Hereditary motor neuropathies

Purpose of review Distal hereditary motor neuropathies (dHMN) are a clinically and genetically diverse group of disorders that are characterized by length-dependent axonal degeneration of lower motor neurons. In this review, we will provide an overview of dHMN, and we will correlate the distinct clinical subtypes with their causative genes, focusing on the most recent advances in the field. Recent findings Despite the massive use of new-generation sequencing (NGS) and the discovery of new genes, only a third of dHMN patients receive a molecular diagnosis. Thanks to international cooperation between researchers, new genes have been implicated in dHMN, such as SORD and VWA1. Mutations in SORD are the most frequent cause of autosomal recessive forms of dHMN. As a result of these findings, the potential benefits of some pharmacological compounds are being studied in cell and animal models, mainly targeting axonal transport and metabolic pathways. Summary Despite the wide use of NGS, the diagnosis of dHMN remains a challenge. The low prevalence of dHMN makes international cooperation necessary in order to discover new genes and causal mechanisms. Genetic diagnosis of patients and identification of new pathomechanism are essential for the development of therapeutical clinical trials.

[1]  M. Reilly,et al.  Unusual upper limb features in SORD neuropathy , 2022, Journal of the peripheral nervous system : JPNS.

[2]  Jing-Xue Ma,et al.  GGC repeat expansions in NOTCH2NLC causing a phenotype of lower motor neuron syndrome , 2022, Journal of Neurology.

[3]  W. Wiszniewski,et al.  Pathogenic missense variants altering codon 336 of GARS1 lead to divergent dominant phenotypes , 2022, Human mutation.

[4]  Jianwen Deng,et al.  Genetic spectrum in a cohort of patients with distal hereditary motor neuropathy , 2022, Annals of clinical and translational neurology.

[5]  D. Pareyson,et al.  DNAJB2‐related Charcot‐Marie‐Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening , 2022, European journal of neurology.

[6]  W. Son,et al.  Genetic and Clinical Studies of Peripheral Neuropathies with Three Small Heat Shock Protein Gene Variants in Korea , 2022, Genes.

[7]  Byung-Ok Choi,et al.  Wide Phenotypic Spectrum of PNMHH Patients With p.R941L Mutation in MYH14 , 2022, Journal of clinical neurology.

[8]  He He,et al.  CHCHD2 and CHCHD10 regulate mitochondrial dynamics and integrated stress response , 2022, Cell Death & Disease.

[9]  Jennifer Hesson,et al.  HDAC6 Inhibition Corrects Electrophysiological and Axonal Transport Deficits in a Human Stem Cell-Based Model of Charcot-Marie-Tooth Disease (Type 2D). , 2021, Advanced biology.

[10]  Mubalake Yilihamu,et al.  Clinical and Genetic Features of Biallelic Mutations in SORD in a Series of Chinese Patients With Charcot-Marie-Tooth and Distal Hereditary Motor Neuropathy , 2021, Frontiers in Neurology.

[11]  Muntoni Francesco,et al.  Muscle “islands”: an MRI signature distinguishing neurogenic from myopathic causes of early onset distal weakness , 2021, Neuromuscular Disorders.

[12]  D. Pareyson,et al.  Challenges in Treating Charcot-Marie-Tooth Disease and Related Neuropathies: Current Management and Future Perspectives , 2021, Brain sciences.

[13]  Z. Sahenk,et al.  AAV1.NT-3 gene therapy in a CMT2D model: phenotypic improvements in GarsP278KY/+ mice , 2021, Brain communications.

[14]  M. Reilly,et al.  Neurogenic arthrogryposis and the power of phenotyping , 2021, Neuromuscular Disorders.

[15]  D. Hill,et al.  The integrated stress response contributes to tRNA synthetase–associated peripheral neuropathy , 2021, Science.

[16]  R. Burgess,et al.  tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase , 2021, Science.

[17]  C. Espinós,et al.  Pediatric inherited peripheral neuropathy: a prospective study at a Spanish referral center , 2021, Annals of clinical and translational neurology.

[18]  H. Lv,et al.  GGC repeat expansions in NOTCH2NLC causing a phenotype of distal motor neuropathy and myopathy , 2021, Annals of clinical and translational neurology.

[19]  N. Bresolin,et al.  Charcot–Marie–Tooth disease type 2F associated with biallelic HSPB1 mutations , 2021, Annals of clinical and translational neurology.

[20]  P. Seeman,et al.  Biallelic variants in the SORD gene are one of the most common causes of hereditary neuropathy among Czech patients , 2021, Scientific Reports.

[21]  Yoan Arribat,et al.  Genetic alterations of VWA1: a new link between extracellular matrix and neuromuscular diseases. , 2021, Brain : a journal of neurology.

[22]  Katherine R. Smith,et al.  An ancestral 10-bp repeat expansion in VWA1 causes recessive hereditary motor neuropathy , 2021, Brain : a journal of neurology.

[23]  B. Schlotter-Weigel,et al.  Bi-allelic truncating mutations in VWA1 cause neuromyopathy. , 2021, Brain : a journal of neurology.

[24]  Hai-Lin Dong,et al.  Biallelic SORD pathogenic variants cause Chinese patients with distal hereditary motor neuropathy , 2021, NPJ genomic medicine.

[25]  A. Pagnamenta,et al.  Presynaptic congenital myasthenic syndrome due to three novel mutations in SLC5A7 encoding the sodium-dependant high-affinity choline transporter , 2020, Neuromuscular Disorders.

[26]  OUP accepted manuscript , 2021, Brain Communications.

[27]  R. Rojas-García,et al.  Distal hereditary motor neuropathies: Mutation spectrum and genotype–phenotype correlation , 2020, European journal of neurology.

[28]  J. Baets,et al.  The expanding genetic landscape of hereditary motor neuropathies. , 2020, Brain : a journal of neurology.

[29]  A. Poliakov,et al.  Identification of a Novel de Novo Variant in the SYT2 Gene Causing a Rare Type of Distal Hereditary Motor Neuropathy , 2020, Genes.

[30]  E. Puffenberger,et al.  De Novo and Inherited Variants in GBF1 are Associated with Axonal Neuropathy Caused by Golgi Fragmentation , 2020, The American Journal of Human Genetics.

[31]  M. Saporta,et al.  Hereditary motor neuropathies , 2020, Current opinion in neurology.

[32]  Dana M. Bis-Brewer,et al.  Assessing non-Mendelian Inheritance in Inherited Axonopathies , 2020, Genetics in Medicine.

[33]  T. Bird,et al.  Mutations in the SIGMAR1 gene cause a distal hereditary motor neuropathy phenotype mimicking ALS: Report of two novel variants , 2020, Neuromuscular Disorders.

[34]  L. Armengol,et al.  VRK1 (Y213H) homozygous mutant impairs Cajal bodies in a hereditary case of distal motor neuropathy , 2020, Annals of clinical and translational neurology.

[35]  Dana M. Bis-Brewer,et al.  Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes , 2020, Nature Genetics.

[36]  V. Timmerman,et al.  Small heat shock proteins in neurodegenerative diseases , 2020, Cell Stress and Chaperones.

[37]  A. López de Munain,et al.  Phenotypic correlations in a large single‐center cohort of patients with BSCL2 nerve disorders: a clinical, neurophysiological and muscle magnetic resonance imaging study , 2020, European journal of neurology.

[38]  D. Fan,et al.  Molecular analysis and clinical diversity of distal hereditary motor neuropathy , 2020, European journal of neurology.

[39]  R. Ghosh,et al.  GARS‐related disease in infantile spinal muscular atrophy: Implications for diagnosis and treatment , 2020, American journal of medical genetics. Part A.

[40]  C. Espinós,et al.  Clinical spectrum of BICD2 mutations , 2020, European journal of neurology.

[41]  B. Udd,et al.  Neuromuscular Diseases Due to Chaperone Mutations: A Review and Some New Results , 2020, International journal of molecular sciences.

[42]  A. Guglielmi.  A complete overview of REEP1: old and new insights on its role in hereditary spastic paraplegia and neurodegeneration , 2020, Reviews in the neurosciences.

[43]  Jinzhong Lin,et al.  SIRT2‐knockdown rescues GARS‐induced Charcot‐Marie‐Tooth neuropathy , 2019, bioRxiv.

[44]  M. Devoto,et al.  Expanding the spectrum of genes responsible for hereditary motor neuropathies , 2019, Journal of Neurology, Neurosurgery, and Psychiatry.

[45]  T. Taniwaki,et al.  TDRKH is a candidate gene for an autosomal dominant distal hereditary motor neuropathy. , 2019, European journal of medical genetics.

[46]  J. Chilton,et al.  Truncating SLC5A7 mutations underlie a spectrum of dominant hereditary motor neuropathies , 2018, Neurology: Genetics.

[47]  A. Antonellis,et al.  Emerging mechanisms of aminoacyl-tRNA synthetase mutations in recessive and dominant human disease , 2017, Human molecular genetics.

[48]  F. Salachas,et al.  Axonal Neuropathies due to Mutations in Small Heat Shock Proteins: Clinical, Genetic, and Functional Insights into Novel Mutations , 2017, Human mutation.

[49]  V. Ramesh,et al.  Genetic heterogeneity of motor neuropathies , 2017, Neurology.

[50]  W. Robberecht,et al.  Development of Improved HDAC6 Inhibitors as Pharmacological Therapy for Axonal Charcot–Marie–Tooth Disease , 2016, Neurotherapeutics.

[51]  C. Espinós,et al.  Phenotype and natural history of inherited neuropathies caused by HSJ1 c.352+1G>A mutation , 2016, Journal of Neurology, Neurosurgery & Psychiatry.

[52]  D. Seelow,et al.  Recessive REEP1 mutation is associated with congenital axonal neuropathy and diaphragmatic palsy , 2015, Neurology: Genetics.

[53]  A. Chaussenot,et al.  CHCHD10-Related Disorders , 2015 .

[54]  T. Prior,et al.  Congenital lethal motor neuron disease with a novel defect in ribosome biogenesis , 2014, Neurology.

[55]  T. Wieland,et al.  Exome sequencing identifies a REEP1 mutation involved in distal hereditary motor neuropathy type V. , 2012, American journal of human genetics.

[56]  B. Kalmar,et al.  The distal hereditary motor neuropathies , 2011, Journal of Neurology, Neurosurgery & Psychiatry.

[57]  W. Robberecht,et al.  Relative contribution of mutations in genes for autosomal dominant distal hereditary motor neuropathies: a genotype-phenotype correlation study. , 2007, Brain : a journal of neurology.