Charcot-Marie-Tooth disease ( CMT ) is a type of inherited peripheral neuropathy ( IPN ) that primarily affects motor and sensory nerves due to abnormalities in the peripheral nervous system. CMT exhibit significant genetic and clinical heterogeneity, with over 140 causative genes identified, encompassing diverse cellular localizations and functional roles. This review discusses advancements in genetic analysis techniques, including gene panel sequencing, whole-exome sequencing ( WES ) , whole-genome sequencing ( WGS ) , and long-read sequencing, which have significantly improved the diagnostic accuracy and yield. Furthermore, we also present the genetic landscape of 3,315 CMT/IPN patients in Japan ( excluding PMP22 duplication/deletion cases ) . Comprehensive analyses are essential to deepen our understanding of CMT/IPN and facilitate the development of targeted therapies and improved patient care. The discovery of repeat expansion mutations emphasizes the necessity for continuous refinements in diagnostic strategies to address novel and emerging genetic mechanisms underlying CMT/IPN.

　Recent advances in genetic analysis technologies have led to significant progress in identifying repeat expansion abnormalities in hereditary neuromuscular diseases. These developments have also increased the importance of repeat expansion analysis in diagnosing hereditary peripheral neuropathies ( IPN ) . In a comprehensive genetic analysis of 3,180 Japanese patients suspected of having IPN, 10.9% of the genetically diagnosed cases were found to be caused by repeat expansions in the LRP12, RFC1 and NOTCH2NLC genes. Each of these repeat expansions is associated with adult-onset symptoms. LRP12-related repeat expansions primarily manifest as motor nerve dysfunction, with most patients presenting muscle weakness and atrophy, while sensory disturbances are relatively rare. In contrast, RFC1 repeat expansions predominantly cause sensory impairments, with most patients displaying sensory neuropathy and minimal muscle weakness. Furthermore, NOTCH2NLC-related expansions are associated with intermediate electrophysiological findings, and about half of the patients also exhibit autonomic nervous system involvement, such as neurogenic bladder. These repeat expansions are critical in refining the diagnosis and understanding of the clinical spectrum of hereditary peripheral neuropathies. This review provides an in-depth overview of the clinical characteristics, electrophysiological findings, and molecular mechanisms of the LRP12, RFC1 and NOTCH2NLC repeat expansions, with a particular focus on their roles in the pathogenesis of hereditary neuropathies.

　Charcot-Marie-Tooth disease ( CMT ) , also known as hereditary motor and sensory neuropathy, is the most prevalent and slowly progressive inherited peripheral neuropathy. Currently, there is no definitive cure for CMT. Symptomatic treatments for CMT, such as rehabilitation and surgical interventions for foot deformities, offer limited improvement. The slow disease progression of CMT is one of the significant problems in developing effective biomarkers for clinical trials, which leads clinical trials to failure. Unfortunately, existing assessments, such as the CMT neuropathy score and nerve conduction study parameters, lack the sensitivity required to detect subtle changes over relatively short timeframes in clinical trial settings. Under these circumstances, researchers are actively seeking more sensitive measures. Developing sensitive biomarkers is crucial for successful clinical trials in CMT and for establishing novel therapeutic agents. This article will review the historical evolution and current state of CMT evaluation, encompassing clinical, physiological, and serological assessments.

　Surgical treatments for Charcot-Marie-Tooth disease primarily target the feet. Common indications include cavovarus deformity, drop foot, equinus foot, hammer toes, and claw toes. Skin ulcers and infections may also require surgical intervention. Soft tissue procedures include joint capsule release, plantar fascia resection, Achilles tendon lengthening, and tendon transfers. Bone-related procedures involve osteotomy and joint fusion. In some cases, acetabular dysplasia of the hip, scoliosis, or hand deformities may necessitate surgery. Nerve decompression is performed to address numbness and pain caused by ulnar or median nerve involvement.

　Rehabilitation for Charcot-Marie-Tooth disease ( CMT ) involves addressing a range of lifelong challenges, including muscle weakness, joint deformities, gait abnormalities, and upper limb disorders that impact daily life and work. This paper focuses on the characteristics of lower limb disorders and strategies to manage them. The primary goals of lower limb orthoses are to prevent deformity progression, enhance walking function, and preserve proximal muscle strength. A flowchart was introduced to guide the selection of lower limb orthoses for individuals with CMT, based on factors such as the presence of pes cavus, foot drop, and knee instability. The study also evaluated the actual creation rates and daily usage rates of these orthoses. For individuals with pes cavus, the deformity often worsens with the outer foot weight walking, leading to calluses and pain. A footplate is recommended to correct the direction of load on the plantar and ankle joints and to slow the progression of deformity, with both the creation rate and usage rate being 100%. In cases of minimal foot deformity and foot drop but without knee instability, the carbon dynamic AFO’s spring-like function allows effective toe-off during walking. The creation rate for this device was 89%, and the usage rate was 87%, making it particularly beneficial for individuals who walk extensively while wearing shoes. Although many people initially hesitate to use lower limb orthoses, especially if they can walk unassisted, the availability of off-the-shelf demo products encourages adoption by allowing users to experience their benefits firsthand. Additionally, insoles and soft ankle supports were often used in combination with other orthotics to accommodate individual lifestyles and shoe preferences.

　Charcot-Marie-Tooth disease ( CMT ) currently lacks effective therapeutic options. This review discusses candidate drugs under investigation in clinical and preclinical trials, along with their mechanisms of action. Furthermore, advancements in gene therapy approaches for the treatment of CMT are highlighted.

　In preclinical studies to evaluate nerve regeneration, animal studies using rodents are inevitable from the viewpoint of compatibility with humans. On the other hand, research on alternative methods using zebrafish has been attracting attention from the perspectives of reduction of experimental animals, cost, and research efficiency. A major advantage of zebrafish is its high throughput, a feature that is very useful in large-scale drug screening and toxicology studies. Therefore, they have been utilized in many fields such as genetics, embryology, and neurology. Zebrafish have many advantages as experimental animals, such as sharing more than 70% of their genome information with humans, relatively easy genetic manipulation, high fecundity, and short transgenerational period, and many disease models have been established. Furthermore, zebrafish have an extremely high capacity for nerve regeneration, both in the central and peripheral regions. For the spinal cord, which belongs to the central nervous system, it is known that it shares some of the regenerative mechanisms that occur in rodent and human peripheral nerves, such as macrophage and microglial responses and glial cell cross-linking. This paper outlines the characteristics and advantages of zebrafish as experimental animals in neuro-regeneration research, as well as examples of their utilization based on recent and our findings.

　Guillain-Barré syndrome ( GBS ) typically present with generalized-symmetrical limb weakness and areflexia, but some cases show asymmetric or multifocal muscle weakness in acute phase. There have been no reports examining a large number of GBS with asymmetric/multifocal weakness in acute phase ( A/M-GBS ) , and the exact incidence and clinical characteristics are unknown. We reviewed the literature on A/M-GBS and examined the clinical features of A/M-GBS. Previous reports have shown that cases of axonal type GBS tend to present with asymmetrical symptoms. Our study with large number ( n=209 ) of GBS showed that the frequency of A/M-GBS was higher than previously reported ( 11% ) . Compared with typical GBS, A/M-GBS had a significantly higher proportion with prior infection, more elderly male cases and more cases positive for anti-glycolipid antibodies. A significantly higher proportion of A/M-GBS sera were positive for AMAN-associated anti-glycolipid antibodies. There was no difference in the severity of symptoms at peak between A/M-GBS and typical GBS cases, indicating the importance of diagnosing A/M-GBS early and initiating appropriate treatment.

　The molecular mechanisms of neuropathy in hereditary transthyretin amyloidosis ( ATTRv ) were studied using the Schwann cell model. We previously established an immortalized Schwann cell line, TgS1 derived from DRG of ATTRv model mice expressing TTR V30M. TgS1 cells were cultured in non-growth medium to generate the repair phenotype. Variant TTR is markedly expressed in the repair phenotype of cells. As TTR deposits close to Schwann cells of peripheral nerves in ATTRv model mice with an Hsf1 null background, TgS1 repair Schwann cells were treated with Hsf1 small interfering ( si ) RNA and TTR aggregates were examined. The aggregates were observed in the cytoplasm and in the middle portions and terminals of cell processes. They did not stain with Thioflavin T.　
　Repair Schwann cells form Büngner bands in the Wallerian degeneration. Our literature review revealed a close association between amyloid and Schwann cells of Büngner bands in ATTRv nerves. These findings suggest that reduced heat stress responses in repair Schwann cells might induce TTR deposits in the nerve of ATTRv.

　It is well established that adipose-derived stem cells ( ADSCs ) , a type of mesenchymal cell present in adipose tissue, possess regenerative effects on peripheral nerves. Consequently, stromal vascular fraction ( SVF ) cells, which is obtained by enzymatically digesting adipose tissue collagen using collagenase, has been explored for clinical applications.
　More recently, a novel method has been reported in which micronized cellular adipose matrix ( MCAM ) is extracted through physical processing of adipose tissue, allowing for the efficient and rapid concentration of stromal cells and extracellular matrix components. Since MCAM production does not require collagenase treatment, it is subject to fewer regulatory constraints than SVF cells and can be used more safely and in a shorter timeframe.　
　Given these advantages, MCAM holds promise as a novel therapeutic product for promoting peripheral nerve regeneration. This review provides an overview of the regenerative effects of MCAM on peripheral nerves and discusses its clinical applicability and future prospects in comparison with SVF cells.

　Diabetic neuropathy ( DN ) is a complication of diabetes mellitus, which have a large number of patients. So far, specific drugs for this disease have not been devised and more studies should be required for the pathogenesis of DN. Recently, extracellular matrix is focused for the development of inflammation, and we studied the relationships of DN and chondroitin sulfate ( CS ) , a type of glycosaminoglycan using CSGalNAcT1 knockout mice ( T1KO ) , which are lacking in a rate-limiting enzyme for CS synthesis. T1KO in hyperglycemia did not induce the hypo-analgesia, the reduced conduction velocity, or loss of peripheral nerves. We also found that interactions between pericytes and vascular endothelial cells were more stable in T1KO mice. Among the RNA-seq results of dorsal root ganglia, we focused on the transforming growth factor β ( TGF-β ) signaling pathway and found that the phosphorylation of Smad2/3 was less upregulated in T1KO mice than in WT mice under hyperglycemic conditions. These results suggest that the development of DN is involved in a malignant cycle of the abnormally activated TGF-β signaling, as other diabetic complications such as nephropathy and retinopathy. Taken together, a reduction in CS level attenuates DN progression, indicating that CS is an important factor in DN pathogenesis.

　We have discovered a novel autoantibody against leucine-rich repeat LGI family member 4 ( LGI4 ) localized at juxtaparanodes and satellite glia in the dorsal root ganglion in patients with chronic inflammatory demyelinating polyneuropathy ( CIDP ) by tissue-based indirect immunofluorescence assay using mouse sciatic nerves and dorsal root ganglia. We have developed a live cell-based assay for LGI4-IgG and found that 8/131 ( 6.1% ) CIDP patients were positive for LGI4-IgG. The dominant tissue-binding IgG subclasses were IgG4 in four patients, IgG1 in two patients, and IgG3 and IgG2 in one patient each. Patients had a relatively old onset age ( median 72 years ) . Four patients had acute/subacute onset and four had chronic onset. Six showed typical CIDP phenotype while two showed multifocal acquired demyelinating sensory and motor ( MADSAM ) neuropathy phenotype. Main symptoms/signs were motor weakness ( eight cases ) , muscle atrophy ( four ) , deep and superficial sensory impairment ( eight and seven, respectively ) , Romberg sign ( four ) , and finger and hand tremor ( five ) . CSF showed extremely high protein levels ( median 253 mg/dL ) . Three chronic cases had nerve hypertrophy. Intravenous immunoglobulin ( IVIg ) administration was partially effective in 7/7 patients. Notably, one patient with predominant LGI4-IgG1/2 and no LGI4-IgG4 showed a moderate reduction of myelinated fibers with endoneurial edema and numerous onion bulbs with numerous macrophage infiltration in the biopsied sural nerve. Schwann cell proliferation was significantly higher after incubation with LGI4-IgG than with HC-IgG in culture, and Krox20 mRNA levels were significantly lower with LGI4-IgG than with CIDP- or HC-IgG. With intraneural injection, both LGI4-IgG4 and -IgG1/2 deposited mainly at the nodes extending towards the paranodes and caused nodal/paranodal alterations. Anti-LGI4 antibody-positive autoimmune nodopathy shows acute monophasic and chronic progressive courses with nerve hypertrophy. LGI4-IgG may be pathogenic, promoting non-myelinating Schwann cell proliferation and potentially disrupting the nodes/paranodes.

　The purpose of this study was to assess the outcomes of anterior submuscular transposition of the ulnar nerve with medial epicondylar osteotomy ( ATMEO ) for friction neuritis in athletes. Eleven athletes with friction neuritis of the ulnar nerve at the elbow were underwent surgery which was ATMEO of the ulnar nerve with medial epicondylar osteotomy. Grip strength, ten test, disability of arm, shoulder and hand ( DASH ) score ( sports ) were evaluated. The time to union, and to return to play their sports were recorded. The mean grip strength compared to the healthy side was 0.56 preoperatively and 0.98 at three months after surgery. The mean ten test improved from 5.6 preoperatively to 10 at three months after surgery. The DASH score ( sports ) improved from 93.2 preoperatively to 0 in all patients at three months after surgery. Time to union was 3.5 months, and time to return to play their sports was 3.2 months. Non-union occurred in a volleyball player, who had removed her bone fragment. ATMEO of the ulnar nerve with medial epicondylar osteotomy is a useful surgical technique for the treatment of friction ulnar neuritis in athletes. Non-union after surgery was considered as the cause of medial elbow pain.

　In 2022, a slit-type artificial nerve conduit was introduced for easier use in cases of partial nerve injury. This report discusses the outcomes of two cases treated with this conduit at our hospital. Both cases had a follow-up period of six months. The injury sites were the superficial branch of the radial nerve in one case and the proper palmar digital nerve in the other. The waiting periods for surgery were seven months and 28 days, respectively, with surgery durations of 136 minutes and 72 minutes. In both cases, numbness and pain improved early in the postoperative period. The slit-type artificial nerve conduit is a simple procedure with a short operative time, making it a potentially valuable treatment option for partial nerve injuries.

　We report two cases of corticosteroid- and immunoglobulin-responsive peripheral neuropathy that developed during remission period of multiple myeloma ( MM ) . Both patients were diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy ( CIDP ) according to the 2021 revised EAN/PNS diagnostic criteria and responded favorably to CIDP treatment. Although MM is associated with chemotherapy-induced peripheral neuropathy, POEMS syndrome, AL amyloidosis, and other peripheral neuropathies, our patients were diagnosed with CIDP given their relapsing and remitting course, demyelinating neurophysiology, and clinical response to immune treatments. Further investigations are required to clarify the relationship between MM and CIDP.

　Background: Diabetic neuropathy ( DN ) has two different phenotypes, painful DN ( PDN ) and painless DN ( PLDN ) . Although the mechanism of pain production in PDN is unclear, peripheral small fiber damage may take part in it. There are two types of small fibers, unmyelinated C-fibers and myelinated Aδ-fibers, and their role in PDN are not clear.　
　Subjects and Methods: We evaluated electrochemical skin conductance ( ESC ) by SUDOSCAN^® and pain threshold of intraepidermal nerve terminal ( PINT ) in 140 patients with diabetes. Simultaneously we scaled abnormality of nerve conduction study by the BDC-index from sural SNAP, tibial CMAP and minimal F-wave latency.　
　Results: ESC, PINT, and BDC-index showed positive correlation with correlation coefficient between 0.67 and 0.77. Among the cases with abnormal ESC and PINT, 20% of the subjects of BDC-0 and -1 groups complained pain, while 40% of the BDC-2, -3, and -4 groups ( p<0.05 ) did it. Among the BDC-0 and -1 patients with abnormal ESC and/or PINT, PDN showed sural SNAP of 6.9±1.2μV, which was lower than 10.6±4.1μV of PLDN ( p<0.01 ) .　
　Interpretation: Abnormal ESC and PINT values represent peripheral C-fiber and Aδ-fiber dysfunction, respectively, while sural SNAP amplitude and BDC-index are determined by large Aβ-fiber density. The two facts that the PDN patients with C- and/or Aδ-dysfunction are more likely in the high BDC group than in the low BDC group, and that SNAP amplitude was lower in PDN than in PLDN among low BDC-patients suggest that spontaneous pain impulses from the impaired C- and Aδ-fibers are suppressed, when input from the Aβ-fibers to the dorsal horn of the spinal cord is sufficient. It is then concluded that Aβ-input reduction to the spinal cord might increases pain-impulse transmission toward the thalamus, which finally produces PDN.

　A 56-year-old male patient presented with peripheral neuropathy since his late 40s and was diagnosed with hereditary transthyretin ( ATTRv ) amyloidosis with a Val30Met mutation. After the diagnosis, the patient received patisiran but discontinued due to an infusion reaction with swelling at the injection site and fever. Subsequently, the patient was treated with tafamidis. At the age of 56, the patient was admitted to our hospital for worsening autonomic symptoms, and after obtaining informed consent, the treatment was switched to vutrisiran. Administration under careful monitoring was successfully completed without any adverse reactions. Considering that the patient had experienced adverse reactions to COVID-19 mRNA vaccines, it is suggested that additives such as PEG were a cause of the infusion reaction. ATTRv amyloidosis is a fatal disease, and nucleic acid therapeutics that improve prognosis should not be abandoned solely because of previous adverse effects. Vutrisiran may be a viable treatment option even for patients who have experienced adverse reactions to patisiran.

　Patients with hereditary transthyretin amyloidosis ( ATTRv ) sometimes presents carpal tunnel syndrome ( CTS ) , the etiology of which is thought to be amyloid deposition in the transverse carpal ligament. We report an autopsy case of Val30Met mutant ATTRv amyloidosis with CTS that showed severe amyloid deposition in the median nerve carpal tunnel compared to the transverse carpal ligament.　
　The patient was a 61-year-old man. He presented with distal numbness in both lower extremities, which was diagnosed by genetic testing. Sensory disturbance was observed in the extremities, especially in the median nerve area, and was thought to be associated with CTS. He was started on tafamidis, but died after 7 years. A pathological autopsy was performed. In the median nerve, amyloid deposition was more pronounced in the carpal tunnel than in the forearm. Conversely, amyloid deposition in the transverse carpal ligament was mild.　
　In this case, the median nerve disorder was thought to result from amyloid deposition within the median nerve itself, rather than from increased intracarpal pressure due to amyloid deposition in the transverse carpal ligament. Amyloid deposition was particularly severe in the carpal tunnel. This is a valuable case for understanding the pathomechanism of CTS in amyloidosis.