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American Journal of Medical Genetics.... Oct 2020The clinical presentation of bilateral perisylvian polymicrogyria (PMG) is highly variable, including oromotor dysfunction, epilepsy, intellectual disability, and...
The clinical presentation of bilateral perisylvian polymicrogyria (PMG) is highly variable, including oromotor dysfunction, epilepsy, intellectual disability, and pyramidal signs. Extrapyramidal features are extremely rare. We present four apparently unrelated patients with a unique association of PMG with dystonia. The clinical, genetic, and radiologic features are described and possible mechanisms of dystonia are discussed. All patients were female and two were born to consanguineous families. All presented with early childhood onset dystonia. Other neurologic symptoms and signs classically seen in bilateral perisylvian PMG were observed, including oromotor dysfunction and speech abnormalities ranging from dysarthria to anarthria (4/4), pyramidal signs (3/4), hypotonia (3/4), postnatal microcephaly (1/4), and seizures (1/4). Neuroimaging showed a unique pattern of bilateral PMG with an infolded cortex originating primarily from the perisylvian region in three out of four patients. Whole exome sequencing was performed in two out of four patients and did not reveal pathogenic variants in known genes for cortical malformations or movement disorders. The dystonia seen in our patients is not described in bilateral PMG and suggests an underlying mechanism of impaired connectivity within the motor network or compromised cortical inhibition. The association of bilateral PMG with dystonia in our patients may represent a new neurogenetic disorder.
Topics: Abnormalities, Multiple; Adolescent; Adult; Cerebral Cortex; Child; Child, Preschool; Dystonia; Dystonic Disorders; Electroencephalography; Epilepsy; Female; Humans; Intellectual Disability; Magnetic Resonance Imaging; Malformations of Cortical Development; Neuroimaging; Polymicrogyria; Young Adult
PubMed: 33001581
DOI: 10.1002/ajmg.a.61795 -
Neurology Jan 2019Hereditary hemorrhagic telangiectasia (HHT) is generally considered a disorder of endothelial dysfunction, characterized by the development of multiple systemic...
Hereditary hemorrhagic telangiectasia (HHT) is generally considered a disorder of endothelial dysfunction, characterized by the development of multiple systemic arteriovenous malformations (AVMs), including within the brain. However, there have recently been a number of reports correlating HHT with malformations of cortical development, of which polymicrogyria is the most common type. Here we present 7 new cases demonstrating polymicrogyria in HHT, 6 of which demonstrate a brain AVM (bAVM) in close spatial proximity, with the aim of providing a common origin for the association. Upon reviewing patient genetics and imaging data and comparing with previously reported findings, we form 2 new conclusions: (1) polymicrogyria in HHT appears exclusively associated with a subset of mutations in the transmembrane protein endoglin that is involved with blood flow-related mechanotransduction signaling during angiogenesis and (2) the polymicrogyria is characteristically unilateral, typically focal, and correlates with vascular regions experiencing low fluid shear stress during corticogenesis in utero. Integrating these with findings in the literature from genetics and molecular biology experiments, we propose a theory suggesting haploinsufficient endoglin mutations, especially those that are dominant-negative, may predispose focal, aberrant hypersprouting angiogenesis during corticogenesis that leads to the production of polymicrogyria. This hypoxic insult may further serve as the revealing trigger for later development of a spatially coincident bAVM. This hypothesis suggests an essential role for endoglin-mediated hemodynamic mechanotransduction in normal corticogenesis.
Topics: Adolescent; Adult; Arteriovenous Malformations; Brain; Child; Child, Preschool; Female; Humans; Infant; Male; Polymicrogyria; Telangiectasia, Hereditary Hemorrhagic
PubMed: 30584075
DOI: 10.1212/WNL.0000000000006686 -
Journal of Neuropathology and... Sep 2023
PubMed: 36864686
DOI: 10.1093/jnen/nlad017 -
Ryoikibetsu Shokogun Shirizu 2000
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Neurology Apr 2021To determine whether specific speech, language, and oromotor profiles are associated with different patterns of polymicrogyria, we assessed 52 patients with...
OBJECTIVE
To determine whether specific speech, language, and oromotor profiles are associated with different patterns of polymicrogyria, we assessed 52 patients with polymicrogyria using a battery of standardized tests and correlated findings with topography and severity of polymicrogyria.
METHODS
Patients were identified via clinical research databases and invited to participate, irrespective of cognitive and verbal language abilities. We conducted standardized assessments of speech, oromotor structure and function, language, and nonverbal IQ. Data were analyzed according to normative assessment data and descriptive statistics. We conducted a correlation analysis between topographic pattern and speech and language findings.
RESULTS
Fifty-two patients (33 male, 63%) were studied at an average age of 12.7 years (range 2.5-36 years). All patients had dysarthria, which ranged from mild impairment to anarthria. Developmental speech errors (articulation and phonology), oral motor structure and function deficits, and language disorder were frequent. A total of 23/29 (79%) had cognitive abilities in the low average to extremely low range. In the perisylvian polymicrogyria group (36/52), speech, everyday language, and oral motor impairments were more severe, compared to generalized (1 patient), frontal (3), polymicrogyria with periventricular nodular heterotopia (3), parasagittal parieto-occipital (1), mesial occipital (1), and other (7) patterns.
CONCLUSIONS
Dysarthria is a core feature of polymicrogyria, often accompanied by receptive and expressive language impairments. These features are associated with all polymicrogyria distribution patterns and more severe in individuals with bilateral polymicrogyria, particularly in the perisylvian region.
Topics: Adolescent; Adult; Child; Child, Preschool; Dysarthria; Female; Humans; Language Development Disorders; Magnetic Resonance Imaging; Male; Polymicrogyria; Young Adult
PubMed: 33589534
DOI: 10.1212/WNL.0000000000011698 -
Journal of Veterinary Internal Medicine 2009Polymicrogyria is a disorder of cerebrocortical migration resulting in increased numbers of small, disorganized gyri. This disorder occurs in Standard Poodles and in...
BACKGROUND
Polymicrogyria is a disorder of cerebrocortical migration resulting in increased numbers of small, disorganized gyri. This disorder occurs in Standard Poodles and in cattle.
OBJECTIVES
To describe the clinical, electroencephalographic, imaging, and histopathologic features in poodles with polymicrogyria.
ANIMALS
Five Standard Poodles with histologically confirmed polymicrogyria.
METHODS
Retrospective case series. Cases were obtained by personal communication with 1 of 2 authors (TJVW, DPO).
RESULTS
All dogs had cortical blindness and other neurologic abnormalities including gait and behavioral changes. Magnetic resonance imaging of 3 dogs showed multiple disorganized gyri, which were especially apparent on T2-weighted dorsal plane images. Electroencephalogram (EEG) of 1 dog revealed epileptiform discharges, including both spike and spike and wave discharges with voltage maximum potentials over the parietal/occipital region. The EEG supported that the repetitive behavior displayed by the dog was a complex partial motor seizure. One dog had concurrent hydrocephalus. All dogs had occipital lobe involvement and 2 dogs had involvement of other lobes.
CLINICAL IMPORTANCE
The cases presented here demonstrate a larger age range (7 weeks to 5 years) and a decreased frequency of associated hydrocephalus when compared with the previous report.
Topics: Animals; Brain; Cattle; Dog Diseases; Dogs; Malformations of Cortical Development
PubMed: 19566852
DOI: 10.1111/j.1939-1676.2009.0338.x -
American Journal of Medical Genetics.... Dec 2019Polymicrogyria (PMG) is a heterogeneous brain malformation that may result from prenatal vascular disruption or infection, or from numerous genetic causes that still...
Polymicrogyria (PMG) is a heterogeneous brain malformation that may result from prenatal vascular disruption or infection, or from numerous genetic causes that still remain difficult to identify. We identified three unrelated patients with polymicrogyria and duplications of chromosome 2p, defined the smallest region of overlap, and performed gene pathway analysis using Cytoscape. The smallest region of overlap in all three children involved 2p16.1-p16.3. All three children have bilateral perisylvian polymicrogyria (BPP), intrauterine and postnatal growth deficiency, similar dysmorphic features, and poor feeding. Two of the three children had documented intellectual disability. Gene pathway analysis suggested a number of developmentally relevant genes and gene clusters that were over-represented in the critical region. We narrowed a rare locus for polymicrogyria to a region of 2p16.1-p16.3 that contains 33-34 genes, 23 of which are expressed in cerebral cortex during human fetal development. Using pathway analysis, we showed that several of the duplicated genes contribute to neurodevelopmental pathways including morphogen, cytokine, hormonal and growth factor signaling, regulation of cell cycle progression, cell morphogenesis, axonal guidance, and neuronal migration. These findings strengthen the evidence for a novel locus associated with polymicrogyria on 2p16.1-p16.3, and comprise the first step in defining the underlying genetic etiology.
Topics: Abnormalities, Multiple; Adolescent; Brain; Chromosome Duplication; Chromosomes, Human, Pair 2; Comparative Genomic Hybridization; Computational Biology; Facies; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Infant, Newborn; Intellectual Disability; Magnetic Resonance Imaging; Male; Malformations of Cortical Development; Phenotype
PubMed: 31660690
DOI: 10.1002/ajmg.a.61342 -
American Journal of Human Genetics Feb 2022Free oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is known about fOS metabolism, the recent...
Free oligosaccharides (fOSs) are soluble oligosaccharide species generated during N-glycosylation of proteins. Although little is known about fOS metabolism, the recent identification of NGLY1 deficiency, a congenital disorder of deglycosylation (CDDG) caused by loss of function of an enzyme involved in fOS metabolism, has elicited increased interest in fOS processing. The catabolism of fOSs has been linked to the activity of a specific cytosolic mannosidase, MAN2C1, which cleaves α1,2-, α1,3-, and α1,6-mannose residues. In this study, we report the clinical, biochemical, and molecular features of six individuals, including two fetuses, with bi-allelic pathogenic variants in MAN2C1; the individuals are from four different families. These individuals exhibit dysmorphic facial features, congenital anomalies such as tongue hamartoma, variable degrees of intellectual disability, and brain anomalies including polymicrogyria, interhemispheric cysts, hypothalamic hamartoma, callosal anomalies, and hypoplasia of brainstem and cerebellar vermis. Complementation experiments with isogenic MAN2C1-KO HAP1 cells confirm the pathogenicity of three of the identified MAN2C1 variants. We further demonstrate that MAN2C1 variants lead to accumulation and delay in the processing of fOSs in proband-derived cells. These results emphasize the involvement of MAN2C1 in human neurodevelopmental disease and the importance of fOS catabolism.
Topics: Adolescent; Alleles; Brain Stem; Cell Line, Tumor; Central Nervous System Cysts; Cerebellar Vermis; Child; Child, Preschool; Congenital Disorders of Glycosylation; Female; Fetus; Glycosylation; Hamartoma; Humans; Hypothalamus; Intellectual Disability; Leukocytes; Male; Mannose; Oligosaccharides; Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase; Polymicrogyria; Tongue; alpha-Mannosidase
PubMed: 35045343
DOI: 10.1016/j.ajhg.2021.12.010 -
Brain : a Journal of Neurology Mar 2018
Topics: Humans; Mutation; Nerve Tissue Proteins; Polymicrogyria; Receptors, N-Methyl-D-Aspartate
PubMed: 30753417
DOI: 10.1093/brain/awy047 -
Ryoikibetsu Shokogun Shirizu 2000
Review
Topics: Cerebral Cortex; Frontal Lobe; Humans; Parietal Lobe
PubMed: 11043295
DOI: No ID Found