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Neurogenetics

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https://www.readbyqxmd.com/read/30392167/novel-case-of-neurodegeneration-with-brain-iron-accumulation-4-nbia4-caused-by-a-pathogenic-variant-affecting-splicing
#1
Peter Sparber, Andrey Marakhonov, Alexandra Filatova, Inna Sharkova, Mikhail Skoblov
Neurodegeneration with brain iron accumulation type 4 (NBIA4) also known as MPAN (mitochondria protein-associated neurodegeneration) is a rare neurological disorder which main feature is brain iron accumulation most frequently in the globus pallidus and substantia nigra. Whole exome sequencing (WES) in a 12-year-old patient revealed 2 variants in the C19orf12 gene, a previously reported common 11 bp deletion c.204_214del11, p.(Gly69Argfs*10) and a novel splicing variant c.193+5G>A. Functional analysis of novel variant showed skipping of the second exon, resulting in a formation of a truncated nonfunctional protein...
November 3, 2018: Neurogenetics
https://www.readbyqxmd.com/read/30343341/ataxia-telangiectasia-alters-the-apob-and-reelin-pathway
#2
Júlia Canet-Pons, Ralf Schubert, Ruth Pia Duecker, Roland Schrewe, Sandra Wölke, Matthias Kieslich, Martina Schnölzer, Andreas Chiocchetti, Georg Auburger, Stefan Zielen, Uwe Warnken
Autosomal recessive ataxia telangiectasia (A-T) is characterized by radiosensitivity, immunodeficiency, and cerebellar neurodegeneration. A-T is caused by inactivating mutations in the ataxia telangiectasiamutated (ATM) gene, a serine-threonine protein kinase involved in DNA damage response and excitatory neurotransmission. The selective vulnerability of cerebellar Purkinje neurons (PN) to A-T is not well understood. Employing global proteomic profiling of cerebrospinal fluid from patients at ages around 15 years, we detected reduced calbindin, reelin, cerebellin-1, cerebellin-3, protocadherin fat 2, sempahorin 7A, and increased apolipoprotein B and J peptides...
October 21, 2018: Neurogenetics
https://www.readbyqxmd.com/read/29982879/fus-1-359-transgenic-mice-as-a-model-of-als-pathophysiological-and-molecular-aspects-of-the-proteinopathy
#3
Sergei Y Funikov, Alexander P Rezvykh, Pavel V Mazin, Alexey V Morozov, Andrey V Maltsev, Maria M Chicheva, Ekaterina A Vikhareva, Mikhail B Evgen'ev, Aleksey A Ustyugov
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder that leads to the eventual death of motor neurons. Described cases of familial ALS have emphasized the significance of protein misfolding and aggregation of two functionally related proteins, FUS (fused in sarcoma) and TDP-43, implicated in RNA metabolism. Herein, we performed a comprehensive analysis of the in vivo model of FUS-mediated proteinopathy (ΔFUS(1-359) mice). First, we used the Noldus CatWalk system and confocal microscopy to determine the time of onset of the first clinical symptoms and the appearance of FUS-positive inclusions in the cytoplasm of neuronal cells...
August 2018: Neurogenetics
https://www.readbyqxmd.com/read/29971521/r106c-tfg-variant-causes-infantile-neuroaxonal-dystrophy-plus-syndrome
#4
A Catania, R Battini, T Pippucci, R Pasquariello, M L Chiapparini, M Seri, B Garavaglia, G Zorzi, N Nardocci, D Ghezzi, V Tiranti
TFG (tropomyosin-receptor kinase fused gene) encodes an essential protein in the regulation of vesicular trafficking between endoplasmic reticulum and Golgi apparatus. The homozygous variant c.316C > T within TFG has been previously associated with a complicated hereditary spastic paraplegia (HSP) phenotype in two unrelated Indian families. Here, we describe the first Italian family with two affected siblings harboring the same variant, who in childhood were classified as infantile neuroaxonal dystrophy (INAD) based on clinical and neuropathological findings...
August 2018: Neurogenetics
https://www.readbyqxmd.com/read/29948376/clinical-and-genetic-study-of-tunisian-families-with-genetic-generalized-epilepsy-contribution-of-cacna1h-and-mast4-genes
#5
Zied Landoulsi, Fatma Laatar, Eric Noé, Saloua Mrabet, Mouna Ben Djebara, Guillaume Achaz, Caroline Nava, Stéphanie Baulac, Imen Kacem, Amina Gargouri-Berrechid, Riadh Gouider, Eric Leguern
Genetic generalized epilepsies (GGE) (childhood absence epilepsy (CAE), juvenile myoclonic epilepsy (JME) and epilepsy with generalized tonic-clonic seizures (GTCS)) are mainly determined by genetic factors. Since few mutations were identified in rare families with autosomal dominant GGE, a polygenic inheritance was suspected in most patients. Recent studies on large American or European cohorts of sporadic cases showed that susceptibility genes were numerous although their variants were rare, making their identification difficult...
August 2018: Neurogenetics
https://www.readbyqxmd.com/read/29926239/incidental-diagnosis-of-tuberous-sclerosis-complex-by-exome-sequencing-in-three-families-with-subclinical-findings
#6
R C Caylor, L Grote, I Thiffault, E G Farrow, L Willig, S Soden, S M Amudhavalli, A J Nopper, K A Horii, E Fleming, J Jenkins, H Welsh, M Ilyas, K Engleman, A Abdelmoity, C J Saunders
Tuberous sclerosis complex (TSC) is an autosomal-dominant neurocutaneous disorder characterized by lesions and benign tumors in multiple organ systems including the brain, skin, heart, eyes, kidneys, and lungs. The phenotype is highly variable, although penetrance is reportedly complete. We report the molecular diagnosis of TSC in individuals exhibiting extreme intra-familial variability, including the incidental diagnosis of asymptomatic family members. Exome sequencing was performed in three families, with probands referred for epilepsy, autism, and absent speech (Family 1); epileptic spasms (Family 2); and connective tissue disorders (Family 3...
August 2018: Neurogenetics
https://www.readbyqxmd.com/read/29846820/whole-exome-sequencing-in-dandy-walker-variant-with-intellectual-disability-reveals-an-activating-cip2a-mutation-as-novel-genetic-cause
#7
Chin-An Yang, I-Ching Chou, Der-Yang Cho, Chien-Yu Lin, Hsi-Yuan Huang, Yu-Chen Ho, Ting-Yuan Liu, Ying-Hsuan Li, Jan-Gowth Chang
Dandy-Walker malformation (DWM) has been reported to have heterogeneous causes, including mutations in genes of fibroblast growth factors and in genes in the sonic hedgehog (Shh) signaling pathway. Here, we identified an activating cancerous inhibitor of protein phosphatase 2A (CIP2A) p.D269V mutation, located at the predicted protein-protein interaction groove, as a novel genetic cause of Dandy-Walker variant (DWV). CIP2A has been reported as an oncoprotein promoting tumor survival via inhibition of protein phosphatase 2A (PP2A)...
August 2018: Neurogenetics
https://www.readbyqxmd.com/read/29808465/a-novel-missense-variant-in-the-sdr-domain-of-the-wwox-gene-leads-to-complete-loss-of-wwox-protein-with-early-onset-epileptic-encephalopathy-and-severe-developmental-delay
#8
Jessika Johannsen, Fanny Kortüm, Georg Rosenberger, Kristin Bokelmann, Markus A Schirmer, Jonas Denecke, René Santer
The human WWOX (WW domain-containing oxidoreductase) gene, originally known as a tumor suppressor gene, has been shown to be important for brain function and development. In recent years, mutations in WWOX have been associated with a wide phenotypic spectrum of autosomal recessively inherited neurodevelopmental disorders. Whole exome sequencing was completed followed by Sanger sequencing to verify segregation of the identified variants. Functional WWOX analysis was performed in fibroblasts of one patient. Transcription and translation were assessed by quantitative real-time PCR and Western blotting...
August 2018: Neurogenetics
https://www.readbyqxmd.com/read/29730780/toward-deciphering-the-mechanistic-role-of-variations-in-the-rep1-repeat-site-in-the-transcription-regulation-of-snca-gene
#9
A Afek, L Tagliafierro, O C Glenn, D B Lukatsky, R Gordan, O Chiba-Falek
Short structural variants-variants other than single nucleotide polymorphisms-are hypothesized to contribute to many complex diseases, possibly by modulating gene expression. However, the molecular mechanisms by which noncoding short structural variants exert their effects on gene regulation have not been discovered. Here, we study simple sequence repeats (SSRs), a common class of short structural variants. Previously, we showed that repetitive sequences can directly influence the binding of transcription factors to their proximate recognition sites, a mechanism we termed non-consensus binding...
August 2018: Neurogenetics
https://www.readbyqxmd.com/read/30043326/homozygous-mutation-in-mfsd2a-encoding-a-lysolipid-transporter-for-docosahexanoic-acid-is-associated-with-microcephaly-and-hypomyelination
#10
Tamar Harel, Debra Q Y Quek, Bernice H Wong, Amaury Cazenave-Gassiot, Markus R Wenk, Hao Fan, Itai Berger, Dorit Shmueli, Avraham Shaag, David L Silver, Orly Elpeleg, Shimon Edvardson
The major facilitator superfamily domain-containing protein 2A (MFSD2A) is a constituent of the blood-brain barrier and functions to transport lysophosphatidylcholines (LPCs) into the central nervous system. LPCs such as that derived from docosahexanoic acid (DHA) are indispensable to neurogenesis and maintenance of neurons, yet cannot be synthesized within the brain and are dependent on MFSD2A for brain uptake. Recent studies have implicated MFSD2A mutations in lethal and non-lethal microcephaly syndromes, with the severity correlating to the residual activity of the transporter...
July 24, 2018: Neurogenetics
https://www.readbyqxmd.com/read/30039206/the-polynucleotide-kinase-3-phosphatase-gene-pnkp-is-involved-in-charcot-marie-tooth-disease-cmt2b2-previously-related-to-med25
#11
Alejandro Leal, Sixto Bogantes-Ledezma, Arif B Ekici, Steffen Uebe, Christian T Thiel, Heinrich Sticht, Martin Berghoff, Corinna Berghoff, Bernal Morera, Michael Meisterernst, André Reis
Charcot-Marie-Tooth disease (CMT) represents a heterogeneous group of hereditary peripheral neuropathies. We previously reported a CMT locus on chromosome 19q13.3 segregating with the disease in a large Costa Rican family with axonal neuropathy and autosomal recessive pattern of inheritance (CMT2B2). We proposed a homozygous missense variant in the Mediator complex 25 (MED25) gene as causative of the disease. Nevertheless, the fact that no other CMT individuals with MED25 variants were reported to date led us to reevaluate the original family...
July 24, 2018: Neurogenetics
https://www.readbyqxmd.com/read/29992365/correction-to-incidental-diagnosis-of-tuberous-sclerosis-complex-by-exome-sequencing-in-three-families-with-subclinical-findings
#12
R C Caylor, L Grote, I Thiffault, E G Farrow, L Willig, S Soden, S M Amudhavalli, A J Nopper, K A Horii, E Fleming, J Jenkins, H Welsh, M Ilyas, K Engleman, A Abdelmoity, C J Saunders
The published online version contain mistake in the author list. Instead of "A.M.Ilyas" it should have been "M.Ilyas ".
July 11, 2018: Neurogenetics
https://www.readbyqxmd.com/read/29754261/compound-heterozygous-mutations-in-two-different-domains-of-aldh18a1-do-not-affect-the-amino-acid-levels-in-a-patient-with-hereditary-spastic-paraplegia
#13
Maria Steenhof, Maria Kibæk, Martin J Larsen, Mette Christensen, Allan Meldgaard Lund, Klaus Brusgaard, Jens Michael Hertz
Mutations in ALDH18A1 can cause autosomal recessive and dominant hereditary spastic paraplegia and autosomal recessive and dominant cutis laxa. ALDH18A1 encodes delta-1-pyrroline-5-carboxylate synthetase (P5CS), which consists of two domains, the glutamate 5-kinase (G5K) and the gamma-glutamyl phosphate reductase (GR5P) domain. The location of the mutations in the gene has influence on whether the amino acid levels are affected. Mutations affecting the G5K domain have previously been found to cause reduced plasma levels of proline, citrulline and arginine, whereas such effect is not seen with mutations affecting the GR5P domain...
May 12, 2018: Neurogenetics
https://www.readbyqxmd.com/read/29691679/the-impact-of-next-generation-sequencing-on-the-diagnosis-of-pediatric-onset-hereditary-spastic-paraplegias-new-genotype-phenotype-correlations-for-rare-hsp-related-genes
#14
Lorena Travaglini, Chiara Aiello, Fabrizia Stregapede, Adele D'Amico, Viola Alesi, Andrea Ciolfi, Alessandro Bruselles, Michela Catteruccia, Simone Pizzi, Ginevra Zanni, Sara Loddo, Sabina Barresi, Gessica Vasco, Marco Tartaglia, Enrico Bertini, Francesco Nicita
Hereditary spastic paraplegias (HSP) are clinical and genetic heterogeneous diseases with more than 80 disease genes identified thus far. Studies on large cohorts of HSP patients showed that, by means of current technologies, the percentage of genetically solved cases is close to 50%. Notably, the percentage of molecularly confirmed diagnoses decreases significantly in sporadic patients. To describe our diagnostic molecular genetic approach on patients with pediatric-onset pure and complex HSP, 47 subjects with HSP underwent molecular screening of 113 known and candidate disease genes by targeted capture and massively parallel sequencing...
May 2018: Neurogenetics
https://www.readbyqxmd.com/read/29589152/genetic-test-utilization-and-diagnostic-yield-in-adult-patients-with-neurological-disorders
#15
Tanya M Bardakjian, Ingo Helbig, Colin Quinn, Lauren B Elman, Leo F McCluskey, Steven S Scherer, Pedro Gonzalez-Alegre
To determine the diagnostic yield of different genetic test modalities in adult patients with neurological disorders, we evaluated all adult patients seen for genetic diagnostic evaluation in the outpatient neurology practice at the University of Pennsylvania between January 2016 and April 2017 as part of the newly created Penn Neurogenetics Program. Subjects were identified through our electronic medical system as those evaluated by the Program's single clinical genetic counselor in that period. A total of 377 patients were evaluated by the Penn Neurogenetics Program in different settings and genetic testing recommended...
May 2018: Neurogenetics
https://www.readbyqxmd.com/read/29549527/in-vitro-efficacy-of-arq-092-an-allosteric-akt-inhibitor-on-primary-fibroblast-cells-derived-from-patients-with-pik3ca-related-overgrowth-spectrum-pros
#16
C Ranieri, S Di Tommaso, D C Loconte, V Grossi, P Sanese, R Bagnulo, F C Susca, G Forte, A Peserico, A De Luisi, A Bartuli, A Selicorni, D Melis, M Lerone, A D Praticò, G Abbadessa, Y Yu, B Schwartz, Martino Ruggieri, Cristiano Simone, Nicoletta Resta
Postzygotic mutations of the PIK3CA [phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha] gene constitutively activate the PI3K/AKT/mTOR pathway in PIK3CA-related overgrowth spectrum (PROS) patients, causing congenital mosaic tissue overgrowth that even multiple surgeries cannot solve. mTOR inhibitors are empirically tested and given for compassionate use in these patients. PROS patients could be ideal candidates for enrolment in trials with PI3K/AKT pathway inhibitors, considering the "clean" cellular setting in which a unique driver, a PIK3CA mutation, is present...
May 2018: Neurogenetics
https://www.readbyqxmd.com/read/29511999/med13l-related-intellectual-disability-involvement-of-missense-variants-and-delineation-of-the-phenotype
#17
T Smol, F Petit, A Piton, B Keren, D Sanlaville, A Afenjar, S Baker, E C Bedoukian, E J Bhoj, D Bonneau, E Boudry-Labis, S Bouquillon, O Boute-Benejean, R Caumes, N Chatron, C Colson, C Coubes, C Coutton, F Devillard, A Dieux-Coeslier, M Doco-Fenzy, L J Ewans, L Faivre, E Fassi, M Field, C Fournier, C Francannet, D Genevieve, I Giurgea, A Goldenberg, A K Green, A M Guerrot, D Heron, B Isidor, B A Keena, B L Krock, P Kuentz, E Lapi, N Le Meur, G Lesca, D Li, I Marey, C Mignot, C Nava, A Nesbitt, G Nicolas, C Roche-Lestienne, T Roscioli, V Satre, A Santani, M Stefanova, S Steinwall Larsen, P Saugier-Veber, S Picker-Minh, C Thuillier, A Verloes, G Vieville, M Wenzel, M Willems, S Whalen, Y A Zarate, A Ziegler, S Manouvrier-Hanu, V M Kalscheuer, B Gerard, Jamal Ghoumid
Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies...
May 2018: Neurogenetics
https://www.readbyqxmd.com/read/29480378/reply-to-letter-to-editor-by-finsterer-j-and-zarrouk-mahjoub-s-phenotypic-manifestations-of-the-m-8969g-a-variant
#18
LETTER
Pirjo Isohanni, Christopher J Carroll, Christopher B Jackson, Max Pohjanpelto, Tuula Lönnqvist, Anu Suomalainen
No abstract text is available yet for this article.
May 2018: Neurogenetics
https://www.readbyqxmd.com/read/29480377/phenotypic-manifestations-of-the-m-8969g-a-variant
#19
LETTER
Josef Finsterer, Sinda Zarrouk-Mahjoub
No abstract text is available yet for this article.
May 2018: Neurogenetics
https://www.readbyqxmd.com/read/29423566/clinical-and-neuroimaging-features-of-autosomal-recessive-spastic-paraplegia-35-spg35-case-reports-new-mutations-and-brief-literature-review
#20
Francesco Mari, Beatrice Berti, Alessandro Romano, Jacopo Baldacci, Riccardo Rizzi, M Grazia Alessandrì, Alessandra Tessa, Elena Procopio, Anna Rubegni, Charles Marques Lourenḉo, Alessandro Simonati, Renzo Guerrini, Filippo Maria Santorelli
Spastic paraplegia 35 (SPG35) is a recessive condition characterized by childhood onset, progressive course, complicated by dystonia, dysarthria, cognitive impairment, and epilepsy. Mutations in the FA2H gene have been described in several families, leading to the proposal of a single entity, named fatty acid hydrolase-associated neurodegeneration (FAHN). Several reports have described a polymorphic radiological picture with white matter lesions of various degrees and a distinct form of neurodegeneration with brain iron accumulation...
May 2018: Neurogenetics
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