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Proceedings of the National Academy of... Jan 2023encodes an evolutionarily conserved widely expressed novel 8-pass transmembrane protein of unknown function in human. Here we identify homozygous hypomorphic missense...
encodes an evolutionarily conserved widely expressed novel 8-pass transmembrane protein of unknown function in human. Here we identify homozygous hypomorphic missense variants in our recessive polymicrogyria (PMG) cohort. Patients carrying mutations exhibit striking neocortical PMG and intellectual disability. knockout mice fail to develop midline hemispheric cleavage, whereas knock-in of patient mutations and patient-derived brain organoids show defects in apical cell polarity and radial glial scaffolding. We found that TMEM161B modulates actin filopodia, functioning upstream of the Rho-GTPase CDC42. Our data link with human PMG, likely regulating radial glia apical polarity during neocortical development.
Topics: Animals; Humans; Mice; Ependymoglial Cells; Mice, Knockout; Neocortex
PubMed: 36669109
DOI: 10.1073/pnas.2209983120 -
Cureus Dec 2022Encephalocraniocutaneous lipomatosis (ECCL) or Haberland syndrome is a neurocutaneous disorder of the skin, eye, and central nervous system. A three-month-old girl was...
Encephalocraniocutaneous lipomatosis (ECCL) or Haberland syndrome is a neurocutaneous disorder of the skin, eye, and central nervous system. A three-month-old girl was referred to our center for further management of a large left eye corneal dermoid. At birth, a small lesion was noted. Magnetic resonance imaging (MRI) around the first week of life showed an extraocular dermoid cyst measuring 1 mm x 7 mm, dysplasia of the left greater wing of sphenoid, closed-lip schizencephaly of the left parietal lobe, and polymicrogyria. During examination under anesthesia at our center, we found that the corneal dermoid had grown in size to 17 mm x 16 mm, with posterior embryotoxon, a hazy cornea, and intraocular pressure of 26 mmHg. With the anterior segment dysgenesis and secondary glaucoma, we started Gutt Timo-Comod BD. Serial MRI imaging at four months of age revealed further enlargement of the dermoid, a new left retrobulbar mass, and multiple intracranial lipomas. A diagnosis of ECCL was made at this point based on the MRI and clinical findings. A multidisciplinary meeting was held among ophthalmology, neurosurgery, radiology, and otorhinolaryngology (ORL) teams, which concluded that surgical intervention such as tumor debulking might cause more harm than benefit. Hence, she was planned to undergo close monitoring with serial MRIs and only for surgical intervention, in the presence of airway compression or any neurological deficits. The ophthalmologist should be aware of the specific radiological and clinical findings in ECCL as management of the condition would be best through a multidisciplinary approach.
PubMed: 36644099
DOI: 10.7759/cureus.32498 -
Epilepsy & Behavior Reports 2023Radiofrequency thermocoagulation (RF-TC) is a wide-used procedure for drug-resistant epilepsy. The technique is considered safe with an overall risk of 1.1% of permanent...
Radiofrequency thermocoagulation (RF-TC) is a wide-used procedure for drug-resistant epilepsy. The technique is considered safe with an overall risk of 1.1% of permanent complications, mainly focal neurological deficits. We report the case of a patient with drug-resistant epilepsy who complained of immediate seizure worsening and an unexpected event seven months following RF-TC. A 35-year-old male with drug-resistant epilepsy from the age of 18 years underwent stereoelectroencephalography (SEEG) implantation for a right peri-silvian polymicrogyria. He was excluded from surgery due to extent of the epileptogenic zone and the risk of visual field deficits. RF-TC was attempted to ablate the most epileptogenic zone identified by SEEG. After RF-TC, the patient reported an increase in seizure severity/frequency and experienced episodes of postictal psychosis. Off-label cannabidiol treatment led to improved seizure control and resolution of postictal psychosis. Patients with polymicrogyria (PwP) may present with a disruption of normal anatomy and the co-existence between epileptogenic zone and eloquent cortex within the malformation. RF-TC should be considered in PwP when they are excluded from surgery for prognostic and palliative purposes. However, given the complex interplay between pathological and electrophysiological networks in these patients, the remote possibility of clinical exacerbation after RF-TC should also be taken into account.
PubMed: 36620478
DOI: 10.1016/j.ebr.2022.100579 -
Molecular Syndromology Dec 2022Autosomal recessive primary microcephaly (MCPH) is a disorder characterized by congenital microcephaly and intellectual disability without extra-central nervous system...
INTRODUCTION
Autosomal recessive primary microcephaly (MCPH) is a disorder characterized by congenital microcephaly and intellectual disability without extra-central nervous system malformation. MCPH is a disease with heterogeneity in genotype and phenotype. For this reason, it is important to determine the genetic causes and genotype-phenotype relationship in MCPH, which causes lifelong impairment. In this study, we aimed to evaluate the clinical, genetic, and brain imaging findings of cases diagnosed with MCPH.
METHODS
Electroencephalogram and brain magnetic resonance imaging were performed for all cases. We evaluated genetic results of the 39 families including cases with suspected MCPH diagnosis.
RESULTS
Genetic diagnosis related to MCPH was provided in 11/39 (28.2%) of these families including 13/41 cases (31.7%). Variants of the gene were the most common (61.5%) cause, and variants of the gene were the second most common cause (38.5%). We have found 6 novel variants and 4 previously reported variants in and genes. Main brain imaging findings in our cases were lissencephaly, polymicrogyria, schizencephaly, pachygyria, and cortical dysplasia. Genetic counseling in 2 families whose genetic diagnosis was determined prevented them from having another child with MCPH.
DISCUSSION/CONCLUSION
Detection and reporting of novel variants is an important step in eliminating this disorder by providing families with appropriate genetic counseling.
PubMed: 36588751
DOI: 10.1159/000524391 -
Epilepsia Open Mar 2023Bilateral frontoparietal polymicrogyria (BFPP) is a rare genetic-related migration disorder. It has been attributed to loss-of-function of the ADGRG1 gene, which encodes... (Review)
Review
Identification and clinical characteristics of a novel missense ADGRG1 variant in bilateral Frontoparietal Polymicrogyria: The electroclinical change from infancy to adulthood after Callosotomy in three siblings.
OBJECTIVE
Bilateral frontoparietal polymicrogyria (BFPP) is a rare genetic-related migration disorder. It has been attributed to loss-of-function of the ADGRG1 gene, which encodes an adhesion G protein-coupled receptor, ADGRG1/GPR56. We report the EEG findings of BFPP in three Asian patients, and confirmed that change in protein function was caused by the novel missense variant (p.Leu290Pro).
METHODS
We reviewed the medical records of three siblings with BFPP including one elder girl and two identical twin boys from birth to adulthood. The clinical symptoms, electroencephalography (EEG), brain MRI, whole-exome sequencing, treatment including medications, neuromodulation, and epilepsy surgery, and clinical outcomes were reviewed. The protein structure of a novel missense variant (p.Leu290Pro) was predicted by in silico studies, and molecular analysis was performed via typical flow cytometry and Western blotting.
RESULTS
The elder girl (Patient 1) was 22 years old and the twin boys (Patients 2 and 3) were 20 years old at the time of publication. All of them presented with typical clinical symptoms/signs and MRI findings of BFPP. Whole-exome sequencing followed by Sanger confirmation showed that all three patients had compound heterozygous variants in the ADGRG1 gene. The missense variant (p.Leu290Pro) was confirmed to be related to a reduction in cell surface GPR56 expression. High-amplitude rhythmic activity was noted in sleep EEG during infancy, which may have been due to excessive sleep spindle, and the rhythm disappeared when they were of pre-school age. Partial callosotomy provided short-term benefits in seizure control in Patients 1 and 2, and combined vagus nerve stimulation and partial callosotomy provided longer benefits in Patient 3.
SIGNIFICANCE
Sleep EEG findings of high-amplitude rhythmic activity in our BFPP cases were only noted during infancy and childhood. We also confirmed that the missense variant (p.Leu290Pro) led to loss of function due to a reduction in cell surface GPR56 expression.
Topics: Male; Female; Humans; Infant; Child, Preschool; Child; Young Adult; Adult; Polymicrogyria; Siblings; Receptors, G-Protein-Coupled; Mutation, Missense
PubMed: 36524291
DOI: 10.1002/epi4.12685 -
Epilepsia Open Mar 2023Fetal intracranial hemorrhage represents a rare event with an estimated prevalence of 1:10 000 pregnancies. We report a patient diagnosed prenatally with intracranial...
Fetal intracranial hemorrhage represents a rare event with an estimated prevalence of 1:10 000 pregnancies. We report a patient diagnosed prenatally with intracranial hemorrhage and ventriculomegaly carrying a novel, previously unreported, likely pathogenic variant in COL4A1. At the gestational age of 27 weeks, dilation of lateral ventricles was detected during a routine prenatal ultrasound scan, confirmed by prenatal MRI at 30 + 3 weeks of gestation. Prenatal examinations included amniocentesis with conventional G-band karyotyping and arrayCGH, and maternal testing for TORCH and parvovirus B19 infections. Virtual gene panel based on whole-exome sequencing data was performed postnatally. At the age of 2.5 months, the patient manifested epileptic seizures that remain difficult to control. Postnatal MRI showed partial thalamic fusion and polymicrogyria, in addition to severe enlargement of lateral ventricles, multiple deposits of hemosiderin in cerebral and cerebellar hemispheres, and thin optic nerve and chiasma. Virtual gene panel based on whole-exome sequencing data led to a detection of a de novo previously unreported in-frame deletion NM_001845.5:c.4688_4711del in COL4A1 located in the highly conserved NC1 domain initiating collagen helix assembly. The presented case lies one a more severe end of the COL4A1 mutation-related disease spectrum, manifesting as fetal intracranial bleeding, malformation of cortical development, drug-resistant epilepsy, and developmental delay.
Topics: Pregnancy; Female; Humans; Infant; Polymicrogyria; Hydrocephalus; Mutation; Intracranial Hemorrhages; Fetus; Collagen Type IV
PubMed: 36504316
DOI: 10.1002/epi4.12681 -
Seizure Dec 2022
Topics: Humans; Periventricular Nodular Heterotopia; Magnetic Resonance Imaging; Malformations of Cortical Development; Cerebral Cortex
PubMed: 36370681
DOI: 10.1016/j.seizure.2022.11.003 -
Frontiers in Pediatrics 2022Pathogenic variants in the gene have been described to be associated with a diverse spectrum of syndromes, such as autosomal recessive bilateral temporooccipital...
BACKGROUND
Pathogenic variants in the gene have been described to be associated with a diverse spectrum of syndromes, such as autosomal recessive bilateral temporooccipital polymicrogyria (OMIM 612691), autosomal dominant amyotrophic lateral sclerosis-11 (ALS11; OMIM 612577), autosomal recessive Charcot-Marie-Tooth disease, type 4J (CMT4J; OMIM 611228), and autosomal recessive Yunis-Varon syndrome (YVS; OMIM 216340). Heterozygous variants are responsible for ALS11 characterized by progressive muscular weakness, atrophy, and bulbar palsy. CMT4J is a disorder of peripheral nervous system defects mainly presenting with a highly variable onset of proximal and/or distal muscle weakness. YVS is a disorder of severe neurological involvement with central nervous system (CNS) dysfunction and extensive skeletal anomalies.
CASE PRESENTATION
We reported two Chinese siblings born with a weakness in all limbs. They experienced rapidly progressive weakness in distal limbs. At the age of 6 years, the elder brother presented with severe scoliosis and cervical kyphosis. They both had global developmental delay and a CNS involvement with cognitive deficits and swallowing problems. Genetic screening in the patients' family for inherited diseases was recommended. Novel compound heterozygous variants in the gene (c.2148delTinsAA and c.317A > G) were found by whole-exome sequencing in the patients. These variants were confirmed by Sanger sequencing in family members.
CONCLUSIONS
Herein, we reported two Chinese male patients with CMT4J who presented with abnormal CNS features. CMT4J with CNS involvement has been very rarely reported. We hoped this study could expand the phenotypic and genetic spectrum of FIG4-related diseases. And we helped physicians to understand the genotype-phenotype correlation.
PubMed: 36340727
DOI: 10.3389/fped.2022.1008251 -
AJNR. American Journal of Neuroradiology Nov 2022The presence of malformations of cortical development in patients with hereditary hemorrhagic telangiectasia has been reported on previous occasions. We evaluated a...
BACKGROUND AND PURPOSE
The presence of malformations of cortical development in patients with hereditary hemorrhagic telangiectasia has been reported on previous occasions. We evaluated a sample of adults with hereditary hemorrhagic telangiectasia for the presence of malformations of cortical development, spatial coincidence of malformations of cortical development and AVMs, and the coincidence of brain and pulmonary AVMs.
MATERIALS AND METHODS
A total of 141 patients 18 years of age or older who were referred to the Augusta University hereditary hemorrhagic telangiectasia clinic and underwent brain MR imaging between January 19, 2018, and December 3, 2020, were identified. MR imaging examinations were reviewed retrospectively by 2 experienced neuroradiologists, and the presence of malformations of cortical development and AVMs was confirmed by consensus. Demographic and clinical information was collected for each case, including age, sex, hereditary hemorrhagic telangiectasia status by the Curacao Criteria, mutation type, presence of malformations of cortical development, presence of brain AVMs, presence of pulmonary AVMs, and a history of seizures or learning disabilities.
RESULTS
Five of 141 (3.5%) patients with hereditary hemorrhagic telangiectasia had malformations of cortical development. Two of the 5 patients with polymicrogyria also had closed-lip schizencephaly. One of the patients had a porencephalic cavity partially lined with heterotopic GM. The incidence of spatially coincident polymicrogyria and brain AVMs was 40% (2/5 cases). Of the patients with hereditary hemorrhagic telangiectasia and malformations of cortical development, 4/5 (80%) had pulmonary AVMs and 2/5 (40%) had brain AVMs.
CONCLUSIONS
To our knowledge, we are the first group to report the presence of schizencephaly in patients with hereditary hemorrhagic telangiectasia. The presence of schizencephaly and porencephaly lends support to the hypothesis of regional in utero cerebral hypoxic events as the etiology of malformations of cortical development in hereditary hemorrhagic telangiectasia.
Topics: Adult; Humans; Adolescent; Telangiectasia, Hereditary Hemorrhagic; Schizencephaly; Polymicrogyria; Retrospective Studies; Arteriovenous Malformations
PubMed: 36265891
DOI: 10.3174/ajnr.A7677 -
AJNR. American Journal of Neuroradiology Nov 2022Zhu-Tokita-Takenouchi-Kim syndrome is a severe multisystem malformation disorder characterized by developmental delay and a diverse array of congenital abnormalities....
BACKGROUND AND PURPOSE
Zhu-Tokita-Takenouchi-Kim syndrome is a severe multisystem malformation disorder characterized by developmental delay and a diverse array of congenital abnormalities. However, these currently identified phenotypic components provide limited guidance in diagnostic situations, due to both the nonspecificity and variability of these features. Here we report a case series of 7 individuals with a molecular diagnosis of Zhu-Tokita-Takenouchi-Kim syndrome, 5 ascertained by their presentation with the neuronal migration disorder, periventricular nodular heterotopia.
MATERIALS AND METHODS
Individuals with a molecular diagnosis of Zhu-Tokita-Takenouchi-Kim syndrome were recruited from 2 sources, a high-throughput sequencing study of individuals with periventricular nodular heterotopia or from clinical diagnostic sequencing studies. We analyzed available brain MR images of recruited individuals to characterize periventricular nodular heterotopia distribution and to identify the presence of any additional brain abnormalities.
RESULTS
Pathogenic variants in , causative of Zhu-Tokita-Takenouchi-Kim syndrome, were identified in 7 individuals. Brain MR images from these individuals were re-analyzed. A characteristic set of imaging anomalies in addition to periventricular nodular heterotopia was identified, including the elongation of the pituitary stalk, cerebellar enlargement with an abnormally shaped posterior fossa, rounding of the caudate nuclei, hippocampal malformations, and cortical anomalies including polymicrogyria or dysgyria.
CONCLUSIONS
The recurrent neuroradiologic changes identified here represent an opportunity to guide diagnostic formulation of Zhu-Tokita-Takenouchi-Kim syndrome on the basis of brain MR imaging evaluation.
Topics: Humans; Periventricular Nodular Heterotopia; Brain; Magnetic Resonance Imaging; Brain Diseases; Intellectual Disability
PubMed: 36229163
DOI: 10.3174/ajnr.A7663