Charcot-Marie-Tooth disease (CMT) comprises a genetically and clinically heterogeneous group of inherited peripheral neuropathies and remains a major indication for gene-based diagnostic evaluations in neuromuscular practice. Although supportive management has traditionally been applied across most subtypes, there has recently been a notable expansion of disease-modifying approaches due to advances in molecular diagnostics and accumulating preclinical and early clinical evidence. Improved genetic classification, including the recognition of metabolically defined and potentially treatable subtypes, has increased diagnostic precision and the development of subtype-specific therapeutics, with an increasing emphasis on mechanism-based stratification. This review summarizes recent progress in inherited neuropathies from a clinical perspective. We describe ongoing developments in clinical interventions, including combination pharmacotherapy for Charcot-Marie-Tooth disease type 1A (CMT1A), pathway-targeted therapy for CMT associated with sorbitol dehydrogenase deficiency and related metabolic neuropathies, and early biological and gene-based approaches that are being applied in selected subtypes. We also review the evolving preclinical approaches aimed at normalizing the peripheral myelin protein 22 dosage in CMT1A and gene-replacement and other precision therapies for loss-of-function and dominant-negative conditions. Because many subtypes of CMT progress slowly and conventional clinical scales have low sensitivity, we further discuss recent advances in the approaches used in clinical trials, including the refinement of clinical outcome assessments and the identification of candidate biomarkers such as the magnetic resonance imaging-based muscle fat fraction and the circulating level of neurofilament light chain. Collectively these developments are making subtype-specific therapeutic approaches increasingly feasible, although continued progress will depend on aligning disease biology, therapeutic approaches, and outcome measurements.
Background The younger generation in Korea easily exposed to nitrous oxide (N2O) under the name “Happy Balloon” may abuse it. N2O can irreversibly oxidize vitamin B12 and cause abnormal hematopoiesis or nervous system toxicity such as subacute combined degeneration (SCD). The objective of this study was to assist in early diagnosis of N2O-induced SCD of spinal cord by characterizing its clinical manifestations.
Methods Four patients with myelopathy after abusing N2O were enrolled. To characterize N2O-induced myelopathy, previously reported cases of N2O-induced SCD were searched through PubMed and KoreaMed. Collected cases and our four patients were analyzed.
Results A total of 30 patients with N2O-induced myelopathy (26 males and 4 females with mean age of 24 years) were analyzed. These patients took a median dose of 650 canisters for a median duration of 3.5 months. All patients presented sensory disturbances, which involved the lower extremities more frequently (100%) than the upper extremities (63.3%). Gait ataxia (76.7%), weakness in the upper (23.3%) and lower (36.7%) extremities, bladder symptoms (26.7%), Rhomberg sign (43.3%), and Lhermitte’s phenomenon (10.0%) were observed. Serum vitamin B12 levels were decreased in many (63.3%) patients and homocysteine levels were elevated in all. Of 20 patients who underwent magnetic resonance imaging (MRI) of the spine, 19 had abnormal findings. Three patients presented with contrast enhancement in lesions.
Conclusions We strongly recommend that history of N2O abuse should be asked for young patients with suspected myelopathy, especially those presenting with gait ataxia and sensory disturbances suggesting posterior column dysfunction and those presenting long-segment lesion involving the upper cervical cord on MRI.
Genetic muscle diseases encompass a group of conditions where genetic alterations affect skeletal muscles, leading to muscle weakness and hypotonia. Presently, the focus of treatment is on managing symptoms rather than addressing the root cause of the disease. However, recent advancements in gene therapy offer potential cure for these diseases, with over 180 genes identified as contributing factors. Encouraging results have emerged from preclinical trials conducted using animal models, prompting the initiation of several clinical trials aimed at assessing the safety and efficacy of gene therapy in human patients. In this review, we aim to provide an overview of the fundamental concept of gene therapy and discuss ongoing clinical trials that hold promise for curing genetic muscle diseases.
Primary central nervous system lymphoma (PCNSL) is a type of non-Hodgkin lymphoma confined to the central nervous system. Its diagnosis requires a stereotactic biopsy, which is an invasive procedure. Cerebrospinal fluid (CSF) analysis is less invasive and easier to perform than a stereotactic biopsy. We hereby report a PCNSL case diagnosed using CSF analysis and treated with systemic chemotherapy.
Subacute combined degeneration (SCD) of the spinal cord, which is a result of vitamin B12 deficiency, may cause irreversible neurological deficits. The lesion in the spinal cord is typically localized to the posterior and lateral columns, as the name implies. In this paper, we report on two patients with SCD, whose lesions involved the bilateral anterior column as well as the posterior and lateral columns. This report illustrates the importance of awareness of clinical and radiologic variable characteristics of SCD.
Background Nitrous oxide (N2O) is used in surgery and dentistry for its anesthetic and analgesic effects. However, neurological and psychiatric manifestations of N2O abuse have been increasingly reported among Korean adults. The aim of this study was to demonstrate laboratory findings of N2O abuse in Korean patients.
Methods Patients diagnosed with N2O-induced neuropathy or myelopathy from August 2018 to December 2019 were enrolled. Their clinical presentations and laboratory and imaging findings were analyzed.
Results Sensory changes and limb weakness were present in nine of the enrolled patients. The laboratory findings revealed that seven patients had high homocysteine levels and five had high methylmalonic acid levels in their blood. Nerve conductions studies indicated that axonal neuropathy was present in four cases and longer F-wave and Hoffman’s-reflex latencies were present in two cases. Signal changes in cervical spine imaging occurred in five patients, while two had normal results.
Conclusions Chronic N2O abuse can cause neurological damage or psychiatric problems. Because N2O is illegal for recreational use in Korea, patients tend to hide their history of use. Even though the spinal imaging results were normal, clinicians should consider the possibility of N2O use, and further electrophysiological tests should be applied for precise evaluations.
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The prevalence, risks, and detection of driving under the influence of nitrous oxide Frederick R. J. Vinckenbosch, Dinesh Durán Jiménez, Hendrik Helmerhorst, Albert Dahan, Leon Aarts, Floris Bikker, Eef Theunissen, Johannes G. Ramaekers WIREs Forensic Science.2024;[Epub] CrossRef
Nitrous‐oxide‐induced polyneuropathy and subacute combined degeneration of the spine: clinical and diagnostic characteristics in 70 patients, with focus on electrodiagnostic studies L. T. Hassing, F. Y. Jiang, R. Zutt, S. Arends European Journal of Neurology.2024;[Epub] CrossRef
Severe Isolated Peripheral Polyneuropathy without Myelopathy after Nitrous Oxide Abuse: A Case Report Seung-Min Baek, Seungbok Lee, Yu-Mi Kim, Eun-Sil Kim Journal of Electrodiagnosis and Neuromuscular Dise.2022; 24(2): 50. CrossRef
New therapeutics in neurology are expanding at an unprecedented pace. In addition to the classic enzyme-replacement therapies, monoclonal antibodies are increasingly being used to modulate autoimmunity. RNA therapeutics are an emerging class, together with gene and cell therapies. The nomenclature of international nonproprietary names helps us to recognize these new drugs according to their class and function. Suffixes denote major categories of the drug, while infixes provide additional information such as the source and target.
Background The purpose of this study was to identify the top-100 cited articles on genetic generalized epilepsy (GGE) published in journals that have made key contributions to the field of epilepsy.
Methods We searched the Web of Science website produced by Clarivate Analytics for articles on GGE, and sorted them according to the number of citations to identify the top-100 cited articles. We then manually reviewed the contents of the top-100 cited articles, which were designated as “citation classics”.
Results The top-100 cited articles were published in 27 journals, with the largest proportion appearing in Epilepsia (19 articles). The articles originated from institutions in 17 countries, with 31 articles from the USA. The institution associated with the largest numbers of articles in the field of GGE was the University of Melbourne, Australia (9 articles). Panayiotopoulos C. P. was the first author of three articles, and was listed most frequently in the GGE citation classics. The publication years were concentrated in the 2000s, when 56 articles were published. The most-common study topics were genetics (35 articles) and neuroimaging (17 articles).
Conclusions This study has identified the top-100 cited articles on GGE. These citation classics represent the landmark articles on GGE, and they provide useful insights into international research leaders and the research trends in the field.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder with numerous causes that include genetic factors. Efforts to reveal the genetics of ALS have identified several candidate genes that are associated with familial and sporadic ALS. Here we report a Korean ALS patient who showed prominent upper motor-neuron-related symptoms with marked brain atrophy and neuropsychological deficits. The findings were highly suggestive of ALS in a patient with a likely pathogenic FIG4 variant.
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Nanoparticles encapsulating phosphatidylinositol derivatives promote neuroprotection and functional improvement in preclinical models of ALS via a long-lasting activation of TRPML1 lysosomal channel Valentina Tedeschi, Valeria Nele, Valeria Valsecchi, Serenella Anzilotti, Antonio Vinciguerra, Laura Zucaro, Maria Josè Sisalli, Chiara Cassiano, Nunzia De Iesu, Giuseppe Pignataro, Lorella Maria Teresa Canzoniero, Anna Pannaccione, Giuseppe De Rosa, Agne Pharmacological Research.2024; 210: 107491. CrossRef
This article provides an overview for understanding the classification and pathogenesis of diabetic neuropathy. Diabetic neuropathies are prevalent disorder. The most common manifestation is distal symmetric polyneuropathy, but various patterns of neuropathy can occur. New information for the pathogenesis of diabetic neuropathy continues to emerge, which will lead to identifying new drug targets.
Iron is an important element for brain oxygen transport, myelination, DNA synthesis and neurotransmission. However, excessive iron can generate reactive oxygen species and contribute neurotoxicity. Although brain iron deposition is the natural process with normal aging, excessive iron accumulation is also observed in various neurological disorders such as neurodegeneration with brain iron accumulation, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, Friedreich ataxia, and others. Magnetic resonance image (MRI) is a useful method for detecting iron deposits in the brain. It can be a powerful tool for diagnosis and monitoring, while furthering our understanding of the role of iron in the pathophysiology of a disease. In this review, we will introduce the mechanism of iron toxicity and the basics of several iron-related MRI techniques. Also, we will summarize the previous results concerning the clinical application of such MR imagings in various neurological disorders.
For the last decades, molecular genetics has achieved great advances that the genes on the list of inherited muscle diseasesare piling up. Those diseases of overlapping clinico-pathologic findings are now understood with discrete molecularpathogeneses. We are facing an exciting era that the long-waited gene therapy may eventually come true. Skipping of dystrophinexon 51 is on successful clinical trials, which will benefit about 13% of the children suffering from Duchenne musculardystrophy. Exon skipping is under active investigation to expand the candidates. Hopefully it may cover majority ofDuchenne muscular dystrophy mutations and some of other diseases. Adeno-associated virus is one of the most versatiletools for gene transfer. It may overcome the limitation of exon skipping. Here we review exon skipping technique ofDuchenne muscular dystrophy and briefly discuss the other strategies being studied to cure inherited muscle diseases.
Background : The generators of N37 and P37 of posterior tibial nerve somatosensory evoked potential(PTSEP) have not been exactly known. Recently, some reports suggested that P37 and N37 might have different generator. We conducted a study to know the generators of P37 and N37 of PTSEP using gating mechanism. Methods : We evaluated subcortical and cortical somatosensory evoked potentials(SEPs) in response to posterior tibial nerve stimulation in 2 experimental conditions of foot movement and compared them with PTSEPs in full relaxation of foot. The experimental conditions were: (a) active flextion-extention of stimulated foot, (b) isometric contraction of the stimulated foot, (c) passive flextion-extention of the stimulate foot. We analyzed the latencies and amplitudes of following potentials;P30, N37, P37, and N50. Results : The amplitude of P30 potential did not change during at any paradigms. Te amplitudes of P37 and N50 were significantly attenuated in all condition. However, the amplitude of N37 showed no significant change during at any paradigms. Conclusions : These results suggest that the generators of P37 and N37 pf PTSEP be different I cortex.
Hippocampal slice models can be a powerful tool to study the mechanism of partial epilepsy. Despite the loss of connection with the rest of the brain, in vitro hippocampal slice preparations allow detailed physiological and pharmacological studies, which would be impossible, in vivo. There are several methods to induce electrographic seizures on hippocampal slice models. Those are electrical pulse train stimulation, 0 Mg2+ artificial cerebrational fluid and high concentration of extracelluar K+ on bath. Among them, the electrically triggered seizure may mimic the physiological communication between neuronal populations without any deterioration of normal physiologic and chemical status of the hippocampal slice models. Presumably, such communication from hyperexcitable areas to other neuronal populations is involved in the development of epilepsy. Eelectrographic seizures in hyppcampal slice models occur in the network of neurons that are involved in epileptic seizures in the hippocampus in vivo. Because these models have many advantages and are very valuable to research of epileptogenesis on partial epilepsy, I would like to introduce the electrophysiological methods to induce electrographic seizure or epilepsy on hippocampal slice models briefly in this paper.
B a c k g r o u n d : Spatial analysis of EEG is a phenomenal assessment and not so informative for phase space anddynamic aspect of EEG data. In contrast, nonlinear EEG analysis attempts to characterize the dynamics of neural networksin the brain. We have analyzed the features of EEG nonlinearly in subjects with white matter change on brainMRI and compared the results with cognitive function in each.Methods : Digital EEG data were taken for 30 seconds in 9 subjects with white matter degeneration and in 5 healthynormal controls without white matter change on MRI. Then we analyzed them nonlinearly to calculate the correlationdimension(D2) using the MATLAB software. The cognitive function was assessed by 3MS(modified mini-mental stateexamination). The severity of white matter change was assessed by Scheltens scale.Results : The mean D2 value of normal control was greater than that of white matter degeneration group. The D2s ofsome channels were correlative with 3MS and degree of white matter degeneration significantly.Conclusions : nonlinear analysis of EEG can be used as one of adjuvant functional studies for prediction of cognitiveimpairment in subjects with white matter degeneration and subcortical white matter change can be influential on cognitivefunction and correlation dimension of EEG.
Background Bcl-2 and Bcl-XL has been known to be members of Bcl-2 family for regulation of long-term cell survival.We investigated the expression of Bcl-2 and Bcl-XL in myblast during myogenesis.Methods: Cultured myoblasts from the C2C12 mouse cell line were isolated at the different stages of myoblast andmyotubes. The mRNA levels for Bcl-2 and Bcl-XL were determined by reverse-transcriptase PCR (RT-PCR). Theimmunocytochemical staining using the antibodies for Bcl-2 and Bcl-XL was performed to examine the expression ofBcl-2 and Bcl-XL in cultured C2C12 cells.Results: By immunocytochemistry, Bcl-2 was strong expressed in cultured myoblasts compared with myotubes. Theexpression of Bcl-XL were observed at similar degree in both myoblasts and myotubes. The RT-PCR assay showed thatC2C12 cells expressed both Bcl-2 and Bcl-XL mRNA level with different pattern of expression at differential stage. Thelevel of expression of Bcl-2 mRNA was observed most highly at early stage of myoblasts, but diminished as differentiationprogressed. However, the level of expression of Bcl-XL didn
Charcot-Marie-Tooth (CMT) disease was described by Charcot and Marie in France and, independently, by Tooth in England in 1886. CMT is the most common form of inherited motor and sensory neuropathy, and is a genetically heterogeneous disorder of the peripheral nervous system. Therefore, many genes have been identified as CMT-causative genes. Traditionally, subclassification of CMT have been divided into autosomal dominant inherited demyelinating (CMT1) and axonal (CMT2) neuropathies, X-linked neuropathy (CMTX), and autosomal recessive inherited neuropathy (CMT4). Recently, intermediate type (CMT-Int) with NCVs between CMT1 and CMT2 is considered as a CMT type. There are several related peripheral neuropathies, such as D??ine-Sottas neuropathy (DSN), congenital hypomyelination (CH), hereditary neuropathy with liability to pressure palsies (HNPP) and giant axonal neuropathy (GAN). Great advances have been made in understanding the molecular basis of CMT, and 17 distinct genetic causes of CMT have been identified. The number of newly discovered mutations and identified genetic loci is rapidly increasing, and this expanding list has proved challenging for physicians trying to keep up with the field. Identifying the genetic cause of inherited neuropathies is often important to determine at risk family members as well as diagnose the patient. In addition, the encouraging studies have been published on rational potential therapies for the CMT1A. Now, wedevelop a model of how the various genes may interact in the pathogenesis of CMT disorder.
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