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BMC Neurol 2022 May 16;22(1):180. Epub 2022 May 16.

Department of Neuromuscular Disease, The Third Affiliated Hospital of Hebei Medical University, 139 Ziqiang Road, Shijiazhuang, Hebei, 050000, PR China.

Background: Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases characterized by lower-limb spastic paraplegia with highly genetic and clinical heterogeneity. However, the clinical sign of spastic paraplegia can also be seen in a variety of hereditary neurologic diseases with bilateral corticospinal tract impairment. The purpose of this study is to identify the disease spectrum of spastic paraplegia, and to broaden the coverage of genetic testing and recognize clinical, laboratorial, electrophysiological and radiological characteristics to increase the positive rate of diagnosis. Read More

Mol Neurobiol 2022 Jul 30;59(7):4159-4178. Epub 2022 Apr 30.

Division of Genetics and Cell Biology, San Raffaele Scientific Institute DIBIT, 20132, Milan, Italy.

Charcot-Marie-Tooth disease type 1A (CMT1A), caused by duplication of the peripheral myelin protein 22 (PMP22) gene, and CMT1B, caused by mutations in myelin protein zero (MPZ) gene, are the two most common forms of demyelinating CMT (CMT1), and no treatments are available for either. Prior studies of the MpzSer63del mouse model of CMT1B have demonstrated that protein misfolding, endoplasmic reticulum (ER) retention and activation of the unfolded protein response (UPR) contributed to the neuropathy. Heterozygous patients with an arginine to cysteine mutation in MPZ (MPZR98C) develop a severe infantile form of CMT1B which is modelled by MpzR98C/ + mice that also show ER stress and an activated UPR. Read More

Neuromuscul Disord 2022 Jun 9;32(6):503-511. Epub 2022 Apr 9.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address:

Focal thickening of the myelin sheath, also known as tomacula, is a characteristic pathological feature of patients with hereditary neuropathy with liability to pressure palsies (HNPP). However, a deeper understanding of the pathology underlying unmyelinated fibers and nonmyelinating Schwann cells is required. Electron microscopic examination of sural nerve biopsy specimens was performed for 14 HNPP patients with peripheral myelin protein 22 (PMP22) deletion, and their results were compared to 12 normal controls and 14 Charcot-Marie-Tooth disease type 1A (CMT1A) patients with PMP22 duplication. Read More

Rev Med Suisse 2022 Apr;18(779):813-816

Service de neurologie, Département des neurosciences cliniques, Centre hospitalier universitaire vaudois et Université de Lausanne, 1011 Lausanne.

Hereditary neuropathies have been the subject of recent major therapeutic advances. Treatments based on antisense oligonucleotides (ASO) and small interfering RNA (siRNA) have been developed and are now commercially available to treat hereditary transthyretin amyloidosis (hTTR) and porphyria. More recently, a CRISPR-Cas9 genomic editing treatment targeting the TTR gene has been developed and is being tested in patients with hTTR. Read More

Mol Neurobiol 2022 Jun 23;59(6):3414-3430. Epub 2022 Mar 23.

Department of Neurosciences, Experimental Neurology and Leuven Brain Institute (LBI), KU Leuven - University of Leuven, B-3000, Leuven, Belgium.

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy, with currently no effective treatment or cure. CMT1A is caused by a duplication of the PMP22 gene, which leads to Schwann cell differentiation defects and dysmyelination of the peripheral nerves. The epigenetic regulator histone deacetylase 3 (HDAC3) has been shown to negatively regulate myelination as well as its associated signaling pathways, PI3K-AKT and MAPK-ERK. Read More

J Neuromuscul Dis 2022 ;9(3):437-446

Institute of Health and Society, University of Oslo, Blindern, Oslo, Norway.

Background: Physical activity may help to promote health in patients with Limb-girdle muscular dystrophy (LGMD) and Charcot-Marie-Tooth disease (CMT).

Objective: To investigate associations between functional ability and other variables, with physical activity in people with LGMD and CMT grouped according to the International Classification of Functioning, Disability, and Health (ICF).

Methods: We did a cross-sectional study, recruiting respondents from the Norwegian registry of inherited neuromuscular disorders. Read More

Mol Genet Genomic Med 2022 02 19;10(2):e1870. Epub 2022 Jan 19.

Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.

Charcot-Marie-Tooth disease (CMT) is the most common hereditary peripheral neuropathy. Mutations in the neurofilament light polypeptide (NEFL) gene produce diverse clinical phenotypes, including demyelinating (CMT1F), axonal (CMT2E), and intermediate (CMTDIG) neuropathies. From 2005 to 2020, 1,143 Korean CMT families underwent gene sequencing, and we investigated the clinical, genetic, and neuroimaging spectra of NEFL-related CMT patients. Read More

J Hum Genet 2022 Jun 14;67(6):353-362. Epub 2022 Jan 14.

Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Background And Aims: Some hereditary transthyretin (ATTRv) amyloidosis patients are misdiagnosed as Charcot-Marie-Tooth disease (CMT) at onset. We assess the findings to identify ATTRv amyloidosis among patients with suspected CMT to screen transthyretin gene variants for treatments.

Methods: We assessed clinical, cerebrospinal fluid, and electrophysiological findings by comparing ATTRv amyloidosis patients with suspected CMT (n = 10) and CMT patients (n = 489). Read More

Curr Opin Pediatr 2022 02;34(1):100-106

Division of Pediatric Orthopedic Surgery, Hospital for Special Surgery, New York, New York, USA.

Purpose Of Review: Acute ankle sprains frequently occur in active children and adolescents but may be the initial clinical presentation of other less common disorders affecting the lower extremities. There are many conditions that may cause one or multiple episodes of ankle injury that are misdiagnosed as an acute ankle sprain. This manuscript highlights diagnoses that should be considered when evaluating and managing a child or adolescent who presents initially and/or repeatedly with an acute ankle sprain. Read More

Genes (Basel) 2021 11 9;12(11). Epub 2021 Nov 9.

Dalton Cardiovascular Research Center, University of Missouri-Columbia, Columbia, MO 65211, USA.

Neurodegenerative diseases result in the progressive deterioration of the nervous system, with motor and cognitive impairments being the two most observable problems. Motor dysfunction could be caused by motor neuron diseases (MNDs) characterized by the loss of motor neurons, such as amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease, or other neurodegenerative diseases with the destruction of brain areas that affect movement, such as Parkinson's disease and Huntington's disease. Nicotinamide adenine dinucleotide (NAD) is one of the most abundant metabolites in the human body and is involved with numerous cellular processes, including energy metabolism, circadian clock, and DNA repair. Read More

J Peripher Nerv Syst 2022 03 1;27(1):38-49. Epub 2021 Dec 1.

Department of Biological Sciences, Kongju National University, Gongju, South Korea.

Charcot-Marie-Tooth disease (CMT) and related diseases are a genetically and clinically heterogeneous group of peripheral neuropathies. Particularly, mutations in several aminoacyl-tRNA synthetase (ARS) genes have been reported to cause axonal CMT (CMT2) or distal hereditary motor neuropathy (dHMN). However, the common pathogenesis among CMT subtypes by different ARS gene defects is not well understood. Read More

Clin Podiatr Med Surg 2022 Jan;39(1):15-35

Department of Neurology, UCONN School of Medicine, Connecticut Children's Medical Center, 505 Farmington Avenue., 2nd Floor, Farmington, CT 06032, USA. Electronic address:

The neurologic causes of foot and leg dysfunction are reviewed. Disorders causing foot and ankle pain, weakness, or other sensorimotor disturbances often cause difficulty with ambulation and prompt patients to seek medical evaluation. Physical signs and symptoms along with targeted diagnostic testing are needed to come to the correct diagnosis and treatment plan. Read More

Neurotherapeutics 2021 10 27;18(4):2425-2435. Epub 2021 Oct 27.

Department of Neurology, Medical Faculty, RWTH Aachen University, Aachen, Germany.

Hereditary neuropathies are of variable genotype and phenotype. With upcoming therapies, there is urgent need for early disease recognition and outcome measures. High-resolution nerve and muscle ultrasound is a dynamic, non-invasive, well-established tool in the field of inflammatory and traumatic neuropathies. Read More

J Peripher Nerv Syst 2021 12 29;26(4):444-448. Epub 2021 Oct 29.

Neurogenetics Unit, 1st Department of Neurology, School of Medicine, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece.

Autosomal recessive axonal neuropathy with neuromyotonia (ARAN-NM) is a rare hereditary neuropathy within the Charcot-Marie-Tooth disease (CMT) spectrum, linked to mutations in the histidine triad nucleotide-binding protein 1 (HINT1) gene. HINT1-related neuropathy is particularly common in selected populations from Central and Eastern Europe but rare in Western European cohorts. It has not been investigated to date in the Greek population. Read More

Orphanet J Rare Dis 2021 10 16;16(1):433. Epub 2021 Oct 16.

Department of Neuromuscular Medicine, Hospital for Special Care, New Britain, USA.

Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0. Read More

J Neurol Neurosurg Psychiatry 2022 01 13;93(1):48-56. Epub 2021 Sep 13.

Centre for Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, UK

Objective: Neurofilaments are the major scaffolding proteins for the neuronal cytoskeleton, and variants in have recently been described to cause axonal Charcot-Marie-Tooth disease type 2CC (CMT2CC).

Methods: In this large observational study, we present phenotype-genotype correlations on 30 affected and 3 asymptomatic mutation carriers from eight families.

Results: The majority of patients presented in adulthood with motor-predominant and lower limb-predominant symptoms and the average age of onset was 31. Read More

J Peripher Nerv Syst 2021 11;26 Suppl 2:S42-S60

Department of Neurology, National Reference Center for "Rare Peripheral Neuropathies", CHU Dupuytren, Limoges, France.

Hereditary neuropathies may result from mutations in genes expressed by Schwann cells or neurons that affect selectively the peripheral nervous system (PNS) or may represent a minor or major component of complex inherited diseases that involve also the central nervous system and/or other organs and tissues. The chapter is constantly expanding and reworking, thanks to advances of molecular genetics; next-generation sequencing is identifying a plethora of new genes and is revolutionizing the diagnostic approach. In the past, diagnostic sural nerve biopsies paved the way to the discovery and elucidation of major genes and molecular pathways associated to most frequent hereditary motor-sensory neuropathies. Read More

Brain 2022 03;145(1):168-178

Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.

Agents that raise cyclic guanosine monophosphate (cGMP) by activating protein kinase G increase 26S proteasome activities, protein ubiquitination and degradation of misfolded proteins. Therefore, they may be useful in treating neurodegenerative and other diseases caused by an accumulation of misfolded proteins. Mutations in myelin protein zero (MPZ) cause the peripheral neuropathy Charcot-Marie-Tooth type 1B (CMT1B). Read More

Biomolecules 2021 07 19;11(7). Epub 2021 Jul 19.

Hunter James Kelly Research Institute, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14203, USA.

Schwann cell development and peripheral nerve myelination are finely orchestrated multistep processes; some of the underlying mechanisms are well described and others remain unknown. Many posttranslational modifications (PTMs) like phosphorylation and ubiquitination have been reported to play a role during the normal development of the peripheral nervous system (PNS) and in demyelinating neuropathies. However, a relatively novel PTM, SUMOylation, has not been studied in these contexts. Read More

FEBS J 2021 12 29;288(23):6677-6679. Epub 2021 Jul 29.

Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC), Departamento de Química Biológica Ranwel Caputto, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Argentina.

There are several examples of single mutations that lead to a well-defined disease through a well-known mechanism. In other cases, a collection of mutations of the same protein produces a pathology with different degrees of severity. The accompanying work by Uusitalo et al. Read More

Ann Clin Transl Neurol 2021 09 29;8(9):1809-1816. Epub 2021 Jul 29.

Neuromuscular & Ataxias Research Group, Instituto de Investigación Sanitaria La Fe, Valencia, Spain.

Background: Single-center clinical series provide important information on genetic distribution that can guide genetic testing. However, there are few such studies on pediatric populations with inherited peripheral neuropathies (IPNs).

Methods: Thorough genetic testing was performed on IPN patients under 20 years of age from a geographically well-defined Mediterranean area (Valencian Community, Spain), annually assessed with the Charcot-Marie-Tooth disease Pediatric Scale (CMTPedS). Read More

Muscle Nerve 2021 10 20;64(4):454-461. Epub 2021 Jul 20.

Department of Neuromuscular Medicine, Hospital for Special Care, New Britain, Connecticut, USA.

Introduction/aims: Advanced genetic testing including next-generation sequencing (AGT/NGS) has facilitated DNA testing in the clinical setting and greatly expanded new gene discovery for the Charcot-Marie-Tooth neuropathies and other hereditary neuropathies (CMT/HN). Herein, we report AGT/NGS results, clinical findings, and diagnostic yield in a cohort of CMT/HN patients evaluated at our neuropathy care center.

Methods: We reviewed the medical records of all patients with suspected CMT/HN who underwent AGT/NGS at the Hospital for Special Care from January 2017 through January 2020. Read More

Int J Mol Sci 2021 Jun 3;22(11). Epub 2021 Jun 3.

Neuroscience Department, The Cyprus Institute of Neurology and Genetics, Cyprus School of Molecular Medicine, Nicosia 2371, Cyprus.

Inherited neuropathies known as Charcot-Marie-Tooth (CMT) disease are genetically heterogeneous disorders affecting the peripheral nerves, causing significant and slowly progressive disability over the lifespan. The discovery of their diverse molecular genetic mechanisms over the past three decades has provided the basis for developing a wide range of therapeutics, leading to an exciting era of finding treatments for this, until now, incurable group of diseases. Many treatment approaches, including gene silencing and gene replacement therapies, as well as small molecule treatments are currently in preclinical testing while several have also reached clinical trial stage. Read More

BMC Med Genomics 2021 06 30;14(1):174. Epub 2021 Jun 30.

Department of Biological Sciences, Kongju National University, 56 Gongjudaehakro, Gongju, 32588, Korea.

Background: Charcot-Marie-Tooth disease (CMT) is a group of genetically and clinically heterogeneous peripheral nervous system disorders. Few studies have identified genetic causes of CMT in the Pakistani patients.

Methods: This study was performed to identify pathogenic mutations in five consanguineous Pakistani CMT families negative for PMP22 duplication. Read More

J Peripher Nerv Syst 2021 09 5;26(3):290-297. Epub 2021 Jul 5.

Department of Neurology, Universidade Federal Fluminese, Niterói, Rio de Janeiro, Brazil.

This study aimed to describe the clinical, genetic, and epidemiological features of Charcot-Marie-Tooth disease (CMT) in Brazilian patients from a tertiary center, and to compare our data with previously published findings. This retrospective observational study conducted between February 2015 and July 2020 evaluated 503 patients (94 families and 192 unrelated individuals), diagnosed with CMT. Clinical and neurophysiological data were obtained from electronic medical records and blood samples were used for genetic analyses. Read More

Eur J Neurol 2021 09 18;28(9):3001-3011. Epub 2021 Jul 18.

Neuromuscular Diseases Unit, Department of Neurology, Hospital Universitari i Politècnic La Fe, Valencia, Spain.

Background And Purpose: MORC2 mutations have been described as a rare cause of axonal Charcot-Marie-Tooth disease (CMT2Z). The aim of this work was to determine the frequency and distribution of these mutations throughout Spain, to provide a comprehensive phenotypical description and, if possible, to establish a genotype-phenotype correlation.

Methods: Retrospectively, data on patients diagnosed with CMT2Z in Spain were collected and clinical, electrophysiological and muscle imaging information were analysed. Read More

BMC Neurol 2021 Jun 25;21(1):243. Epub 2021 Jun 25.

Department of Neurology, Fukushima Medical University, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan.

Background: Hereditary motor and sensory neuropathy, also referred to as Charcot-Marie-Tooth disease (CMT), is most often caused by a duplication of the peripheral myelin protein 22 (PMP22) gene. This duplication causes CMT type 1A (CMT1A). CMT1A rarely occurs in combination with other hereditary neuromuscular disorders. Read More

Exp Neurol 2021 09 19;343:113786. Epub 2021 Jun 19.

Department of Neurology, Section of Developmental Neurobiology, University Hospital Würzburg, Würzburg, Germany.. Electronic address:

Inherited neuropathies of the Charcot-Marie-Tooth (CMT) type 1 are still untreatable diseases of the peripheral nervous system. We have previously shown that macrophages substantially amplify neuropathic changes in various mouse models of CMT1 subforms and that targeting innate immune cells substantially ameliorates disease outcome. However, up to date, specific approaches targeting macrophages pharmacologically might entail side effects. Read More

BMC Med Genomics 2021 06 12;14(1):157. Epub 2021 Jun 12.

Department of Medical Basic Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Piazza G. Cesare, 11, 70124, Bari, Italy.

Background: Charcot-Marie-Tooth disease (CMT) type 4B3 (CMT4B3) is a rare form of genetic neuropathy associated with variants in the MTMR5/SBF1 gene. MTMR5/SBF1 is a pseudophosphatase predicted to regulate endo-lysosomal trafficking in tandem with other MTMRs. Although almost ubiquitously expressed, pathogenic variants primarily impact on the peripheral nervous system, corroborating the involvement of MTMR5/SBF1 and its molecular partners in Schwann cells-mediated myelinization. Read More

Brain 2021 11;144(10):3239-3250

National Institutes of Health, Neuromuscular and Neurogenetic Disorders of Childhood Section, Bethesda, MD 20892, USA.

Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease with early childhood onset that presents as a prominent sensorimotor neuropathy and commonly progresses to affect both the PNS and CNS. The disease is caused by biallelic mutations in the GAN gene located on 16q23.2, leading to loss of functional gigaxonin, a substrate specific ubiquitin ligase adapter protein necessary for the regulation of intermediate filament turnover. Read More