Multicenter, randomized, double-blind, placebo-controlled phase 3 study of mogamulizumab with open-label extension study in a minimum number of patients with human T-cell leukemia virus type-1-associated myelopathy.

Human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic neurodegenerative disease. This multicenter, randomized phase 3 study evaluated the efficacy and safety of 0.3 mg/kg intravenous mogamulizumab, a monoclonal antibody targeting-CC chemokine receptor 4, every 12 weeks in HAM/TSP patients. This study comprised a 24-week double-blind, placebo-controlled period, 24-week open-label period, and extension treatment period. The primary endpoint was the proportion of patients with a ≥ 1-grade improvement in the Osame motor disability score (OMDS). Secondary endpoints were changes in HTLV-1 proviral load, 10-m timed walk, cerebrospinal fluid (CSF) neopterin levels, and safety. The exploratory endpoint was CSF chemokine C-X-C motif ligand 10 (CXCL10) levels. Thirty-four and 33 patients were randomized to mogamulizumab and placebo arms, respectively. At the end of the double-blind period, no significant difference was found in the OMDS improvement rate or other secondary efficacy endpoints assessing motor activities. However, the mogamulizumab arm showed a significant decrease in HTLV-1 proviral load (- 59.39 ± 29.91% vs. placebo 2.32 ± 36.31%) and CSF neopterin (p < 0.001)/CXCL10 levels (p = 0.004). The baseline OMDS pattern and the 60-80% HTLV-1 proviral load reduction were sustained through the open-label and extension treatment periods. Although a higher incidence of rash (69.2%) was reported, the safety profile was similar compared with a previous phase 1/2a study. We found no significant difference in clinical benefit; however, mogamulizumab may provide long-term clinical benefit by preventing disease progression, as CSF neopterin/CXCL10 levels are associated with long-term prognosis in HAM/TSP.Clinical Trial Registration Number: NCT03191526 (registered date: 6-June-2017).

Anti-HTLV-1 immunity combined with proviral load as predictive biomarkers for adult T-cell leukemia-lymphoma.

Human T-cell leukemia virus type 1 (HTLV-1) establishes chronic infection in humans and induces a T-cell malignancy called adult T-cell leukemia-lymphoma (ATL) and several inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Persistent HTLV-1 infection is established under the pressure of host immunity, and therefore the immune response against HTLV-1 is thought to reflect the status of the disease it causes. Indeed, it is known that cellular immunity against viral antigens is suppressed in ATL patients compared to HAM/TSP patients. In this study, we show that profiling the humoral immunity to several HTLV-1 antigens, such as Gag, Env, and Tax, and measuring proviral load are useful tools for classifying disease status and predicting disease development. Using targeted sequencing, we found that several carriers whom this profiling method predicted to be at high risk for developing ATL indeed harbored driver mutations of ATL. The clonality of HTLV-1-infected cells in those carriers was still polyclonal; it is consistent with an early stage of leukemogenesis. Furthermore, this study revealed significance of anti-Gag proteins to predict high risk group in HTLV-1 carriers. Consistent with this finding, anti-Gag cytotoxic T lymphocytes (CTLs) were increased in patients who received hematopoietic stem cell transplantation and achieved remission state, indicating the significance of anti-Gag CTLs for disease control. Our findings suggest that our strategy that combines anti-HTLV-1 antibodies and proviral load may be useful for prediction of the development of HTLV-1-associated diseases.

AAV-mediated editing of PMP22 rescues Charcot-Marie-Tooth disease type 1A features in patient-derived iPS Schwann cells.

BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is one of the most common hereditary peripheral neuropathies caused by duplication of 1.5 Mb genome region including PMP22 gene. We aimed to correct the duplication in human CMT1A patient-derived iPS cells (CMT1A-iPSCs) by genome editing and intended to analyze the effect on Schwann cells differentiated from CMT1A-iPSCs. METHODS: We designed multiple gRNAs targeting a unique sequence present at two sites that sandwich only a single copy of duplicated peripheral myelin protein 22 (PMP22) genes, and selected one of them (gRNA3) from screening their efficiencies by T7E1 mismatch detection assay. AAV2-hSaCas9-gRNAedit was generated by subcloning gRNA3 into pX601-AAV-CMV plasmid, and the genome editing AAV vector was infected to CMT1A-iPSCs or CMT1A-iPSC-derived Schwann cell precursors. The effect of the genome editing AAV vector on myelination was evaluated by co-immunostaining of myelin basic protein (MBP), a marker of mature myelin, and microtubule-associated protein  2(MAP2), a marker of neurites or by electron microscopy. RESULTS: Here we show that infection of CMT1A-iPS cells (iPSCs) with AAV2-hSaCas9-gRNAedit expressing both hSaCas9 and gRNA targeting the tandem repeat sequence decreased PMP22 gene duplication by 20-40%. Infection of CMT1A-iPSC-derived Schwann cell precursors with AAV2-hSaCas9-gRNAedit normalized PMP22 mRNA and PMP22 protein expression levels, and also ameliorated increased apoptosis and impaired myelination in CMT1A-iPSC-derived Schwann cells. CONCLUSIONS: In vivo transfer of AAV2-hSaCas9-gRNAedit to peripheral nerves could be a potential therapeutic modality for CMT1A patient after careful examinations of toxicity including off-target mutations.

Charcot-Marie-Tooth disease type 1A (CMT1A) is a common heritable form of the condition that develops when nerves in the body's extremities, such as the hands, feet and arms, are damaged due to an extra copy of PMP22 gene being incorrectly produced. Currently, no known therapies exist. Here, we developed a method to delete the additional copy of PMP22 gene by 20­40% to prevent overproduction. Our results show that this method can reduce PMP22 protein production, leading to near normal production in patient's nerve cells. Further safety assessments should now be undertaken. If the treatment is safe for patients it could become a therapeutic option for CMT1A patients.

Altered properties of amyloidogenic prion protein in genetic Creutzfeldt-Jakob disease with PRNP V180I mutation in response to pentosan polysulfate.

Genetic Creutzfeldt-Jakob disease (gCJD) with V180I prion protein gene (PRNP) mutation shows weaker prion protein (PrP) deposition histologically compared with sporadic CJD, and it is more difficult to detect protease-resistant prion protein in immunoblotting. However, we previously reported the autopsy case of a patient with V180I gCJD who was treated with pentosan polysulfate sodium (PPS); this case had increased protease-resistant PrP deposition. It has been suggested that PPS might reduce protease-resistant PrP; however, the detailed pharmacological and histopathological effects of PPS in humans remain unknown. We examined autopsied human brain tissue from four cases with V180I gCJD that were added to our archives between 2011 and 2021: two cases treated with PPS and two cases without PPS. We conducted a neuropathological assessment, including immunohistochemistry for PrP. We also performed immunoblotting for PrP on homogenate samples from each brain to detect protease-resistant PrP using both a conventional procedure and size-exclusion gel chromatography for the purification of oligomeric PrP. Both PPS-treated cases showed long survival time over 5 years from onset and increased PrP deposition with a characteristic pattern of coarse granular depositions and congophilic PrP microspheres, whereas the cases without PPS showed around 1-year survival from onset and relatively mild neuronal loss and synaptic PrP deposition. Although cortical gliosis seemed similar among all cases, aquaporin 4-expression as a hallmark of astrocytic function was increased predominantly in PPS cases. Immunoblotting of non-PPS cases revealed protease-resistant PrP in the oligomeric fraction only, whereas the PPS-treated cases showed clear signals using conventional procedures and in the oligomeric fraction. These unique biochemical and histopathological changes may reflect the progression of V180I gCJD and its modification by PPS, suggesting the possible existence of toxic PrP-oligomer in the pathophysiology of V180I gCJD and beneficial effects of PPS toward the aggregation and detoxication of toxic PrP-oligomer.

[Charcot-Marie-Tooth disease Patient Registry in Japan].

To clarify the natural courses, medical conditions, and problems in daily life and medical care of the patients with Charcot-Marie-Tooth disease (CMT) in Japan, we have developed a patient registration system (CMT Patient Registry (CMTPR)). We analyzed data of questionnaires from 303 patients (males: 162, females: 141, mean age: 45.9 years old) who registered for CMTPR. The age of onset was less than 15 years old in 45% and more than 60 years old in 5% of the patients. Genetic testing was performed in 65%, and about half of the patients with genetic testing had a duplication of the PMP22 gene. Seventy-six percent of the patients had regular visits to medical facilities. Five percent of patients had no history of hospital visits. Fifteen percent of all patients needed assistance with daily activities due to motor function impairment in the upper extremities, and 25% required assistance due to lower limb impairment. There were no significant differences in the need for assistance by gender or age. Of the 267 adult patients, 18% had difficulty working due to reasons related to the disease, although none of the junior patients reported any problem attending school. This was the first nationwide epidemiological study with healthcare and welfare information on patients with CMT in Japan. We hope the results of this study will lead to better welfare and medical care in CMT patients.

Compound muscle action potential duration ratio for differentiation between Charcot-Marie-Tooth disease and CIDP.

OBJECTIVE: To elucidate the utility of the proximal to distal compound muscle action potential (CMAP) duration ratio to distinguish between demyelinating Charcot-Marie-Tooth disease (CMT) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) compared with nerve ultrasound. METHODS: Thirty-nine demyelinating CMT patients and 19 CIDP patients underwent nerve conduction studies (NCS) and nerve ultrasound. NCS parameters including CMAP duration ratio calculated by dividing the value at the proximal site by that at the distal site and nerve cross-sectional area (CSA) measured by ultrasound were compared between the two groups. The diagnostic sensitivity and specificity of each parameter were analysed. RESULTS: CMT patients showed a significantly lower CMAP duration ratio than CIDP patients (p < 0.05). The area under the curve (AUC) value of the CMAP duration ratio exceeded 0.95 when CMT was considered "positive", and a cut-off value of 1.13 resulted in high diagnostic sensitivity and specificity (84.6 and 100 % for median nerve, 97.4 and 85.7 % for ulnar nerve, respectively), whereas the AUC value of nerve CSA ranged from 0.70 to 0.81. CONCLUSIONS: The CMAP duration ratio could effectively distinguish between demyelinating CMT and CIDP. SIGNIFICANCE: Adding the CMAP duration ratio to a routine NCS may improve the accuracy of the diagnosis of demyelinating CMT.

Hospital at Home for Elderly COVID-19 Patients: A Preliminary Report with 100 Patients.

Hospital-at-home (HaH) care is useful for patients with COVID-19 and an alternative strategy when hospital capacity is under pressure due to patient surges. However, the efficacy and safety of HaH in elderly patients with COVID-19 remain unknown. In Kyoto city, we conducted a retrospective medical record review of HaH care focused on elderly COVID-19 patients from 4 February to 25 June 2021. Eligible patients were (1) COVID-19 patients aged ≥70 years and those who lived with them or (2) COVID-19 patients aged <70 years with special circumstances and those who lived with them. During the study period, 100 patients received HaH care. Their median age was 76 years (interquartile range 56−83), and 65% were over 70 years. Among 100 patients, 36 (36%) had hypoxia (oxygen saturation ≤ 92%), 21 (21%) received steroid medication, and 34 (34%) received intravenous fluids. Although 22 patients were admitted to the hospital and 3 patients died there, no patients died during HaH care. HaH care may be safe and effective in elderly patients with COVID-19. Our study shows that HaH provides an alternative strategy for treating COVID-19 patients and can reduce the healthcare burden at hospitals.

[Neuronal intranuclear inclusion disease in a patient who exhibited abnormal behavior].

A 63-year-old woman with no medical history of note developed acute-onset abnormal behavior persisting for one week. Mild disturbance of consciousness was noted on physical examination. Her blood and spinal fluid test results were normal. On brain MRI, diffusion-weighted image showed a high-intensity signal in U-fiber areas of the bilateral frontal lobes, and fluid-attenuated inversion recovery showed white matter lesions. We suspected neuronal intranuclear inclusion disease (NIID) based on brain MRI findings; therefore, we performed a skin biopsy and genetic test. Pathological findings of the skin biopsy revealed the presence of anti-p62-positive intranuclear inclusion bodies in fibroblasts and adipocytes. The genetic test showed GGC repeat expansion of NOTCH2NLC, but no mutation of FMR1. Thus, we diagnosed her with NIID. The acute-onset abnormal behavior was improved by levetiracetam. The present case indicates that patients with a high-intensity area in the corticomedullary junction should undergo a skin biopsy, even though they may present with non-specific symptoms such as acute-onset abnormal behavior.

Pleomorphic rhabdomyosarcoma in a young adult harboring a novel germline MSH2 variant.

Most cases of rhabdomyosarcoma (RMS) are sporadic and not associated with the Lynch syndrome (LS) spectrum. We report a young adult patient with RMS and a family history of colorectal cancer. Comprehensive cancer genomic profiling (CGP) of his tumor revealed a likely pathogenic variant of MSH2, NM_000251.3:c.1741delA (p.I581Lfs*9), which was also present in his blood sample. The widespread use of CGP may reveal that RMS can be a rare manifestation of LS.

Elderly patients with suspected Charcot-Marie-Tooth disease should be tested for the TTR gene for effective treatments.

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). RESULTS: The median (interquartile range) age at onset of neurological symptoms was 69 (64.2-70) years in the ATTRv amyloidosis vs 12 (5-37.2) years in CMT group (Mann-Whitney U, p < 0.01). The proportion of patients with initial sensory symptoms was 70% in the ATTRv amyloidosis group vs 7.1% in CMT group (Fisher's exact, p < 0.01). The proportion of patients with histories of suspected chronic inflammatory demyelinating polyneuropathy (CIDP) were 50% in the ATTRv amyloidosis group vs 8.7% in CMT group (Fisher's exact, p < .01). Other measures and outcomes were not different between the two groups. Five of the six patients with ATTRv amyloidosis received treatment and survived. INTERPRETATION: For effective treatments, the transthyretin gene should be screened in patients with suspected CMT with old age at onset of neurological symptoms, initial sensory symptoms, and histories of suspected CIDP.

Efficacy of Corticosteroid Therapy for HTLV-1-Associated Myelopathy: A Randomized Controlled Trial (HAMLET-P).

Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were assigned (1:1) to receive or not receive a 3-day course of intravenous methylprednisolone in addition to oral prednisolone therapy. Meanwhile, slow progressors were assigned (1:1) to receive oral prednisolone or placebo. The primary outcomes were a composite of ≥1-grade improvement in the Osame Motor Disability Score or ≥30% improvement in the 10 m walking time (10 mWT) at week 2 for rapid progressors and changes from baseline in 10 mWT at week 24 for slow progressors. In the rapid progressor trial, all four patients with but only one of four without intravenous methylprednisolone achieved the primary outcome (p = 0.14). In the slow progressor trial, the median changes in 10 mWT were -13.8% (95% CI: -20.1--7.1; p < 0.001) and -6.0% (95% CI: -12.8-1.3; p = 0.10) with prednisolone and placebo, respectively (p for between-group difference = 0.12). Whereas statistical significance was not reached for the primary endpoints, the overall data indicated the benefit of corticosteroid therapy. (Registration number: UMIN000023798, UMIN000024085).

Radiological and Laboratory Features of Multiple Sclerosis Patients With Immunosuppressive Therapy: A Multicenter Retrospective Study in Japan.

Background: Multiple sclerosis (MS) is a relapsing, inflammatory, and demyelinating disease of central nervous system showing marked clinical heterogeneity. Many factors might influence the choice of relapse prevention drug, and treatment response varies among patients. Despite the enlargement of disease-modifying drugs for MS (MS-DMDs), some patients have been treated with corticosteroid and/or immunosuppressant (CS/IS). Objective: To clarify the radiological and laboratory features of MS treated with CS/IS for relapse prevention. Methods: Clinical records including radiological and laboratory findings, and drugs used for relapse prevention were reviewed retrospectively. Results: Out of 92 consecutive MS patients, 25 (27%) were treated with CS/IS. The followings were observed less frequently in patients treated with CS/IS than in those with MS-DMDs: three or more periventricular lesions, ovoid lesions, subcortical lesions, typical contrast-enhancing lesions, negative for serum autoantibodies, and positive for oligoclonal bands in the cerebrospinal fluid. Multiple logistic regression analysis revealed that the absence of typical contrast-enhancing lesions and positivity for serum autoantibodies were independent factors associated with CS/IS prescription (odds ratio 25.027 and 14.537, respectively). Conclusion: In this cohort of Japanese patients clinically diagnosed with MS, radiological and serological findings atypical of MS were observed more frequently in patients treated with CS/IS than in those with MS-DMDs as a part of MS therapy. The absence of contrast-enhancing lesions typical of MS and positivity for serum autoantibodies were independent factors strongly associated with CS/IS use.

Cybernic treatment with wearable cyborg Hybrid Assistive Limb (HAL) improves ambulatory function in patients with slowly progressive rare neuromuscular diseases: a multicentre, randomised, controlled crossover trial for efficacy and safety (NCY-3001).

BACKGROUND: Rare neuromuscular diseases such as spinal muscular atrophy, spinal bulbar muscular atrophy, muscular dystrophy, Charcot-Marie-Tooth disease, distal myopathy, sporadic inclusion body myositis, congenital myopathy, and amyotrophic lateral sclerosis lead to incurable amyotrophy and consequent loss of ambulation. Thus far, no therapeutic approaches have been successful in recovering the ambulatory ability. Thus, the aim of this trial was to evaluate the efficacy and safety of cybernic treatment with a wearable cyborg Hybrid Assistive Limb (HAL, Lower Limb Type) in improving the ambulatory function in those patients. RESULTS: We conducted an open-label, randomised, controlled crossover trial to test HAL at nine hospitals between March 6, 2013 and August 8, 2014. Eligible patients were older than 18 years and had a diagnosis of neuromuscular disease as specified above. They were unable to walk for 10 m independently and had neither respiratory failure nor rapid deterioration in gait. The primary endpoint was the distance passed during a two-minute walk test (2MWT). The secondary endpoints were walking speed, cadence, and step length during the 10-m walk test (10MWT), muscle strength by manual muscle testing (MMT), and a series of functional measures. Adverse events and failures/problems/errors with HAL were also evaluated. Thirty patients were randomly assigned to groups A or B, with each group of 15 receiving both treatments in a crossover design. The efficacy of a 40-min walking program performed nine times was compared between HAL plus a hoist and a hoist only. The final analysis included 13 and 11 patients in groups A and B, respectively. Cybernic treatment with HAL resulted in a 10.066% significantly improved distance in 2MWT (95% confidence interval, 0.667-19.464; p = 0.0369) compared with the hoist only treatment. Among the secondary endpoints, the total scores of MMT and cadence at 10MWT were the only ones that showed significant improvement. The only adverse effects were slight to mild myalgia, back pain, and contact skin troubles, which were easily remedied. CONCLUSIONS: HAL is a new treatment device for walking exercise, proven to be more effective than the conventional method in patients with incurable neuromuscular diseases. TRIAL REGISTRATION: JMACTR, JMA-IIA00156.

Quantitative assessment of muscle echogenicity in Charcot-Marie-Tooth disease type 1A by automatic thresholding methods.

OBJECTIVE: To investigate the utility of automatic thresholding methods for quantitative muscle echogenicity assessment as a marker of disease severity in Charcot-Marie-Tooth disease type 1A (CMT1A). METHODS: Muscle ultrasound was performed in 15 CMT1A patients and 7 healthy controls. Muscle echogenicity of six limb muscles in each subject was assessed by 16 automatic thresholding methods and conventional grey-scale analysis. Echogenicity of each method in CMT1A patients was compared with that in controls. A correlation between the echogenicity and CMT neuropathy score (CMTNS) was also analysed in CMT1A patients. RESULTS: Significant differences in mean echogenicity of the 6 muscles between CMT1A patients and controls were found both in grey-scale analysis (p < 0.01) and 11 of the 16 automatic thresholding methods (p < 0.05 in each method). In CMT1A patients, mean echogenicity of the 6 muscles was positively correlated with CMTNS in 8 of the 16 automatic thresholding methods, but not in grey-scale analysis. CONCLUSION: Automatic thresholding methods can be used to detect the difference in muscle echogenicity between CMT1A patients and controls. Echogenicity parameters correlate with the disease severity. SIGNIFICANCE: Quantitative muscle echogenicity assessment by automatic thresholding methods shows potential as a surrogate marker of disease progression in CMT1A.

Genome wide association study of HTLV-1-associated myelopathy/tropical spastic paraparesis in the Japanese population.

HTLV-1-associated myelopathy (HAM/TSP) is a chronic and progressive inflammatory disease of the central nervous system. The aim of our study was to identify genetic determinants related to the onset of HAM/TSP in the Japanese population. We conducted a genome-wide association study comprising 753 HAM/TSP patients and 899 asymptomatic HTLV-1 carriers. We also performed comprehensive genotyping of HLA-A, -B, -C, -DPB1, -DQB1, and -DRB1 genes using next-generation sequencing technology for 651 HAM/TSP patients and 804 carriers. A strong association was observed in HLA class I (P = 1.54 × 10-9) and class II (P = 1.21 × 10-8) loci with HAM/TSP. Association analysis using HLA genotyping results showed that HLA-C*07:02 (P = 2.61 × 10-5), HLA-B*07:02 (P = 4.97 × 10-10), HLA-DRB1*01:01 (P = 1.15 × 10-9) and HLA-DQB1*05:01 (P = 2.30 × 10-9) were associated with disease risk, while HLA-B*40:06 (P = 3.03 × 10-5), HLA-DRB1*15:01 (P = 1.06 × 10-5) and HLA-DQB1*06:02 (P = 1.78 × 10-6) worked protectively. Logistic regression analysis identified amino acid position 7 in the G-BETA domain of HLA-DRB1 as strongly associated with HAM/TSP (P = 9.52 × 10-10); individuals homozygous for leucine had an associated increased risk of HAM/TSP (odds ratio, 9.57), and proline was protective (odds ratio, 0.65). Both associations were independent of the known risk associated with proviral load. DRB1-GB-7-Leu was not significantly associated with proviral load. We have identified DRB1-GB-7-Leu as a genetic risk factor for HAM/TSP development independent of proviral load. This suggests that the amino acid residue may serve as a specific marker to identify the risk of HAM/TSP even without knowledge of proviral load. In light of its allele frequency worldwide, this biomarker will likely prove useful in HTLV-1 endemic areas across the globe.

Prediction Model of Amyotrophic Lateral Sclerosis by Deep Learning with Patient Induced Pluripotent Stem Cells.

In amyotrophic lateral sclerosis (ALS), early diagnosis is essential for both current and potential treatments. To find a supportive approach for the diagnosis, we constructed an artificial intelligence-based prediction model of ALS using induced pluripotent stem cells (iPSCs). Images of spinal motor neurons derived from healthy control subject and ALS patient iPSCs were analyzed by a convolutional neural network, and the algorithm achieved an area under the curve of 0.97 for classifying healthy control and ALS. This prediction model by deep learning algorithm with iPSC technology could support the diagnosis and may provide proactive treatment of ALS through future prospective research. ANN NEUROL 2021;89:1226-1233.

A 10-year longitudinal study of deep white matter lesions on magnetic resonance imaging.

PURPOSE: Deep white matter lesions (DWMLs), T2 high-intensity areas in the subcortical white matter on magnetic resonance imaging (MRI), are a clinical phenotype of cerebral small vessel disease. Factors such as age and hypertension have been reported to significantly contribute to the presence and severity of DWMLs in cross-sectional studies. We herein report a 10-year longitudinal study on DWMLs in elderly Japanese subjects to reveal the clinical variables contributing to the progression of DWMLs. METHODS: A total of 469 Japanese subjects were invited to participate in the study. Of the participants at baseline, 259 subjects completed the revisit MRI study 10 years later. In those 259 subjects, we evaluated the correlation between the progression of DWMLs and clinical variables, such as the gender, age, and overt vascular risk factors. To clarify the role of hypertension, 200 subjects with grade 1 DWMLs at baseline were categorized into three groups according to their status of hypertension and its treatment. RESULTS: Of the 200 subjects with grade 1 DWMLs, 47 subjects (23.5%) showed progression of DWMLs (progression group). In the progression group, the percentage of subjects with hypertension and the systolic blood pressure values were higher than in the non-progression group. In addition, subjects ≥ 60 years old at baseline tended to show deterioration of DWMLs in the group with hypertension without antihypertensive treatment. CONCLUSION: The results of this 10-year longitudinal study imply a positive correlation between long-standing hypertension and the progression of DWMLs.

High-density surface electromyography to assess motor unit firing rate in Charcot-Marie-Tooth disease type 1A patients.

OBJECTIVE: The aim of this study was to elucidate the characteristics of the motor unit (MU) firing rate in Charcot-Marie-Tooth disease type 1A (CMT1A) patients and its longitudinal change using high-density surface-electromyography (surface-EMG) and MU decomposition analysis. METHODS: Nineteen patients with CMT1A and 21 force-matched healthy controls prospectively underwent surface-EMG recording of the vastus lateralis muscle during ramp-up and sustained contractions on performing isometric knee extension. After decomposition analysis, instantaneous firing rates (IFRs) of individually identified MUs were calculated. In CMT1A patients, follow-up measurements were performed one year after the baseline. Comparison of IFRs and clinical variables between CMT1A patients and controls at the baseline and between the baseline and after one year in CMT1A patients was performed. RESULTS: Mean IFRs of MUs were lower in CMT1A patients than in controls. This was true at various force levels in ramp-up contractions (p < 0.01. e.g., 10.3 (CMT1A patients) vs. 12.2 (controls) pulses-per-second (pps) at 22.5-27.5% of maximal voluntary contraction (MVC) in MUs recruited at <7.5% of MVC) and at any time-point during sustained contractions (p < 0.001. e.g., 8.0 vs. 9.3 pps, respectively, at 10-20 seconds). In CMT1A patients, mean IFRs at 0-10 seconds of sustained contraction were significantly decreased over one year (from 8.06 to 7.52 pps; p = 0.027), whereas the disease severity score and MVC of knee extension did not change over time. CONCLUSION: CMT1A patients had a lower individual MU firing rate. SIGNIFICANCE: The MU firing rate is a potential short-term biomarker of axonal damage in CMT1A patients.

Genetic spectrum of Charcot-Marie-Tooth disease associated with myelin protein zero gene variants in Japan.

We aimed to reveal the genetic features associated with MPZ variants in Japan. From April 2007 to August 2017, 64 patients with 23 reported MPZ variants and 21 patients with 17 novel MPZ variants were investigated retrospectively. Variation in MPZ variants and the pathogenicity of novel variants was examined according to the American College of Medical Genetics standards and guidelines. Age of onset, cranial nerve involvement, serum creatine kinase (CK), and cerebrospinal fluid (CSF) protein were also analyzed. We identified 64 CMT patients with reported MPZ variants. The common variants observed in Japan were different from those observed in other countries. We identified 11 novel pathogenic variants from 13 patients. Six novel MPZ variants in eight patients were classified as likely benign or uncertain significance. Cranial nerve involvement was confirmed in 20 patients. Of 30 patients in whom serum CK levels were evaluated, eight had elevated levels. Most of the patients had age of onset >20 years. In another subset of 30 patients, 18 had elevated CSF protein levels; four of these patients had spinal diseases and two had enlarged nerve root or cauda equina. Our results suggest genetic diversity across patients with MPZ variants.