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  • Expanding the clinical spectrum of the mitochondrial mutation A13084T in the ND5 gene
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-01
    Roberta Brusa; Eleonora Mauri; Laura Dell’Arti; Francesca Magri; Dario Ronchi; Valeria Minorini; Claudia Mainetti; Delia Gagliardi; Irene Faravelli; Megi Meneri; Nereo Bresolin; Francesco Viola; Stefania Corti; Giacomo Pietro Comi

    Our group previously published about a patient with a LS/MELAS (Leigh syndrome/mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes) overlap phenotype associated with a novel mitochondrial mutation in the ND5 gene.1 At that time, his 38-year-old mother presented only migraine and asymptomatic bilateral optic atrophy, without other neurologic signs or symptoms. Headache

    更新日期:2020-09-16
  • Matrix metalloproteinase-degraded type I collagen is associated with APOE/TOMM40 variants and preclinical dementia
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-05
    Man-Hung Eric Tang; Joseph P.M. Blair; Cecilie Liv Bager; Anne-Christine Bay-Jensen; Kim Henriksen; Claus Christiansen; Morten Asser Karsdal

    Objective Dysregulation of type I collagen metabolism has a great impact on human health. We have previously seen that matrix metalloproteinase–degraded type I collagen (C1M) is associated with early death and age-related pathologies. To dissect the biological impact of type I collagen dysregulation, we have performed a genome-wide screening of the genetic factors related to type I collagen turnover

    更新日期:2020-09-11
  • Novel dominant MPAN family with a complex genetic architecture as a basis for phenotypic variability
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-05
    Peter Balicza; Renata Bencsik; Andras Lengyel; Aniko Gal; Zoltan Grosz; Dora Csaban; Gabor Rudas; Krisztina Danics; Gabor G. Kovacs; Maria Judit Molnar

    Objective Our aim was to study a Hungarian family with autosomal dominantly inherited neurodegeneration with brain iron accumulation (NBIA) with markedly different intrafamilial expressivity. Methods Targeted sequencing and multiplex ligation-dependent probe amplification (MLPA) of known NBIA-associated genes were performed in many affected and unaffected members of the family. In addition, a trio

    更新日期:2020-09-08
  • Identification of a novel mutation in ATP13A2 associated with a complicated form of hereditary spastic paraplegia
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-05
    Yasuko Odake; Kishin Koh; Yoshihisa Takiyama; Hiroyuki Ishiura; Shoji Tsuji; Masahito Yamada; Mitsuhiro Yoshita

    Objective To establish molecular diagnosis for a family with a complicated form of autosomal recessive hereditary spastic paraplegia with intellectual disability, cognitive decline, psychosis, peripheral neuropathy, upward gaze palsy, and thin corpus callosum (TCC). Methods Physical examinations, laboratory tests, structural neuroimaging studies, and exome sequence analysis were carried out. Results

    更新日期:2020-09-08
  • KCNQ2 encephalopathy manifesting with Rett-like features: A follow-up into adulthood
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-05
    Mario Mastrangelo; Filippo Manti; Maria Teresa Giannini; Renzo Guerrini; Vincenzo Leuzzi

    Kv7.2 (KCNQ2) channel dysfunctions cause a rare form of neonatal and infantile epileptic and developmental encephalopathy (MIM 613720).1 Unlike early clinical features and the epilepsy phenotype of KCNQ2 encephalopathy, data about the long-term developmental outcome are lacking. We followed up for over 3 decades a girl with this disease.

    更新日期:2020-09-08
  • Genetic risk for Alzheimer disease predicts hippocampal volume through the human lifespan
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-05
    Kristine B. Walhovd; Anders M. Fjell; Øystein Sørensen; Athanasia Monika Mowinckel; Céline Sonja Reinbold; Ane-Victoria Idland; Leiv Otto Watne; Andre Franke; Valerija Dobricic; Fabian Kilpert; Lars Bertram; Yunpeng Wang

    Objective To test the hypothesis that genetic risk for Alzheimer disease (AD) may represent a stable influence on the brain from early in life, rather than being primarily age dependent, we investigated in a lifespan sample of 1,181 persons with a total of 2,690 brain scans, whether higher polygenic risk score (PGS) for AD and presence of APOE 4 was associated with lower hippocampal volumes to begin

    更新日期:2020-09-08
  • Manifesting carriers of X-linked myotubular myopathy: Genetic modifiers modulating the phenotype
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-01
    Lucas Santos Souza; Camila Freitas Almeida; Guilherme Lopes Yamamoto; Rita de Cássia Mingroni Pavanello; Juliana Gurgel-Giannetti; Silvia Souza da Costa; Isabela Pessa Anequini; Silvana Amanda do Carmo; Jaqueline Yu Ting Wang; Marília de Oliveira Scliar; Erick C. Castelli; Paulo Alberto Otto; Edmar Zanoteli; Mariz Vainzof

    Objective To analyze the modulation of the phenotype in manifesting carriers of recessive X-linked myotubular myopathy (XLMTM), searching for possible genetic modifiers. Methods Twelve Brazilian families with XLMTM were molecularly and clinically evaluated. In 2 families, 4 of 6 and 2 of 5 manifesting female carriers were identified. These females were studied for X chromosome inactivation. In addition

    更新日期:2020-09-05
  • Integrative analysis identifies the association between CASZ1 methylation and ischemic stroke
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-05
    Xing-Bo Mo; Huan Zhang; Ai-Li Wang; Tan Xu; Yong-Hong Zhang

    Objective To highlight potential epigenetic risk factors for blood pressure (BP) and ischemic stroke (IS) in loci identified by genome-wide association studies (GWASs). Methods We detected DNA methylation for BP (317,756 individuals from UK Biobank) and IS (521,612 individuals from MEGASTROKE) in Europeans by using the summary data–based mendelian randomization (SMR) method. We selected the most relevant

    更新日期:2020-09-02
  • Intragenic variants in the SMN1 gene determine the clinical phenotype in 5q spinal muscular atrophy
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-01
    Rodrigo de Holanda Mendonça; Ciro Matsui; Graziela Jorge Polido; André Macedo Serafim Silva; Leslie Kulikowski; Alexandre Torchio Dias; Evelin Aline Zanardo; Davi Jorge Fontoura Solla; Juliana Gurgel-Giannetti; Ana Carolina Monteiro Lessa de Moura; Gabriela Palhares Campolina Sampaio; Acary Souza Bulle Oliveira; Paulo Victor Sgobbi de Souza; Wladimir Bocca Vieira de Rezende Pinto; Eduardo Augusto Gonçalves;

    Objective The aim of the study was to report the proportion of homozygous and compound heterozygous variants in the survival motor neuron 1 (SMN1) gene in a large population of patients with spinal muscular atrophy (SMA) and to correlate the severity of the disease with the presence of specific intragenic variants in SMN1 and with the SMN2 copy number. Methods Four hundred fifty Brazilian patients

    更新日期:2020-09-02
  • Disease duration in autosomal dominant familial Alzheimer disease: A survival analysis
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-05
    Ivanna M. Pavisic; Jennifer M. Nicholas; Antoinette O'Connor; Helen Rice; Kirsty Lu; Nick C. Fox; Natalie S. Ryan

    Objective To use survival modeling to estimate disease duration in autosomal dominant familial Alzheimer disease (ADAD) and ascertain whether factors influencing age at onset also affect survival. Methods Symptomatic mutation carriers (201 presenilin 1 [PSEN1] and 55 amyloid precursor protein [APP]) from ADAD families referred to the Dementia Research Centre, between 1987 and 2019, were included. Survival

    更新日期:2020-08-19
  • Variant repeats within the DMPK CTG expansion protect function in myotonic dystrophy type 1.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-01
    Jacob N Miller,Ellen van der Plas,Mark Hamilton,Timothy R Koscik,Laurie Gutmann,Sarah A Cumming,Darren G Monckton,Peggy C Nopoulos

    Objective We tested the hypothesis that variant repeat interruptions (RIs) within the DMPK CTG repeat tract lead to milder symptoms compared with pure repeats (PRs) in myotonic dystrophy type 1 (DM1). Methods We evaluated motor, neurocognitive, and behavioral outcomes in a group of 6 participants with DM1 with RI compared with a case-matched sample of 12 participants with DM1 with PR and a case-matched

    更新日期:2020-08-14
  • Rapid progressive ALS in a patient with a DNAJC7 loss-of-function mutation
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-01
    Kang-Yang Jih; Pei-Chien Tsai; Yu-Shuen Tsai; Yi-Chu Liao; Yi-Chung Lee

    Recently, DNAJC7 was found to be associated with amyotrophic lateral sclerosis (ALS) in a single large-scale exome sequencing study.1 Multiple protein-truncating variants were detected in individuals with ALS that were absent in control subjects.1 DNAJC7 encodes a member of the DnaJ heat-shock protein family (HspP40), which functions in protein homeostasis, including protein folding and degradation

    更新日期:2020-08-06
  • LINS1-associated neurodevelopmental disorder: Family with novel mutation expands the phenotypic spectrum.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-01
    Christiane M Neuhofer,Claudia B Catarino,Heinrich Schmidt,Klaus Seelos,Bader Alhaddad,Tobias B Haack,Thomas Klopstock

    Objective Clinical, neuroimaging, and genetic characterization of 3 patients with LINS1-associated developmental regression, intellectual disability, dysmorphism, and further neurologic deficits. Methods Three affected brothers from a consanguineous family from Afghanistan, their 2 healthy siblings, and both parents were all assessed in the clinic. General and neurologic examination, expert dysmorphology

    更新日期:2020-08-05
  • D-DEMØ, a distinct phenotype caused by ATP1A3 mutations.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-01
    Lyndsey Prange,Milton Pratt,Kristin Herman,Raphael Schiffmann,David M Mueller,Melissa McLean,Mary Moya Mendez,Nicole Walley,Erin L Heinzen,David Goldstein,Vandana Shashi,Arsen Hunanyan,Vijay Pagadala,Mohamad A Mikati

    Objective To describe a phenotype caused by ATP1A3 mutations, which manifests as dystonia, dysmorphism of the face, encephalopathy with developmental delay, brain MRI abnormalities always including cerebellar hypoplasia, no hemiplegia (Ø) (D-DEMØ), and neonatal onset. Methods Review and analysis of clinical and genetic data. Results Patients shared the above traits and had whole-exome sequencing that

    更新日期:2020-08-05
  • Isoform-specific loss of dystonin causes hereditary motor and sensory neuropathy.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-01
    William W Motley,Stephan Züchner,Steven S Scherer

    Objective To determine the genetic cause of axonal Charcot-Marie-Tooth disease in a small family with 2 affected siblings, one of whom had cerebellar features on examination. Methods Whole-exome sequencing of genomic DNA and analysis for recessively inherited mutations; PCR-based messenger RNA/complementary DNA analysis of transcripts to characterize the effects of variants identified by exome sequencing

    更新日期:2020-08-01
  • Integrated sequencing and array comparative genomic hybridization in familial Parkinson disease.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-01
    Laurie A Robak,Renqian Du,Bo Yuan,Shen Gu,Isabel Alfradique-Dunham,Vismaya Kondapalli,Evelyn Hinojosa,Amanda Stillwell,Emily Young,Chaofan Zhang,Xiaofei Song,Haowei Du,Tomasz Gambin,Shalini N Jhangiani,Zeynep Coban Akdemir,Donna M Muzny,Anusha Tejomurtula,Owen A Ross,Chad Shaw,Joseph Jankovic,Weimin Bi,Jennifer E Posey,James R Lupski,Joshua M Shulman

    Objective To determine how single nucleotide variants (SNVs) and copy number variants (CNVs) contribute to molecular diagnosis in familial Parkinson disease (PD), we integrated exome sequencing (ES) and genome-wide array-based comparative genomic hybridization (aCGH) and further probed CNV structure to reveal mutational mechanisms. Methods We performed ES on 110 subjects with PD and a positive family

    更新日期:2020-07-29
  • Three-dimensional imaging in myotonic dystrophy type 1: Linking molecular alterations with disease phenotype.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Alfonsina Ballester-Lopez,Judit Núñez-Manchón,Emma Koehorst,Ian Linares-Pardo,Miriam Almendrote,Giuseppe Lucente,Nicolau Guanyabens,Marta Lopez-Osias,Adrián Suárez-Mesa,Shaliza Ann Hanick,Jakub Chojnacki,Alejandro Lucia,Guillem Pintos-Morell,Jaume Coll-Cantí,Alicia Martínez-Piñeiro,Alba Ramos-Fransi,Gisela Nogales-Gadea

    Objective We aimed to determine whether 3D imaging reconstruction allows identifying molecular:clinical associations in myotonic dystrophy type 1 (DM1). Methods We obtained myoblasts from 6 patients with DM1 and 6 controls. We measured cytosine-thymine-guanine (CTG) expansion and detected RNA foci and muscleblind like 1 (MBNL1) through 3D reconstruction. We studied dystrophia myotonica protein kinase

    更新日期:2020-07-22
  • Genetic risk scores and hallucinations in patients with Parkinson disease.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-01
    Cynthia D J Kusters,Kimberly C Paul,Aline Duarte Folle,Adrienne M Keener,Jeff M Bronstein,Valerija Dobricic,Ole-Bjørn Tysnes,Lars Bertram,Guido Alves,Janet S Sinsheimer,Christina M Lill,Jodi Maple-Grødem,Beate R Ritz

    Objective We examine the hypothesized overlap of genetic architecture for Alzheimer disease (AD), schizophrenia (SZ), and Parkinson disease (PD) through the use of polygenic risk scores (PRSs) with the occurrence of hallucinations in PD. Methods We used 2 population-based studies (ParkWest, Norway, and Parkinson's Environment and Gene, USA) providing us with 399 patients with PD with European ancestry

    更新日期:2020-07-21
  • Childhood-onset epileptic encephalopathy due to FGF12 exon 1-4 tandem duplication.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-01
    Sarah Verheyen,Michael R Speicher,Barbara Ramler,Barbara Plecko

    Fibroblast growth factor 12 (FGF12) spans 5 exons and encodes for a cytosolic voltage-gated sodium channel binding protein that modulates neuronal excitability.1,2 A recurrent activating FGF12 mutation (NM_021032, [GRCh37] 192053223C>T, p.R114H in A-isoform, p.R52H in B-isoform) causes epileptic encephalopathy (EE) with neonatal onset and intellectual disability (ID).2–6 Recently, a tandem duplication

    更新日期:2020-07-18
  • Homoplasmic mitochondrial tRNAPro mutation causing exercise-induced muscle swelling and fatigue.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Karine Auré,Guillemette Fayet,Ivan Chicherin,Benoit Rucheton,Sandrine Filaut,Anne-Marie Heckel,Julie Eichler,Florence Caillon,Yann Péréon,Nina Entelis,Ivan Tarassov,Anne Lombès

    Objective To demonstrate the causal role in disease of the MT-TP m.15992A>T mutation observed in patients from 5 independent families. Methods Lactate measurement, muscle histology, and mitochondrial activities in patients; PCR-based analyses of the size, amount, and sequence of muscle mitochondrial DNA (mtDNA) and proportion of the mutation; respiration, mitochondrial activities, proteins, translation

    更新日期:2020-07-16
  • Delineating the phenotypic spectrum of sulfite oxidase and molybdenum cofactor deficiency.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Albert L Misko,Ye Liang,Joshua B Kohl,Florian Eichler

    Objective To define the phenotypic spectrum of isolated sulfite oxidase (ISOD) and molybdenum cofactor deficiency (MoCD), aiming to promote timely diagnosis and assist in future clinical trial design. Methods We analyzed clinical, radiographic, biochemical, and genetic data from 146 patients reported in the literature. Results We stratified patients into 2 phenotypic subgroups based on clinical and

    更新日期:2020-07-15
  • Hydrocephalus and diffuse choroid plexus hyperplasia in primary ciliary dyskinesia-related MCIDAS mutation.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Evie Alexandra Robson,Luke Dixon,Liam Causon,William Dawes,Massimo Benenati,Mahmoud Fassad,Robert Anthony Hirst,Priti Kenia,Eduardo Fernandez Moya,Mitali Patel,Daniel Peckham,Andrew Rutman,Hannah M Mitchison,Kshitij Mankad,Christopher O'Callaghan

    Objective To report a neuroradiologic phenotype associated with reduced generation of multiple motile cilia (RGMC) and mutations in the multicilin gene. We hypothesize that the observed phenotype may reflect the emerging role that ependymal cilia play in regulating CSF production. Method Clinical and radiologic records were retrospectively reviewed for 7 consecutive patients diagnosed by the Leicester

    更新日期:2020-07-14
  • Late-onset leukoencephalopathy in a patient with recessive EARS2 mutations.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-01
    Edoardo Monfrini,Dario Ronchi,Giulia Franco,Manuela Garbellini,Letizia Straniero,Elisa Scola,Federica Arienti,Stefano Duga,Giacomo Pietro Comi,Nereo Bresolin,Alessio Di Fonzo

    Mitochondrial aminoacyl-transfer RNA (tRNA) synthetases catalyze the attachment of specific amino acids to their cognate tRNA, enabling intramitochondrial protein synthesis. Recessive mutations in their coding nuclear genes are associated with heterogeneous clinical presentations, often displaying leukoencephalopathy.1

    更新日期:2020-07-14
  • What does a defect in N-glycosylation mean for neuronal migration and function?
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Alica M Goldman

    Patients with epilepsy have not benefitted equally from the availability of next-generation sequencing. Although the diagnostic yield in epileptic encephalopathies is up to 50%, it is only approximately 12% in non-acquired focal epilepsies (NAFE).1 However, somatic mosaicism has emerged as an important cause of genetic causation in NAFE. This is hardly surprising, considering the scale of cellular

    更新日期:2020-07-08
  • SLC1A3 variant associated with hemiplegic migraine and acetazolamide-responsive MRS changes.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Martin Paucar,Tobias Granberg,Kristina Lagerstedt-Robinson,Elisabet Waldenlind,Sven Petersson,Love Nordin,Per Svenningsson

    Familial hemiplegic migraine (FHM) is a group of rare familial disorders caused, in most cases, by mutations in CACNA1A and ATP1A2.1 Heterozygous mutations in solute carrier family 1 member 3 (SLC1A3), encoding glial glutamate transporter, are associated with episodic ataxia type 6 (EA6).2–5 In addition to episodic ataxia (EA), alternating hemiplegia and hemiplegic migraine have been reported twice

    更新日期:2020-07-08
  • APOE ϵ4 modifies the relationship between infectious burden and poor cognition.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Chen Zhao,Kevin Strobino,Yeseon Park Moon,Ying Kuen Cheung,Ralph L Sacco,Yaakov Stern,Mitchell S V Elkind

    Objective We investigated whether APOE 4 is an effect modifier of the association between infectious burden (IB) and poor cognition in a multiethnic cohort, the Northern Manhattan Study. Methods IB was assessed by a quantitative weighted index of exposure to common pathogens associated with vascular risk, infectious burden index (IBI), and by serology for individual infections. Cognition was assessed

    更新日期:2020-07-08
  • SLC12A2 mutations cause NKCC1 deficiency with encephalopathy and impaired secretory epithelia.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Tommy Stödberg,Måns Magnusson,Nicole Lesko,Anna Wredenberg,Daniel Martin Munoz,Henrik Stranneheim,Anna Wedell

    Objective To describe the phenotype in 2 sisters with a rare constellation of neurologic symptoms and secretory impairments and to identify the etiology by the use of whole-genome sequencing (WGS). Methods After an extensive workup failed to reveal the cause of disease, in a girl with a previously not reported phenotype, WGS of the proband, her diseased older sister, an older healthy brother, and their

    更新日期:2020-07-03
  • Disease-modifying effects of an SCAF4 structural variant in a predominantly SOD1 ALS cohort.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Julia Pytte,Loren L Flynn,Ryan S Anderton,Frank L Mastaglia,Frances Theunissen,Ian James,Abigail Pfaff,Sulev Koks,Ann M Saunders,Richard Bedlack,Daniel K Burns,Michael W Lutz,Nailah Siddique,Teepu Siddique,Allen D Roses,P Anthony Akkari

    Objective To test the hypothesis that rs573116164 will have disease-modifying effects in patients with superoxide dismutase 1 (SOD1) familial amyotrophic lateral sclerosis (fALS), we characterized rs573116164 within a cohort of 190 patients with fALS and 560 healthy age-matched controls to assess the variant for association with various measures of disease. Methods Using a previously described bioinformatics

    更新日期:2020-07-01
  • Congenital myasthenic syndrome caused by a frameshift insertion mutation in GFPT1.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Szabolcs Szelinger,Jonida Krate,Keri Ramsey,Samuel P Strom,Perry B Shieh,Hane Lee,Newell Belnap,Chris Balak,Ashley L Siniard,Megan Russell,Ryan Richholt,Matt De Both,Ana M Claasen,Isabelle Schrauwen,Stanley F Nelson,Matthew J Huentelman,David W Craig,Samuel P Yang,Steven A Moore,Kumaraswamy Sivakumar,Vinodh Narayanan,Sampathkumar Rangasamy,

    Objective Description of a new variant of the glutamine-fructose-6-phosphate transaminase 1 (GFPT1) gene causing congenital myasthenic syndrome (CMS) in 3 children from 2 unrelated families. Methods Muscle biopsies, EMG, and whole-exome sequencing were performed. Results All 3 patients presented with congenital hypotonia, muscle weakness, respiratory insufficiency, head lag, areflexia, and gastrointestinal

    更新日期:2020-06-30
  • Fibulin-5 mutation featuring Charcot-Marie-Tooth disease, joint hyperlaxity, and scoliosis.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Mohamed Kazamel,Michael A Lopez,Martina Bebin,Kevin Bowling,Bruce R Korf,Gregory S Barsh,Gregory M Cooper,Anna C E Hurst,Eroboghene E Ubogu

    Fibulin-5 (FBLN5) is an extracellular matrix glycoprotein expressed in elastic fiber-rich tissues.1 Mutations affecting the first epidermal growth factor domain feature a spinal Charcot-Marie-Tooth (CMT) phenotype, whereas the C-terminus c.1117C>T variant causes demyelinating sensorimotor polyneuropathy.2 Besides CMT, FBLN5 mutations also feature age-related macular degeneration and cutis laxa.3 FBLN5-associated

    更新日期:2020-06-26
  • GLUT1 deficiency: Retinal detrimental effects of gliovascular modulation.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Matt Henry,John Kitchens,Juan M Pascual,Ramiro S Maldonado

    Most patients with glucose transporter type 1 (GLUT1) deficiency syndrome (G1D) experience anticonvulsant-refractory epilepsy and abnormal cognitive and motor development.1 Ninety percent of patients with G1D harbor a causative loss-of-function mutation in the SLC2A1 gene; in the others, brain fluorodeoxyglucose (FDG) PET can confirm the diagnosis.

    更新日期:2020-06-26
  • The Helix: Editorial Changes
    Neurol. Genet. (IF 3.509) Pub Date : 2020-06-01
    Stefan M. Pulst

    It gives me great pleasure to welcome Dr. Suman Jayadev to the group of Associate Editors of Neurology® Genetics. She is a board-certified neurologist and Assistant Professor of Neurology at the University of Washington. She runs an adult neurogenetics clinic at the University of Washington and is also the Clinical Core Leader of the University of Washington Alzheimer Disease Research Center. Her neurogenetics

    更新日期:2020-06-19
  • Somatic SLC35A2 mosaicism correlates with clinical findings in epilepsy brain tissue.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Katherine E Miller,Daniel C Koboldt,Kathleen M Schieffer,Tracy A Bedrosian,Erin Crist,Adrienne Sheline,Kristen Leraas,Vincent Magrini,Huachun Zhong,Patrick Brennan,Jocelyn Bush,James Fitch,Natalie Bir,Anthony R Miller,Catherine E Cottrell,Jeffrey Leonard,Jonathan A Pindrik,Jerome A Rusin,Summit H Shah,Peter White,Richard K Wilson,Elaine R Mardis,Christopher R Pierson,Adam P Ostendorf

    Objective Many genetic studies of intractable epilepsy in pediatric patients primarily focus on inherited, constitutional genetic deficiencies identified in patient blood. Recently, studies have revealed somatic mosaicism associated with epilepsy in which genetic variants are present only in a subset of brain cells. We hypothesize that tissue-specific, somatic mosaicism represents an important genetic

    更新日期:2020-06-18
  • COX deficiency and leukoencephalopathy due to a novel homozygous APOPT1/COA8 mutation.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Carola Hedberg-Oldfors,Niklas Darin,Christer Thomsen,Christopher Lindberg,Anders Oldfors

    Objective To describe the long-term follow-up and pathogenesis in a child with leukoencephalopathy and cytochrome c oxidase (COX) deficiency due to a novel homozygous nonsense mutation in APOPT1/COA8. Methods The patient was clinically investigated at 3, 5, 9, and 25 years of age. Brain MRI, repeat muscle biopsies with biochemical, morphologic, and protein expression analyses were performed, and whole-genome

    更新日期:2020-06-16
  • Brainstem ischemic syndrome in juvenile NF2.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    John W Henson,Tara Benkers,Connor McCormick

    Objective A new case of brainstem ischemic necrosis in a young woman with de novo neurofibromatosis type 2 (NF2) is reported, and given notable similarities to 7 prior cases of brainstem stroke in the literature, features defining a possible syndrome were sought. Methods Case review including detailed clinical assessment, neuroimaging analysis, genetic testing, and brain biopsy, followed by a multicase

    更新日期:2020-06-16
  • Expanded genetic insight and clinical experience of DNMT1-complex disorder.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Hongyan Bi,Kaori Hojo,Masashi Watanabe,Christina Yee,Kiran Maski,Sadaf Saba,Jonathan Graff-Radford,Mary M Machulda,Erik K St Louis,Ilona Spitsyna Humes,Eoin P Flanagan,Stefan Nicolau,David T Jones,Marc C Patterson,Suresh Kotagal,Yael Raz,Zhiyv Niu,Jun Li,Christopher J Klein

    Objective To report novel causal mutations, expanded clinical phenotypes, and clinical management of DNA methyltransferase 1 (DNMT1)-complex disorder. Methods Neurophysiologic testing, imaging, and genetic findings were summarized in clinical context for 5 cases with DNMT1-complex disorder. Results We identified 2 novel DNMT1 mutations (p.E510K and p.P1546A) by whole-exome sequencing (WES). Case 1

    更新日期:2020-06-13
  • Cerebral arteriopathy associated with heterozygous variants in the casitas B-lineage lymphoma gene.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Ying Hong,Annette Keylock,Barbara Jensen,Thomas S Jacques,Olumide Ogunbiyi,Ebun Omoyinmi,Dawn Saunders,Andrew A Mallick,Madeleine Tooley,Ruth Newbury-Ecob,Julia Rankin,Hywel J Williams,Vijeya Ganesan,Paul A Brogan,Despina Eleftheriou

    Objective To report a series of patients with cerebral arteriopathy associated with heterozygous variants in the casitas B-lineage lymphoma (CBL) gene and examine the functional role of the identified mutant Cbl protein. We hypothesized that mutated Cbl fails to act as a negative regulator of the RAS-mitogen-activated protein kinases (MAPK) signaling pathway, resulting in enhanced vascular fibroblast

    更新日期:2020-06-11
  • Novel truncating mutations of MYO18B causing congenital myopathy in a Swiss patient.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Violeta Mihaylova,Fabian Chablais,Yvan Herenger,Roland Spiegel,Hans Heinrich Jung

    Congenital myopathies (CMs) are a group of rare inherited myopathies most commonly presenting in infancy with hypotonia and weakness. They have been classified on the basis of distinctive myopathologic features. Mutations in more than 25 genes can cause CM.1

    更新日期:2020-06-10
  • Synonymous variants associated with Alzheimer disease in multiplex families.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Min Tang,Maria Eugenia Alaniz,Daniel Felsky,Badri Vardarajan,Dolly Reyes-Dumeyer,Rafael Lantigua,Martin Medrano,David A Bennett,Philip L de Jager,Richard Mayeux,Ismael Santa-Maria,Christiane Reitz

    Objective Synonymous variants can lead to disease; nevertheless, the majority of sequencing studies conducted in Alzheimer disease (AD) only assessed coding variation. Methods To detect synonymous variants modulating AD risk, we conducted a whole-genome sequencing study on 67 Caribbean Hispanic (CH) families multiply affected by AD. Identified disease-associated variants were further assessed in an

    更新日期:2020-06-09
  • A novel PRNP-G131R variant associated with familial prion disease.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Jumana T Alshaikh,Kefeng Qin,Lili Zhao,James A Mastrianni

    Roughly 40 autosomal dominant mutations of the prion protein gene (PRNP) cosegregate with familial Creutzfeldt-Jakob disease (CJD), fatal familial insomnia, or Gerstmann-Sträussler-Scheinker disease (GSS).1,2 Genetic prion disease in African Americans is rarely reported. We sequenced the PRNP coding segment of a 43-year-old African American woman with rapidly progressive dementia and a positive family

    更新日期:2020-06-07
  • Genetic background of ataxia in children younger than 5 years in Finland.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Erika Ignatius,Pirjo Isohanni,Max Pohjanpelto,Päivi Lahermo,Simo Ojanen,Virginia Brilhante,Eino Palin,Anu Suomalainen,Tuula Lönnqvist,Christopher J Carroll

    Objective To characterize the genetic background of molecularly undefined childhood-onset ataxias in Finland. Methods This study examined a cohort of patients from 50 families with onset of an ataxia syndrome before the age of 5 years collected from a single tertiary center, drawing on the advantages offered by next generation sequencing. A genome-wide genotyping array (Illumina Infinium Global Screening

    更新日期:2020-06-07
  • A splice variant in ATAD3A expands the clinical and genetic spectrum of Harel-Yoon syndrome.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Ilana Hanes,Hugh J McMillan,Yoko Ito,Kristin D Kernohan,Joanna Lazier,Matthew A Lines,David A Dyment

    ATAD3A is a mitochondrial AAA + ATPase protein localized between the inner and outer mitochondrial membrane1; its role includes the stabilization of mitochondrial DNA, the regulation of mitochondrial fission/fusion, and the regulation of cholesterol homeostasis.1,2 Harel-Yoon syndrome (HYS) can result from biallelic deletions in the ATAD3 gene cluster (containing ATAD3A, ATAD3B, and ATAD3C) and is

    更新日期:2020-06-05
  • Cerebellar ataxia, neuropathy, hearing loss, and intellectual disability due to AIFM1 mutation.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-06-18
    Massimo Pandolfo,Myriam Rai,Gauthier Remiche,Laurence Desmyter,Isabelle Vandernoot

    Objective To describe the clinical and molecular genetic findings in a family segregating a novel mutation in the AIFM1 gene on the X chromosome. Methods We studied the clinical features and performed brain MRI scans, nerve conduction studies, audiometry, cognitive testing, and clinical exome sequencing (CES) in the proband, his mother, and maternal uncle. We used in silico tools, X chromosome inactivation

    更新日期:2020-06-02
  • Biallelic LINE insertion mutation in HACD1 causing congenital myopathy.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-06-18
    Fatema Al Amrani,Carolina Gorodetsky,Lili-Naz Hazrati,Kimberly Amburgey,Hernan D Gonorazky,James J Dowling

    Congenital myopathies are clinically and genetically heterogeneous, resulting from mutations in at least 30 different genes.1 The classical presentation is neonatal hypotonia and nonprogressive weakness with normal creatine phosphokinase, although there is a broad range in terms of age at onset and clinical presentation. Historically, congenital myopathies have been defined and diagnosed based on muscle

    更新日期:2020-06-02
  • TGM6 L517W is not a pathogenic variant for spinocerebellar ataxia type 35.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-06-18
    Yanxing Chen,Dengchang Wu,Benyan Luo,Guohua Zhao,Kang Wang

    Objective To investigate the pathogenicity of the TGM6 variant for spinocerebellar ataxia 35 (SCA35), which was previously reported to be caused by pathogenic mutations in the gene TGM6. Methods Neurologic assessment and brain MRI were performed to provide detailed description of the phenotype. Whole-exome sequencing and dynamic mutation analysis were performed to identify the genotype. Results The

    更新日期:2020-06-02
  • Adult-onset leukoencephalopathy with homozygous LAMB1 missense mutation.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-08-01
    Rei Yasuda,Tomokatsu Yoshida,Ikuko Mizuta,Masashi Watanabe,Masakazu Nakano,Ryuichi Sato,Yuichi Tokuda,Natsue Omi,Norio Sakai,Masanori Nakagawa,Kei Tashiro,Toshiki Mizuno

    LAMB1 encodes laminin subunit beta 1, a constituent of the extracellular matrix glycoprotein of basement membranes.1 Mutations of LAMB1 have been reported in patients with congenital or infantile- to childhood-onset leukoencephalopathy and severe developmental retardation.2,3 We report an adulthood-onset case with mild leukoencephalopathy and a novel homozygous LAMB1 missense mutation. Our findings

    更新日期:2020-06-02
  • Phenotypic variability in chorea-acanthocytosis associated with novel VPS13A mutations.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-06-01
    Valter Niemelä,Ammar Salih,Daniela Solea,Björn Lindvall,Jan Weinberg,Gabriel Miltenberger,Tobias Granberg,Aikaterini Tzovla,Love Nordin,Torsten Danfors,Irina Savitcheva,Niklas Dahl,Martin Paucar

    Objective To perform a comprehensive characterization of a cohort of patients with chorea-acanthocytosis (ChAc) in Sweden. Methods Clinical assessments, targeted genetic studies, neuroimaging with MRI, [18F]-fluorodeoxyglucose (FDG) PET, and dopamine transporter with 123I FP-CIT (DaTscan) SPECT. One patient underwent magnetic resonance spectroscopy (MRS). Results Four patients living in Sweden but

    更新日期:2020-06-01
  • Expanding the phenotype of MTOR-related disorders and the Smith-Kingsmore syndrome.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-06-01
    Anasofia Elizondo-Plazas,Marisol Ibarra-Ramírez,Azalea Garza-Báez,Laura Elia Martínez-de-Villarreal

    Heterozygous germline mutations in mammalian target of rapamycin (MTOR) (OMIM 601231) are known to underlie Smith-Kingsmore syndrome (SKS; OMIM 616638), an infrequent entity with autosomal dominant inheritance, also known as macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome (ORPHA 457485).1 Among the clinical features of SKS, the most common features include intellectual

    更新日期:2020-06-01
  • Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy revisited: Genotype-phenotype correlations of all published cases.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-06-01
    Georgia Xiromerisiou,Chrysoula Marogianni,Katerina Dadouli,Christina Zompola,Despoina Georgouli,Antonios Provatas,Aikaterini Theodorou,Paschalis Zervas,Christina Nikolaidou,Stergios Stergiou,Panagiotis Ntellas,Maria Sokratous,Pantelis Stathis,Georgios P Paraskevas,Anastasios Bonakis,Konstantinos Voumvourakis,Christos Hadjichristodoulou,Georgios M Hadjigeorgiou,Georgios Tsivgoulis

    Objective The aim of this study was to evaluate the correlation between the various NOTCH3 mutations and their clinical and genetic profile, along with the presentation of a novel mutation in a patient. Methods Here, we describe the phenotype of a patient with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) harboring a novel mutation. We also performed

    更新日期:2020-06-01
  • Expanding the phenotypic and molecular spectrum of RNA polymerase III-related leukodystrophy.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-06-01
    Stefanie Perrier,Laurence Gauquelin,Catherine Fallet-Bianco,Megan K Dishop,Mackenzie A Michell-Robinson,Luan T Tran,Kether Guerrero,Lama Darbelli,Myriam Srour,Kevin Petrecca,Deborah L Renaud,Michael Saito,Seth Cohen,Steffen Leiz,Bader Alhaddad,Tobias B Haack,Ingrid Tejera-Martin,Fernando I Monton,Norberto Rodriguez-Espinosa,Daniela Pohl,Savithri Nageswaran,Annette Grefe,Emma Glamuzina,Geneviève Bernard

    Objective To expand the phenotypic spectrum of severity of POLR3-related leukodystrophy and identify genotype-phenotype correlations through study of patients with extremely severe phenotypes. Methods We performed an international cross-sectional study on patients with genetically proven POLR3-related leukodystrophy and atypical phenotypes to identify 6 children, 3 males and 3 females, with an extremely

    更新日期:2020-06-01
  • Genotyping single nucleotide polymorphisms for allele-selective therapy in Huntington disease.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-06-01
    Daniel O Claassen,Jody Corey-Bloom,E Ray Dorsey,Mary Edmondson,Sandra K Kostyk,Mark S LeDoux,Ralf Reilmann,H Diana Rosas,Francis Walker,Vicki Wheelock,Nenad Svrzikapa,Kenneth A Longo,Jaya Goyal,Serena Hung,Michael A Panzara

    Background The huntingtin gene (HTT) pathogenic cytosine-adenine-guanine (CAG) repeat expansion responsible for Huntington disease (HD) is phased with single nucleotide polymorphisms (SNPs), providing targets for allele-selective treatments. Objective This prospective observational study defined the frequency at which rs362307 (SNP1) or rs362331 (SNP2) was found on the same allele with pathogenic CAG

    更新日期:2020-06-01
  • Prevalence of RFC1-mediated spinocerebellar ataxia in a North American ataxia cohort.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-06-01
    Dona Aboud Syriani,Darice Wong,Sameer Andani,Claudio M De Gusmao,Yuanming Mao,May Sanyoura,Giacomo Glotzer,Paul J Lockhart,Sharon Hassin-Baer,Vikram Khurana,Christopher M Gomez,Susan Perlman,Soma Das,Brent L Fogel

    Objective We evaluated the prevalence of pathogenic repeat expansions in replication factor C subunit 1 (RFC1) and disabled adaptor protein 1 (DAB1) in an undiagnosed ataxia cohort from North America. Methods A cohort of 596 predominantly adult-onset patients with undiagnosed familial or sporadic cerebellar ataxia was evaluated at a tertiary referral ataxia center and excluded for common genetic causes

    更新日期:2020-06-01
  • Intronic pentanucleotide expansion in the replication factor 1 gene (RFC1) is a major cause of adult-onset ataxia.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-06-01
    Sylvia M Boesch,Martha A Nance

    The ataxias comprise diseases of both genetic and nongenetic origin with extreme clinical and genetic heterogeneity. They may present as a pure cerebellar form or as part of a more complex neurologic syndrome. Progressive, neurodegenerative sporadic adult-onset ataxias (SAOAs) without a known cause have a prevalence rate of 2.2–12.4 per 100,000. In several ataxia cohorts, repetitive genetic screening

    更新日期:2020-06-01
  • Mutations in the m-AAA proteases AFG3L2 and SPG7 are causing isolated dominant optic atrophy.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-06-01
    Majida Charif,Arnaud Chevrollier,Naïg Gueguen,Céline Bris,David Goudenège,Valérie Desquiret-Dumas,Stéphanie Leruez,Estelle Colin,Audrey Meunier,Catherine Vignal,Vasily Smirnov,Sabine Defoort-Dhellemmes,Isabelle Drumare Bouvet,Cyril Goizet,Marcela Votruba,Neringa Jurkute,Patrick Yu-Wai-Man,Francesca Tagliavini,Leonardo Caporali,Chiara La Morgia,Valerio Carelli,Vincent Procaccio,Xavier Zanlonghi,Isabelle

    Objective To improve the genetic diagnosis of dominant optic atrophy (DOA), the most frequently inherited optic nerve disease, and infer genotype-phenotype correlations. Methods Exonic sequences of 22 genes were screened by new-generation sequencing in patients with DOA who were investigated for ophthalmology, neurology, and brain MRI. Results We identified 7 and 8 new heterozygous pathogenic variants

    更新日期:2020-06-01
  • Clinical and pathologic phenotype of a large family with heterozygous STUB1 mutation.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-06-01
    Merel O Mol,Jeroen G J van Rooij,Esther Brusse,Annemieke J M H Verkerk,Shamiram Melhem,Wilfred F A den Dunnen,Patrizia Rizzu,Chiara Cupidi,John C van Swieten,Laura Donker Kaat

    Objective To describe the clinical and pathologic features of a novel pedigree with heterozygous STUB1 mutation causing SCA48. Methods We report a large pedigree of Dutch decent. Clinical and pathologic data were reviewed, and genetic analyses (whole-exome sequencing, whole-genome sequencing, and linkage analysis) were performed on multiple family members. Results Patients presented with adult-onset

    更新日期:2020-06-01
  • Acute encephalopathy after head trauma in a patient with a RHOBTB2 mutation.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-06-01
    Annemarie C S Knijnenburg,Joost Nicolai,Levinus A Bok,Akin Bay,Alexander P A Stegmann,Margje Sinnema,Maaike Vreeburg

    Objective De novo missense mutations in the RHOBTB2 gene have been described as causative for developmental and epileptic encephalopathy. Methods The clinical phenotype of this disorder includes early-onset epilepsy, severe intellectual disability, postnatal microcephaly, and movement disorder. Three RHOBTB2 patients have been described with acute encephalopathy and febrile epileptic status. All showed

    更新日期:2020-06-01
  • Polygenic risk scores of several subtypes of epilepsies in a founder population.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-06-01
    Claudia Moreau,Rose-Marie Rébillard,Stefan Wolking,Jacques Michaud,Frédérique Tremblay,Alexandre Girard,Joanie Bouchard,Berge Minassian,Catherine Laprise,Patrick Cossette,Simon L Girard

    Objective Polygenic risk scores (PRSs) are used to quantify the cumulative effects of a number of genetic variants, which may individually have a very small effect on susceptibility to a disease; we used PRSs to better understand the genetic contribution to common epilepsy and its subtypes. Methods We first replicated previous single associations using 373 unrelated patients. We then calculated PRSs

    更新日期:2020-06-01
  • Neurologic outcomes in Friedreich ataxia: Study of a single-site cohort.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-06-01
    Massimo Pandolfo

    Objective To investigate the pattern of progression of neurologic impairment in Friedreich ataxia (FRDA) and identify patients with fast disease progression as detected by clinical rating scales. Methods Clinical, demographic, and genetic data were analyzed from 54 patients with FRDA included at the Brussels site of the European Friedreich's Ataxia Consortium for Translational Studies, with an average

    更新日期:2020-06-01
  • Neuraxial dysraphism in EPAS1-associated syndrome due to improper mesenchymal transition.
    Neurol. Genet. (IF 3.509) Pub Date : 2020-06-01
    Jared S Rosenblum,Anthony J Cappadona,Davis P Argersinger,Ying Pang,Herui Wang,Matthew A Nazari,Jeeva P Munasinghe,Danielle R Donahue,Abhishek Jha,James G Smirniotopoulos,Markku M Miettinen,Russell H Knutsen,Beth A Kozel,Zhengping Zhuang,Karel Pacak,John D Heiss

    Objective To investigate the effect of somatic, postzygotic, gain-of-function mutation of Endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) encoding hypoxia-inducible factor-2α (HIF-2α) on posterior fossa development and spinal dysraphism in EPAS1 gain-of-function syndrome, which consists of multiple paragangliomas, somatostatinoma, and polycythemia. Methods Patients referred to our institution

    更新日期:2020-06-01