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Neurogenetics

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https://www.readbyqxmd.com/read/29322350/monogenic-disorders-that-mimic-the-phenotype-of-rett-syndrome
#1
Siddharth Srivastava, Sonal Desai, Julie Cohen, Constance Smith-Hicks, Kristin Barañano, Ali Fatemi, SakkuBai Naidu
Rett syndrome (RTT) is caused by mutations in methyl-CpG-binding protein 2 (MECP2), but defects in a handful of other genes (e.g., CDKL5, FOXG1, MEF2C) can lead to presentations that resemble, but do not completely mirror, classical RTT. In this study, we attempted to identify other monogenic disorders that share features with RTT. We performed a retrospective chart review on n = 319 patients who had undergone clinical whole exome sequencing (WES) for further etiological evaluation of neurodevelopmental diagnoses that remained unexplained despite extensive prior workup...
January 10, 2018: Neurogenetics
https://www.readbyqxmd.com/read/29260337/the-contribution-of-7q33-copy-number-variations-for-intellectual-disability
#2
Fátima Lopes, Fátima Torres, Sally Ann Lynch, Arminda Jorge, Susana Sousa, João Silva, Paula Rendeiro, Purificação Tavares, Ana Maria Fortuna, Patrícia Maciel
Copy number variations (CNVs) at the 7q33 cytoband are very rarely described in the literature, and almost all of the cases comprise large deletions affecting more than just the q33 segment. We report seven patients (two families with two siblings and their affected mother and one unrelated patient) with neurodevelopmental delay associated with CNVs in 7q33 alone. All the patients presented mild to moderate intellectual disability (ID), dysmorphic features, and a behavioral phenotype characterized by aggressiveness and disinhibition...
December 19, 2017: Neurogenetics
https://www.readbyqxmd.com/read/29247375/a-novel-mutation-in-lamc3-associated-with-generalized-polymicrogyria-of-the-cortex-and-epilepsy
#3
J L Zambonin, D A Dyment, Y Xi, R E Lamont, T Hartley, E Miller, M Kerr, K M Boycott, J S Parboosingh, S Venkateswaran
Occipital cortical malformation is a rare neurodevelopmental disorder characterized by pachygyria and polymicrogyria of the occipital lobes as well as global developmental delays and seizures. This condition is due to biallelic, loss-of-function mutations in LAMC3 and has been reported in four unrelated families to date. We report an individual with global delays, seizures, and polymicrogyria that extends beyond the occipital lobes and includes the frontal, parietal, temporal, and occipital lobes. Next-generation sequencing identified a homozygous nonsense mutation in LAMC3: c...
December 15, 2017: Neurogenetics
https://www.readbyqxmd.com/read/29209898/clinical-application-of-next-generation-sequencing-in-hereditary-spinocerebellar-ataxia-increasing-the-diagnostic-yield-and-broadening-the-ataxia-spasticity-spectrum-a-retrospective-analysis
#4
REVIEW
Daniele Galatolo, Alessandra Tessa, Alessandro Filla, Filippo M Santorelli
One of the hardest challenges in medical genetics is to reach a molecular diagnosis in the presence of rare brain disorders. Hereditary spinocerebellar ataxia (HA), characterized by high clinical and genetic heterogeneity, is among the diseases that present this challenge. HA can have features overlapping with those of other neurological diseases, especially hereditary spastic paraplegia (HSP), as routine clinical application of next generation sequencing (NGS) has confirmed. This article reviews different NGS methods applied in heterogeneous cohorts of patients with suspected HA and suggests that exome sequencing should be considered the first-tier genetic approach in this setting...
December 6, 2017: Neurogenetics
https://www.readbyqxmd.com/read/29197946/first-large-genomic-inversion-in-familial-cerebral-cavernous-malformation-identified-by-whole-genome-sequencing
#5
Stefanie Spiegler, Matthias Rath, Sabine Hoffjan, Philipp Dammann, Ulrich Sure, Axel Pagenstecher, Tim Strom, Ute Felbor
Familial cerebral cavernous malformations (CCMs) predispose to seizures and hemorrhagic stroke. Molecular genetic analyses of CCM1, CCM2, and CCM3 result in a mutation detection rate of up to 98%. However, only whole genome sequencing (WGS) in combination with the Manta algorithm for analyses of structural variants revealed a heterozygous 24 kB inversion including exon 1 of CCM2 in a 12-year-old boy with familial CCMs. Its breakpoints were fine-mapped, and quantitative analysis on RNA confirmed reduced CCM2 expression...
December 2, 2017: Neurogenetics
https://www.readbyqxmd.com/read/29164503/developing-the-field-of-neurogenetics
#6
EDITORIAL
Ulrich Müller, Georg Auburger, Manuel B Graeber, Louis J Ptacek
No abstract text is available yet for this article.
November 21, 2017: Neurogenetics
https://www.readbyqxmd.com/read/29151244/identification-of-rare-noncoding-sequence-variants-in-gamma-aminobutyric-acid-a-receptor-alpha-4-subunit-in-autism-spectrum-disorder
#7
Anthony J Griswold, Derek Van Booven, Michael L Cuccaro, Jonathan L Haines, John R Gilbert, Margaret A Pericak-Vance
Alterations of the gamma-aminobutyric acid (GABA) signaling system has been strongly linked to the pathophysiology of autism spectrum disorder (ASD). Genetic associations of common variants in GABA receptor subunits, in particular GABRA4 on chromosome 4p12, with ASD have been replicated by several studies. Moreover, molecular investigations have identified altered transcriptional and translational levels of this gene and protein in brains of ASD individuals. Since the genotyped common variants are likely not the functional variants contributing to the molecular consequences or underlying ASD phenotype, this study aims to examine rare sequence variants in GABRA4, including those outside the protein coding regions of the gene...
November 18, 2017: Neurogenetics
https://www.readbyqxmd.com/read/29130122/arhgef9-mutations-in-epileptic-encephalopathy-intellectual-disability-toward-understanding-the-mechanism-underlying-phenotypic-variation
#8
Jing-Yang Wang, Peng Zhou, Jie Wang, Bin Tang, Tao Su, Xiao-Rong Liu, Bing-Mei Li, Heng Meng, Yi-Wu Shi, Yong-Hong Yi, Na He, Wei-Ping Liao
ARHGEF9 resides on Xq11.1 and encodes collybistin, which is crucial in gephyrin clustering and GABAA receptor localization. ARHGEF9 mutations have been identified in patients with heterogeneous phenotypes, including epilepsy of variable severity and intellectual disability. However, the mechanism underlying phenotype variation is unknown. Using next-generation sequencing, we identified a novel mutation, c.868C > T/p.R290C, which co-segregated with epileptic encephalopathy, and validated its association with epileptic encephalopathy...
November 13, 2017: Neurogenetics
https://www.readbyqxmd.com/read/29086072/gne-missense-mutation-in-recessive-familial-amyotrophic-lateral-sclerosis
#9
Çiğdem Köroğlu, Rezzak Yılmaz, Mine Hayriye Sorgun, Seyhun Solakoğlu, Özden Şener
Amyotrophic lateral sclerosis (ALS) is a motor neuron disease eventually leading to death from respiratory failure. Recessive inheritance is very rare. Here, we describe the clinical findings in a consanguineous family with five men afflicted with recessive ALS and the identification of the homozygous mutation responsible for the disorder. The onset of the disease ranged from 12 to 35 years of age, with variable disease progressions. We performed clinical investigations including metabolic and paraneoplastic screening, cranial and cervical imaging, and electrophysiology...
October 31, 2017: Neurogenetics
https://www.readbyqxmd.com/read/29075935/novel-gfm2-variants-associated-with-early-onset-neurological-presentations-of-mitochondrial-disease-and-impaired-expression-of-oxphos-subunits
#10
Ruth I C Glasgow, Kyle Thompson, Inês A Barbosa, Langping He, Charlotte L Alston, Charu Deshpande, Michael A Simpson, Andrew A M Morris, Axel Neu, Ulrike Löbel, Julie Hall, Holger Prokisch, Tobias B Haack, Maja Hempel, Robert McFarland, Robert W Taylor
Mitochondrial diseases are characterised by clinical, molecular and functional heterogeneity, reflecting their bi-genomic control. The nuclear gene GFM2 encodes mtEFG2, a protein with an essential role during the termination stage of mitochondrial translation. We present here two unrelated patients harbouring different and previously unreported compound heterozygous (c.569G>A, p.(Arg190Gln); c.636delA, p.(Glu213Argfs*3)) and homozygous (c.275A>C, p.(Tyr92Ser)) recessive variants in GFM2 identified by whole exome sequencing (WES) together with histochemical and biochemical findings to support the diagnoses of pathological GFM2 variants in each case...
October 26, 2017: Neurogenetics
https://www.readbyqxmd.com/read/28849312/molecular-diversity-of-combined-and-complex-dystonia-insights-from-diagnostic-exome-sequencing
#11
Michael Zech, Robert Jech, Matias Wagner, Tobias Mantel, Sylvia Boesch, Michael Nocker, Angela Jochim, Riccardo Berutti, Petra Havránková, Anna Fečíková, David Kemlink, Jan Roth, Tim M Strom, Werner Poewe, Evžen Růžička, Bernhard Haslinger, Juliane Winkelmann
Combined and complex dystonias are heterogeneous movement disorders combining dystonia with other motor and/or systemic signs. Although we are beginning to understand the diverse molecular causes of these disease entities, clinical pattern recognition and conventional genetic workup achieve an etiological diagnosis only in a minority of cases. Our goal was to provide a window into the variable genetic origins and distinct clinical patterns of combined/complex dystonia more broadly. Between August 2016 and January 2017, we applied whole-exome sequencing to a cohort of nine patients with varied combined and/or complex dystonic presentations, being on a diagnostic odyssey...
December 2017: Neurogenetics
https://www.readbyqxmd.com/read/28993909/coexistence-of-clcn1-and-scn4a-mutations-in-one-family-suffering-from-myotonia
#12
Lorenzo Maggi, Sabrina Ravaglia, Alessandro Farinato, Raffaella Brugnoni, Concetta Altamura, Paola Imbrici, Diana Conte Camerino, Alessandro Padovani, Renato Mantegazza, Pia Bernasconi, Jean-François Desaphy, Massimiliano Filosto
Non-dystrophic myotonias are characterized by clinical overlap making it challenging to establish genotype-phenotype correlations. We report clinical and electrophysiological findings in a girl and her father concomitantly harbouring single heterozygous mutations in SCN4A and CLCN1 genes. Functional characterization of N1297S hNav1.4 mutant was performed by patch clamp. The patients displayed a mild phenotype, mostly resembling a sodium channel myotonia. The CLCN1 c.501C>G (p.F167L) mutation has been already described in recessive pedigrees, whereas the SCN4A c...
October 9, 2017: Neurogenetics
https://www.readbyqxmd.com/read/28975462/a-newly-distal-hereditary-motor-neuropathy-caused-by-a-rare-aifm1-mutation
#13
Paula Sancho, Ana Sánchez-Monteagudo, Antonio Collado, Clara Marco-Marín, Cristina Domínguez-González, Ana Camacho, Erwin Knecht, Carmen Espinós, Vincenzo Lupo
In two siblings, who suffer from an early childhood-onset axonal polyneuropathy with exclusive involvement of motor fibers, the c.629T>C (p.F210S) mutation was identified in the X-linked AIFM1 gene, which encodes for the apoptosis-inducing factor (AIF). The mutation was predicted as deleterious, according to in silico analysis. A decreased expression of the AIF protein, altered cellular morphology, and a fragmented mitochondrial network were observed in the proband's fibroblasts. This new form of motor neuropathy expands the phenotypic spectrum of AIFM1 mutations and therefore, the AIFM1 gene should be considered in the diagnosis of hereditary motor neuropathies...
October 3, 2017: Neurogenetics
https://www.readbyqxmd.com/read/28942489/molecular-genetic-and-clinical-characterization-of-myotonic-dystrophy-type-1-patients-carrying-variant-repeats-within-dmpk-expansions
#14
Jovan Pešović, S Perić, M Brkušanin, G Brajušković, V Rakočević-Stojanović, Dušanka Savić-Pavićević
Myotonic dystrophy type 1 (DM1) is caused by a highly unstable expansion of CTG repeats in the DMPK gene. Its huge phenotypic variability cannot be explained solely by the repeat number. Recently, variant repeats within the DMPK expansions have emerged as potential disease modifiers. The frequency of variant expanded alleles was estimated in 242 DM1 patients from 174 Serbian families using repeat-primed PCR (RP-PCR). The patterns of variant repeats were determined by direct sequencing of RP-PCR or PCR products...
September 23, 2017: Neurogenetics
https://www.readbyqxmd.com/read/28891013/acknowledgement-to-referees-2016-2017
#15
(no author information available yet)
No abstract text is available yet for this article.
September 11, 2017: Neurogenetics
https://www.readbyqxmd.com/read/28842795/x-linked-hypomyelination-with-spondylometaphyseal-dysplasia-h-smd-associated-with-mutations-in-aifm1
#16
Noriko Miyake, Nicole I Wolf, Ferdy K Cayami, Joanna Crawford, Annette Bley, Dorothy Bulas, Alex Conant, Stephen J Bent, Karen W Gripp, Andreas Hahn, Sean Humphray, Shihoko Kimura-Ohba, Zoya Kingsbury, Bryan R Lajoie, Dennis Lal, Dimitra Micha, Amy Pizzino, Richard J Sinke, Deborah Sival, Irene Stolte-Dijkstra, Andrea Superti-Furga, Nicole Ulrick, Ryan J Taft, Tsutomu Ogata, Keiichi Ozono, Naomichi Matsumoto, Bernd A Neubauer, Cas Simons, Adeline Vanderver
An X-linked condition characterized by the combination of hypomyelinating leukodystrophy and spondylometaphyseal dysplasia (H-SMD) has been observed in only four families, with linkage to Xq25-27, and recent genetic characterization in two families with a common AIFM1 mutation. In our study, 12 patients (6 families) with H-SMD were identified and underwent comprehensive assessment accompanied by whole-exome sequencing (WES). Pedigree analysis in all families was consistent with X-linked recessive inheritance...
August 26, 2017: Neurogenetics
https://www.readbyqxmd.com/read/28707163/characterization-of-snps-in-the-dopamine-%C3%AE-hydroxylase-gene-providing-new-insights-into-its-structure-function-relationship
#17
Toyanji Joseph Punchaichira, Sanjay Kumar Dey, Anirban Mukhopadhyay, Suman Kundu, B K Thelma
Dopamine-β-hydroxylase (DBH, EC 1.14.17.1), an oxido-reductase that catalyses the conversion of dopamine to norepinephrine, is largely expressed in sympathetic neurons and adrenal medulla. Several regulatory and structural variants in DBH associated with various neuropsychiatric, cardiovascular diseases and a few that may determine enzyme activity have also been identified. Due to paucity of studies on functional characterization of DBH variants, its structure-function relationship is poorly understood. The purpose of the study was to characterize five non-synonymous (ns) variants that were prioritized either based on previous association studies or Sorting Tolerant From Intolerant (SIFT) algorithm...
July 2017: Neurogenetics
https://www.readbyqxmd.com/read/28669061/male-patients-affected-by-mosaic-pcdh19-mutations-five-new-cases
#18
I M de Lange, P Rump, R F Neuteboom, P B Augustijn, K Hodges, A I Kistemaker, O F Brouwer, G M S Mancini, H A Newman, Y J Vos, K L Helbig, C Peeters-Scholte, M Kriek, N V Knoers, D Lindhout, B P C Koeleman, M J A van Kempen, E H Brilstra
Pathogenic variants in the PCDH19 gene are associated with epilepsy, intellectual disability (ID) and behavioural disturbances. Only heterozygous females and mosaic males are affected, likely due to a disease mechanism named cellular interference. Until now, only four affected mosaic male patients have been described in literature. Here, we report five additional male patients, of which four are older than the oldest patient reported so far. All reported patients were selected for genetic testing because of developmental delay and/or epilepsy...
July 2017: Neurogenetics
https://www.readbyqxmd.com/read/28664294/rare-causes-of-early-onset-dystonia-parkinsonism-with-cognitive-impairment-a-de-novo-psen-1-mutation
#19
Miryam Carecchio, Marina Picillo, Lorella Valletta, Antonio E Elia, Tobias B Haack, Autilia Cozzolino, Annalisa Vitale, Barbara Garavaglia, Arcangela Iuso, Caterina F Bagella, Sabina Pappatà, Paolo Barone, Holger Prokisch, Luigi Romito, Valeria Tiranti
Mutations in PSEN1 are responsible for familial Alzheimer's disease (FAD) inherited as autosomal dominant trait, but also de novo mutations have been rarely reported in sporadic early-onset dementia cases. Parkinsonism in FAD has been mainly described in advanced disease stages. We characterized a patient presenting with early-onset dystonia-parkinsonism later complicated by dementia and myoclonus. Brain MRI showed signs of iron accumulation in the basal ganglia mimicking neurodegeneration with brain iron accumulation (NBIA) as well as fronto-temporal atrophy...
July 2017: Neurogenetics
https://www.readbyqxmd.com/read/28620870/severe-growth-deficiency-microcephaly-intellectual-disability-and-characteristic-facial-features-are-due-to-a-homozygous-qars-mutation
#20
Esther Leshinsky-Silver, Jiqiang Ling, Jiang Wu, Chana Vinkler, Keren Yosovich, Sarit Bahar, Miri Yanoov-Sharav, Tally Lerman-Sagie, Dorit Lev
Glutaminyl tRNA synthase is highly expressed in the developing fetal human brain. Mutations in the glutaminyl-tRNA synthetase (QARS) gene have been reported in patients with progressive microcephaly, cerebral-cerebellar atrophy, and intractable seizures. We have previously reported a new recessive syndrome of severe linear growth retardation, poor weight gain, microcephaly, characteristic facial features, cutaneous syndactyly of the toes, high myopia, and intellectual disability in two sisters of Ashkenazi-Jewish origin (Eur J Med Genet 2014;57(6):288-92)...
July 2017: Neurogenetics
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