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  • Herpes simplex virus 2 encephalitis in a patient heterozygous for a TLR3 mutation
    Neurol. Genet. (IF 3.509) Pub Date : 2020-12-01
    Timo Hautala; Jie Chen; Laura Tervonen; Terhi Partanen; Satu Winqvist; Johanna Lehtonen; Janna Saarela; Minna Kraatari; Outi Kuismin; Tytti Vuorinen; Virpi Glumoff; Pirjo Åström; Usko Huuskonen; Lazaro Lorenzo; Jean-Laurent Casanova; Shen-Ying Zhang; Mikko R.J. Seppänen

    Susceptibility to herpes simplex virus type 1 (HSV-1) encephalitis (HSE-1) in otherwise healthy individuals, in the course of primary infection, can be caused by single-gene inborn errors of Toll-like receptor 3 (TLR3) dependent, interferon (IFN)-α/β-mediated immunity,1,2 or by single-gene inborn errors of snoRNA31.3 These variations underlie infections of the forebrain, whereas mutations of DBR1 underlie

  • Ketogenic diet reduces Lafora bodies in murine Lafora disease
    Neurol. Genet. (IF 3.509) Pub Date : 2020-12-01
    Lori Israelian; Peixiang Wang; Shoghig Gabrielian; Xiaochu Zhao; Berge A. Minassian

    Lafora disease (LD) is a teenage-onset fatal progressive myoclonus epilepsy caused by loss-of-function mutations in the EPM2A gene encoding the glycogen phosphatase laforin or EPM2B encoding the laforin-interacting ubiquitin E3 ligase malin. Concerted actions of glycogen synthase (GS) and branching enzyme generate normal short-branched soluble glycogen. In LD, some glycogen molecules develop long branches

  • Neuronal intranuclear inclusion disease presenting with an MELAS-like episode in chronic polyneuropathy
    Neurol. Genet. (IF 3.509) Pub Date : 2020-12-01
    Tasuku Ishihara; Tomoko Okamoto; Ken Saida; Yuji Saitoh; Shinji Oda; Terunori Sano; Takuhiro Yoshida; Yuki Morita; Atsushi Fujita; Hiromi Fukuda; Noriko Miyake; Takeshi Mizuguchi; Yuko Saito; Yoshiki Sekijima; Naomichi Matsumoto; Yuji Takahashi

    Neuronal intranuclear inclusion disease (NIID) exhibits diverse clinical phenotypes caused by the intronic repeat expansion of NOTCH2NLC.1,2 An acute encephalopathic episode can manifest in some patients with NIID.3,4 Herein, we report an NIID patient harboring a de novo {(GGA)n(GGC)n}n repeat expansion in NOTCH2NLC, who developed abrupt mitochondrial encephalomyopathy, lactic acidosis, and stroke-like

  • Practical guidelines to manage discordant situations of SMN2 copy number in patients with spinal muscular atrophy
    Neurol. Genet. (IF 3.509) Pub Date : 2020-12-01
    Ivon Cuscó; Sara Bernal; Laura Blasco-Pérez; Maite Calucho; Laura Alias; Pablo Fuentes-Prior; Eduardo F. Tizzano

    Objective Assessment of SMN2 copy number in patients with spinal muscular atrophy (SMA) is essential to establish careful genotype-phenotype correlations and predict disease evolution. This issue is becoming crucial in the present scenario of therapeutic advances with the perspective of SMA neonatal screening and early diagnosis to initiate treatment, as this value is critical to stratify patients

  • Heterozygous variants in DCC: Beyond congenital mirror movements
    Neurol. Genet. (IF 3.509) Pub Date : 2020-12-01
    Sebastian Thams; Mominul Islam; Marie Lindefeldt; Ann Nordgren; Tobias Granberg; Bianca Tesi; Gisela Barbany; Daniel Nilsson; Martin Paucar

    Objective To perform a comprehensive characterization of a cohort of patients with congenital mirror movements (CMMs) in Sweden. Methods Clinical examination with the Woods and Teuber scale for mirror movements (MMs), neuroimaging, navigated transcranial magnetic stimulation (nTMS), and massive parallel sequencing (MPS) were applied. Results The cohort is ethnically diverse and includes a total of

  • The SPID-GBA study: Sex distribution, Penetrance, Incidence, and Dementia in GBA-PD
    Neurol. Genet. (IF 3.509) Pub Date : 2020-12-01
    Letizia Straniero; Rosanna Asselta; Salvatore Bonvegna; Valeria Rimoldi; Giada Melistaccio; Giulia Soldà; Massimo Aureli; Matteo Della Porta; Ugo Lucca; Alessio Di Fonzo; Anna Zecchinelli; Gianni Pezzoli; Roberto Cilia; Stefano Duga

    Objective To provide a variant-specific estimate of incidence, penetrance, sex distribution, and association with dementia of the 4 most common Parkinson disease (PD)-associated GBA variants, we analyzed a large cohort of 4,923 Italian unrelated patients with primary degenerative parkinsonism (including 3,832 PD) enrolled in a single tertiary care center and 7,757 ethnically matched controls. Methods

  • Primary mitochondrial myopathy: Clinical features and outcome measures in 118 cases from Italy
    Neurol. Genet. (IF 3.509) Pub Date : 2020-12-01
    Vincenzo Montano; Francesco Gruosso; Valerio Carelli; Giacomo Pietro Comi; Massimiliano Filosto; Costanza Lamperti; Tiziana Mongini; Olimpia Musumeci; Serenella Servidei; Paola Tonin; Antonio Toscano; Angela Modenese; Guido Primiano; Maria Lucia Valentino; Sara Bortolani; Silvia Marchet; Megi Meneri; Graziana Tavilla; Gabriele Siciliano; Michelangelo Mancuso

    Objective To determine whether a set of functional tests, clinical scales, patient-reported questionnaires, and specific biomarkers can be considered reliable outcome measures in patients with primary mitochondrial myopathy (PMM), we analyzed a cohort of Italian patients. Methods Baseline data were collected from 118 patients with PMM, followed by centers of the Italian network for mitochondrial diseases

  • Biotinidase deficiency: A treatable cause of hereditary spastic paraparesis
    Neurol. Genet. (IF 3.509) Pub Date : 2020-12-01
    Florentine Radelfahr; Korbinian M. Riedhammer; Leonie F. Keidel; Gwendolyn Gramer; Thomas Meitinger; Thomas Klopstock; Matias Wagner

    Objective To expand the genetic spectrum of hereditary spastic paraparesis by a treatable condition and to evaluate the therapeutic effects of biotin supplementation in an adult patient with biotinidase deficiency (BD). Methods We performed exome sequencing (ES) in a patient with the clinical diagnosis of complex hereditary spastic paraparesis. The patient was examined neurologically, including functional

  • POLR1C variants dysregulate splicing and cause hypomyelinating leukodystrophy
    Neurol. Genet. (IF 3.509) Pub Date : 2020-12-01
    Hitoshi Kashiki; Heng Li; Sachiko Miyamoto; Hiroe Ueno; Yoshinori Tsurusaki; Chizuru Ikeda; Hirofumi Kurata; Takumi Okada; Tomoyuki Shimazu; Hoseki Imamura; Yumi Enomoto; Jun-ichi Takanashi; Kenji Kurosawa; Hirotomo Saitsu; Ken Inoue

    Objective To further clarify the molecular pathogenesis of RNA polymerase III (Pol III)-related leukodystrophy caused by biallelic POLR1C variants at a cellular level and potential effects on its downstream genes. Methods Exome analysis and molecular functional studies using cell expression and long-read sequencing analyses were performed on 1 family with hypomyelinating leukodystrophy showing no clinical

  • Cerebrospinal fluid abnormalities in developmental and epileptic encephalopathy with a de novo CDK19 variant
    Neurol. Genet. (IF 3.509) Pub Date : 2020-12-01
    Yuji Sugawara; Tomoko Mizuno; Kengo Moriyama; Hisako Ishiwata; Mitsuhiro Kato; Mitsuko Nakashima; Takeshi Mizuguchi; Naomichi Matsumoto

    Developmental and epileptic encephalopathy (DEE) is a spectrum of neurodevelopmental conditions in which psychomotor delay or regression arises in association with frequent epileptic activity. In the past decade, molecular genetics studies showed that DEE is caused by environmental insults and by genetic factors; several de novo pathogenic variants were also identified.1

  • Neurodevelopmental regression, severe generalized dystonia, and metabolic acidosis caused by POLR3A mutations
    Neurol. Genet. (IF 3.509) Pub Date : 2020-12-01
    Vanessa Zanette; Aurelio Reyes; Mark Johnson; Daniel do Valle; Alan J. Robinson; Vaneisse Monteiro; Bruno Augusto Telles; Ricardo L.R. Souza; Mara L S.F. Santos; Cristiane Benincá; Massimo Zeviani

    Objective To expand the clinical phenotype of POLR3A mutations by assessing the functional consequences of a missense and a splicing acceptor mutation. Methods We performed whole-exome sequencing for identification of likely pathogenic mutations in a 9-year-old female patient with severe generalized dystonia, metabolic acidosis, leukocytosis, hypotonia, and dysphagia. Brain MRI showed basal ganglia

  • Late-onset vs nonmendelian early-onset Alzheimer disease: A distinction without a difference?
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-01
    Christiane Reitz; Ekaterina Rogaeva; Gary W. Beecham

    There is mounting evidence that only a small fraction of early-onset Alzheimer disease cases (onset <65 years) are explained by known mutations. Even multiplex families with early onset often also have late-onset cases, suggesting that the commonly applied categorization of Alzheimer disease into early- and late-onset forms may not reflect distinct underlying etiology. Nevertheless, this categorization

  • Blended phenotype of adult-onset Alexander disease and spinocerebellar ataxia type 6
    Neurol. Genet. (IF 3.509) Pub Date : 2020-12-01
    Takashi Odo; Tomoko Okamoto; Noriko Sato; Yuji Takahashi

    Alexander disease is an autosomal dominant hereditary disease characterized by progressive spastic paraplegia, ataxia, and bulbar symptoms caused by mutations in the glial fibrillary acidic protein (GFAP) gene. Previous nation-wide surveillance revealed that the prevalence rate in Japan is estimated at 1 in 2.7 million people.1 Meanwhile, SCA6 is an autosomal dominant spinocerebellar ataxia characterized

  • Association of blood-based transcriptional risk scores with biomarkers for Alzheimer disease
    Neurol. Genet. (IF 3.509) Pub Date : 2020-12-01
    Young Ho Park; Angela Hodges; Andrew Simmons; Simon Lovestone; Michael W. Weiner; SangYun Kim; Andrew J. Saykin; Kwangsik Nho; For the AddNeuroMed consortium and the Alzheimer's Disease Neuroimaging Initiative

    Objective To determine whether transcriptional risk scores (TRSs), a summation of polarized expression levels of functional genes, reflect the risk of Alzheimer disease (AD). Methods Blood transcriptome data were from Caucasian participants, which included AD, mild cognitive impairment, and cognitively normal controls (CN) in the Alzheimer's Disease Neuroimaging Initiative (ADNI, n = 661) and AddNeuroMed

  • Genetic risk for Alzheimer disease affects the brain throughout the lifespan
    Neurol. Genet. (IF 3.509) Pub Date : 2020-10-01
    David E.J. Linden

    Neuronal cell death and loss of synapses are hallmarks of the pathology of Alzheimer disease (AD). The incidence of AD increases with age, and both regional and global brain atrophies have been identified as pathological correlates. Thus, AD can, in many respects, be regarded as a paradigmatic neurodegenerative disorder. However, disrupted function of the presenilin genes, the most common cause of

  • Congenital immobility and stiffness related to biallelic ATAD1 variants
    Neurol. Genet. (IF 3.509) Pub Date : 2020-12-01
    Roxane Bunod; Diane Doummar; Sandra Whalen; Boris Keren; Sandra Chantot-Bastaraud; Kim Maincent; Marie-Charlotte Villy; Michèle Mayer; Diana Rodriguez; Lydie Burglen; Pierre-Louis Léger; François Kieffer; Isabelle Martin; Delphine Héron; Julien Buratti; Arnaud Isapof; Alexandra Afenjar; Thierry Billette de Villemeur; Cyril Mignot

    Objective To delineate the phenotype associated with biallelic ATAD1 variants. Methods We describe 2 new patients with ATAD1-related disorder diagnosed by whole-exome sequencing and compare their phenotype to 6 previous patients. Results Patients 1 and 2 had a similar distinctive phenotype comprising congenital stiffness of limbs, absent spontaneous movements, weak sucking, and hypoventilation. Both

  • 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

  • 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

  • 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

  • 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

  • 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.

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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.

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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