Compound Heterozygous Mutations of SACS in a Korean Cohort Study of Charcot-Marie-Tooth Disease Concurrent Cerebellar Ataxia and Spasticity.

Mutations in the SACS gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of Charcot-Marie-Tooth disease (CMT). This study aimed to identify SACS mutations in a Korean CMT cohort with cerebellar ataxia and spasticity by whole exome sequencing (WES). As a result, eight pathogenic SACS mutations in four families were identified as the underlying causes of these complex phenotypes. The prevalence of CMT families with SACS mutations was determined to be 0.3%. All the patients showed sensory, motor, and gait disturbances with increased deep tendon reflexes. Lower limb magnetic resonance imaging (MRI) was performed in four patients and all had fatty replacements. Of note, they all had similar fatty infiltrations between the proximal and distal lower limb muscles, different from the neuromuscular imaging feature in most CMT patients without SACS mutations who had distal dominant fatty involvement. Therefore, these findings were considered a characteristic feature in CMT patients with SACS mutations. Although further studies with more cases are needed, our results highlight lower extremity MRI findings in CMT patients with SACS mutations and broaden the clinical spectrum. We suggest screening for SACS in recessive CMT patients with complex phenotypes of ataxia and spasticity.

Variants of aminoacyl-tRNA synthetase genes in Charcot-Marie-Tooth disease: A Korean cohort study.

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. This study was performed to investigate ARS gene mutations in a CMT cohort of 710 Korean families. Whole-exome sequencing was applied to 710 CMT patients who were negative for PMP22 duplication. We identified 12 disease-causing variants (from 13 families) in GARS1, AARS1, HARS1, WARS1, and YARS1 genes. Seven variants were determined to be novel. The frequency of overall ARS gene mutations was 1.22% among all independent patients diagnosed with CMT and 1.83% in patients negative for PMP22 duplication. WARS1 mutations have been reported to cause dHMN; however, in our patients with WARS1 variants, CMT was associated with sensory involvement. We analyzed genotype-phenotype correlations and expanded the phenotypic spectrum of patients with CMT possessing ARS gene variants. We also characterized clinical phenotypes according to ARS genes. This study will be useful for performing exact molecular and clinical diagnoses and providing reference data for other population studies.

Texture analysis using T1-weighted images for muscles in Charcot-Marie-Tooth disease patients and volunteers.

OBJECTIVES: To explore whether texture features using T1-weighted images correlate with fat fraction, and whether they differ between Charcot-Marie-Tooth (CMT) disease patients and volunteers. METHODS: The institutional review board approved this retrospective study, and the requirement for informed consent was waived; data of eighteen CMT patients and eighteen healthy volunteers from a previous study was used. Texture features of the muscles including mean, standard deviation (SD), skewness, kurtosis, and entropy of the signal intensity were derived from T1-weighted images. Spearman's correlation analysis was used to assess the relationship between texture features and fat fraction measured by 3D multiple gradient echo Dixon-based sequence. Mann-Whitney U test was used to compare the texture features between CMT patients and volunteers. Intraobserver and interobserver agreements for the texture features were assessed using the intraclass correlation coefficient. RESULTS: The SD (ρ = 0.256, p < 0.001) and entropy (ρ = 0.263, p < 0.001) were significantly and positively correlated with fat fraction; skewness (ρ = - 0.110, p = 0.027) and kurtosis (ρ = - 0.149, p = 0.003) were significantly and inversely correlated with fat fraction. The CMT patients showed a significantly higher SD (63.45 vs. 49.26; p < 0.001), skewness (1.06 vs. 0.56; p < 0.001), kurtosis (4.00 vs. 1.81; p < 0.001), and entropy (3.20 vs. 3.02; p < 0.001) than did the volunteers. Intraobserver and interobserver agreements were almost perfect for mean, SD, and entropy. CONCLUSIONS: Texture features using T1-weighted images correlated with fat fraction and differed between CMT patients and volunteers. KEY POINTS: • Standard deviation and entropy of muscles derived from T1-weighted images were significantly and positively correlated with the muscle fat fraction. • Mean, standard deviation, and entropy were considered highly reliable in muscle analyses. • Texture features may have the potential to diagnose early stage of intramuscular fatty infiltration.

Diffusion tensor imaging of the sciatic nerve in Charcot-Marie-Tooth disease type I patients: a prospective case-control study.

OBJECTIVES: This study aimed to evaluate whether diffusion tensor imaging (DTI) parameters and cross-sectional area (CSA) can differentiate between the sciatic nerve of Charcot-Marie-Tooth (CMT) disease type I (demyelinating form) patients and that of controls. METHODS: This prospective comparison study included 18 CMT type I patients and 18 age/sex-matched volunteers. Magnetic resonance imaging including DTI and axial T2-weighted Dixon sequence was performed for each subject. Region of interest analysis was independently performed by two radiologists on each side of the sciatic nerve at four levels: hamstring tendon origin (level 1), lesser trochanter of the femur (level 2), gluteus maximus tendon insertion (level 3), and mid-femur (level 4). Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) were calculated. The CSA of the sciatic nerve bundle was measured using axial water-only image at each level. Comparisons of DTI parameters between the two groups were performed using the two-sample t test and Mann-Whitney U test. Interobserver agreement analysis was also conducted. RESULTS: Interobserver agreement was excellent for all DTI parameter analyses. FA was significantly lower at all four levels in CMT patients than controls. RD, MD, and CSA were significantly higher at all four levels in CMT patients. AD was significantly higher at level 2 in CMT patients. CONCLUSION: DTI assessment of the sciatic nerve is reproducible and can discriminate the demyelinating nerve pathology of CMT type I patients from normal nerves. The CSA of the sciatic nerve is also a potential parameter for diagnosing nerve abnormality in CMT type I patients. KEY POINTS: • Diffusion tensor imaging parameters of the sciatic nerve at proximal to mid-femur level revealed significant differences between the Charcot-Marie-Tooth disease patients and controls. • The cross-sectional area of the sciatic nerve was significantly larger in the Charcot-Marie-Tooth disease patients. • Interobserver agreement was excellent (intraclass coefficient > 0.8) for all diffusion tensor imaging parameter analyses.

Risk Factors for Fracture Nonunion and Transverse Atlantal Ligament Injury After Isolated Atlas Fractures: A Case Series of 97 Patients.

BACKGROUND: The management of atlas fractures is controversial and hinges on the integrity of transverse atlantal ligament (TAL). OBJECTIVE: To identify risk factors for atlas fracture nonunion, with and without TAL injury. METHODS: All isolated, traumatic atlas fractures treated at our institution between 1999 and 2016 were analyzed. Multivariable logistic regression was used to identify variables associated with TAL injury confirmed on MRI, occult TAL injury seen on MRI but not suspected on computed tomography (CT), and with fracture nonunion on follow-up CT at 12 weeks. RESULTS: Lateral mass displacement (LMD) ≥ 7 mm had a 48.2% sensitivity, 98.3% specificity, and 82.6% accuracy for identifying TAL injury. MRI-confirmed TAL injury was independently associated with LMD > 7 mm ( P = .004) and atlanto-dental interval ( P = .039), and occult TAL injury was associated with atlanto-dental interval ( P = .019). Halo immobilization was associated with having a Gehweiler type 3 fracture ( P = .020), a high-risk injury mechanism ( P = .023), and an 18.1% complication rate. Thirteen patients with TAL injury on MRI and/or LMD ≥ 7 mm were treated with a cervical collar only, and 11 patients (84.6%) healed at 12 weeks. Nonunion rates at 12 weeks were equivalent between halo (11.1%) and cervical collar (12.5%). Only age independently predicted nonunion at 12 weeks ( P = .026). CONCLUSION: LMD > 7 mm on CT is not sensitive for TAL injury. Some atlas fractures with TAL injury can be managed with a cervical collar. Nonunion rates are not different between halo immobilization and cervical collar, but a strong selection bias precludes directly comparing the efficacy of these modalities. Age independently predicts nonunion.

Magnetic resonance imaging-based lower limb muscle evaluation in Charcot-Marie-Tooth disease type 1A patients and its correlation with clinical data.

We aimed to derive comprehensive MRI parameters that reflect intramuscular fat infiltration severity for designated lower extremity levels, based on semiquantitative analyses in Charcot-Marie-Tooth disease type 1A (CMT1A) patients. We reviewed lower extremity MRIs of 116 CMT1A patients. Intramuscular fat infiltration grading using the Mercuri scale was performed for the non-dominant lower extremity at three levels (proximal, mid, and distal) for the thigh and at two levels (proximal and distal) for the lower leg. Based on MRI results, the following parameters were calculated for each level and for entire muscles: fat infiltration proportion (FIP), significant fat infiltration proportion (SigFIP), and severe fat infiltration proportion (SevFIP). The relationships between the MRI parameters and clinical data were evaluated using Spearman's correlation analysis. FIP, SigFIP, and SevFIP measured for entire muscles significantly correlated with Charcot-Marie-Tooth Neuropathy Score (p < 0.001), functional disability scale (p < 0.001), 10-m walk test time (p = 0.0003, 0.0010, and 0.0011), and disease duration (p < 0.001). Similar correlations were demonstrated for FIP, SigFIP, and SevFIP acquired from the lower leg. Our MRI parameters obtained through semiquantitative analyses of muscles significantly correlated with clinical parameters in CMT1A patients, suggesting their potential applicability as imaging markers for clinical severity.

Identification and clinical characterization of Charcot-Marie-Tooth disease type 1C patients with LITAF p.G112S mutation.

BACKGROUND: Charcot-Marie-Tooth disease type 1C (CMT1C) is a rare subtype associated with LITAF gene mutations. Until now, only a few studies have reported the clinical features of CMT1C. OBJECTIVE: This study was performed to find CMT1C patients with mutation of LITAF in a Korean CMT cohort and to characterize their clinical features. METHODS: In total, 1,143 unrelated Korean families with CMT were enrolled in a cohort. We performed whole exome sequencing to identify LITAF mutations, and examined clinical phenotypes including electrophysiological and MRI features for the identified CMT1C patients. RESULTS: We identified 10 CMT1C patients from three unrelated families with p.G112S mutation in LITAF. The frequency of CMT1C among CMT1 patients was 0.59%, which is similar to reports from Western populations. CMT1C patients showed milder symptoms than CMT1A patients. The mean CMT neuropathy score version 2 was 7.7, and the mean functional disability scale was 1.0. Electrophysiological findings showed a conduction block in 22% of affected individuals. Lower extremity MRIs showed that the superficial posterior and anterolateral compartments of the calf were predominantly affected. CONCLUSIONS: We found a conduction block in Korean CMT1C patients with p.G112S mutation and first described the characteristic MRI findings of the lower extremities in patients with LITAF mutation. These findings will be helpful for genotype-phenotype correlation and will widen understanding about the clinical spectrum of CMT1C.

Phenotypic heterogeneity in patients with NEFL-related Charcot-Marie-Tooth disease.

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. Ten NEFL mutations in 17 families (1.49%) were identified, of which three (p.L312P, p.Y443N, and p.K467N) were novel. Eight de novo cases were identified at a rate of 0.47 based on a cosegregation analysis. The age of onset was ≤3 years in five cases (13.5%). The patients revealed additional features including delayed walking, ataxia, dysphagia, dysarthria, dementia, ptosis, waddling gait, tremor, hearing loss, and abnormal visual evoked potential. Signs of ataxia were found in 26 patients (70.3%). In leg MRI analyses, various degrees of intramuscular fat infiltration were found. All compartments were evenly affected in CMT1F patients. The anterior and anterolateral compartments were affected in CMT2E, and the posterior compartment was affected in CMTDIG. Thus, NEFL-related CMT patients showed phenotypic heterogeneities. This study's clinical, genetic, and neuroimaging results could be helpful in the evaluation of novel NEFL variants and differential diagnosis against other CMT subtypes.

Clinical and Neuroimaging Features in Charcot-Marie-Tooth Patients with GDAP1 Mutations.

BACKGROUND AND PURPOSE: Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) are known to cause Charcot-Marie-Tooth disease (CMT). These mutations are very rare in most countries, but not in certain Mediterranean countries. The purpose of this study was to identify the clinical and neuroimaging characteristics of Korean CMT patients with GDAP1 mutations. METHODS: Gene sequencing was applied to 1,143 families in whom CMT had been diagnosed from 2005 to 2020. PMP22 duplication was found in 344 families, and whole-exome sequencing was performed in 699 patients. Magnetic resonance imaging (MRI) were obtained using either a 1.5-T or 3.0-T MRI system. RESULTS: We found ten patients from eight families with GDAP1 mutations: five with autosomal dominant (AD) CMT type 2K (three families with p.R120W and two families with p.Q218E) and three with autosomal recessive (AR) intermediate CMT type A (two families with homozygous p.H256R and one family with p.P111H and p.V219G mutations). The frequency was about 1.0% exclusive of the PMP22 duplication, which is similar to that in other Asian countries. There were clinical differences among AD GDAP1 patients according to mutation sites. Surprisingly, fat infiltrations evident in lower-limb MRI differed between AD and AR patients. The posterior-compartment muscles in the calf were affected early and predominantly in AD patients, whereas AR patients showed fat infiltration predominantly in the anterolateral-compartment muscles. CONCLUSIONS: This is the first cohort report on Korean patients with GDAP1 mutations. The patients with AD and AR inheritance routes exhibited different clinical and neuroimaging features in the lower extremities. We believe that these results will help to expand the knowledge of the clinical, genetic, and neuroimaging features of CMT.

Intraepineurial fat quantification and cross-sectional area analysis of the sciatic nerve using MRI in Charcot-Marie-Tooth disease type 1A patients.

The objectives of this study were to assess the fat fraction (FF) and cross-sectional area (CSA) of the sciatic nerve in Charcot-Marie-Tooth disease type 1A (CMT1A) patients using Dixon-based proton density fat quantification MRI and to elucidate its potential association with clinical parameters. Thigh MRIs of 18 CMT1A patients and 18 age- and sex-matched volunteers enrolled for a previous study were reviewed. Analyses for FF and CSA of the sciatic nerve were performed at three levels (proximal to distal). CSA and FF were compared between the two groups and among the different levels within each group. The relationship between the MRI parameters and clinical data were assessed in the CMT1A patients. The CMT1A patients showed significantly higher FF at level 3 (p = 0.0217) and significantly larger CSA at all three levels compared with the control participants (p < 0.0001). Comparisons among levels showed significantly higher FF for levels 2 and 3 than for level 1 and significantly larger CSA for level 2 compared with level 1 in CMT1A patients. CSA at level 3 correlated positively with the CMT neuropathy score version 2 (CMTNSv2). In conclusion, the sciatic nerve FF of CMT1A patients was significantly higher on level 3 compared with both the controls and the measurements taken on more proximal levels, suggesting the possibility of increased intraepineurial fat within the sciatic nerves of CMT1A patients, with a possible distal tendency. Sciatic nerve CSA at level 3 correlated significantly and positively with CMTNSv2, suggesting its potential value as an imaging marker for clinical severity.

Clinical and Neuroimaging Features in Charcot-Marie-Tooth Patients with GNB4 Mutations.

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy. Mutations in the GNB4 gene cause dominant intermediate CMT type F (CMTDIF). The aim of this study is to investigate phenotypic heterogeneities and characteristics of CMT patients with GNB4 mutations. We enrolled 1143 Korean CMT families and excluded 344 families with a PMP22 duplication. We further analyzed the 799 remaining families to find their GNB4 mutations using whole-exome sequencing (WES). We identified two mutations (p.Gly77Arg and p.Lys89Glu) in three families, among which a heterozygous p.Gly77Arg mutation was novel. In addition, a significant uncertain variant (p.Thr177Asn) was observed in one family. The frequency of the GNB4 mutation in the Korean population is 0.38% in PMP22 duplication-negative families. All three families showed de novo mutation. Electrophysiological findings regarding the p.Lys89Glu mutation showed that the motor nerve conduction velocity (MNCV) of the median nerve was markedly reduced, indicating demyelinating neuropathy, and sural nerve biopsy revealed severe loss of myelinated axons with onion bulb formation. Lower extremity Magnetic Resonance Imaging (MRI) demonstrated relatively more severe intramuscular fat infiltrations in demyelinating type (p.Lys89Glu mutation) patients compared to intermediate type (p.Gly77Arg mutation) patients. The anterolateral and superficial posterior compartment muscles of the distal calf were preferentially affected in demyelinating type patients. Therefore, it seems that the investigated GNB4 mutations do cause not only the known intermediate type but also demyelinating-type neuropathy. We first presented three Korean families with GNB4 mutations and found phenotypic heterogeneities of both intermediate and demyelinating neuropathy. We suggest that those findings are useful for the differential diagnosis of CMT patients with unknown GNB4 variants.

Genetic and clinical spectrums in Korean Charcot-Marie-Tooth disease patients with myelin protein zero mutations.

BACKGROUND: Charcot-Marie-Tooth disease (CMT) is the most common disorder of inherited peripheral neuropathies characterized by distal muscle weakness and sensory loss. CMT is usually classified into three types, demyelinating, axonal, and intermediate neuropathies. Mutations in myelin protein zero (MPZ) gene which encodes a transmembrane protein of the Schwann cells as a major component of peripheral myelin have been reported to cause various type of CMT. METHODS: This study screened MPZ mutations in Korean CMT patients (1,121 families) by whole exome sequencing and targeted sequencing. RESULTS: We identified 22 pathogenic or likely pathogenic MPZ mutations in 36 families as the underlying cause of the CMT1B, CMTDID, or CMT2I subtypes. Among them, five mutations were novel. The frequency of CMT patients with the MPZ mutations was similar or slightly lower compared to other ethnic groups. CONCLUSIONS: We showed that the median onset ages and clinical phenotypes varied by subtypes: the most severe in the CMT1B group, and the mildest in the CMT2I group. This study also observed a clear correlation that earlier onsets cause more severe symptoms. We believe that this study will provide useful reference data for genetic and clinical information on CMT patients with MPZ mutations in Korea.

The antimicrobial activity of compounds from the leaf and stem of Vitis amurensis against two oral pathogens.

Nine compounds isolated from the leaf and stem of Vitis amurensis Rupr. (Vitaceae) were evaluated for their antimicrobial activity against two oral pathogens, Streptococcus mutans and Streptococcus sanguis, which are associated with caries and periodontal disease, respectively. The results of several antimicrobial tests, including MIC, MBC, and TBAI, showed that three compounds inhibited the growth of the test bacteria at concentrations ranging from 12.5 to 50 microg/mL. Among these compounds, compound 5, trans-epsilon-viniferin, displayed the strongest activity against S. mutans and S. sanguis with MIC values of 25 and 12.5 microg/mL, respectively. This is the first report on the antimicrobial activity of stilbenes and oligostilbenes isolated from the leaf and stem of V. amurensis. Thus, this result suggests that natural antimicrobial compounds derived from V. amurensis may benefit oral health as plaque-control agents for the prevention of dental caries and periodontal disease.

Muscle fat quantification using magnetic resonance imaging: case-control study of Charcot-Marie-Tooth disease patients and volunteers.

BACKGROUND: This study aimed to evaluate the potential value of 3D multiple gradient echo Dixon-based magnetic resonance imaging (MRI) sequence as a tool for thigh intramuscular fat quantification in Charcot-Marie-Tooth disease (CMT) patients. METHODS: A prospective comparison study comprising 18 CMT patients and 18 age/sex-matched volunteers was performed. MRI including 3D multiple gradient echo Dixon-based imaging was performed for each subject. Region of interest analyses were performed at the upper and lower third of both thighs. The two-sample t-test or Wilcoxon rank sum test was used for intergroup comparison of the mean muscle fat fraction. Intraclass correlation coefficients were used to evaluate the interobserver agreement and test-retest reproducibility. Semiquantitive analysis using the Goutallier classification (Grades 0-4) was performed on T1-weighted images in upper thigh muscles. For Goutallier Grade 0 muscles, comparison of the mean intramuscular fat fraction between volunteers and CMT patients was performed. RESULTS: The interobserver agreements were excellent for all measurements (intraclass correlation coefficients > 0.8). Mean muscle fat fractions were significantly higher in all the measured muscles of CMT patients (P < 0.05) except in the adductor magnus in the upper thigh (P = 0.109). Goutallier Grade 0 muscles of the CMT patients showed a significantly higher mean fat fraction compared with that of the volunteers (P < 0.05). CONCLUSIONS: 3D multiple gradient echo Dixon-based MRI is a reproducible and sensitive technique which can reveal a significant difference in the fat fraction of thigh muscle, including comparison between Goutallier Grade 0 muscles, between CMT patients and volunteers.

Application of quantitative light-induced fluorescence to determine the depth of demineralization of dental fluorosis in enamel microabrasion: a case report.

Enamel microabrasion has become accepted as a conservative, nonrestorative method of removing intrinsic and superficial dysmineralization defects from dental fluorosis, restoring esthetics with minimal loss of enamel. However, it can be difficult to determine if restoration is necessary in dental fluorosis, because the lesion depth is often not easily recognized. This case report presents a method for analysis of enamel hypoplasia that uses quantitative light-induced fluorescence (QLF) followed by a combination of enamel microabrasion with carbamide peroxide home bleaching. We describe the utility of QLF when selecting a conservative treatment plan and confirming treatment efficacy. In this case, the treatment plan was based on QLF analysis, and the selected combination treatment of microabrasion and bleaching had good results.

[Therapeutic effect of the endoscopic N-butyl-2-cyanoacrylate injection for acute esophagogastric variceal bleeding: comparison with transjugular intrahepatic portosystemic shunt].

BACKGROUND/AIMS: Though endoscopic therapies such as variceal ligation and sclerotherapy has been performed, bleeding from the large esophageal and gastric varices still poses significant risk of death. Decrease of portal pressure by TIPS (transjugular intrahepatic portosystemic shunt) or surgical shunt was indicated as cause of failure of endoscopic therapies. Treatment of N-butyl-2-cyanoacrylate has been especially effective for gastric variceal bleeding, but comparison with other treatments had not been reported yet. In this study, the effect of cyanoacrylate injection therapy was cross-examined with the result of TIPS in acute esophagogastric variceal bleedings. METHODS: From April 1995 to June 2002, endoscopic cyanoacrylate injection therapy (43 cases) and TIPS (63 cases) were performed in our hospital. Each group was analysed regarding their clinical results including initial hemostasis rate, rebleeding rate, survival duration, mortality and morbidity. RESULTS: Initial hemostasis rate was 95.3% in cyanoacrylate group and 92.1% in TIPS group. Cumulative probability of rebleeding was not different between two groups. Overall complication rates associated with the procedure were 50.8% in TIPS group and 9.3% in cyanoacrylate group. There was no significant difference between two groups in their survival rates. CONCLUSIONS: Cyanoacrylate injection therapy was relatively safe, and has comparable results with TIPS for uncontrollable and severe esophagogastric variceal bleedings.