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Advanced Biomedical Research 2017Adams-Oliver syndrome (AOS) is a rare congenital disorder with unknown etiology commonly presented with aplasia cutis and terminal limb defects. Central nervous and...
Adams-Oliver syndrome (AOS) is a rare congenital disorder with unknown etiology commonly presented with aplasia cutis and terminal limb defects. Central nervous and cardiopulmonary systems may also be affected. It is commonly inherited as an autosomal dominant disorder but autosomal recessive and sporadic cases have also been reported. Here, we present a 10-year-old boy with extensive aplasia cutis congenita and limb anomalies as well as mild pachygyria and focal acrania in neuroimaging. No other internal organ involvement was obvious in this patient. Family history was negative for this syndrome. AOS is a multisystem disorder, and so it is crucial to investigate for internal organ involvements.
PubMed: 29387678
DOI: 10.4103/2277-9175.221861 -
European Journal of Human Genetics :... Jan 2024Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one...
Lissencephaly (LIS) is a malformation of cortical development due to deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. Thirty-one LIS-associated genes have been previously described. Recently, biallelic pathogenic variants in CRADD and PIDD1, have associated with LIS impacting the previously established role of the PIDDosome in activating caspase-2. In this report, we describe biallelic truncating variants in CASP2, another subunit of PIDDosome complex. Seven patients from five independent families presenting with a neurodevelopmental phenotype were identified through GeneMatcher-facilitated international collaborations. Exome sequencing analysis was carried out and revealed two distinct novel homozygous (NM_032982.4:c.1156delT (p.Tyr386ThrfsTer25), and c.1174 C > T (p.Gln392Ter)) and compound heterozygous variants (c.[130 C > T];[876 + 1 G > T] p.[Arg44Ter];[?]) in CASP2 segregating within the families in a manner compatible with an autosomal recessive pattern. RNA studies of the c.876 + 1 G > T variant indicated usage of two cryptic splice donor sites, each introducing a premature stop codon. All patients from whom brain MRIs were available had a typical fronto-temporal LIS and pachygyria, remarkably resembling the CRADD and PIDD1-related neuroimaging findings. Other findings included developmental delay, attention deficit hyperactivity disorder, hypotonia, seizure, poor social skills, and autistic traits. In summary, we present patients with CASP2-related ID, anterior-predominant LIS, and pachygyria similar to previously reported patients with CRADD and PIDD1-related disorders, expanding the genetic spectrum of LIS and lending support that each component of the PIDDosome complex is critical for normal development of the human cerebral cortex and brain function.
Topics: Humans; Caspase 2; Lissencephaly; Alleles; Neurodevelopmental Disorders; Codon, Nonsense; Phenotype; Cysteine Endopeptidases
PubMed: 37880421
DOI: 10.1038/s41431-023-01461-2 -
American Journal of Medical Genetics.... Jun 2017Lissencephaly ("smooth brain," LIS) is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral...
Lissencephaly ("smooth brain," LIS) is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. The LIS spectrum includes agyria, pachygyria, and subcortical band heterotopia. Our first classification of LIS and subcortical band heterotopia (SBH) was developed to distinguish between the first two genetic causes of LIS-LIS1 (PAFAH1B1) and DCX. However, progress in molecular genetics has led to identification of 19 LIS-associated genes, leaving the existing classification system insufficient to distinguish the increasingly diverse patterns of LIS. To address this challenge, we reviewed clinical, imaging and molecular data on 188 patients with LIS-SBH ascertained during the last 5 years, and reviewed selected archival data on another ∼1,400 patients. Using these data plus published reports, we constructed a new imaging based classification system with 21 recognizable patterns that reliably predict the most likely causative genes. These patterns do not correlate consistently with the clinical outcome, leading us to also develop a new scale useful for predicting clinical severity and outcome. Taken together, our work provides new tools that should prove useful for clinical management and genetic counselling of patients with LIS-SBH (imaging and severity based classifications), and guidance for prioritizing and interpreting genetic testing results (imaging based- classification).
Topics: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Adolescent; Adult; Cerebral Cortex; Child; Child, Preschool; Classical Lissencephalies and Subcortical Band Heterotopias; Doublecortin Domain Proteins; Doublecortin Protein; Female; Humans; Infant; Infant, Newborn; Lissencephaly; Magnetic Resonance Imaging; Male; Microtubule-Associated Proteins; Mutation; Neuropeptides; Phenotype; Young Adult
PubMed: 28440899
DOI: 10.1002/ajmg.a.38245 -
Indian Journal of Psychological Medicine 2015Psychiatric manifestation of pachygyria, a neuronal migration disorder is rare in literature; rarer if it is bipolar disorder specifically. Here, we report a case of...
Psychiatric manifestation of pachygyria, a neuronal migration disorder is rare in literature; rarer if it is bipolar disorder specifically. Here, we report a case of mania and seizure who subsequently diagnosed as pachygyria. Proper literature about pathophysiology is discussed and recently discovered putative genetic role in bipolar disorder explained. This case also emphasis the importance of detailed history taking and imaging investigation even in a pure psychiatric presentation.
PubMed: 26702182
DOI: 10.4103/0253-7176.168595 -
JNMA; Journal of the Nepal Medical... Nov 2022Lissencephaly is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. The...
UNLABELLED
Lissencephaly is a malformation of cortical development associated with deficient neuronal migration and abnormal formation of cerebral convolutions or gyri. The lissencephaly spectrum consists of agyria, pachygyria, and subcortical band heterotopia. At least 19 genes have been identified in the causation of lissencephaly and related syndrome. Lissencephaly is associated with many other congenital disorders but the association of lissencephaly with congenital hypothyroidism is rarely reported. We report a case of a 10-year-old girl having lissencephaly with congenital hypothyroidism. Early diagnosis of lissencephaly and genetic counselling can be made in suspected cases and further possible interventions can be taken. Also, regular follow-up, monitoring, and better conservative management lead to a better prognosis.
KEYWORDS
congenital abnormalities; hypothyroidism; lissencephaly; neuronal migration disorders.
Topics: Female; Humans; Child; Congenital Hypothyroidism; Lissencephaly; Classical Lissencephalies and Subcortical Band Heterotopias; Phenotype
PubMed: 36705174
DOI: 10.31729/jnma.7893 -
Trends in Molecular Medicine Jul 2016A key aspect of cellular function is the proper assembly and utilization of ribonucleoproteins (RNPs). Recent studies have shown that hyper- or hypo-assembly of various... (Review)
Review
A key aspect of cellular function is the proper assembly and utilization of ribonucleoproteins (RNPs). Recent studies have shown that hyper- or hypo-assembly of various RNPs can lead to human diseases. Defects in the formation of RNPs lead to 'RNP hypo-assembly diseases', which can be caused by RNA degradation outcompeting RNP assembly. By contrast, excess RNP assembly, either in higher order RNP granules, or due to the expression of repeat-containing RNAs, can lead to 'RNP hyper-assembly diseases'. Here, we discuss the most recent advances in understanding the cause of disease onset, as well as potential therapies from the aspect of modulating RNP assembly in the cell, which presents a novel route to the treatment of these diseases.
Topics: Animals; Dwarfism; Dyskeratosis Congenita; Fetal Growth Retardation; Hair; Hirschsprung Disease; Humans; Immunologic Deficiency Syndromes; Mallory Bodies; Microcephaly; Muscular Atrophy, Spinal; Muscular Dystrophies; Mutation; Osteochondrodysplasias; Parkinson Disease; Primary Immunodeficiency Diseases; RNA Stability; Ribonucleoproteins; Scoliosis; Walker-Warburg Syndrome
PubMed: 27263464
DOI: 10.1016/j.molmed.2016.05.005 -
Anales de Pediatria (Barcelona, Spain :... Mar 2009
Topics: Classical Lissencephalies and Subcortical Band Heterotopias; Humans; Infant; Male
PubMed: 19409251
DOI: 10.1016/j.anpedi.2008.11.003 -
Journal of Neuroscience Methods Feb 2016Malformations of cortical development constitute a variety of pathological brain abnormalities that commonly cause severe, medically-refractory epilepsy, including focal... (Review)
Review
Malformations of cortical development constitute a variety of pathological brain abnormalities that commonly cause severe, medically-refractory epilepsy, including focal lesions, such as focal cortical dysplasia, heterotopias, and tubers of tuberous sclerosis complex, and diffuse malformations, such as lissencephaly. Although some cortical malformations result from environmental insults during cortical development in utero, genetic factors are increasingly recognized as primary pathogenic factors across the entire spectrum of malformations. Genes implicated in causing different cortical malformations are involved in a variety of physiological functions, but many are focused on regulation of cell proliferation, differentiation, and neuronal migration. Advances in molecular genetic methods have allowed the engineering of increasingly sophisticated animal models of cortical malformations and associated epilepsy. These animal models have identified some common mechanistic themes shared by a number of different cortical malformations, but also revealed the diversity and complexity of cellular and molecular mechanisms that lead to the development of the pathological lesions and resulting epileptogenesis.
Topics: Animals; Animals, Genetically Modified; Cerebral Cortex; Disease Models, Animal; Epilepsy; Freezing; Genetic Engineering; Genetic Predisposition to Disease; Malformations of Cortical Development; Mice; Nerve Net; Rats; Rodentia; Species Specificity
PubMed: 25911067
DOI: 10.1016/j.jneumeth.2015.04.007 -
European Journal of Human Genetics :... Aug 2021The PIDDosome is a multiprotein complex, composed by the p53-induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD (also known as RAIDD) and the...
The PIDDosome is a multiprotein complex, composed by the p53-induced death domain protein 1 (PIDD1), the bipartite linker protein CRADD (also known as RAIDD) and the proform of caspase-2 that induces apoptosis in response to DNA damage. In the recent years, biallelic pathogenic variants in CRADD have been associated with a neurodevelopmental disorder (MRT34; MIM 614499) characterized by pachygyria with a predominant anterior gradient, megalencephaly, epilepsy and intellectual disability. More recently, biallelic pathogenic variants in PIDD1 have been described in a few families with apparently nonsydnromic intellectual disability. Here, we aim to delineate the genetic and radio-clinical features of PIDD1-related disorder. Exome sequencing was carried out in six consanguineous families. Thorough clinical and neuroradiological evaluation was performed for all the affected individuals as well as reviewing all the data from previously reported cases. We identified five distinct novel homozygous variants (c.2584C>T p.(Arg862Trp), c.1340G>A p.(Trp447*), c.2116_2120del p.(Val706Hisfs*30), c.1564_1565delCA p.(Gln522fs*44), and c.1804_1805del p.(Gly602fs*26) in eleven subjects displaying intellectual disability, behaviorial and psychiatric features, and a typical anterior-predominant pachygyria, remarkably resembling the CRADD-related neuroimaging pattern. In summary, we outlin`e the phenotypic and molecular spectrum of PIDD1 biallelic variants supporting the evidence that the PIDD1/CRADD/caspase-2 signaling is crucial for normal gyration of the developing human neocortex as well as cognition and behavior.
Topics: Adolescent; Adult; Child; Child, Preschool; Death Domain Receptor Signaling Adaptor Proteins; Developmental Disabilities; Female; Genes, Recessive; Humans; Intellectual Disability; Lissencephaly; Male; Mutation; Pedigree; Syndrome
PubMed: 34163010
DOI: 10.1038/s41431-021-00910-0 -
The New England Journal of Medicine Aug 2014Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the...
BACKGROUND
Although there is increasing recognition of the role of somatic mutations in genetic disorders, the prevalence of somatic mutations in neurodevelopmental disease and the optimal techniques to detect somatic mosaicism have not been systematically evaluated.
METHODS
Using a customized panel of known and candidate genes associated with brain malformations, we applied targeted high-coverage sequencing (depth, ≥200×) to leukocyte-derived DNA samples from 158 persons with brain malformations, including the double-cortex syndrome (subcortical band heterotopia, 30 persons), polymicrogyria with megalencephaly (20), periventricular nodular heterotopia (61), and pachygyria (47). We validated candidate mutations with the use of Sanger sequencing and, for variants present at unequal read depths, subcloning followed by colony sequencing.
RESULTS
Validated, causal mutations were found in 27 persons (17%; range, 10 to 30% for each phenotype). Mutations were somatic in 8 of the 27 (30%), predominantly in persons with the double-cortex syndrome (in whom we found mutations in DCX and LIS1), persons with periventricular nodular heterotopia (FLNA), and persons with pachygyria (TUBB2B). Of the somatic mutations we detected, 5 (63%) were undetectable with the use of traditional Sanger sequencing but were validated through subcloning and subsequent sequencing of the subcloned DNA. We found potentially causal mutations in the candidate genes DYNC1H1, KIF5C, and other kinesin genes in persons with pachygyria.
CONCLUSIONS
Targeted sequencing was found to be useful for detecting somatic mutations in patients with brain malformations. High-coverage sequencing panels provide an important complement to whole-exome and whole-genome sequencing in the evaluation of somatic mutations in neuropsychiatric disease. (Funded by the National Institute of Neurological Disorders and Stroke and others.).
Topics: Cerebral Cortex; Classical Lissencephalies and Subcortical Band Heterotopias; DNA Mutational Analysis; Humans; Lissencephaly; Magnetic Resonance Imaging; Malformations of Cortical Development; Mutation; Periventricular Nodular Heterotopia
PubMed: 25140959
DOI: 10.1056/NEJMoa1314432