affects up to 5% of the pediatric population and is defined as an abnormally large head with an occipitofrontal circumference (OFC) >2 standard deviations (SD) above the mean for a given age and sex. Taking into account that about 2-3% of the healthy population has an OFC between 2 and 3 SD, macrocephaly is considered as "clinically relevant" when OFC is above 3 SD. This implies the urgent need for a diagnostic workflow to use in the clinical setting to dissect the several causes of increased OFC, from the benign form of familial macrocephaly and the Benign enlargement of subarachnoid spaces (BESS) to many pathological conditions, including genetic disorders. Moreover, macrocephaly should be differentiated by megalencephaly (MEG), which refers exclusively to brain overgrowth, exceeding twice the SD (3SD-"clinically relevant" megalencephaly). While macrocephaly can be isolated and benign or may be the first indication of an underlying congenital, genetic, or acquired disorder, megalencephaly is most likely due to a genetic cause. Apart from the head size evaluation, a detailed family and personal history, neuroimaging, and a careful clinical evaluation are crucial to reach the correct diagnosis. In this review, we seek to underline the clinical aspects of macrocephaly and megalencephaly, emphasizing the main differential diagnosis with a major focus on common genetic disorders. We thus provide a clinico-radiological algorithm to guide pediatricians in the assessment of children with macrocephaly.
PubMed: 35096710
DOI: 10.3389/fped.2021.794069 -
Life (Basel, Switzerland) May 2022This paper describes the contemporary state of knowledge regarding processes that regulate normal development of the embryonic-fetal central nervous system (CNS). The... (Review)
Review
This paper describes the contemporary state of knowledge regarding processes that regulate normal development of the embryonic-fetal central nervous system (CNS). The processes are described according to the developmental timetable: dorsal induction, ventral induction, neurogenesis, neuronal migration, post-migration neuronal development, and cortical organization. We review the current literature on CNS malformations associated with these regulating processes. We specifically address neural tube defects, holoprosencephaly, malformations of cortical development (including microcephaly, megalencephaly, lissencephaly, cobblestone malformations, gray matter heterotopia, and polymicrogyria), disorders of the corpus callosum, and posterior fossa malformations. Fetal ventriculomegaly, which frequently accompanies these disorders, is also reviewed. Each malformation is described with reference to the etiology, genetic causes, prenatal sonographic imaging, associated anomalies, differential diagnosis, complimentary diagnostic studies, clinical interventions, neurodevelopmental outcome, and life quality.
PubMed: 35743840
DOI: 10.3390/life12060809 -
Human Mutation Sep 2018Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals....
Malan syndrome is an overgrowth disorder described in a limited number of individuals. We aim to delineate the entity by studying a large group of affected individuals. We gathered data on 45 affected individuals with a molecularly confirmed diagnosis through an international collaboration and compared data to the 35 previously reported individuals. Results indicate that height is > 2 SDS in infancy and childhood but in only half of affected adults. Cardinal facial characteristics include long, triangular face, macrocephaly, prominent forehead, everted lower lip, and prominent chin. Intellectual disability is universally present, behaviorally anxiety is characteristic. Malan syndrome is caused by deletions or point mutations of NFIX clustered mostly in exon 2. There is no genotype-phenotype correlation except for an increased risk for epilepsy with 19p13.2 microdeletions. Variants arose de novo, except in one family in which mother was mosaic. Variants causing Malan and Marshall-Smith syndrome can be discerned by differences in the site of stop codon formation. We conclude that Malan syndrome has a well recognizable phenotype that usually can be discerned easily from Marshall-Smith syndrome but rarely there is some overlap. Differentiation from Sotos and Weaver syndrome can be made by clinical evaluation only.
Topics: Abnormalities, Multiple; Adolescent; Adult; Bone Diseases, Developmental; Child; Child, Preschool; Chromosome Deletion; Congenital Hypothyroidism; Craniofacial Abnormalities; Developmental Disabilities; Exons; Female; Hand Deformities, Congenital; Humans; Intellectual Disability; Male; Megalencephaly; Mutation, Missense; NFI Transcription Factors; Phenotype; Septo-Optic Dysplasia; Sotos Syndrome; Young Adult
PubMed: 29897170
DOI: 10.1002/humu.23563 -
Brain : a Journal of Neurology Sep 2019The underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and...
The underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and genome sequencing as well as array analysis of 13 individuals that point to pathogenic, heterozygous, mostly de novo variants in WDFY3 (significant de novo enrichment P = 0.003) as a monogenic cause of mild and non-specific neurodevelopmental delay. Nine variants were protein-truncating and four missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders (autism spectrum disorders/attention deficit hyperactivity disorder). One proband presented with an opposing phenotype of microcephaly and the only missense-variant located in the PH-domain of WDFY3. Findings of this case are supported by previously published data, demonstrating that pathogenic PH-domain variants can lead to microcephaly via canonical Wnt-pathway upregulation. In a separate study, we reported that the autophagy scaffolding protein WDFY3 is required for cerebral cortical size regulation in mice, by controlling proper division of neural progenitors. Here, we show that proliferating cortical neural progenitors of human embryonic brains highly express WDFY3, further supporting a role for this molecule in the regulation of prenatal neurogenesis. We present data on Wnt-pathway dysregulation in Wdfy3-haploinsufficient mice, which display macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. Consequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway. In summary, we present WDFY3 as a novel gene linked to mild to moderate neurodevelopmental delay and intellectual disability and conclude that variants putatively causing haploinsufficiency lead to macrocephaly, while an opposing pathomechanism due to variants in the PH-domain of WDFY3 leads to microcephaly.
Topics: Adaptor Proteins, Signal Transducing; Adolescent; Animals; Autophagy-Related Proteins; Brain; Child; Child, Preschool; Female; Genetic Variation; Humans; Male; Mice; Mice, Transgenic; Neurodevelopmental Disorders; Organ Size; Protein Structure, Secondary
PubMed: 31327001
DOI: 10.1093/brain/awz198 -
Neurobiology of Disease Jun 2023The mechanistic target of rapamycin (mTOR) signaling pathway is an essential regulator of numerous cellular activities such as metabolism, growth, proliferation, and... (Review)
Review
The mechanistic target of rapamycin (mTOR) signaling pathway is an essential regulator of numerous cellular activities such as metabolism, growth, proliferation, and survival. The mTOR cascade recently emerged as a critical player in the pathogenesis of focal epilepsies and cortical malformations. The 'mTORopathies' comprise a spectrum of cortical malformations that range from whole brain (megalencephaly) and hemispheric (hemimegalencephaly) abnormalities to focal abnormalities, such as focal cortical dysplasia type II (FCDII), which manifest with drug-resistant epilepsies. The spectrum of cortical dysplasia results from somatic brain mutations in the mTOR pathway activators AKT3, MTOR, PIK3CA, and RHEB and from germline and somatic mutations in mTOR pathway repressors, DEPDC5, NPRL2, NPRL3, TSC1 and TSC2. The mTORopathies are characterized by excessive mTOR pathway activation, leading to a broad range of structural and functional impairments. Here, we provide a comprehensive literature review of somatic mTOR-activating mutations linked to epilepsy and cortical malformations in 292 patients and discuss the perspectives of targeted therapeutics for personalized medicine.
Topics: Humans; Mosaicism; Mutation; Brain; Epilepsy; TOR Serine-Threonine Kinases; Malformations of Cortical Development; GTPase-Activating Proteins
PubMed: 37149062
DOI: 10.1016/j.nbd.2023.106144 -
Nature Communications Nov 2018Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in...
Chromatin remodeling is of crucial importance during brain development. Pathogenic alterations of several chromatin remodeling ATPases have been implicated in neurodevelopmental disorders. We describe an index case with a de novo missense mutation in CHD3, identified during whole genome sequencing of a cohort of children with rare speech disorders. To gain a comprehensive view of features associated with disruption of this gene, we use a genotype-driven approach, collecting and characterizing 35 individuals with de novo CHD3 mutations and overlapping phenotypes. Most mutations cluster within the ATPase/helicase domain of the encoded protein. Modeling their impact on the three-dimensional structure demonstrates disturbance of critical binding and interaction motifs. Experimental assays with six of the identified mutations show that a subset directly affects ATPase activity, and all but one yield alterations in chromatin remodeling. We implicate de novo CHD3 mutations in a syndrome characterized by intellectual disability, macrocephaly, and impaired speech and language.
Topics: Adenosine Triphosphatases; Child, Preschool; Chromatin Assembly and Disassembly; DNA Helicases; Developmental Disabilities; Female; Gene Expression; Genotype; HEK293 Cells; Humans; Intellectual Disability; Language Disorders; Male; Megalencephaly; Mi-2 Nucleosome Remodeling and Deacetylase Complex; Models, Molecular; Mutation, Missense; Neurodevelopmental Disorders; Phenotype; Protein Domains; Speech Disorders; Whole Genome Sequencing
PubMed: 30397230
DOI: 10.1038/s41467-018-06014-6 -
American Journal of Human Genetics Nov 2018Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by...
Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α-subunit of the voltage-gated Ca2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed Ca2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.
Topics: Adolescent; Adult; Calcium Channels, R-Type; Cation Transport Proteins; Child; Child, Preschool; Contracture; Dyskinesias; Epilepsy; Female; Genetic Variation; Humans; Infant; Male; Megalencephaly; Neurodevelopmental Disorders; Spasms, Infantile
PubMed: 30343943
DOI: 10.1016/j.ajhg.2018.09.006 -
Science (New York, N.Y.) Dec 2012Exome sequencing studies of autism spectrum disorders (ASDs) have identified many de novo mutations but few recurrently disrupted genes. We therefore developed a...
Exome sequencing studies of autism spectrum disorders (ASDs) have identified many de novo mutations but few recurrently disrupted genes. We therefore developed a modified molecular inversion probe method enabling ultra-low-cost candidate gene resequencing in very large cohorts. To demonstrate the power of this approach, we captured and sequenced 44 candidate genes in 2446 ASD probands. We discovered 27 de novo events in 16 genes, 59% of which are predicted to truncate proteins or disrupt splicing. We estimate that recurrent disruptive mutations in six genes-CHD8, DYRK1A, GRIN2B, TBR1, PTEN, and TBL1XR1-may contribute to 1% of sporadic ASDs. Our data support associations between specific genes and reciprocal subphenotypes (CHD8-macrocephaly and DYRK1A-microcephaly) and replicate the importance of a β-catenin-chromatin-remodeling network to ASD etiology.
Topics: Cephalometry; Child; Child Development Disorders, Pervasive; Child, Preschool; Chromatin Assembly and Disassembly; Cohort Studies; DNA Probes; DNA-Binding Proteins; Exome; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Male; Megalencephaly; Microcephaly; Mutation; Nuclear Proteins; PTEN Phosphohydrolase; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Receptors, Cytoplasmic and Nuclear; Receptors, N-Methyl-D-Aspartate; Repressor Proteins; Sequence Analysis, DNA; T-Box Domain Proteins; Transcription Factors; beta Catenin; Dyrk Kinases
PubMed: 23160955
DOI: 10.1126/science.1227764