2016 in Review and Message from the Editors to our Reviewers
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For this Helix, the editors of Neurology® Genetics have chosen some of their favorite articles of the past year. It is an eclectic collection drawing on different journals including Neurology: Genetics and varied topics.
Two articles report major advances in the understanding of how the C9orf72 GGGGCC repeat expansion exerts its pathogenic effect.1,2 This mutation is a major cause of familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) as well as the cause of 5%–10% of what appears to be sporadic ALS. Understanding the molecular and cellular mechanisms of its pathogenicity is an essential step toward finding therapies for these devastating diseases. The work reported in these articles is remarkable as it identifies effects of both toxic RNA and repeat associated non-AUG (RAN)-translation products generated by this repeat and links them to pathogenic mechanisms shared by other ALS/FTD-causing mutations.
A landmark publication this year describes the generation and characterization of a C9orf72 bacterial artificial chromosome transgenic mouse.3 This mouse model will be important in helping to clarify the pathogenesis of ALS and FTD and can be used to explore the efficacy of potential treatments.
Two articles analyzed white matter changes in FTD due to GRN and C9orf72 mutations and in primary familial brain calcifications due to a novel PDGFB mutation.4,5 The white matter changes preceded atrophy/calcifications and could be a premanifest marker in primary familial brain calcification. White matter changes could therefore exacerbate the pathogenic cascades in neurodegenerative diseases characterized by motor and cognitive signs. These changes may include oligodendroglial dysfunction, as suspected for the GRN haploinsufficiency. Extensive white matter changes are present also in mouse models of neurodegeneration, and effects of altered oligodendrocyte function on disease progression are suspected.
Adams et al.6 provide an example of how “crowdsourcing” data collection may provide enough power to detect genetic variants affecting normal variation as well as disease susceptibility. Combining data from many contributors allowed them to identify genetic variants affecting intracranial volume, strictly related to brain volume, which in turn affects the risk of cognitive impairment.
The use of gene therapy to treat peripheral neuropathies faces a number of challenges including ones related to delivery. A recent study describes rescue of an X-linked demyelinating form of Charcot-Marie-Tooth disease (CMT1X) in gap junction beta 1 gene (GJB1) null mice, which lack connexin32 (CX32) protein.7 One intrathecal injection of a lentiviral vector expressing GJB1 gene under the control of the myelin protein zero (MPZ) promoter led to stable and cell-specific expression of CX32 in up to 50% of Schwann cells in multiple lumbar spinal roots and peripheral nerves. The treated mice had improved motor function and electrophysiologic indices, as well as less pathology. The virus vector presumably diffused from the spinal fluid in the subarachnoid space into the epineurium of the peripheral nerve, demonstrating that this delivery route could be used in the treatment of other peripheral neuropathies.
Phuah et al.8 extended the clinical phenotype of APOE ε4 carriers, long known as the major risk factor for Alzheimer disease. They found that APOE ε4 carriers had a significantly greater decline in serum total cholesterol and low-density lipoprotein in the 6 months preceding an intracerebral hemorrhage, relative to APOE ε2 carriers. APOE remains one of the most interesting genes in the CNS, and one of the most important. Despite being identified as a risk factor for Alzheimer disease in 1989, its function in that regard is still not fully understood. Mutations in the gene in humans and mice support its role in lipoprotein metabolism. It is fascinating to note that almost 30 years after its rise to clinical importance, we continue to identify its association with major neurologic events.
An impressive multinational effort characterized the variability of dysferlin mutations, including symptoms and rate of progression of their associated disease.9 Missense mutations were a frequent cause of the disease. The characterization of the mutation, which may cause a spectrum of disease syndromes, is increasingly important in neuromuscular disease as novel therapeutics may be broadly applicable across phenotypes. Indeed, it is likely that the mutation (e.g., missense, nonsense, etc.) is more likely to select the therapeutic trial population rather than the phenotype. Additional, similar, studies in other limb-girdle muscular dystrophies are now possible as the Jain Foundation, Muscular Dystrophy Association, and other patient advocacy foundations have subsidized genetic testing for limb-girdle muscular dystrophies. These resources will extend the knowledge of the genotype-phenotype variability and offer a more accurate understanding of the prevalence of these conditions.
Genome-wide association studies have identified many risk variants, most of them not changing the coding sequence of a gene, but potentially regulating gene expression. Several DNA variants upstream of the SNCA gene encoding α-synuclein have been identified, but their direct relationship to regulating SNCA expression was not known. Soldner et al.10(p1) made use of a novel method to manipulate the genome, called CRISPR/Cas9, to delete or change specific sequences encompassing previously identified variants. They accomplished these genetic engineering feats in embryonic stem cells that they differentiated into neurons so that SNCA expression could be measured in the correct cell type. Indeed, the variant with the greatest associated risk for Parkinson disease increased SNCA expression in neurons.
The final selection does not directly relate to the nervous system, but is relevant in the context of neurogenetics, as it deals with the evaluation of DNA variants as causative for disease. The Kohane group examined variants that had previously been considered causal in hypertrophic cardiomyopathy.11 Variants that were falsely classified as pathogenic occurred predominantly in African Americans. Simulations showed that the inclusion of even small numbers of African Americans in control cohorts probably would have prevented these misclassifications, highlighting the importance of diversity in variant databases. The problem of erroneously assigning mutation status to rare, sometimes population-dependent benign DNA variants is widespread. It is of most actionable importance in the clinical arena, but as editors of Neurology: Genetics, we face similar challenges when deciding on acceptance of manuscripts reporting novel mutations in established disease-causing genes.
We wish to acknowledge the individuals who have completed reviews for the journal since its launch in April 2015. Your thoughtful comments are tremendously helpful and highly appreciated. We are also grateful for your cooperation in returning reviews in a timely manner. Please follow the guidelines for reviewing articles accessed by selecting the Information for Reviewers (IFR) link on the Neurology.org/ng website. The IFR provides information on expectations of reviewers regarding confidentiality, timeliness, and reviewer conflicts of interest; it also provides instructions for formatting the comments to editors and authors to enable the most effective communication with authors. Please email ngjournal{at}neurology.org if you would like to do more reviews or if you have never reviewed for the journal but are interested in doing so. Include a description of your credentials and expertise in the areas in which you are qualified to review. We look forward to hearing from you!
Our 2016 reviewers are listed at the end of this article.
STUDY FUNDING
No targeted funding reported.
DISCLOSURE
S.M. Pulst serves on the editorial boards of Journal of Cerebellum, NeuroMolecular Medicine, Continuum, Experimental Neurology, Neurogenetics, and Nature Clinical Practice Neurology and as Editor-in-Chief of Current Genomics; receives research support from NIH, Target ALS, National Ataxia Foundation, and ISIS Pharmaceuticals; has consulted for Ataxion Therapeutics; is a stockholder of Progenitor Life Sciences; has received license fee payments from Cedars-Sinai Medical Center; has given expert testimony for Hall & Evans, LLC; holds multiple patents; and receives an honorarium from the AAN as the Editor of Neurology: Genetics. N.E. Johnson has served as Associate Editor for Neurology: Genetics; has consulted for AMO Pharma and AveXis; has received research support from Ionis Pharmaceuticals, Biogen Idec, Valerion Therapeutics, Cytokinetics, Acceleron, National Institute of Neurological Disorders and Stroke (1K23NS091511-01), Muscular Dystrophy Association and Myotonic Dystrophy Foundation. A. Durr has served on scientific advisory boards for INSERM (NIH and research), International Science Advisory Board of the Helmholtz Initiative on Personalized Medicine and Grenoble Neuroscience Institute; has served on the editorial boards of Journal of Huntington's Disease, Archives of Neurology; holds patents and receives royalties for Anaplerotic therapy of Huntington disease and other polyglutamine diseases; has received research support from CoEn. M. Pandolfo has served on scientific advisory boards for Apopharma, Voyager Therapeutics; has served on editorial boards of Acta Neurologica Belgica, Orphanet Journal of Rare Diseases, and as Associate Editor of Neurology: Genetics; holds patents and receives royalties for Direct molecular diagnosis of Friedreich's ataxia; has consulted for Biomarin and UCB; and has received research support from Biomarin, Fonds National de la Recherche Scientifique, Offrez-moi-la-lune, Friedreich's Ataxia Research Alliance, and Association Belge contre les Maladies neuro-Musculaires. R.P. Roos serves on the editorial board of Virology and MedLink. He conducts research supported by the NIH, the ALS Association, the Judith and Jean Pape Adams Charitable Foundation, the Ralph and Marian Falk Medical Research Trust Grant, and the Chicago Biomedical Consortium. He is a stockholder of Amgen, Merck, Ionis Pharmaceuticals, and Express Scripts. J.M. Vance has received funding for travel or speaker honoraria from NETPR, Department of Defense, and NIH; serves on the editorial boards of American Journal of Neurodegenerative Diseases and as Associate Editor of Neurology: Genetics; holds patents for method of detecting Charcot-Marie-Tooth disease type 2A, TRPC6 involved in glomerulonephritis, and methods for identifying an individual at increased risk of developing coronary artery disease; has received research support from NIH/National Institute of Neurological Disorders and Stroke and Hussman Foundation; and receives royalties from Duke University. Go to Neurology.org/ng for full disclosure forms.
Gregory L. Krauss
Margaret A. Pericak-Vance
Orrin Devinsky
Stephen C. Cannon
Marsel M. Mesulam
Guy A. Rouleau
Jeffery M. Vance
Carlos H. Schenck
Hiroshi-Mitsumoto
Michael E. Shy
William T. Dauer
Samuel F. Berkovic
Salvatore DiMauro
Patrick F. Chinnery
Denise Anne Figlewicz
Tetsuo Ashizawa
Kousuke Kanemoto
Ronald G. Haller
Antonio Gambardella
Brian G. Weinshenker
Renzo Guerrini
Alessandro Filla
Joanna C. Jen
Ichizo Nishino
John Vissing
Hideshi Kawakami
Jerome de Seze
Joseph James Higgins
Daniela Berg
Peter Hedera
Oliver Bandmann
Alexandra Durr
Corrado I. Angelini
Massimo Pandolfo
Henry L. Paulson
Rivka Inzelberg
Jordi Perez-Tur
Helio A.G. Teive
Anders Oldfors
Franco Antonio Laccone
Merit E. Cudkowicz
David N. Herrmann
Filippo M. Santorelli
John Hardy
Katrin Bürk
Gary Gronseth
Raymond P. Roos
Hidehiro Mizusawa
Huw R. Morris
Dominique Campion
Marina Fanin
Peter M. Andersen
Christine Van Broeckhoven
Olga O. Favorova
Matthew P. Wicklund
Massimo Zeviani
Iscia Lopes-Cendes
Cyril Goizet
Hyder Azad Jinnah
Carsten G. Bonnemann
Alexander G. Bassuk
Roberto De Simone
Alfredo Brusco
Garth A. Nicholson
Shoji Tsuji
Bart P.C. van de Warrenburg
Heather Adams
Liu Lin Thio
Orhun H. Kantarci
Tom Britton
Daniela Galimberti
Jennifer Juhl Majersik
Nicole I. Wolf
Hiroshi Takashima
Jan Herman Veldink
Beate Ritz
Peter Huppke
Mary M. Reilly
Patricia Maciel
Margaret Elizabeth Ross
Christiane Reitz
Nobutaka Hattori
Brent L. Fogel
Shinichi Hirose
Elliott H. Sherr
John C. Carey
Susanne A. Schneider
Marcondes C. França Jr.
Marc W. Halterman
Geoffrey L. Heyer
Conrad Christian Weihl
Chantal M.E. Tallaksen
Pau Pastor
Owen A. Ross
Manu Sharma
Maite Mendioroz
Gabriella Silvestri
Antonio V. Delgado-Escueta
Margherita Milone
Sudha Seshadri
Alison M. Goate
David Q. Beversdorf
Roy N. Alcalay
Christopher M. Gomez
Wolfram S. Kunz
Jonathan Daniel Rohrer
Pawel P. Piotr Liberski
Henry Houlden
Giovanni Stevanin
Andrew H. Crosby
Shawn K. Westaway
Lee-Jun C. Wong
Andreas Puschmann
Naoki Suzuki
Mario Masellis
Renato Borgatti
Robert B. Weiss
Ulrike Schara
Wendy Gilmore
Roser Pons
William K. Scott
Marta San Luciano
John B. Moeschler
Mitsuhiro Kato
Simon Mead
Chantal Depondt
Marie Vidailhet
Dick Lindhout
Fanny Mochel
Emmanuelle Plaisier
Antonio Toscano
Michael C. Kruer
Jocelyn F. Laporte
Paul A. Nyquist
Nicholas E. Johnson
Michael Nalls
Han-Xiang Deng
Anne Ducros
A. James Barkovich
S. H. Subramony
Kathrin Brockmann
Ignacio F. Mata
Gerard D. Schellenberg
Marie-Christine Chartier-Harlin
Robert D.S. Pitceathly
Franziska Johanna Hopfner
Ellen Sidransky
Marka van Blitterswijk
John A. Damiano
Katell Peoc'h
Thomas Gasser
Sylvia M. Boesch
Heather C. Mefford
Stefan M. Pulst
Gianpiero Cavalleri
Kinya Ishikawa
Stephanie Baulac
Wilson Marques
Charlotte J. Sumner
Renaud Touraine
Sonja W. Scholz
Anna Bersano
Michael T. Heneka
Michael J. Chao
Timothy Lynch
Danielle M. Andrade
Jonathan L. Haines
Lars Bertram
Damien Sanlaville
Michael Farris Waters
Ammar Al-Chalabi
Cyril Mignot
Jennifer S. Yokoyama
Adriano Chio
Michel Willemsen
Kanwaljit Singh
Jason Lazarou
James J. Dowling
William D. Graf
Karen Nuytemans
Masharip Atadzhanov
Mohamad Mikati
Perry B. Shieh
Joseph Paul Taylor
Russell J. Butterfield
Ricardo Horacio Roda
Takayuki Kondo
Shakkottai G. Vikram
Cyrus Boelman
Stanley Iyadurai
Pasquale Striano
Satoshi Yamashita
Vera Fridman
Karla P. Figueroa
Tara M. Newcomb
Thomas E. Lloyd
Toni Pearson
Ingo Helbig
Angela Vincent
Andrea L. Gropman
Keith P. Van Haren
Salvador Soriano
Rainer Malik
Salvatore Spina
Steffan D. Bos
Jun Li
Jan Senderek
Lawrence Wrabetz
Ashutosh K. Mangalam
Liwen Wu
Edward C. Cooper
Noah Allan Kolb
Carly E. Siskind
Cinzia Coppola
Steven Estus
Timothy M. Shepherd
Rodolfo Savica
Rita J. Guerreiro
Jose M. Bras
Isaac Marin-Valencia
Marina Konakova
Stephanie Sherman
Julie R. Korenberg
Holly N. Cukier
Allison Ashley-Koch
David Viskochil
Fuki Marie Hisama
Stefano F. Cappa
Craig Blackstone
Donald S. McCorquodale
Susan Halloran Blanton
Maria do Carmo Costa
Goldie Smith Byrd
Josiah Leong
David G. Munoz
Anthony J. Griswold
Daniel Scoles
Alexandre de Mendonca
Kenneth Nakamura
Footnotes
Funding information and disclosures are provided at the end of the editorial. Go to Neurology.org/ng for full disclosure forms.
- Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology
This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.
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