-
JAMA Neurology Sep 2023Polymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and...
IMPORTANCE
Polymicrogyria is the most commonly diagnosed cortical malformation and is associated with neurodevelopmental sequelae including epilepsy, motor abnormalities, and cognitive deficits. Polymicrogyria frequently co-occurs with other brain malformations or as part of syndromic diseases. Past studies of polymicrogyria have defined heterogeneous genetic and nongenetic causes but have explained only a small fraction of cases.
OBJECTIVE
To survey germline genetic causes of polymicrogyria in a large cohort and to consider novel polymicrogyria gene associations.
DESIGN, SETTING, AND PARTICIPANTS
This genetic association study analyzed panel sequencing and exome sequencing of accrued DNA samples from a retrospective cohort of families with members with polymicrogyria. Samples were accrued over more than 20 years (1994 to 2020), and sequencing occurred in 2 stages: panel sequencing (June 2015 to January 2016) and whole-exome sequencing (September 2019 to March 2020). Individuals seen at multiple clinical sites for neurological complaints found to have polymicrogyria on neuroimaging, then referred to the research team by evaluating clinicians, were included in the study. Targeted next-generation sequencing and/or exome sequencing were performed on probands (and available parents and siblings) from 284 families with individuals who had isolated polymicrogyria or polymicrogyria as part of a clinical syndrome and no genetic diagnosis at time of referral from clinic, with sequencing from 275 families passing quality control.
MAIN OUTCOMES AND MEASURES
The number of families in whom genetic sequencing yielded a molecular diagnosis that explained the polymicrogyria in the family. Secondarily, the relative frequency of different genetic causes of polymicrogyria and whether specific genetic causes were associated with co-occurring head size changes were also analyzed.
RESULTS
In 32.7% (90 of 275) of polymicrogyria-affected families, genetic variants were identified that provided satisfactory molecular explanations. Known genes most frequently implicated by polymicrogyria-associated variants in this cohort were PIK3R2, TUBB2B, COL4A1, and SCN3A. Six candidate novel polymicrogyria genes were identified or confirmed: de novo missense variants in PANX1, QRICH1, and SCN2A and compound heterozygous variants in TMEM161B, KIF26A, and MAN2C1, each with consistent genotype-phenotype relationships in multiple families.
CONCLUSIONS AND RELEVANCE
This study's findings reveal a higher than previously recognized rate of identifiable genetic causes, specifically of channelopathies, in individuals with polymicrogyria and support the utility of exome sequencing for families affected with polymicrogyria.
Topics: Humans; Polymicrogyria; Exome Sequencing; Retrospective Studies; Mutation, Missense; Siblings; Nerve Tissue Proteins; Connexins
PubMed: 37486637
DOI: 10.1001/jamaneurol.2023.2363 -
Developmental Cell Dec 2023The cerebral cortex-the brain's covering and largest region-has increased in size and complexity in humans and supports higher cognitive functions such as language and... (Review)
Review
The cerebral cortex-the brain's covering and largest region-has increased in size and complexity in humans and supports higher cognitive functions such as language and abstract thinking. There is a growing understanding of the human cerebral cortex, including the diversity and number of cell types that it contains, as well as of the developmental mechanisms that shape cortical structure and organization. In this review, we discuss recent progress in our understanding of molecular and cellular processes, as well as mechanical forces, that regulate the folding of the cerebral cortex. Advances in human genetics, coupled with experimental modeling in gyrencephalic species, have provided insights into the central role of cortical progenitors in the gyrification and evolutionary expansion of the cerebral cortex. These studies are essential for understanding the emergence of structural and functional organization during cortical development and the pathogenesis of neurodevelopmental disorders associated with cortical malformations.
Topics: Humans; Cerebral Cortex; Brain; Biological Evolution; Neurogenesis
PubMed: 38113850
DOI: 10.1016/j.devcel.2023.11.004 -
International Journal of Developmental... Nov 2023Cortical development depends on neuronal migration of both excitatory and inhibitory interneurons. Neuronal migration disorders (NMDs) are conditions characterised by... (Review)
Review
Cortical development depends on neuronal migration of both excitatory and inhibitory interneurons. Neuronal migration disorders (NMDs) are conditions characterised by anatomical cortical defects leading to varying degrees of neurocognitive impairment, developmental delay and seizures. Refractory epilepsy affects 15 million people worldwide, and it is thought that cortical developmental disorders are responsible for 25% of childhood cases. However, little is known about the epidemiology of these disorders, nor are their aetiologies fully understood, though many are associated with sporadic genetic mutations. In this review, we aim to highlight X-linked NMDs including lissencephaly, periventricular nodular heterotopia and polymicrogyria because of their mostly familial inheritance pattern. We focus on the most prominent genes responsible: including DCX, ARX, FLNA, FMR1, L1CAM, SRPX2, DDX3X, NSHDL, CUL4B and OFD1, outlining what is known about their prevalence among NMDs, and the underlying pathophysiology. X-linked disorders are important to recognise clinically, as females often have milder phenotypes. Consequently, there is a greater chance they survive to reproductive age and risk passing the mutations down. Effective genetic screening is important to prevent and treat these conditions, and for this, we need to know gene mutations and have a clear understanding of the function of the genes involved. This review summarises the knowledge base and provides clear direction for future work by both scientists and clinicians alike.
Topics: Female; Humans; Epilepsy; Sex Factors; Genetic Testing; Mutation; Malformations of Cortical Development, Group II; Fragile X Mental Retardation Protein; Cullin Proteins
PubMed: 37574439
DOI: 10.1002/jdn.10290 -
Developmental Medicine and Child... Feb 2024Malformations of cortical development (MCDs) represent a heterogeneous spectrum of disorders characterized by atypical development of the cerebral cortex. MCDs are most... (Review)
Review
Malformations of cortical development (MCDs) represent a heterogeneous spectrum of disorders characterized by atypical development of the cerebral cortex. MCDs are most often diagnosed on the basis of imaging, although subtle lesions, such as focal cortical dysplasia, may only be revealed on neuropathology. Different subtypes have been defined, including lissencephaly, heterotopia, cobblestone malformation, polymicrogyria, and dysgyria. Many MCDs are of genetic origin, although acquired factors, such as congenital cytomegalovirus infections and twinning sequence, can lead to similar phenotypes. In this narrative review, we provide an overview of the diagnostic approach to MCDs, which is illustrated with clinical vignettes, on diagnostic pitfalls such as somatic mosaicism and consanguinity, and recognizable phenotypes on imaging, such as tubulinopathies, the lissencephaly spectrum, tuberous sclerosis complex, and FLNA-related periventricular nodular heterotopia.
PubMed: 38394064
DOI: 10.1111/dmcn.15882 -
Brain Communications 2023Polymicrogyria is estimated to be one of the most common brain malformations, accounting for ∼16% of malformations of cortical development. However, the prevalence and...
Polymicrogyria is estimated to be one of the most common brain malformations, accounting for ∼16% of malformations of cortical development. However, the prevalence and incidence of polymicrogyria is unknown. Our aim was to estimate the prevalence, incidence rate, neuroimaging diversity, aetiology, and clinical phenotype of polymicrogyria in a population-based paediatric cohort. We performed a systematic search of MRI scans at neuroradiology department databases in Stockholm using the keyword polymicrogyria. The study population included all children living in the Stockholm region born from January 2004 to June 2021 with polymicrogyria. Information on the number of children living in the region during 2004-21 was collected from records from Statistics Sweden, whereas the number of births for each year during the study period was collected from the Swedish Medical Birth Register. All MRI scans were re-evaluated, and malformations were classified by a senior paediatric neuroradiologist. The prevalence and yearly incidence were estimated. Clinical data were collected from medical records. A total of 109 patients with polymicrogyria were included in the study. The overall polymicrogyria prevalence in Stockholm was 2.3 per 10 000 children, and the overall estimated yearly incidence between 2004 and 2020 was 1.9 per 10 000 person-years. The most common polymicrogyria distribution was in the frontal lobe (71%), followed by the parietal lobe (37%). Polymicrogyria in the peri-sylvian region was observed in 53%. Genetic testing was performed in 90 patients revealing pathogenic variants in 32%. Additionally, 12% had variants of uncertain significance. Five patients had a confirmed congenital infection, and in six individuals, the cause of polymicrogyria was assumed to be vascular. Epilepsy was diagnosed in 54%. Seizure onset during the first year of life was observed in 44%. The most common seizure types were focal seizures with impaired awareness, followed by epileptic spasms. Thirty-three of 59 patients with epilepsy (56%) were treated with more than two anti-seizure medications, indicating that pharmacoresistant epilepsy is common in polymicrogyria patients. Neurodevelopmental symptoms were observed in 94% of the individuals. This is the first population-based study on polymicrogyria prevalence and incidence. Confirmed genetic aetiology was present in one-third of individuals with polymicrogyria. Epilepsy was common in this patient group, and the majority had pharmacoresistant epilepsy. These findings increase our knowledge about polymicrogyria and will help in counselling patients and their families.
PubMed: 37614989
DOI: 10.1093/braincomms/fcad213 -
Genetic and phenotypic findings in 34 novel Spanish patients with DDX3X neurodevelopmental disorder.Clinical Genetics Feb 2024DDX3X is a multifunctional ATP-dependent RNA helicase involved in several processes of RNA metabolism and in other biological pathways such as cell cycle control, innate...
DDX3X is a multifunctional ATP-dependent RNA helicase involved in several processes of RNA metabolism and in other biological pathways such as cell cycle control, innate immunity, apoptosis and tumorigenesis. Variants in DDX3X have been associated with a developmental disorder named intellectual developmental disorder, X-linked syndromic, Snijders Blok type (MRXSSB, MIM #300958) or DDX3X neurodevelopmental disorder (DDX3X-NDD). DDX3X-NDD is mainly characterized by intellectual disability, brain abnormalities, hypotonia and behavioral problems. Other common findings include gastrointestinal abnormalities, abnormal gait, speech delay and microcephaly. DDX3X-NDD is predominantly found in females who carry de novo variants in DDX3X. However, hemizygous pathogenic DDX3X variants have been also found in males who inherited their variants from unaffected mothers. To date, more than 200 patients have been reported in the literature. Here, we describe 34 new patients with a variant in DDX3X and reviewed 200 additional patients previously reported in the literature. This article describes 34 additional patients to those already reported, contributing with 25 novel variants and a deep phenotypic characterization. A clinical review of our cohort of DDX3X-NDD patients is performed comparing them to those previously published.
Topics: Male; Female; Humans; Neurodevelopmental Disorders; Intellectual Disability; Muscle Hypotonia; Nervous System Malformations; Brain Diseases; DEAD-box RNA Helicases
PubMed: 37904618
DOI: 10.1111/cge.14440 -
Pediatric Neurology Oct 2023Inactivating mutations in PTEN are among the most common causes of megalencephaly. Activating mutations in other nodes of the PI3K/AKT/MTOR signaling pathway are...
BACKGROUND
Inactivating mutations in PTEN are among the most common causes of megalencephaly. Activating mutations in other nodes of the PI3K/AKT/MTOR signaling pathway are recognized as a frequent cause of cortical brain malformations. Only recently has PTEN been associated with cortical malformations, and analyses of their prognostic significance have been limited.
METHODS
Retrospective neuroimaging analysis and detailed chart review were conducted on 20 participants identified with pathogenic or likely pathogenic mutations in PTEN and a cortical brain malformation present on brain magnetic resonance imaging.
RESULTS
Neuroimaging analysis revealed four main cerebral phenotypes-hemimegalencephaly, focal cortical dysplasia, polymicrogyria (PMG), and a less severe category, termed "macrocephaly with complicated gyral pattern" (MCG). Although a high proportion of participants (90%) had neurodevelopmental findings on presentation, outcomes varied and were favorable in over half of participants. Consistent with prior work, 39% of participants had autism spectrum disorder and 19% of participants with either pure-PMG or pure-MCG phenotypes had epilepsy. Megalencephaly and systemic overgrowth were common, but other systemic features of PTEN-hamartoma tumor syndrome were absent in over one-third of participants.
CONCLUSIONS
A spectrum of cortical dysplasias is present in individuals with inactivating mutations in PTEN. Future studies are needed to clarify the prognostic significance of each cerebral phenotype, but overall, we conclude that despite a high burden of neurodevelopmental disease, long-term outcomes may be favorable. Germline testing for PTEN mutations should be considered in cases of megalencephaly and cortical brain malformations even in the absence of other findings, including cognitive impairment.
Topics: Humans; Autism Spectrum Disorder; Phosphatidylinositol 3-Kinases; Retrospective Studies; Megalencephaly; Brain; Polymicrogyria; PTEN Phosphohydrolase
PubMed: 37619436
DOI: 10.1016/j.pediatrneurol.2023.06.015 -
Journal of Psychiatric Practice Sep 2023Patients may present with manic symptoms in medical settings such as emergency rooms and on inpatient medical floors, leading to psychiatric consultation to try to...
Patients may present with manic symptoms in medical settings such as emergency rooms and on inpatient medical floors, leading to psychiatric consultation to try to determine the etiology of the symptoms. It is crucial to clarify whether the mania is secondary to a medical illness or whether the patient's symptoms are from a primary bipolar disorder. In this issue, we publish 2 case reports of patients presenting with manic symptoms in medical settings. The first case involves polymicrogyria in the frontal lobe of the brain as a cause of secondary mania. The second case involves a patient who was previously diagnosed with bipolar disorder and subsequently developed symptoms of Behçet's disease. In this case, it appears likely that the bipolar disorder was primary, and that the Behçet disease and the bipolar disorder may have exacerbated each other. Given the complexities involved in assessing and treating patients, especially in acute or emergency settings, it is important for primary medical and psychiatric providers to collaborate and communicate well in assuring that they obtain a thorough history of their patients' symptoms and that patients receive a comprehensive medical evaluation before psychiatric treatment is started.
Topics: Humans; Mania; Bipolar Disorder; Brain; Inpatients; Emergency Service, Hospital
PubMed: 37678372
DOI: 10.1097/PRA.0000000000000731 -
Orphanet Journal of Rare Diseases Mar 2024Pallister-Killian syndrome (PKS) is a rare genetic disorder caused by mosaic tetrasomy of 12p with wide neurological involvement. Intellectual disability, developmental... (Review)
Review
BACKGROUND
Pallister-Killian syndrome (PKS) is a rare genetic disorder caused by mosaic tetrasomy of 12p with wide neurological involvement. Intellectual disability, developmental delay, behavioral problems, epilepsy, sleep disturbances, and brain malformations have been described in most individuals, with a broad phenotypic spectrum. This observational study, conducted through brain MRI scan analysis on a cohort of patients with genetically confirmed PKS, aims to systematically investigate the neuroradiological features of this syndrome and identify the possible existence of a typical pattern. Moreover, a literature review differentiating the different types of neuroimaging data was conducted for comparison with our population.
RESULTS
Thirty-one individuals were enrolled (17 females/14 males; age range 0.1-17.5 years old at first MRI). An experienced pediatric neuroradiologist reviewed brain MRIs, blindly to clinical data. Brain abnormalities were observed in all but one individual (compared to the 34% frequency found in the literature review). Corpus callosum abnormalities were found in 20/30 (67%) patients: 6 had callosal hypoplasia; 8 had global hypoplasia with hypoplastic splenium; 4 had only hypoplastic splenium; and 2 had a thin corpus callosum. Cerebral hypoplasia/atrophy was found in 23/31 (74%) and ventriculomegaly in 20/31 (65%). Other frequent features were the enlargement of the cisterna magna in 15/30 (50%) and polymicrogyria in 14/29 (48%). Conversely, the frequency of the latter was found to be 4% from the literature review. Notably, in our population, polymicrogyria was in the perisylvian area in all 14 cases, and it was bilateral in 10/14.
CONCLUSIONS
Brain abnormalities are very common in PKS and occur much more frequently than previously reported. Bilateral perisylvian polymicrogyria was a main aspect of our population. Our findings provide an additional tool for early diagnosis.Further studies to investigate the possible correlations with both genotype and phenotype may help to define the etiopathogenesis of the neurologic phenotype of this syndrome.
Topics: Male; Female; Humans; Child; Infant; Child, Preschool; Adolescent; Polymicrogyria; Chromosome Disorders; Neuroimaging; Brain; Brain Diseases; Chromosomes, Human, Pair 12; Observational Studies as Topic
PubMed: 38459574
DOI: 10.1186/s13023-024-03065-5