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Clinical Radiology May 2023To describe the evolution of the intracranial features of congenital cytomegalovirus (cCMV) on magnetic resonance imaging (MRI).
AIM
To describe the evolution of the intracranial features of congenital cytomegalovirus (cCMV) on magnetic resonance imaging (MRI).
MATERIALS AND METHODS
Sixteen infants with polymerase chain reaction (PCR)-confirmed cCMV who had undergone at least two MRI examinations of the brain were identified. Two paediatric neuroradiologists reviewed the baseline studies retrospectively for intracranial features of cCMV, including white matter signal abnormalities, subependymal cysts, malformations of cortical development, and intracranial calcification. The subsequent MRI studies were then reviewed and directly compared to the baseline examinations.
RESULTS
White matter signal abnormalities were seen on all 16 baseline studies (100%); these persisted on all subsequent examinations but were patchier, more focal, and associated with an interval reduction in white matter volume. Subependymal cysts were present on 11 (69%) of the baseline scans; these almost universally regressed (in 10 of the 11 cases [91%]), with no new cysts appreciable on subsequent imaging. Malformations of cortical development, exclusively in the form of polymicrogyria, were seen in six (38%) patients and persisted, unchanged, on subsequent imaging. Intracranial calcification was seen in a minority of baseline studies (4 [25%]) and remained stable on subsequent scans.
CONCLUSION
Children with cCMV who present later in life without an established or suspected underlying pathology can pose a challenge to the assessing radiologist. The radiological sequelae of cCMV can be non-specific; in some cases, white matter signal abnormalities and focal loss of white matter volume may be the only intracranial features. It is therefore important that radiologists are aware of cCMV as a potential differential for these findings.
Topics: Infant; Child; Humans; Cytomegalovirus; Retrospective Studies; Cytomegalovirus Infections; Magnetic Resonance Imaging; Malformations of Cortical Development
PubMed: 36702711
DOI: 10.1016/j.crad.2022.12.007 -
Frontiers in Genetics 2022Malformations of cortical development (MCDs) can lead to peculiar neuroradiological patterns and clinical presentations (i.e., seizures, cerebral palsy, and...
Malformations of cortical development (MCDs) can lead to peculiar neuroradiological patterns and clinical presentations (i.e., seizures, cerebral palsy, and intellectual disability) according to the specific genetic pathway of the brain development involved; and yet a certain degree of phenotypic heterogeneity exists even when the same gene is affected. Here we report a man with an malformations of cortical development extending beyond occipital lobes associated with a novel stop-gain variant in . The patient is a 28-year-old man suffering from drug-resistant epilepsy and moderate intellectual disability. He underwent a brain magnetic resonance imaging showing polymicrogyria involving occipital and temporal lobes bilaterally. After performing exome sequencing, a novel stop-gain variant in (c.3871C>T; p. Arg1291*) was identified. According to the cortical alteration of the temporal regions, temporal seizures were detected; instead, the patient did not report occipital seizures. Different pharmacological and non-pharmacological interventions ( vagus nerve stimulation) were unsuccessful, even though a partial seizure reduction was obtained after cenobamate administration. Our case report confirms that variants of a gene known to be related to specific clinical and neuroradiological pictures can unexpectedly lead to new phenotypes involving different areas of the brain.
PubMed: 36685914
DOI: 10.3389/fgene.2022.990350 -
Genes Dec 2022Polymicrogyria is a brain malformation characterized by excessive folding of the cortex. To date, numerous causes of polymicrogyria have been identified, including...
Polymicrogyria is a brain malformation characterized by excessive folding of the cortex. To date, numerous causes of polymicrogyria have been identified, including variants in the genes associated with tubulinopathies. Herein, we present a child with severe intellectual disability, refractory to treatment seizures, microcephaly and MRI findings consistent with polymicrogyria, closed-lip schizencephaly, periventricular heterotopia and a dysplastic corpus callosum. Exome sequencing identified a de novo missense variant in TUBG2, a gene not associated with human disease. The variant, NM_016437.3 c.747G>A p.(Met249Ile), is absent from available control databases and is predicated to be deleterious by in silico prediction programs. Laboratory studies show that cultured lymphoblasts derived from the patient grew significantly faster than controls. Recombinant protein was expressed (recombinant wild type and mutant TUBG2-FLAG) in 293T cells and lower levels of TUBG2 mutant compared with controls were observed. Furthermore, co-immuno-precipitation in cells transfected demonstrated that the TUBG2−GCP2 interaction is increased due to the MUT recombinant protein versus WT recombinant protein. In closing, this work provides preliminary evidence that TUBG2 may represent a novel disease gene responsible for polymicrogyria.
Topics: Humans; Child; Polymicrogyria; Microcephaly; Drug Resistant Epilepsy; Mutation, Missense; Intellectual Disability
PubMed: 36672848
DOI: 10.3390/genes14010108 -
Proceedings of the National Academy of... Jan 2023Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly...
Sonic hedgehog signaling regulates processes of embryonic development across multiple tissues, yet factors regulating context-specific Shh signaling remain poorly understood. Exome sequencing of families with polymicrogyria (disordered cortical folding) revealed multiple individuals with biallelic deleterious variants in , which encodes a multi-pass transmembrane protein of unknown function. null mice demonstrated holoprosencephaly, craniofacial midline defects, eye defects, and spinal cord patterning changes consistent with impaired Shh signaling, but were without limb defects, suggesting a CNS-specific role of Tmem161b. depletion impaired the response to Smoothened activation in vitro and disrupted cortical histogenesis in vivo in both mouse and ferret models, including leading to abnormal gyration in the ferret model. Tmem161b localizes non-exclusively to the primary cilium, and scanning electron microscopy revealed shortened, dysmorphic, and ballooned ventricular zone cilia in the null mouse, suggesting that the Shh-related phenotypes may reflect ciliary dysfunction. Our data identify as a regulator of cerebral cortical gyration, as involved in primary ciliary structure, as a regulator of Shh signaling, and further implicate Shh signaling in human gyral development.
Topics: Animals; Female; Humans; Mice; Pregnancy; Central Nervous System; Cilia; Ferrets; Hedgehog Proteins; Mice, Knockout; Signal Transduction
PubMed: 36669111
DOI: 10.1073/pnas.2209964120 -
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 -
Epilepsy & Behavior : E&B Jan 2023Continuous Spike-Wave during slow Sleep (CSWS) syndrome associates a clinically important neurocognitive regression with strong activation of non-REM sleep spikes. Its...
OBJECTIVE
Continuous Spike-Wave during slow Sleep (CSWS) syndrome associates a clinically important neurocognitive regression with strong activation of non-REM sleep spikes. Its mechanisms remain unknown, but a contribution of rare perinatal thalamic injuries has been highlighted. We determine the incidence of such lesions in a cohort of CSWS patients.
METHODS
N = 65 patients with CSWS and a control group (N = 51) were studied. Spikes were quantified in long-term ambulatory EEGs, brain Magnetic Ressonance Imaging (MRI) structural lesions were assessed and thalamic volumetry was performed. A neurocognitive scale was used to assess dysfunction.
RESULTS
The most common etiologies in the control patients were not represented in the CSWS group. Structural lesions were detected in a minority of CSWS patients (25/53) but included a thalamic injury in the large majority (24/25). This ratio was 4/40 in controls. Lesions belonged to one of five types: 1. Circumscribed to the thalamus (N = 11); 2. Extending beyond the thalamus (N = 3); 3. Hypothalamic-Hamartomas (N = 4); 4. Periventricular-Leukomalacia (N = 4); 5. Hypoplasia-Polymicrogyria (N = 1). Most lesions were lateralized to one hemisphere, which in all cases corresponded to the lateralization of the CSWS.
SIGNIFICANCE
Thalamic lesions are present in most CSWS patients with abnormal MRIs, supporting an important role in its genesis.
Topics: Female; Pregnancy; Humans; Incidence; Sleep, Slow-Wave; Electroencephalography; Brain; Thalamus; Sleep
PubMed: 36512931
DOI: 10.1016/j.yebeh.2022.109031