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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 -
Seizure Apr 2024PAFAH1B1, also known as LIS1, is associated with type I lissencephaly in humans, which is a severe developmental brain disorder believed to result from abnormal neuronal...
PURPOSE
PAFAH1B1, also known as LIS1, is associated with type I lissencephaly in humans, which is a severe developmental brain disorder believed to result from abnormal neuronal migration. Our objective was to characterize the genotypes and phenotypes of PAFAH1B1-related epilepsy.
METHODS
We conducted a comprehensive analysis of the medical histories, magnetic resonance imaging findings, and video-electroencephalogram recordings of 11 patients with PAFAH1B1 variants at the Neurology Department of Beijing Children's Hospital from June 2017 to November 2022.
RESULTS
The age of onset of epilepsy ranged from 2 months to 4 years, with a median onset age of 5 months. Among these 11 patients (comprising 6 boys and 5 girls), all were diagnosed with lissencephaly type 1. Predominantly, generalized tonic-clonic and spasm seizures characterized PAFAH1B1-related epilepsy. Additionally, 10 out of the 11 patients exhibited severe developmental disorders. All patients exhibited de novo variants, with three individuals displaying 17p13.3 deletions linked to haploinsufficiency of PAFAH1B1. Four variants were previously unreported. Notably, three patients with 17p13.3 deletions displayed developmental delay and drug resistant epilepsy, whereas the single patient with mild developmental delay, Intelligence Quotient (IQ) 57 and well-controlled seizures had a splicing-site variant.
CONCLUSION
The severity of the phenotype in patients with PAFAH1B1 variants ranged from drug-responsive seizures to severe epileptic encephalopathy. These observations underscore the clinical heterogeneity of PAFAH1B1-related disorders, with most patients exhibiting developmental disorders. Moreover, the severity of epilepsy appears to be linked to genetic variations.
Topics: Humans; Male; Female; 1-Alkyl-2-acetylglycerophosphocholine Esterase; Child, Preschool; Infant; Epilepsy; Electroencephalography; Phenotype; Magnetic Resonance Imaging; Developmental Disabilities; Child; Microtubule-Associated Proteins
PubMed: 38364333
DOI: 10.1016/j.seizure.2024.01.020 -
Epileptic Disorders : International... Apr 2024The ILAE Neuroimaging Task Force publishes educational case reports that highlight basic aspects of neuroimaging in epilepsy consistent with the ILAE's educational...
The ILAE Neuroimaging Task Force publishes educational case reports that highlight basic aspects of neuroimaging in epilepsy consistent with the ILAE's educational mission. Subcortical laminar heterotopia, also known as subcortical band heterotopia (SBH) or "double cortex," is an intriguing and rare congenital malformation of cortical development. SBH lesions are part of a continuum best designated as agyria-pachygyria-band-spectrum. The malformation is associated with epilepsy that is often refractory, as well as variable degrees of developmental delay. Moreover, in an increasing proportion of cases, a distinct molecular-genetic background can be found. Diagnosing SBH can be a major challenge for many reasons, including more subtle lesions, and "non-classic" or unusual MRI-appearances. By presenting an illustrative case, we address the challenges and needs of diagnosing and treating SBH patients in epilepsy, especially the value of high-resolution imaging and specialized MRI-protocols.
Topics: Humans; Classical Lissencephalies and Subcortical Band Heterotopias; Cerebral Cortex; Epilepsy; Neuroimaging; Magnetic Resonance Imaging
PubMed: 38353525
DOI: 10.1002/epd2.20206 -
Cureus Feb 2024The dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly, and lissencephaly (DREAM-PL) syndrome is a rare autosomal recessive disorder...
Extensive Phenotypic Variability in Syndrome Dysmorphic Facies, Renal Agenesis, Ambiguous Genitalia, Microcephaly, Polydactyly, and Lissencephaly (DREAM-PL): A Case Report Highlighting Diagnostic and Management Challenges.
The dysmorphic facies, renal agenesis, ambiguous genitalia, microcephaly, polydactyly, and lissencephaly (DREAM-PL) syndrome is a rare autosomal recessive disorder characterized by dysmorphic facies, renal agenesis, ambiguous genitalia in males, microcephaly, polydactyly, and lissencephaly. The CTU2 gene, which encodes a protein involved in the post-transcriptional modification of tRNAs is the source of the syndrome's mutation. Several developmental abnormalities can result from a disruption of this modification, which is necessary for the proper translation of genes. The severity of the symptoms of DREAM-PL syndrome can range from moderate to severe, and its clinical characteristics are quite diverse. Some patients might have some of the distinguishing characteristics, whereas others might have all of them. The most typical characteristics include ambiguous genitalia, dysmorphic facies, and microcephaly. DREAM-PL syndrome is diagnosed based on clinical signs and genetic testing which can show mutations in the CTU2 gene. Although there is no known cure for this syndrome, the treatment aims to manage the symptoms. Other lines of treatment like surgical correction of birth defects can sometimes be beneficial to these patients in addition to supportive care. This study is a report of a 37-week-old male neonate, delivered by lower segment cesarean section. The baby's birth weight is 2.760 kg with a heterozygous confirmed pathogenic mutation of the CTU2 gene confirmed by whole-exome sequencing.
PubMed: 38348206
DOI: 10.7759/cureus.54043 -
Neurogenetics Apr 2024Congenital muscular dystrophies (CMDs) are a group of rare muscle disorders characterized by early onset hypotonia and motor developmental delay associated with brain...
Congenital muscular dystrophies (CMDs) are a group of rare muscle disorders characterized by early onset hypotonia and motor developmental delay associated with brain malformations with or without eye anomalies in the most severe cases. In this study, we aimed to uncover the genetic basis of severe CMD in Egypt and to determine the efficacy of whole exome sequencing (WES)-based genetic diagnosis in this population. We recruited twelve individuals from eleven families with a clinical diagnosis of CMD with brain malformations that fell into two groups: seven patients with suspected dystroglycanopathy and five patients with suspected merosin-deficient CMD. WES was analyzed by variant filtering using multiple approaches including splicing and copy number variant (CNV) analysis. We identified likely pathogenic variants in FKRP in two cases and variants in POMT1, POMK, and B3GALNT2 in three individuals. All individuals with merosin-deficient CMD had truncating variants in LAMA2. Further analysis in one of the two unsolved cases showed a homozygous protein-truncating variant in Feline Leukemia Virus subgroup C Receptor 1 (FLVCR1). FLVCR1 loss of function has never been previously reported. Yet, loss of function of its paralog, FLVCR2, causes lethal hydranencephaly-hydrocephaly syndrome (Fowler Syndrome) which should be considered in the differential diagnosis for dystroglycanopathy. Overall, we reached a diagnostic rate of 86% (6/7) for dystroglycanopathies and 100% (5/5) for merosinopathy. In conclusion, our results provide further evidence that WES is an important diagnostic method in CMD in developing countries to improve the diagnostic rate, management plan, and genetic counseling for these disorders.
Topics: Humans; Male; Egypt; Female; Muscular Dystrophies; Exome Sequencing; Child, Preschool; Brain; Child; Infant; Laminin; Receptors, Virus; Mannosyltransferases; Pedigree; Pentosyltransferases; DNA Copy Number Variations; Mutation; Adolescent; Nervous System Malformations; N-Acetylglucosaminyltransferases
PubMed: 38296890
DOI: 10.1007/s10048-024-00745-z -
Molecular Genetics & Genomic Medicine Jan 2024Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations is a rare neurological disorder that is associated with typical clinical and imaging...
BACKGROUND
Mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations is a rare neurological disorder that is associated with typical clinical and imaging features. The syndrome is caused by pathogenic variants in the MAST1 gene, which encodes a microtubule-associated protein that is predominantly expressed in postmitotic neurons in the developing nervous system.
METHODS
Fetal DNA from umbilical cord blood samples and genomic DNA from peripheral blood lymphocytes were subjected to whole-exome sequencing. The potential causative variants were verified by Sanger sequencing.
RESULTS
A 26-year-old primigravid woman was referred to our prenatal center at 25 weeks of gestation due to abnormal ultrasound findings in the brain of the fetus. The brain abnormalities included wide cavum septum pellucidum, shallow and incomplete bilateral lateral fissure cistern, bilateral dilated lateral ventricles, hyperplastic corpus callosum, lissencephaly, and cortical dysplasia. No obvious abnormalities were observed in the brainstem or cerebellum hemispheres, but the cerebellum vermis was small. Whole-exome sequencing identified a de novo, heterozygous missense variant, c.695T>C(p.Leu232Pro), in the MAST1 gene and a genetic diagnosis of mega-corpus-callosum syndrome was considered.
CONCLUSION
This study is the first prenatal case of MAST1-related disorder reported in the Chinese population and has expanded the mutation spectrum of the MAST1 gene.
Topics: Pregnancy; Female; Humans; Adult; Cerebellar Vermis; Cerebellum; Malformations of Cortical Development; Fetus; Leukoencephalopathies; DNA; Developmental Disabilities; Nervous System Malformations
PubMed: 38284444
DOI: 10.1002/mgg3.2358 -
Developmental Medicine and Child... Jul 2024Hydrocephalus is rarely described in Joubert-Boltshauser syndrome (JBTS). The aim of this study was to investigate whether this association is a chance occurrence or...
Hydrocephalus is rarely described in Joubert-Boltshauser syndrome (JBTS). The aim of this study was to investigate whether this association is a chance occurrence or potentially signifies a new phenotypic subtype. The databases of Wolfson Medical Center, Sourasky Medical Center, and EB's personal collection were reviewed. Records from an additional family were obtained from RG. The patients' medical records, prenatal ultrasounds, and magnetic resonance imaging were assessed. In addition, we reviewed the medical literature for the association of ventriculomegaly/hydrocephalus (VM/HC) in JBTS. Only seven cases (from five families) were found with prenatal onset of VM/HC, diagnosed during the second trimester; three pregnancies were terminated, one was stillborn and three were born, of which one died within a week, and another died at the age of 6 years. Additional central nervous system findings included dysgenesis of the corpus callosum, delayed sulcation, polymicrogyria, and pachygyria. We found 16 publications describing 54 patients with JBTS and VM/HC: only five were diagnosed at birth and three were diagnosed prenatally. Hydrocephalus is extremely rare in JBTS. The recurrence of this association, reported in several publications in multiple family members, suggests that it might represent a new phenotypic subtype of JBTS possibly associated with specific genes or variants. Further genetic studies are needed to confirm this hypothesis. WHAT THIS PAPER ADDS: The association of fetal hydrocephalus with Joubert-Boltshauser syndrome (JBTS) is very rare but not a chance association. This association represents a new phenotypic subtype of JBTS possibly linked to specific genes or variants.
Topics: Humans; Hydrocephalus; Cerebellum; Eye Abnormalities; Abnormalities, Multiple; Female; Kidney Diseases, Cystic; Male; Retina; Cerebellar Vermis; Magnetic Resonance Imaging; Phenotype; Cerebellar Diseases; Child; Infant, Newborn
PubMed: 38247023
DOI: 10.1111/dmcn.15845 -
Development (Cambridge, England) Jan 2024Lissencephaly is a neurodevelopmental disorder characterised by a loss of brain folds. In a new study, Jin-Wu Tsai and colleagues uncover a new variant of BAIAP2 that is...
Lissencephaly is a neurodevelopmental disorder characterised by a loss of brain folds. In a new study, Jin-Wu Tsai and colleagues uncover a new variant of BAIAP2 that is associated with lissencephaly. To learn more about the story behind the paper, we caught up with first authors Meng-Han Tsai and Wan-Cian Lin, and corresponding author Jin-Wu Tsai, Professor at National Yang Ming Chiao Tung University, Taiwan.
Topics: Humans; Lissencephaly
PubMed: 38240361
DOI: 10.1242/dev.202653 -
Acta Neuropathologica Jan 2024The development of the cerebral cortex involves a series of dynamic events, including cell proliferation and migration, which rely on the motor protein dynein and its...
The development of the cerebral cortex involves a series of dynamic events, including cell proliferation and migration, which rely on the motor protein dynein and its regulators NDE1 and NDEL1. While the loss of function in NDE1 leads to microcephaly-related malformations of cortical development (MCDs), NDEL1 variants have not been detected in MCD patients. Here, we identified two patients with pachygyria, with or without subcortical band heterotopia (SBH), carrying the same de novo somatic mosaic NDEL1 variant, p.Arg105Pro (p.R105P). Through single-cell RNA sequencing and spatial transcriptomic analysis, we observed complementary expression of Nde1/NDE1 and Ndel1/NDEL1 in neural progenitors and post-mitotic neurons, respectively. Ndel1 knockdown by in utero electroporation resulted in impaired neuronal migration, a phenotype that could not be rescued by p.R105P. Remarkably, p.R105P expression alone strongly disrupted neuronal migration, increased the length of the leading process, and impaired nucleus-centrosome coupling, suggesting a failure in nucleokinesis. Mechanistically, p.R105P disrupted NDEL1 binding to the dynein regulator LIS1. This study identifies the first lissencephaly-associated NDEL1 variant and sheds light on the distinct roles of NDE1 and NDEL1 in nucleokinesis and MCD pathogenesis.
Topics: Humans; Lissencephaly; Cell Movement; Cell Proliferation; Cerebral Cortex; Dyneins; Carrier Proteins; Microtubule-Associated Proteins
PubMed: 38194050
DOI: 10.1007/s00401-023-02665-y -
Neurology India 2023Incomplete hippocampal inversion (IHI) is a developmental failure of normal hippocampal inversion. Previous studies have described IHI in epilepsy and non-epilepsy...
BACKGROUND AND PURPOSE
Incomplete hippocampal inversion (IHI) is a developmental failure of normal hippocampal inversion. Previous studies have described IHI in epilepsy and non-epilepsy subjects. IHI has also been reported with malformations of cortical development (MCDs) and corpus callosal agenesis that have association with neuropsychiatric disorders such as autism spectrum disorder (ASD). This study aims to describe the clinical profile of magnetic resonance imaging (MRI)-diagnosed IHI.
MATERIALS AND METHODS
We studied patients with IHI who were identified after a retrospective review of the MRI archives of the past 3 years. The MRI findings of partial and total IHI were included. The clinical profiles associated with IHI were classified into epilepsy and non-epilepsy categories.
RESULTS
A retrospective review of MRI done over 3 years revealed 54 cases of IHI (32 left-sided, 20 bilateral, and 2 isolated right-sided), and out of 74 IHI, 59 were of total type and 15 partial. Thirty-six subjects (61.1%) had epilepsy (9 with neurodevelopmental problems), 17 subjects (31.5%) had ASD, and 4 subjects (7.4%) had only neurodevelopmental disorders. MCDs were seen in 7 (12.9%): polymicrogyria (4), periventricular heterotopia (2), and pachygyria (1). Hippocampal volume loss was seen in 10, and contralateral mesial temporal sclerosis was seen in 2 patients.
CONCLUSION
Hippocampal inversion has been reported in MRI scans of patients with epilepsy, ASD, MCDs, and many other related disorders. Further studies are required to know its occurrence among patients who get MRI scans due to many other disorders such as headaches, psychiatric disorders, minor hear trauma, and perinatal insults. If possible, studies among normal populations also need to be done.
Topics: Humans; Autism Spectrum Disorder; Hippocampus; Epilepsy; Magnetic Resonance Imaging; Neuroimaging
PubMed: 38174460
DOI: 10.4103/0028-3886.391380