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Estimated Familial Amyotrophic Lateral Sclerosis Proportion: A Literature Review and Meta-analysis Neurol. Genet. (IF 3.1) Pub Date : 2023-12-01 Julie Barberio, Cathy Lally, Varant Kupelian, Orla Hardiman, W. Dana Flanders
Background and Objectives Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disorder. Familial (fALS) cases are usually reported to constitute 5%–10% of all ALS cases; however, no recent literature review or meta-analysis of this proportion (referred to throughout as "proportion fALS") has been conducted. Our objective was to estimate the proportion fALS by geographic region and to assess
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A Phenotypic Atlas for Huntington Disease Based on Data From the Enroll-HD Cohort Study Neurol. Genet. (IF 3.1) Pub Date : 2023-12-01 Douglas R. Langbehn, Swati S. Sathe, Clement Loy, Cristina Sampaio, Elizabeth A. Mccusker
Background and Objectives The variable CAG repeat expansion in the huntingtin gene and its inverse relationship to motor dysfunction onset are fundamental features of Huntington disease (HD). However, the wider phenotype (including non-motor features) at particular CAG lengths, ages, and functional levels is less well-characterized. The large number of participants in the Enroll-HD observational study
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Ataxia Syndrome With Hearing Loss and Nephronophthisis Associated With a Novel Homozygous Variant in XPNPEP3 Neurol. Genet. (IF 3.1) Pub Date : 2023-12-01 Ilan Ben-Shabat, Malin Kvarnung, Wolfgang Sperker, Helene Bruhn, Anna Wredenberg, Rolf Wibom, Inger Nennesmo, Martin Engvall, Martin Paucar
Objectives Biallelic variants in XPNPEP3 are associated with a rare mitochondrial syndrome characterized by nephronophthisis leading to kidney failure, essential tremor, hearing loss, seizures, and intellectual disability. Only 2 publications on this condition are available. We report a man with a complex ataxia syndrome, hearing loss, and kidney failure associated with a new biallelic variant in XPNPEP3
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Molecular Diagnosis of Facioscapulohumeral Muscular Dystrophy in Patients Clinically Suspected of FSHD Using Optical Genome Mapping Neurol. Genet. (IF 3.1) Pub Date : 2023-12-01 Naga M. Guruju, Vanessa Jump, Richard Lemmers, Silvere Van Der Maarel, Ruby Liu, Babi R. Nallamilli, Suresh Shenoy, Alka Chaubey, Pratik Koppikar, Rajiv Rose, Satish Khadilkar, Madhuri Hegde
Background and Objectives Facioscapulohumeral muscular dystrophy (FSHD) represents the third most common muscular dystrophy in the general population and is characterized by progressive and often asymmetric muscle weakness of the face, upper extremities, arms, lower leg, and hip girdle. In FSHD type 1, contraction of the number of D4Z4 repeats to 1–10 on the chromosome 4–permissive allele (4qA) results
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Genetic Patterns of Selected Muscular Dystrophies in the Muscular Dystrophy Surveillance, Tracking, and Research Network Neurol. Genet. (IF 3.1) Pub Date : 2023-12-01 Peter B. Kang, Magali Jorand-Fletcher, Wanfang Zhang, Suzanne W. McDermott, Reba Berry, Chelsea Chambers, Kristen N. Wong, Yara Mohamed, Shiny Thomas, Y Swamy Venkatesh, Christina Westfield, Nedra Whitehead, Nicholas E. Johnson, for the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet)
Background and Objectives To report the genetic etiologies of Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle muscular dystrophy (LGMD), congenital muscular dystrophy (CMD), and distal muscular dystrophy (DD) in 6 geographically defined areas of the United States. Methods This was a cross-sectional, population-based study in which we studied the genes and variants associated with muscular dystrophy
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Adult Phenotype of SYNGAP1-DEE Neurol. Genet. (IF 3.1) Pub Date : 2023-11-17 Rong, M., Benke, T., Zulfiqar Ali, Q., Aledo-Serrano, A., Bayat, A., Rossi, A., Devinsky, O., Qaiser, F., Ali, A. S., Fasano, A., Bassett, A. S., Andrade, D. M.
Background and Objectives SYNGAP1 variants are associated with rare developmental and epileptic encephalopathies (DEEs). Although SYNGAP1-related childhood phenotypes are well characterized, the adult phenotype remains ill-defined. We sought to investigate phenotypes and outcomes in adults with SYNGAP1 variants and epilepsy. Methods Patients 18 years or older with DEE carrying likely pathogenic and
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PMPCA-Related Encephalopathy: Novel Variants, Phenotype Extension, and Mitochondrial Morphology Neurol. Genet. (IF 3.1) Pub Date : 2023-12-01 Vibhuti Rambani, Miriam Kolnikova, Michal Cagalinec, Martina Skopkova, Daniela Gasperikova
Objectives The PMPCA gene encodes the α-subunit of mitochondrial processing peptidase (α-MPP), an enzyme responsible for cleavage of nuclear-encoded mitochondrial precursor proteins after their import into mitochondria. Mutations in this gene have been described in patients with nonprogressive or slow progressive cerebellar ataxia, with variable age at onset and severity. Cerebellar atrophy and striatum
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Expanding the Clinical Spectrum of UBTF-Related Neurodevelopmental Disorder Neurol. Genet. (IF 3.1) Pub Date : 2023-11-15 Pietra, A., Palombo, F., Giannotta, M., Maffei, M., Fiorini, C., Costa, R., Cenacchi, G., Carelli, V., Cordelli, D. M., Pini, A., Garone, C.
Objectives UBTF1 gene encodes for Upstream Binding Transcription Factor, an essential protein for RNA metabolism. A recurrent de novo variant (c.628G>A; p.Glu210Lys) has recently been associated with a childhood-onset neurodegenerative disorder characterized by motor and language regression, ataxia, dystonia, and acquired microcephaly. In this study, we report the clinical, metabolic, molecular genetics
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mTOR Pathway Somatic Pathogenic Variants in Focal Malformations of Cortical Development: Novel Variants, Topographic Mapping, and Clinical Outcomes Neurol. Genet. (IF 3.1) Pub Date : 2023-10-26 Krochmalnek, E., Accogli, A., St-Onge, J., Addour-Boudrahem, N., Prakash, G., Kim, S.-H., Brunette-Clement, T., Alhajaj, G., Mougharbel, L., Bruneau, E., Myers, K. A., Dubeau, F., Karamchandani, J., Farmer, J.-P., Atkinson, J., Hall, J., Chantal Poulin, C., Rosenblatt, B., Lafond-Lapalme, J., Weil, A., Fallet-Bianco, C., Albrecht, S., Sonenberg, N., Riviere, J.-B., Dudley, R. W., Srour, M.
Background and Objectives Somatic and germline pathogenic variants in genes of the mammalian target of rapamycin (mTOR) signaling pathway are a common mechanism underlying a subset of focal malformations of cortical development (FMCDs) referred to as mTORopathies, which include focal cortical dysplasia (FCD) type II, subtypes of polymicrogyria, and hemimegalencephaly. Our objective is to screen resected
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FOLR1 Gene Variation With Adult-Onset Cerebral Folate Deficiency and Stable Clinical and MRI Features up to 2 Years Neurol. Genet. (IF 3.1) Pub Date : 2023-10-25 Manco, C., Cortese, R., Alberti, M., Bianchi, S., Monti, L., De Stefano, N., Battisti, C.
Objectives The objective of this case report was to describe the first report of FOLR1 variants associated with adult-onset paucisymptomatic leukoencephalopathy associated with cerebral folate deficiency (CFD). Methods Considering the patient's symptoms, a nonprogressive leukoencephalopathy was suspected. CSF 5-methyltetrahydrofolate levels were low (10 nmol/L, normal range 41–117). With no other identifiable
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IRF2BPL Causes Mild Intellectual Disability Followed by Late-Onset Ataxia Neurol. Genet. (IF 3.1) Pub Date : 2023-12-01 Solveig Heide, Claire-Sophie Davoine, Paulina Cunha, Clarisse Scherer-Gagou, Boris Keren, Giovanni Stevanin, Perrine Charles, Delphine Heron, Alexis Brice, Alexandra Durr
Background and Objectives Neurodevelopmental and neurodegenerative disorders have long been considered as different clinical and molecular entities, and only a few genes are known to be involved in both processes. The IRF2BPL (interferon regulatory factor 2 binding protein like) gene was implicated in a severe pediatric phenotype characterized by developmental and epileptic encephalopathy and early
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Agenesis of Pectoralis Major Muscle in Late-Onset GFPT1-Related Congenital Myasthenic Syndrome: A Case Report Neurol. Genet. (IF 3.1) Pub Date : 2023-12-01 Erika K. Williams, Cristina Shea, Paloma Gonzalez-Perez
Objectives The objective of this study was to expand the phenotypic spectrum of glutamine-fructose-6-phosphate transaminase 1 (GFPT1)–related congenital myasthenia syndrome (CMS). Methods A 61-year-old man with agenesis of the left pectoralis major muscle presented with progressive muscle weakness for a decade that transiently improved after exertion. Results His examination revealed proximal and distal
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Novel SLC13A3 Variants and Cases of Acute Reversible Leukoencephalopathy and {alpha}-Ketoglutarate Accumulation and Literature Review Neurol. Genet. (IF 3.1) Pub Date : 2023-09-26 Wong, K. N., Botto, L. D., He, M., Baker, P. R., Vanderver, A. L., Bonkowsky, J. L.
Objectives Acute reversible leukoencephalopathy with increased urinary alpha-ketoglutarate (ARLIAK) is a recently described autosomal recessive leukoencephalopathy caused by pathogenic variants in the SLC13A3 gene. ARLIAK is characterized by acute neurologic involvement, often precipitated by febrile illness, with largely reversible clinical symptoms and imaging findings. Three patients have been reported
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Biallelic SOX8 Variants Associated With Novel Syndrome With Myopathy, Skeletal Deformities, Intellectual Disability, and Ovarian Dysfunction Neurol. Genet. (IF 3.1) Pub Date : 2023-10-01 Jodi Warman-Chardon, Taila Hartley, Aren Elizabeth Marshall, Arran McBride, Madeline Couse, William Macdonald, Mellissa R.W. Mann, Pierre R. Bourque, Ari Breiner, Hanns Lochmüller, John Woulfe, Marcos Loreto Sampaio, Gerd Melkus, Bernard Brais, David A. Dyment, Kym M. Boycott, Kristin Kernohan
Background and Objectives The human genome contains ~20,000 genes, each of which has its own set of complex regulatory systems to govern precise expression in each developmental stage and cell type. Here, we report a female patient with congenital weakness, respiratory failure, skeletal dysplasia, contractures, short stature, intellectual delay, respiratory failure, and amenorrhea who presented to
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A Case of Multiple Intracranial Major Artery Stenoses With Coexisting PCSK9 p.E32K and RNF213 p.R4810K Variants Neurol. Genet. (IF 3.1) Pub Date : 2023-10-01 Kotaro Noda, Yorito Hattori, Mika Hori, Mariko Harada-Shiba, Masafumi Ihara
Objectives Familial hypercholesterolemia (FH), caused by PCSK9 p.E32K, is characterized by early-onset coronary artery disease. However, the relationship between PCSK9 p.E32K and cerebrovascular disease is unclear. One of our patients with the PCSK9 p.E32K had several intracranial artery stenoses (ICAS). The objective of this case series was to identify factors that may be associated with ICAS in the
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Cerebral Aneurysms and Recurrent TIAs in a 42-Year-Old Patient With DADA2 Mutation: A Case Report Neurol. Genet. (IF 3.1) Pub Date : 2023-10-01 Netta Agajany, Liran Horev, Netanel Agajany, Gilad Kenan
Objectives Deficiency of adenosine deaminase 2 (DADA2) is a rare, recessively inherited autoinflammatory disease with a wide clinical spectrum of manifestations, including strokes and vasculitis. Methods We report a case of a patient with DADA2 who presented with neurologic manifestations. Results A 42-year-old woman with a known diagnosis of polyarteritis nodosa experienced several episodes of TIAs
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Frequency of GAA-FGF14 Ataxia in a Large Cohort of Brazilian Patients With Unsolved Adult-Onset Cerebellar Ataxia Neurol. Genet. (IF 3.1) Pub Date : 2023-10-01 Luiz Eduardo Novis, Rodrigo S. Frezatti, David Pellerin, Pedro J. Tomaselli, Shahryar Alavi, Marcus Vinícius Della Coleta, Mariana Spitz, Marie-Josée Dicaire, Pablo Iruzubieta, José Luiz Pedroso, Orlando Barsottini, Andrea Cortese, Matt C. Danzi, Marcondes C. França, Bernard Brais, Stephan Zuchner, Henry Houlden, Salmo Raskin, Wilson Marques, Helio A. Teive
Objectives Intronic FGF14 GAA repeat expansions have recently been found to be a common cause of hereditary ataxia (GAA-FGF14 ataxia; SCA27B). The global epidemiology and regional prevalence of this newly reported disorder remain to be established. In this study, we investigated the frequency of GAA-FGF14 ataxia in a large cohort of Brazilian patients with unsolved adult-onset ataxia. Methods We recruited
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Clinical Classification of Variants in the Valosin-Containing Protein Gene Associated With Multisystem Proteinopathy Neurol. Genet. (IF 3.1) Pub Date : 2023-10-01 Marianela Schiava, Chiseko Ikenaga, Ana Topf, Marta Caballero-Ávila, Tsui-Fen Chou, Shan Li, Feng Wang, Jil Daw, Tanya Stojkovic, Rocio Villar-Quiles, Ichizo Nishino, Michio Inoue, Yukako Nishimori, Yoshihiko Saito, Masahisa Katsuno, Seiya Noda, Chihiro Ito, Mieko Otsuka, Sruthi Nahir, Georgios Manousakis, David Walk, Colin Quinn, Lindsay Alfano, Zarife Sahenk, Giorgio Tasca, Mauro Monforte, Mario
Background and Objectives Pathogenic variants in the valosin-containing protein (VCP) gene cause a phenotypically heterogeneous disorder that includes myopathy, motor neuron disease, Paget disease of the bone, frontotemporal dementia, and parkinsonism termed multisystem proteinopathy. This hallmark pleiotropy makes the classification of novel VCP variants challenging. This retrospective study describes
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Genome-wide Analysis of Motor Progression in Parkinson Disease Neurol. Genet. (IF 3.1) Pub Date : 2023-10-01 Alejandro Martínez Carrasco, Raquel Real, Michael Lawton, Regina Hertfelder Reynolds, Manuela Tan, Lesley Wu, Nigel Williams, Camille Carroll, Jean-Christophe Corvol, Michele Hu, Donald Grosset, John Hardy, Mina Ryten, Yoav Ben-Shlomo, Maryam Shoai, Huw R. Morris
Background and Objectives The genetic basis of Parkinson disease (PD) motor progression is largely unknown. Previous studies of the genetics of PD progression have included small cohorts and shown a limited overlap with genetic PD risk factors from case-control studies. Here, we have studied genomic variation associated with PD motor severity and early-stage progression in large longitudinal cohorts
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Full-length Isoform Sequencing for Resolving the Molecular Basis of Charcot-Marie-Tooth 2A Neurol. Genet. (IF 3.1) Pub Date : 2023-10-01 Andrew B. Stergachis, Elizabeth E. Blue, Madelyn A. Gillentine, Lee-Kai Wang, Ulrike Schwarze, Adriana Sedeño Cortés, Jane Ranchalis, Aimee Allworth, Austin E. Bland, Sirisak Chanprasert, Jingheng Chen, Daniel Doherty, Andrew B. Folta, Ian Glass, Martha Horike-Pyne, Alden Y. Huang, Alyna T. Khan, Kathleen A. Leppig, Danny E. Miller, Ghayda Mirzaa, Azma Parhin, Wendy H. Raskind, Elisabeth A. Rosenthal
Objectives Transcript sequencing of patient-derived samples has been shown to improve the diagnostic yield for solving cases of suspected Mendelian conditions, yet the added benefit of full-length long-read transcript sequencing is largely unexplored. Methods We applied short-read and full-length transcript sequencing and mitochondrial functional studies to a patient-derived fibroblast cell line from
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Improvement of an External Predictive Model Based on New Information Using a Synthetic Data Approach: Application to CADASIL Neurol. Genet. (IF 3.1) Pub Date : 2023-10-01 Henri Chhoa, Hugues Chabriat, Adelina Joanita Anato, Mamadou Bamba, Florent Zittoun, Sylvie Chevret, Lucie Biard
Background and Objectives Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent hereditary cerebral small vessel disease. It is caused by mutations of the NOTCH3 gene. The disease evolves progressively over decades leading to stroke, disability, cognitive decline, and functional dependency. The course and clinical severity of CADASIL
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Genomic Diagnoses for Ectopic Intracerebral Calcifications Neurol. Genet. (IF 3.1) Pub Date : 2023-10-01 Changrui Xiao, Thomas Cassini, Daniel Benavides, Anusha Ebrahim, David Adams, Camilo Toro
Background and Objectives Ectopic intracerebral calcifications (EICs) in the basal ganglia, thalamus, cerebellum, or white matter are seen in a variety of disease states or may be found incidentally on brain imaging. The clinical significance and proportion of cases attributable to an underlying genetic cause is unknown. Methods This retrospective cohort study details the clinical, imaging, and genomic
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LAMA2-Related Muscular Dystrophy Across the Life Span: A Cross-sectional Study Neurol. Genet. (IF 3.1) Pub Date : 2023-10-01 Karlijn Bouman, Jan T. Groothuis, Jonne Doorduin, Nens van Alfen, Floris E.A. Udink ten Cate, Frederik M.A. van den Heuvel, Robin Nijveldt, Erik-Jan Kamsteeg, Anne T.M. Dittrich, Jos M.T. Draaisma, Mirian C.H. Janssen, Baziel G.M. van Engelen, Corrie E. Erasmus, Nicol C. Voermans
Background and Objectives LAMA2-related muscular dystrophy (LAMA2-MD) is a rare neuromuscular disease characterized by proximal and axial muscle weakness, rigidity of the spine, scoliosis, and respiratory impairment. No curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data, and appropriate clinical and functional outcome
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CWH43 Variants Are Associated With Disease Risk and Clinical Phenotypic Measures in Patients With Normal Pressure Hydrocephalus Neurol. Genet. (IF 3.1) Pub Date : 2023-10-01 Philip W. Tipton, Merve Atik, Alexandra I. Soto-Beasley, Gregory S. Day, Sanjeet S. Grewal, Kaisorn Chaichana, Olga P. Fermo, Colleen T. Ball, Michael G. Heckman, Launia J. White, Zachary S. Quicksall, Joseph S. Reddy, Vijay K. Ramanan, Prashanthi Vemuri, Benjamin D. Elder, Nilufer Ertekin-Taner, Owen Ross, Neill Graff-Radford
Background and Objectives Variants in the CWH43 gene have been associated with normal pressure hydrocephalus (NPH). We aimed to replicate these findings, identify additional CWH43 variants, and further define the clinical phenotype associated with CWH43 variants. Methods We determined the prevalence of CWH43 variants by whole-genome sequencing (WGS) in 94 patients with NPH. The odds of having CWH43
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Phenotype Presentation and Molecular Diagnostic Yield in Non-5q Spinal Muscular Atrophy Neurol. Genet. (IF 3.1) Pub Date : 2023-08-01 Gorka Fernández-Eulate, Julian Theuriet, Christopher J. Record, Giorgia Querin, Marion Masingue, Sarah Leonard-Louis, Anthony Behin, Nadine Le Forestier, Antoine Pegat, Maud Michaud, Jean-Baptiste Chanson, Aleksandra Nadaj-Pakleza, Celine Tard, Anne-Laure Bedat-Millet, Guilhem Sole, Marco Spinazzi, Emmanuelle Salort-Campana, Andoni Echaniz-Laguna, Vianney Poinsignon, Philippe Latour, Mary M. Reilly
Background and Objectives Spinal muscular atrophy (SMA) is mainly caused by homozygous SMN1 gene deletions on 5q13. Non-5q SMA patients’ series are lacking, and the diagnostic yield of next-generation sequencing (NGS) is largely unknown. The aim of this study was to describe the clinical and genetic landscape of non-5q SMA and evaluate the performance of neuropathy gene panels in these disorders. Methods
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Ataxia and Diplopia: A New SCN8A-Related Phenotype Neurol. Genet. (IF 3.1) Pub Date : 2023-08-01 Alexandra Laliberté, Kenneth A. Myers
Objectives The objective of this study was to describe the first patient with recurrent ataxia and diplopia in association with a pathogenic variant in SCN8A. Methods We identified a girl with a heterozygous SCN8A pathogenic variant and performed thorough phenotyping. Results A 10-year-old girl was previously well with normal intelligence. She had recurrent diplopia, dysmetria, and unsteady gait, which
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Longitudinal Analysis of Respiratory Function of Different Types of Limb Girdle Muscular Dystrophies Reveals Independent Trajectories Neurol. Genet. (IF 3.1) Pub Date : 2023-08-01 Robert Muni-Lofra, Eduard Juanola-Mayos, Marianela Schiava, Dionne Moat, Maha Elseed, Jassi Michel-Sodhi, Elizabeth Harris, Michelle McCallum, Ursula Moore, Mark Richardson, Christina Trainor, Karen Wong, Monika Malinova, Carla Bolano-Diaz, Michael John Keogh, Elisabetta Ghimenton, Jose Verdu-Diaz, Anna Mayhew, Michela Guglieri, Volker Straub, Meredith K. James, Chiara Marini-Bettolo, Jordi Diaz-Manera
Background and Objectives The prevalence and progression of respiratory muscle dysfunction in patients with limb girdle muscular dystrophies (LGMDs) has been only partially described to date. Most reports include cross-sectional data on a limited number of patients making it difficult to gain a wider perspective on respiratory involvement throughout the course of the disease and to compare the most
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Clinicoradiologic Criteria for the Diagnosis of Stroke-like Episodes in MELAS Neurol. Genet. (IF 3.1) Pub Date : 2023-08-01 Vadim Khasminsky, Eitan Auriel, Judith Luckman, Ruth Eliahou, Edna Inbar, Keshet Pardo, Yuval Landau, Rani Barnea, Maor Mermelstein, Shahar Shelly, Jonathan Naftali, Shlomi Peretz
Background and Objectives Stroke-like episodes (SLEs) in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome are often misdiagnosed as acute ischemic stroke (AIS). We aimed to determine unique clinical and neuroimaging features for SLEs and formulate diagnostic criteria. Methods We retrospectively identified patients with MELAS admitted for SLEs
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Identification of an 85-kb Heterozygous 4p Microdeletion With Full Genome Analysis in Autosomal Dominant Charcot-Marie-Tooth Disease Neurol. Genet. (IF 3.1) Pub Date : 2023-08-01 Hsueh Wen Hsueh, Hsiao-Jung Kao, Chi-Chao Chao, Sung-Ju Hsueh, Yu-Ning Huang, Wan-Jia Lin, Jen-Ping Su, Horng-Tzer Shy, Ti-Yen Yeh, Cheng-Chen Lin, Pui-Yan Kwok, Ni-Chung Lee, Sung-Tsang Hsieh
Background and Objectives Charcot-Marie-Tooth disease (CMT) is a syndrome of a hereditary neurodegenerative condition affecting the peripheral nervous system and is a single gene disorder. Deep phenotyping coupled with advanced genetic techniques is critical in discovering new genetic defects of rare genetic disorders such as CMT. Methods We applied multidisciplinary investigations to examine the neurophysiology
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Analysis of Structural Variants Previously Associated With ALS in Europeans Highlights Genomic Architectural Differences in Africans Neurol. Genet. (IF 3.1) Pub Date : 2023-08-01 Nomakhosazana R. Monnakgotla, Amokelani C. Mahungu, Jeannine M. Heckmann, Gerrit Botha, Nicola J. Mulder, Gang Wu, Evadnie Rampersaud, Jason Myers, Marka Van Blitterswijk, Rosa Rademakers, J. Paul Taylor, Joanne Wuu, Michael Benatar, Melissa Nel
Background and Objectives Amyotrophic lateral sclerosis (ALS) is a degenerative condition of the brain and spinal cord in which protein-coding variants in known ALS disease genes explain a minority of sporadic cases. There is a growing interest in the role of noncoding structural variants (SVs) as ALS risk variants or genetic modifiers of ALS phenotype. In small European samples, specific short SV
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Systemic Capillary Leak Syndrome With Cerebral Involvement in a C9orf72 Expansion Carrier: Case Report and Review of the Literature Neurol. Genet. (IF 3.1) Pub Date : 2023-08-01 Stefan Sennfält, Oskar Aspegren, Martin Engvall, Tobias Granberg, Fredrik Piehl
Objective Systemic capillary leak syndrome (SCLS) is a rare condition associated with episodes of hypotension, hemoconcentration, hypoalbuminemia, and rhabdomyolysis. We describe a middle-aged man presenting with several distinct SCLS-like episodes, the last being fatal. In addition, in the year before the final event, he developed rapid cognitive decline with contrast-enhancing lesions on MRI and
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Cumulative Genetic Score and C9orf72 Repeat Status Independently Contribute to Amyotrophic Lateral Sclerosis Risk in 2 Case-Control Studies Neurol. Genet. (IF 3.1) Pub Date : 2023-08-01 John Dou, Kelly Bakulski, Kai Guo, Junguk Hur, Lili Zhao, Sara Saez-Atienzar, Ali Stark, Ruth Chia, Alberto García-Redondo, Ricardo Rojas-Garcia, Juan Francisco Vázquez Costa, Ruben Fernandez Santiago, Sara Bandres-Ciga, Pilar Gómez-Garre, Maria Teresa Periñán, Pablo Mir, Jordi Pérez-Tur, Fernando Cardona, Manuel Menendez-Gonzalez, Javier Riancho, Daniel Borrego-Hernández, Lucia Galán-Dávila, Jon Infante
Background and Objectives Most patients with amyotrophic lateral sclerosis (ALS) lack a monogenic mutation. This study evaluates ALS cumulative genetic risk in an independent Michigan and Spanish replication cohort using polygenic scores. Methods Participant samples from University of Michigan were genotyped and assayed for the chromosome 9 open reading frame 72 hexanucleotide expansion. Final cohort
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Complex 4q35 and 10q26 Rearrangements: A Challenge for Molecular Diagnosis of Patients With Facioscapulohumeral Dystrophy Neurol. Genet. (IF 3.1) Pub Date : 2023-06-01 Megane Delourme, Chaix Charlene, Laurene Gerard, Benjamin Ganne, Pierre Perrin, Catherine Vovan, Karine Bertaux, Karine Nguyen, Rafaëlle Bernard, Frederique Magdinier
Background and Objectives After clinical evaluation, the molecular diagnosis of type 1 facioscapulohumeral dystrophy (FSHD1) relies in most laboratories on the detection of a shortened D4Z4 array at the 4q35 locus by Southern blotting. In many instances, this molecular diagnosis remains inconclusive and requires additional experiments to determine the number of D4Z4 units or identify somatic mosaicism
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Autosomal Recessive Spinocerebellar Ataxia Type 9 With a Response to Phosphate Repletion: A Case Report Neurol. Genet. (IF 3.1) Pub Date : 2023-06-01 Shotaro Haji, Ryosuke Miyamoto, Hiroyuki Morino, Yusuke Osaki, Seijiro Tsuji, Ichizo Nishino, Masahiro Abe, Yuishin Izumi
Objective Autosomal recessive spinocerebellar ataxia type 9 (SCAR9) has received attention due to its potential response to coenzyme Q10 (CoQ10) supplementation; however, the response has so far been limited and variable. Methods We report a SCAR9 patient with severe hypophosphatemia who responded well to CoQ10 and phosphate repletion. Results A 70-year-old man (the offspring of a consanguineous marriage)
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Metabolic Stroke as a Clinical Manifestation of Zhu-Tokita-Takenouchi-Kim Syndrome: A Case Series Neurol. Genet. (IF 3.1) Pub Date : 2023-06-01 Angie El-Said, Jorge Luis Morales, Gian Rossi, Neha Longani
Objective This study reports 2 unrelated individuals with Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome who presented with a metabolic stroke, which has not been commonly reported as a clinical manifestation of this syndrome. Methods Two female children were identified after presenting to our institution with a metabolic stroke and carried a diagnosis of ZTTK syndrome because of their clinical characteristics
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CircPDS5B Reduction Improves Angiogenesis Following Ischemic Stroke by Regulating MicroRNA-223-3p/NOTCH2 Axis Neurol. Genet. (IF 3.1) Pub Date : 2023-06-01 Ling Kui, Zongyu Li, Guoyun Wang, Xuzhen Li, Feng Zhao, Yinming Jiao
Background and Objectives Ischemic stroke (IS) is responsible for major causes of global death and disability, for which promoting angiogenesis is a promising therapeutic strategy. This study analyzed circular RNA PDS5B (circPDS5B) and its related mechanisms in angiogenesis in IS. Methods In the permanent middle cerebral artery occlusion (pMCAO) mouse model, circPDS5B, microRNA (miR)-223-3p, and NOTCH2
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Machine Learning Approach for the Prediction of Age-Specific Probability of SCA3 and DRPLA by Survival Curve Analysis Neurol. Genet. (IF 3.1) Pub Date : 2023-06-01 Yuya Hatano, Tomohiko Ishihara, Sachiko Hirokawa, Osamu Onodera
Background and Objectives As the number of repeats in the expansion increases, polyglutamine diseases tend to show at a younger age. From this relationship, attempts have been made to predict age at onset by parametric survival analysis. However, a method for a more accurate prediction has been desirable. In this study, we examined 2 methods for survival analysis using machine learning and 6 conventional
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Acknowledgment to Reviewers Neurol. Genet. (IF 3.1) Pub Date : 2023-06-01 Stefan M. Pulst
On behalf of all handling editors we wish to acknowledge the individuals who have completed reviews for the journal from January 2022 until February 28, 2023. The thoughtful comments and insights are essential for scientific publishing, highly appreciated, and imperative for excellence in the field of neurogenetics. We are also grateful for your cooperation in returning reviews in a timely manner.
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Exome Sequencing and Multigene Panel Testing in 1,411 Patients With Adult-Onset Neurologic Disorders Neurol. Genet. (IF 3.1) Pub Date : 2023-06-01 Nika Schuermans, Hannah Verdin, Jody Ghijsels, Madeleine Hellemans, Elke Debackere, Elke Bogaert, Sofie Symoens, Leslie Naesens, Elien Lecomte, David Crosiers, Bruno Bergmans, Kristof Verhoeven, Bruce Poppe, Guy Laureys, Sarah Herdewyn, Tim Van Langenhove, Patrick Santens, Jan L. De Bleecker, Dimitri Hemelsoet, Bart Dermaut, for Program for Undiagnosed Rare Diseases (UD-PrOZA)
Background and Objectives Owing to their extensive clinical and molecular heterogeneity, hereditary neurologic diseases in adults are difficult to diagnose. The current knowledge about the diagnostic yield and clinical utility of exome sequencing (ES) for neurologic diseases in adults is limited. This observational study assesses the diagnostic value of ES and multigene panel analysis in adult-onset
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Distinguishing Loss-of-Function and Gain-of-Function SCN8A Variants Using a Random Forest Classification Model Trained on Clinical Features Neurol. Genet. (IF 3.1) Pub Date : 2023-06-01 Joshua B. Hack, Kyle Horning, Denise M. Juroske Short, John M. Schreiber, Joseph C. Watkins, Michael F. Hammer
Background and Objectives Pathogenic variants at the voltage-gated sodium channel gene, SCN8A, are associated with a wide spectrum of clinical disease outcomes. A critical challenge for neurologists is to determine whether patients carry gain-of-function (GOF) or loss-of-function (LOF) variants to guide treatment decisions, yet in vitro studies to infer channel function are often not feasible in the
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Parent-of-Origin Effect on the Age at Symptom Onset in Myotonic Dystrophy Type 2 Neurol. Genet. (IF 3.1) Pub Date : 2023-06-01 Paloma Gonzalez-Perez, Eleonora S. D'Ambrosio, Vincent Picher-Martel, Kathy Chuang, William S. David, Anthony A. Amato
Background and Objectives The existence of clinical anticipation, congenital form, and parent-of-origin effect in myotonic dystrophy type 2 (DM2) remains uncertain. Here, we aimed at investigating whether there is a parent-of-origin effect on the age at the first DM2-related clinical manifestation. Methods We identified patients with genetically confirmed DM2 with known parental inheritance from (1)
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Identifying Aging and Alzheimer Disease-Associated Somatic Variations in Excitatory Neurons From the Human Frontal Cortex Neurol. Genet. (IF 3.1) Pub Date : 2023-06-01 Meng Zhang, Gerard A. Bouland, Henne Holstege, Marcel J.T. Reinders
Background and Objectives With age, somatic mutations accumulated in human brain cells can lead to various neurologic disorders and brain tumors. Because the incidence rate of Alzheimer disease (AD) increases exponentially with age, investigating the association between AD and the accumulation of somatic mutation can help understand the etiology of AD. Methods We designed a somatic mutation detection
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Extension of the Clinicoradiologic Spectrum of Newly Described End-Truncating LAMB1 Variations Neurol. Genet. (IF 3.1) Pub Date : 2023-06-01 Hélène Morel, Laurent Bailly, Cédric Urbanczyk, Dominique Hervé, Stéphane Berroir, Raphaël Le Bouc, Richard Levy, Mylène Meyer, Chaker Aloui, Elisabeth Tournier-Lasserve, Guillaume Mathey
Objectives To refine the clinical spectrum of a very recently identified phenotype associated with LAMB1 end-truncating pathogenic variations. Methods Detailed clinical, neuropsychological, and MRI investigation of 6 patients from 2 unrelated families segregating end-truncating LAMB1 variations. Results All patients harbored a LAMB1 end-truncating pathogenic variation. The specific association of a
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SON-Related Zhu-Tokita-Takenouchi-Kim Syndrome With Recurrent Hemiplegic Migraine: Putative Role of PRRT2 Neurol. Genet. (IF 3.1) Pub Date : 2023-06-01 Jordan Langford, Lana Vukadin, John C. Carey, Lorenzo D. Botto, Matt Velinder, Rong Mao, Christine E. Miller, Francis Filloux, Eun-Young Erin Ahn
Background and Objectives Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome (OMIM 617140) is a recently identified neurodevelopmental disorder caused by heterozygous loss-of-function (LoF) variants in SON. Because the SON protein functions as an RNA-splicing regulator, it has been shown that some clinical features of ZTTK syndrome can be attributed to abnormal RNA splicing. Several neurologic features have
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Cerebellar Ataxia and Peripheral Neuropathy in a Family With PNPLA8-Associated Disease Neurol. Genet. (IF 3.1) Pub Date : 2023-06-01 Birute Burnyte, Ramune Vilimiene, Kristina Grigalioniene, Irina Adomaitiene, Algirdas Utkus
Objectives To describe clinical and genetic findings in 2 siblings with slowly progressive ataxia. Methods We studied 2 adult siblings through detailed physical and instrumental examinations. Whole-exome sequencing was used to identify an underlying genetic cause. Results Both siblings presented with adolescence-onset ataxia, progressive sensorimotor polyneuropathy, and preserved cognition over time
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A Phase 1 Study of Oral Vitamin D3 in Boys and Young Men With X-Linked Adrenoleukodystrophy Neurol. Genet. (IF 3.1) Pub Date : 2023-04-01 Keith P. Van Haren, Kristen Cunanan, Avni Awani, Meng Gu, Dalia Peña, Lindsay C. Chromik, Michal Považan, Nicole C. Rossi, Jordan Goodman, Vandana Sundaram, Jennifer Winterbottom, Gerald V. Raymond, Tina Cowan, Gregory M. Enns, Emmanuelle Waubant, Lawrence Steinman, Peter B. Barker, Daniel Spielman, Ali Fatemi
Background and Objectives There are no therapies for preventing cerebral demyelination in X-linked adrenoleukodystrophy (ALD). Higher plasma vitamin D levels have been linked to lower risk of inflammatory brain lesions. We assessed the safety and pharmacokinetics of oral vitamin D dosing regimens in boys and young men with ALD. Methods In this open-label, multicenter, phase 1 study, we recruited boys
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Novel SERAC1 Variant Presenting With Adult-Onset Extrapyramidal Dystonia-Parkinsonism Phenotype: A Case Report Neurol. Genet. (IF 3.1) Pub Date : 2023-04-01 Catherine Ashton, Mark Davis, Nigel Laing, Gianina Ravenscroft, Philippa Lamont
Objectives To report a novel likely pathogenic variant in the SERAC1 gene associated with early adult-onset parkinsonism and progressive dystonia. Methods Clinical, biochemical, and imaging assessments were performed on 2 affected adult brothers with a genetically unsolved progressive neurologic disorder followed by whole-genome sequencing. Results A homozygous likely pathogenic variant in the SERAC1
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New-Onset Refractory Status Epilepticus Due to a Novel MT-TF Variant: Time for Acute Genetic Testing Before Treatment? Neurol. Genet. (IF 3.1) Pub Date : 2023-04-01 Elisabetta Indelicato, Johannes Pfeilstetter, Michael Zech, Iris Unterberger, Julia Wanschitz, Steffen Berweck, Sylvia Boesch
Objective The gene MT-TF encodes the mitochondrial tRNA of phenylalanine (tRNAphe). Its variations have been described as extremely rare etiologies of a variety of mitochondrial phenotypes. Methods By means of whole-exome sequencing (WES), we detected a novel likely causative MT-TF variant (m.610T>C) in a family presenting with a combined movement disorder and epilepsy phenotype. The variant was present
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Transcriptome and Genome Analysis Uncovers a DMD Structural Variant: A Case Report Neurol. Genet. (IF 3.1) Pub Date : 2023-04-01 Chiara Folland, Vijay Ganesh, Ben Weisburd, Catriona McLean, Andrew J. Kornberg, Anne O'Donnell-Luria, Heidi L. Rehm, Igor Stevanovski, Sanjog R. Chintalaphani, Paul Kennedy, Ira W. Deveson, Gianina Ravenscroft
Objective Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the dystrophin gene (DMD). Hypermethylated CGG expansions within DIP2B 5' UTR are associated with an intellectual development disorder. Here, we demonstrate the diagnostic utility of genomic short-read sequencing (SRS) and transcriptome sequencing to identify a novel DMD structural variant (SV) and a DIP2B CGG expansion
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Whole-Exome Sequencing Study of Fibroblasts Derived From Patients With Cerebellar Ataxia Referred to Investigate CoQ10 Deficiency Neurol. Genet. (IF 3.1) Pub Date : 2023-03-14 Monfrini, E., Pesini, A., Biella, F., Sobreira, C. F. R., Emmanuele, V., Brescia, G., Lopez, L. C., Tadesse, S., Hirano, M., Comi, G. P., Quinzii, C. M., Di Fonzo, A.
Background and Objectives Coenzyme Q10 (CoQ10)–deficient cerebellar ataxia can be due to pathogenic variants in genes encoding for CoQ10 biosynthetic proteins or associated with defects in protein unrelated to its biosynthesis. Diagnosis is crucial because patients may respond favorably to CoQ10 supplementation. The aim of this study was to identify through whole-exome sequencing (WES) the pathogenic
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Clinical Features and Classification of Neuronal Intranuclear Inclusion Disease Neurol. Genet. (IF 3.1) Pub Date : 2023-04-01 Hongfei Tai, An Wang, Yumei Zhang, Shaocheng Liu, Yunzhu Pan, Kai Li, Guixian Zhao, Mengwen Wang, Guode Wu, Songtao Niu, Hua Pan, Bin Chen, Wei Li, Xingao Wang, Gehong Dong, Wei Li, Ying Zhang, Sheng Guo, Xiaoyun Liu, Mingxia Li, Hui Liang, Ming Huang, Wei'an Chen, Zaiqiang Zhang
Background and Objectives Neuronal intranuclear inclusion body disease (NIID) is a neurodegenerative disease with highly heterogeneous clinical manifestations. The present study aimed to characterize clinical features and propose a classification system based on a large cohort of NIID in China. Methods The Chinese NIID registry was launched from 2017, and participants' demographics and clinical features
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Copy Number Variant Analysis of Spinocerebellar Ataxia Genes in a Cohort of Dutch Patients With Cerebellar Ataxia Neurol. Genet. (IF 3.1) Pub Date : 2023-02-01 Fatemeh Ghorbani, Eddy N. de Boer, Marloes Benjamins-Stok, Corien C. Verschuuren-Bemelmans, Jurjen Knapper, Jelkje de Boer-Bergsma, Jeroen J. de Vries, Birgit Sikkema-Raddatz, Dineke S. Verbeek, Helga Westers, Cleo C. van Diemen
Background and Objectives The spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of neurodegenerative disorders generally caused by single nucleotide variants (SNVs) or indels in coding regions or by repeat expansions in coding and noncoding regions of SCA genes. Copy number variants (CNVs) have now also been reported for 3 genes—ITPR1, FGF14, and SPTBN2—but not all SCA genes have
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Genetic Risk for Alzheimer Disease and Plasma Tau Are Associated With Accelerated Parietal Cortex Thickness Change in Middle-Aged Adults Neurol. Genet. (IF 3.1) Pub Date : 2023-02-01 Jasmeet Pannu Hayes, Meghan E. Pierce, Emma Brown, David Salat, Mark W. Logue, Julie Constantinescu, Kate Valerio, Mark W. Miller, Richard Sherva, Bertrand Russell Huber, William Milberg, Regina McGlinchey
Background and Objectives Neuroimaging and biomarker studies in Alzheimer disease (AD) have shown well-characterized patterns of cortical thinning and altered biomarker concentrations of tau and β-amyloid (Aβ). However, earlier identification of AD has great potential to advance clinical care and determine candidates for drug trials. The extent to which AD risk markers relate to cortical thinning patterns
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Clinical Manifestation of Nebulin-Associated Nemaline Myopathy Neurol. Genet. (IF 3.1) Pub Date : 2023-02-01 Cristiane Araujo Martins Moreno, Mariana Cunha Artilheiro, Alulin Tacio Quadros Santos Monteiro Fonseca, Clara Gontijo Camelo, Gisele Chagas de Medeiros, Fernanda Chiarion Sassi, Claudia Regina Furquim de Andrade, Sandra Donkervoort, Andre Macedo Serafim Silva, Luiz Dalfior-Junior, Osorio Lopes Abath-Neto, Umbertina Conti Reed, Carsten Bönnemann, Edmar Zanoteli
Background and Objectives Nemaline myopathy (NM) is a genetically heterogeneous inherited myopathy related with at least 12 genes, whereas pathogenic variants in NEB gene are the most common genetic cause. The clinical spectrum of NM caused by NEB pathogenic variants (NM-NEB) is very broad, ranging from mild to severe presentations manifesting with generalized weakness, as well as respiratory and bulbar
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Novel Homozygous Variant in COQ7 in Siblings With Hereditary Motor Neuropathy Neurol. Genet. (IF 3.1) Pub Date : 2023-02-01 Ian C. Smith, Chantal A. Pileggi, Ying Wang, Kristin Kernohan, Taila Hartley, Hugh J. McMillan, Marcos Loreto Sampaio, Gerd Melkus, John Woulfe, Gaganvir Parmar, Pierre R. Bourque, Ari Breiner, Jocelyn Zwicker, C. Elizabeth Pringle, Olga Jarinova, Hanns Lochmüller, David A. Dyment, Bernard Brais, Kym M. Boycott, for the Care4Rare Canada Consortium,, Siegfried Hekimi, Mary-Ellen Harper, Jodi Warman-Chardon
Background and Objectives Coenzyme Q10 (CoQ10) is an important electron carrier and antioxidant. The COQ7 enzyme catalyzes the hydroxylation of 5-demethoxyubiquinone-10 (DMQ10), the second-to-last step in the CoQ10 biosynthesis pathway. We report a consanguineous family presenting with a hereditary motor neuropathy associated with a homozygous c.1A > G p.? variant of COQ7 with abnormal CoQ10 biosynthesis
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Expanding the Allelic Heterogeneity of ANO10-Associated Autosomal Recessive Cerebellar Ataxia Neurol. Genet. (IF 3.1) Pub Date : 2023-02-01 Sean Massey, Yiran Guo, Lisa G. Riley, Nicole J. Van Bergen, Sarah A. Sandaradura, Elizabeth McCusker, Michel Tchan, Christel Thauvin-Robinet, Quentin Thomas, Thibault Moreau, Mark Davis, Daphne Smits, Grazia M.S. Mancini, Hakon Hakonarson, Sandra Cooper, John Christodoulou
Background and Objectives The term autosomal recessive cerebellar ataxia (ARCA) encompasses a diverse group of heterogeneous degenerative disorders of the cerebellum. Spinocerebellar ataxia autosomal recessive 10 (SCAR10) is a distinct classification of cerebellar ataxia caused by variants in the ANO10 gene. Little is known about the molecular role of ANO10 or its role in disease. There is a wide phenotypic
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Neurologic, Neuropsychologic, and Neuroradiologic Features of EBF3-Related Syndrome Neurol. Genet. (IF 3.1) Pub Date : 2023-01-23 Ciaccio, C., Pantaleoni, C., Moscatelli, M., Chiapparini, L., Nigro, V., Valente, E. M., Sciacca, F., Canafoglia, L., Bulgheroni, S., D'Arrigo, S.
Background and Objectives Heterozygous mutations or deletions of the EBF3 gene are known to cause a syndrome characterized by intellectual disability, neurodevelopmental disorders, facial dysmorphisms, hypotonia, and ataxia; the latter is quite common despite in most patients brain MRI is reported to be normal. Despite the predominant neurologic involvement of EBF3-related syndrome, a systematic definition
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Neuropathology-Independent Association Between APOE Genotype and Cognitive Decline Rate in the Normal Aging-Early Alzheimer Continuum Neurol. Genet. (IF 3.1) Pub Date : 2023-02-01 Jing Qian, Yiding Zhang, Rebecca A. Betensky, Bradley T. Hyman, Alberto Serrano-Pozo
Background and Objectives We previously found that the APOE genotype affects the rate of cognitive decline in mild-to-moderate Alzheimer disease (AD) dementia independently of its effects on AD neuropathologic changes (ADNC) and copathologies. In this study, we tested the hypothesis that the APOE alleles differentially affect the rate of cognitive decline at the normal aging-early AD continuum and
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High-Depth PRNP Sequencing in Brains With Sporadic Creutzfeldt-Jakob Disease Neurol. Genet. (IF 3.1) Pub Date : 2023-02-01 Alexander G. Murley, Yu Nie, Zoe Golder, Michael John Keogh, Colin Smith, James W. Ironside, Patrick F. Chinnery
Background and Objectives Sporadic Creutzfeldt-Jakob disease (sCJD) has established genetic risk factors, but, in contrast to genetic and acquired CJD, the initial trigger for misfolded prion aggregation and spread is not known. In this study, we tested the hypotheses that pathologic somatic variants in the prion gene PRNP are increased in sCJD, potentially leading to the seeding of misfolded prion
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Prevalence of Frontotemporal Dementia in Females of 5 Hispanic Families With R159H VCP Multisystem Proteinopathy Neurol. Genet. (IF 3.1) Pub Date : 2023-01-11 Shmara, A., Gibbs, L., Mahoney, R. P., Hurth, K., Goodwill, V. S., Cuber, A., Im, R., Pizzo, D. P., Brown, J., Laukaitis, C., Mahajan, S., Kimonis, V.
Background and Objectives Missense variants of the valosin-containing protein (VCP) gene cause a progressive, autosomal dominant disease termed VCP multisystem proteinopathy (MSP1). The disease is a constellation of clinical features including inclusion body myopathy (IBM), Paget disease of bone (PDB), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS), typically reported at a frequency