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American Journal of Medical Genetics.... May 2020PTEN hamartoma tumor syndrome (PHTS) is a spectrum of hereditary cancer syndromes caused by germline mutations in PTEN. PHTS is of high interest, because of its high...
PTEN hamartoma tumor syndrome (PHTS) is a spectrum of hereditary cancer syndromes caused by germline mutations in PTEN. PHTS is of high interest, because of its high rate of neurological comorbidities including macrocephaly, autism spectrum disorder, and intellectual dysfunction. Since detailed brain morphology and connectivity of PHTS remain unclear, we quantitatively evaluated brain magnetic resonance imaging (MRI) in PHTS. Sixteen structural T1-weighted and 9 diffusion-weighted MR images from 12 PHTS patients and neurotypical controls were used for structural and high-angular resolution diffusion MRI (HARDI) tractography analyses. Mega-corpus callosum was observed in 75%, polymicrogyria in 33%, periventricular white matter lesions in 83%, and heterotopia in 17% of the PHTS participants. While gyrification index and hemispheric cortical thickness showed no significant differences between the two groups, significantly increased global and regional brain volumes, and regionally thicker cortices in PHTS participants were observed. HARDI tractography showed increased volume and length of callosal pathways, increased volume of the arcuate fasciculi (AF), and increased length of the bilateral inferior longitudinal fasciculi (ILF), bilateral inferior fronto-occipital fasciculi (IFOF), and bilateral uncinate fasciculus. A decrease in fractional anisotropy and an increased in apparent diffusion coefficient values of the AF, left ILF, and left IFOF in PHTS.
Topics: Anisotropy; Autism Spectrum Disorder; Brain; Child; Corpus Callosum; Female; Hamartoma Syndrome, Multiple; Humans; Magnetic Resonance Imaging; Male; PTEN Phosphohydrolase; White Matter
PubMed: 32162846
DOI: 10.1002/ajmg.a.61532 -
Frontiers in Psychiatry 2012Epilepsy is characterized by spontaneous recurrent seizures and comprises a diverse group of syndromes with different etiologies. Epileptogenesis refers to the process...
Epilepsy is characterized by spontaneous recurrent seizures and comprises a diverse group of syndromes with different etiologies. Epileptogenesis refers to the process whereby the brain becomes epileptic and can be related to several factors, such as acquired structural brain lesions, inborn brain malformations, alterations in neuronal signaling, and defects in maturation and plasticity of neuronal networks. In this review, we will focus on alterations of brain development that lead to an hyperexcitability phenotype in adulthood, providing examples from both animal and human studies. Malformations of cortical development (including focal cortical dysplasia, lissencephaly, heterotopia, and polymicrogyria) are frequently epileptogenic and result from defects in cell proliferation in the germinal zone and/or impaired neuronal migration and differentiation. Delayed or reduced arrival of inhibitory interneurons into the cortical plate is another possible cause of epileptogenesis. GABAergic neurons are generated during early development in the ganglionic eminences, and failure to pursue migration toward the cortex alters the excitatory/inhibitory balance resulting in aberrant network hyperexcitability. More subtle defects in the developmental assembly of excitatory and inhibitory synapses are also involved in epilepsy. For example, mutations in the presynaptic proteins synapsins and SNAP-25 cause derangements of synaptic transmission and plasticity which underlie appearance of an epileptic phenotype. Finally, there is evidence that defects in synapse elimination and remodeling during early "critical periods" can trigger hyperexcitability later in life. Further clarification of the developmental pathways to epilepsy has important implications for disease prevention and therapy.
PubMed: 22457654
DOI: 10.3389/fpsyt.2012.00019 -
Medicina 2019Around 15% of childhood epilepsies are resistant to antiepileptic drugs, 40% of which are caused by malformations of cortical development (MCD). The current...
Around 15% of childhood epilepsies are resistant to antiepileptic drugs, 40% of which are caused by malformations of cortical development (MCD). The current classification scheme for MCD is based on the primary developmental steps of cell proliferation, neuronal migration, and cortical organization. Considering the clinic and molecular alterations, a classification based on main pathways disruption and imaging phenotype has been proposed. MCD were divided into four groups: megalencephaly and focal cerebral dysplasia; tubulinopathies and lissencephalies; polymicrogyria syndromes and heterotopia syndromes. More than 100 genes have been reported to be associated with different types of MCD. Genetic and biological mechanisms include different stages of cell cycle regulation - especially cell division -, apoptosis, cell-fate specification, cytoskeletal structure and function, neuronal migration, and basement-membrane function. The associated epileptic syndromes are varied ranging from early-onset epileptic encephalopathies to focal epilepsies. As MCD are common causes of refractory epilepsy, a prompt diagnosis and the development of different therapeutic options in order to improve the outcome of the patients are essential.
Topics: Child; Child, Preschool; Electroencephalography; Epilepsy; Humans; Magnetic Resonance Imaging; Male; Malformations of Cortical Development
PubMed: 31603842
DOI: No ID Found -
The American Journal of Case Reports May 2023BACKGROUND The Col4a1 gene encodes a portion of type IV collagen, a major component of the tissue basement membrane. Col4a1 mutations are rare, most frequently affect...
BACKGROUND The Col4a1 gene encodes a portion of type IV collagen, a major component of the tissue basement membrane. Col4a1 mutations are rare, most frequently affect neonates, and occur at a de novo mutation rate between 27% and 40%. Mutations are commonly missense and pleiotropic, presenting with cerebrovascular, renal, ophthalmological, and muscular abnormalities, collectively known as Gould Syndrome. Cerebral small vessel disease is commonly associated with Gould Syndrome and Col4a1 mutations. Children can present with infantile hemiplegia/quadriplegia, stroke, epilepsy, motor dysfunction, or white matter changes of the eye. CASE REPORT A male infant at 38-week, 4-day gestation presented with microcephaly, scattered multifocal hemorrhagic/ischemic infarcts, ex-vacuo dilatation, polymicrogyria, ventricular septal defect, and narrowed aortic arch, seen on prenatal ultrasound and confirmed by fetal echocardiogram and fetal brain magnetic resonance imaging (MRI). Electroencephalogram showed frequent subclinical seizures that were difficult to control, requiring multiple agents. Ophthalmology evaluation demonstrated small, hypoplastic optic nerves of both eyes, concerning for septo-optic dysplasia. Postnatal brain MRI confirmed fetal findings. Postnatal genetic testing showed a de novo heterozygous variant of Col4a1 and 1 nonspecific contiguous region of copy neutral absence of heterozygosity on chromosome 11. CONCLUSIONS This neonate was prenatally diagnosed with central nervous system (CNS) abnormalities and postnatally found to have a de novo heterozygous Col4a1 variant. CNS, cardiac, renal, and hematological findings were likely associated with the Col4a1 mutation and, possibly, a recessive genetic disorder of chromosome 11. Col4a1 mutations are rare and have no definitive treatments. Subspecialist follow-up and supportive care are essential to reduce long-term complications.
Topics: Child; Infant; Infant, Newborn; Pregnancy; Female; Humans; Male; Central Nervous System; Collagen Type IV; Stroke; Magnetic Resonance Imaging; Mutation
PubMed: 37157232
DOI: 10.12659/AJCR.938651 -
Human Molecular Genetics Jan 2023DEPDC5 (DEP Domain-Containing Protein 5) encodes an inhibitory component of the mammalian target of rapamycin (mTOR) pathway and is commonly implicated in sporadic and...
DEPDC5 (DEP Domain-Containing Protein 5) encodes an inhibitory component of the mammalian target of rapamycin (mTOR) pathway and is commonly implicated in sporadic and familial focal epilepsies, both non-lesional and in association with focal cortical dysplasia. Germline pathogenic variants are typically heterozygous and inactivating. We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5. Cases were identified clinically. Available records, including magnetic resonance imaging and electroencephalography, were reviewed. Genetic testing was performed by whole exome and whole-genome sequencing and cascade screening. In addition, immunohistochemistry was performed on skin biopsy. The phenotype was identified in nine children, eight of which are described in detail herein. Six of the children were of Irish Traveller, two of Tunisian and one of Lebanese origin. The Irish Traveller children shared the same DEPDC5 germline homozygous missense variant (p.Thr337Arg), whereas the Lebanese and Tunisian children shared a different germline homozygous variant (p.Arg806Cys). Consistent phenotypic features included extensive bilateral polymicrogyria, congenital macrocephaly and early-onset refractory epilepsy, in keeping with other mTOR-opathies. Eye and cardiac involvement and severe neutropenia were also observed in one or more patients. Five of the children died in infancy or childhood; the other four are currently aged between 5 months and 6 years. Skin biopsy immunohistochemistry was supportive of hyperactivation of the mTOR pathway. The clinical, histopathological and genetic evidence supports a causal role for the homozygous DEPDC5 variants, expanding our understanding of the biology of this gene.
Topics: Humans; Mutation; Polymicrogyria; GTPase-Activating Proteins; TOR Serine-Threonine Kinases; Epilepsies, Partial; Megalencephaly; Epileptic Syndromes
PubMed: 36067010
DOI: 10.1093/hmg/ddac225 -
World Journal of Radiology Oct 2015Malformation of cortical development (MCD) is a term representing an inhomogeneous group of central nervous system abnormalities, referring particularly to... (Review)
Review
Malformation of cortical development (MCD) is a term representing an inhomogeneous group of central nervous system abnormalities, referring particularly to embriyological aspect as a consequence of any of the three developmental stages, i.e., cell proliferation, cell migration and cortical organization. These include cotical dysgenesis, microcephaly, polymicrogyria, schizencephaly, lissencephaly, hemimegalencephaly, heterotopia and focal cortical dysplasia. Since magnetic resonance imaging is the modality of choice that best identifies the structural anomalies of the brain cortex, we aimed to provide a mini review of MCD by using 3T magnetic resonance scanner images.
PubMed: 26516429
DOI: 10.4329/wjr.v7.i10.329 -
Brain : a Journal of Neurology May 2010Polymicrogyria is one of the most common malformations of cortical development and is associated with a variety of clinical sequelae including epilepsy, intellectual...
Polymicrogyria is one of the most common malformations of cortical development and is associated with a variety of clinical sequelae including epilepsy, intellectual disability, motor dysfunction and speech disturbance. It has heterogeneous clinical manifestations and imaging patterns, yet large cohort data defining the clinical and imaging spectrum and the relative frequencies of each subtype are lacking. The aims of this study were to determine the types and relative frequencies of different polymicrogyria patterns, define the spectrum of their clinical and imaging features and assess for clinical/imaging correlations. We studied the imaging features of 328 patients referred from six centres, with detailed clinical data available for 183 patients. The ascertainment base was wide, including referral from paediatricians, geneticists and neurologists. The main patterns of polymicrogyria were perisylvian (61%), generalized (13%), frontal (5%) and parasagittal parieto-occipital (3%), and in 11% there was associated periventricular grey matter heterotopia. Each of the above patterns was further divided into subtypes based on distinguishing imaging characteristics. The remaining 7% were comprised of a number of rare patterns, many not described previously. The most common clinical sequelae were epileptic seizures (78%), global developmental delay (70%), spasticity (51%) and microcephaly (50%). Many patients presented with neurological or developmental abnormalities prior to the onset of epilepsy. Patients with more extensive patterns of polymicrogyria presented at an earlier age and with more severe sequelae than those with restricted or unilateral forms. The median age at presentation for the entire cohort was 4 months with 38% presenting in either the antenatal or neonatal periods. There were no significant differences between the prevalence of epilepsy for each polymicrogyria pattern, however patients with generalized and bilateral forms had a lower age at seizure onset. There was significant skewing towards males with a ratio of 3:2. This study expands our understanding of the spectrum of clinical and imaging features of polymicrogyria. Progression from describing imaging patterns to defining anatomoclinical syndromes will improve the accuracy of prognostic counselling and will aid identification of the aetiologies of polymicrogyria, including genetic causes.
Topics: Age of Onset; Child, Preschool; Cohort Studies; Developmental Disabilities; Epilepsy; Female; Humans; Infant; Infant, Newborn; Magnetic Resonance Imaging; Male; Malformations of Cortical Development; Microcephaly; Muscle Spasticity; Prevalence; Sex Distribution
PubMed: 20403963
DOI: 10.1093/brain/awq078 -
American Journal of Medical Genetics.... Nov 2008Aicardi syndrome is a rare neurodevelopmental disorder characterized by congenital chorioretinal lacunae, corpus callosum dysgenesis, seizures, polymicrogyria, cerebral...
Aicardi syndrome is a rare neurodevelopmental disorder characterized by congenital chorioretinal lacunae, corpus callosum dysgenesis, seizures, polymicrogyria, cerebral heterotopias, intracranial cysts, and costovertebral defects. Cerebellar abnormalities have been described occasionally. Aicardi syndrome is sporadic and has been observed only in females and 47,XXY males. Therefore, it is thought to result from a mutation in an X-linked gene. Improved definition of the clinical phenotype should focus the selection of functional candidate genes for mutation analysis. Because central nervous system abnormalities are the most prominent component of the phenotype, we performed a detailed characterization of abnormalities identified on magnetic resonance neuroimaging studies from 23 girls with Aicardi syndrome, the largest cohort to undergo such review by a single group of investigators. All patients had polymicrogyria that was predominantly frontal and perisylvian and often associated with underopercularization. Periventricular nodular heterotopias, present in all patients, were more frequent than previously reported; 10 had single and 11 had multiple intracranial cysts. Posterior fossa abnormalities were also more frequent than previously described. Cerebellar abnormalities were noted in 95% of studies where they could be evaluated. As a novel finding, we noted tectal enlargement in 10 patients. Since mildly affected girls with variable callosal dysgenesis have now been reported, the constellation of frontal-dominant and perisylvian polymicrogyria, periventricular nodular heterotopias, intracranial cysts, and posterior fossa abnormalities, including tectal enlargement, should prompt consideration of the diagnosis of Aicardi syndrome. We further propose that improved characterization of the neurological phenotype will benefit the selection of candidate genes for mutation analysis.
Topics: Abnormalities, Multiple; Brain; Central Nervous System Cysts; Cerebellum; Child; Child, Preschool; Female; Humans; Infant; Infant, Newborn; Magnetic Resonance Imaging; Male; Malformations of Cortical Development; Periventricular Nodular Heterotopia; Syndrome
PubMed: 18925666
DOI: 10.1002/ajmg.a.32537 -
Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics.Brain : a Journal of Neurology Apr 2019Recessive mutations in RTTN, encoding the protein rotatin, were originally identified as cause of polymicrogyria, a cortical malformation. With time, a wide variety of...
Recessive mutations in RTTN, encoding the protein rotatin, were originally identified as cause of polymicrogyria, a cortical malformation. With time, a wide variety of other brain malformations has been ascribed to RTTN mutations, including primary microcephaly. Rotatin is a centrosomal protein possibly involved in centriolar elongation and ciliogenesis. However, the function of rotatin in brain development is largely unknown and the molecular disease mechanism underlying cortical malformations has not yet been elucidated. We performed both clinical and cell biological studies, aimed at clarifying rotatin function and pathogenesis. Review of the 23 published and five unpublished clinical cases and genomic mutations, including the effect of novel deep intronic pathogenic mutations on RTTN transcripts, allowed us to extrapolate the core phenotype, consisting of intellectual disability, short stature, microcephaly, lissencephaly, periventricular heterotopia, polymicrogyria and other malformations. We show that the severity of the phenotype is related to residual function of the protein, not only the level of mRNA expression. Skin fibroblasts from eight affected individuals were studied by high resolution immunomicroscopy and flow cytometry, in parallel with in vitro expression of RTTN in HEK293T cells. We demonstrate that rotatin regulates different phases of the cell cycle and is mislocalized in affected individuals. Mutant cells showed consistent and severe mitotic failure with centrosome amplification and multipolar spindle formation, leading to aneuploidy and apoptosis, which could relate to depletion of neuronal progenitors often observed in microcephaly. We confirmed the role of rotatin in functional and structural maintenance of primary cilia and determined that the protein localized not only to the basal body, but also to the axoneme, proving the functional interconnectivity between ciliogenesis and cell cycle progression. Proteomics analysis of both native and exogenous rotatin uncovered that rotatin interacts with the neuronal (non-muscle) myosin heavy chain subunits, motors of nucleokinesis during neuronal migration, and in human induced pluripotent stem cell-derived bipolar mature neurons rotatin localizes at the centrosome in the leading edge. This illustrates the role of rotatin in neuronal migration. These different functions of rotatin explain why RTTN mutations can lead to heterogeneous cerebral malformations, both related to proliferation and migration defects.
Topics: Adult; Brain; Carrier Proteins; Cell Cycle; Cell Cycle Proteins; Cilia; Female; Genetic Association Studies; HEK293 Cells; Humans; Induced Pluripotent Stem Cells; Infant; Infant, Newborn; Male; Malformations of Cortical Development; Microcephaly; Mutation; Nervous System Malformations; Polymicrogyria
PubMed: 30879067
DOI: 10.1093/brain/awz045 -
Congenital Anomalies Nov 2022Congenital cytomegalovirus (CMV) infection can cause severe neurological sequelae or even fetal death. We present a 17-year-old pregnant woman with fetal CMV infection,...
Congenital cytomegalovirus (CMV) infection can cause severe neurological sequelae or even fetal death. We present a 17-year-old pregnant woman with fetal CMV infection, leading to voluntary termination of pregnancy. Fetopsy demonstrated a brainstem hemorrhage and focal polymicrogyria. CMV inclusions were observed in the lung, liver, thyroid, pancreas, kidneys, adrenal, placenta, and central nervous system. Intracranial hemorrhage is a rare finding in the context of congenital CMV infection, with isolated brainstem hemorrhage being an exceptional form of presentation. Polymicrogyria appears to be a more frequent finding, although its actual incidence is unknown. Future studies are needed to determine the causal association.
Topics: Pregnancy; Female; Humans; Adolescent; Polymicrogyria; Cytomegalovirus Infections; Pregnancy Complications, Infectious; Brain Stem; Hemorrhage
PubMed: 35941838
DOI: 10.1111/cga.12488