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Cerebrospinal fluid (CSF) amyloid-beta 1-42 (Aβ1-42) and amyloid positron emission tomography (PET) are the 2 main Alzheimer disease amyloid biomarkers that have been validated in neuropathologically confirmed Alzheimer disease cases. Although many studies have shown concordance of amyloid positivity or negativity between CSF Aβ1-42 and amyloid PET, several studies also reported discrepancies between these 2 Aβ biomarkers. We conducted a comparison of CSF Aβ1-42 level, amyloid PET, and autopsy findings in a case with progressive supranuclear palsy in which biomarker acquisition and postmortem pathologic examination were conducted almost at the same time. Our case with antemortem CSF Aβ1-42 (+)/amyloid PET (-) who was pathologically confirmed with Aβ pathology in the cerebral cortex may indicate CSF Aβ1-42 is more sensitive for assessing in vivo Aβ than amyloid PET.

Ocular albinism type 1 (OA1) is an X-linked inherited disease characterized by impaired visual acuity, congenital nystagmus, foveal hypoplasia, hypopigmentation of iris and fundus. It is caused by mutations in the G protein-coupled receptor 143 (GPR143) gene. The genetic characteristics of OA1 have not been well defined in Asians. In this study, six members from three consecutive generations of a Korean family with OA1 were enrolled. We performed whole-exome sequencing followed by validation and segregation analysis. Two affected patients underwent detailed ophthalmic examinations and eye movement recordings. Of the two affected males, the proband had all classical phenotypes of OA1, but the other showed isolated foveal hypoplasia without nystagmus. We identified a hemizygous missense ( $$\hbox {c.623C}>\hbox {A}$$ , p.Ala208Glu) mutation of GPR143 in affected males. This mutation was also present as heterozygous in two obligate female carriers, and was not found in unaffected members. Our data expands the spectrum of phenotypes and genotype in GPR143 in Asians, and highlights the phenotypic heterogeneity in OA1.

Young-onset dementia (YOD, age at onset below 45 y) has a broad differential diagnosis. We describe a 41-year-old man with atypical manifestations of YOD syndrome in cerebral thromoboangiitis obliterans (CTAO). Extensive antemortem workup including clinical assessment, laboratory investigations, neuroimaging, and genetic testing did not elucidate a diagnosis. Postmortem neuropathologic examination revealed cortical sickle-shaped granular atrophy, resulting from numerous remote infarcts and cortical microinfarcts that mainly affected the bilateral frontal and parietal lobe, confirming CTAO. Although CTAO is a rare cause of vascular dementia, it should be considered as one of the differentials in patients with YOD with a history of heavy smoking and presence of symmetric damages of watershed-territory on neuroimaging.

OBJECTIVE: This study aimed to investigate the underlying pathogenesis of acute unilateral vestibulopathy (AUV) using gene expression profiling combined with bioinformatics analysis. METHODS: Total RNA was extracted from the peripheral blood mononuclear cells of ten AUV patients in the acute phase and from ten controls. The differentially expressed genes (DEGs) between these two groups were screened using microarray analysis with the cut-off criteria (|fold changes| > 1.5 and p-value

Among the three isoforms encoded by Rtn4, Nogo-A has been intensely investigated as a central nervous system inhibitor. Although Nogo-A expression is increased in muscles of patients with amyotrophic lateral sclerosis, its role in muscle homeostasis and regeneration is not well elucidated. In this study, we discovered a significant increase in Nogo-A expression in various muscle-related pathological conditions. Nogo−/− mice displayed dystrophic muscle structure, dysregulated muscle regeneration following injury, and altered gene expression involving lipid storage and muscle cell differentiation. We hypothesized that increased Nogo-A levels might regulate muscle regeneration. Differentiating myoblasts exhibited Nogo-A upregulation and silencing Nogo-A abrogated myoblast differentiation. Nogo-A interacted with filamin-C, suggesting a role for Nogo-A in cytoskeletal arrangement during myogenesis. In conclusion, Nogo-A maintains muscle homeostasis and integrity, and pathologically altered Nogo-A expression mediates muscle regeneration, suggesting Nogo-A as a novel target for the treatment of myopathies in clinical settings.

Hyperventilation-induced downbeat nystagmus (HV-DBN) has been reported in cerebellar disorders and explained by a loss of the inhibitory cerebellar output via a metabolic effect on cerebellar Ca2+ channels. The aim of this study was to determine the clinical characteristics and underlying pathogenesis of episodic vestibular syndrome (EVS) with HV-DBN. Of 667 patients with EVS, we recruited 22 with HV-DBN and assessed their clinical characteristics, video-oculographic findings, and the results of molecular genetic analyses. The age at symptom onset was 47.5 ± 13.0 years (mean ± SD), and there was a female preponderance (n = 15, 68%). The duration of vertigo/dizziness attacks ranged from minutes to a few days, and 11 patients (50%) fulfilled the diagnostic criteria for vestibular migraine. HV-induced new-onset DBN in 8 patients, while the remaining 14 showed augmentation of spontaneous DBN by HV. The maximum slow-phase velocity of HV-DBN ranged from 2.2 to 11.9°/s, which showed a statistical difference with that of spontaneous DBN (median = 4.95, IQR = 3.68–6.55 vs. median = 1.25, IQR = 0.20–2.15, p

Background: Nogo-A (Rtn 4A), a member of the reticulon 4 (Rtn4) protein family, is a neurite outgrowth inhibitor protein that is primarily expressed in the central nervous system (CNS). However, the role of Nogo-A in inflammatory mechanisms remains unclear. Therefore, in this study, we used Nogo-knockout (KO) mice to explore its potential role in the inflammatory process. Here, we investigated whether Nogo-A affects the inflammatory process through transcription factor C/EBP homologous protein (CHOP). Results: Our results demonstrated that Nogo-A, CHOP, and pro-inflammatory factors were activated in the following: notexin-induced muscle injury, in human Duchenne muscular dystrophy (DMD) patients, in dystrophin-deficient (mdx) mice, in differentiated C2C12 myoblast cells, and in lipopolysaccharide (LPS)-stimulated bone marrow-derived macrophages (BMDM). Moreover, we found that Nogo-KO BMDM exhibited lower migratory ability compared with wild type (WT) BMDM after LPS treatment. Conclusion: Our data demonstrated that the Nogo-A-CHOP signaling pathway regulated the inflammatory process in notexin-induced injured muscle, in mdx mice, in DMD patients, in differentiated C2C12 cells, and in LPS-stimulated BMDM. Taken together, these results suggest that Nogo-A plays a vital role in inflammatory processes, which resembles the pathological mechanisms observed in the CNS.

Objectives: Vestibular migraine (VM) is a common vestibular disorder, and familial aggregation of VM with autosomal-dominant inheritance has been described, which supports a genetic background. This study aimed to describe the clinical phenotype of a family with VM, and identify a candidate gene for VM.Methods: We recruited six individuals (four affected and two unaffected) from three consecutive generations of a Korean family with VM, and performed whole-exome sequencing to search for candidate genes.Results: All affected individuals presented with recurrent vertigo, headache, and nausea/vomiting that fulfilled the diagnostic criteria of VM. Two individuals also experienced transient hemiparesis or dysarthria during the episodes. The symptoms were triggered by physical or emotional stress. Interictal examinations showed uni- or bi-directional horizontal gaze-evoked nystagmus in three of the individuals. They had no causative mutations in genes causing familial hemiplegic migraine or episodic ataxia. Through whole-exome sequencing from three affected individuals, we identified a nonsense mutation c.3526C>T in TRPM7 that encodes a cation channel selective to Ca2+ and Mg2+.Conclusions: Alterations in intracellular Ca2+ and Mg2+ homeostasis by TRPM7 mutation may contribute to the development of the VM phenotype. Our result suggest that TRPM7 is a novel candidate gene for VM.

Objectives: The cause of Meniere's disease (MD) is unclear but likely involves genetic and environmental factors. The aim of this study was to investigate the genetic basis underlying MD by screening putative candidate genes for MD.Methods: Sixty-eight patients who met the diagnostic criteria for MD of the Barany Society were included. We performed targeted gene sequencing using next generation sequencing (NGS) panel composed of 45 MD-associated genes. We identified the rare variants causing non-synonymous amino acid changes, stop codons, and insertions/deletions in the coding regions, and excluded the common variants with minor allele frequency >0.01 in public databases. The pathogenicity of the identified variants was analyzed by various predictive tools and protein structural modeling.Results: The average read depth for the targeted regions was 1446.3-fold, and 99.4% of the targeted regions were covered by 20 or more reads, achieving the high quality of the sequencing. After variant filtering, annotation, and interpretation, we identified a total of 15 rare heterozygous variants in 12 (17.6%) sporadic patients. Among them, four variants were detected in familial MD genes (DTNA, FAM136A, DPT), and the remaining 11 in MD-associated genes (PTPN22, NFKB1, CXCL10, TLR2, MTHFR, SLC44A2, NOS3, NOTCH2). Three patients had the variants in two or more genes. All variants were not detected in our healthy controls (n = 100). No significant differences were observed between patients with and without a genetic variant in terms of sex, mean age of onset, bilaterality, the type of MD, and hearing threshold at diagnosis.Conclusions: Our study identified rare variants of putative candidate genes in some of MD patients. The genes were related to the formation of inner ear structures, the immune-associated process, or systemic hemostasis derangement, suggesting the multiple genetic predispositions in the development of MD.

Miller Fisher syndrome (MFS) is characterized by a clinical triad of ophthalmoplegia, ataxia, and areflexia, and is closely associated with serum anti-GQ1b antibody. Although the clinical triad is the cardinal diagnostic clue, a variety of other symptoms and signs beyond the triad have been reported. To elucidate the frequency and characteristics of atypical clinical manifestations of MFS, we recruited 38 patients with MFS and evaluated the symptoms or signs beyond the classic triad. Eleven (29%) of 38 patients had atypical clinical manifestations of MFS such as headache (n = 6), delayed facial palsy (n = 3), divergence insufficiency (n = 2), and taste impairment (n = 2). Headache was localized to the periorbital (n = 3), temporal (n = 2), or whole (n = 1) area. Only one of them showed bilateral papilledema and an elevated opening pressure in cerebrospinal fluid analysis. Delayed facial palsy developed after the other signs have reached nadir (n = 1) or started to improve (n = 2), and did not follow a pattern of descending paralysis with other cranial neuropathies. Two patients showed divergence insufficiency without external ophthalmoplegia, and another two had taste impairment over the entire tongue without the other signs of facial and glossopharyngeal nerve involvements. Our study shows that approximately 30% of MFS patients can have atypical clinical manifestations beyond the classic triad. These results reflect the broad clinical spectrum of MFS, and might be associated with the presence of additional antiganglioside antibodies besides anti-GQ1b in patients with MFS.

INTRODUCTION Congenital myopathies are muscle diseases characterized by specific histopathologic features, generalized hypotonia from birth, and perinatal complications, although some cases develop during childhood or, rarely, in adulthood. We undertook this study to characterize congenital myopathies among patients registered at our institution. METHODS Clinical, histopathologic, and genetic features were evaluated in 34 patients recruited for this study. RESULTS The majority of patients experienced a childhood onset, and no disease-related mortality was recorded during follow-up. Functional outcomes were no better for those with late-onset disease, indicating later disease progression can be significant. Nemaline myopathy was the most frequent pathology, followed by central core disease and centronuclear myopathy. Among the 18 (54.5%) genetically confirmed patients, NEB and RYR1 mutations were the most common, followed by DNM2 mutations. DISCUSSION This study shows features not previously reported and suggests that congenital myopathy should be considered an important issue among adult patients. Muscle Nerve 58: 235-244, 2018.

Corticobasal syndrome (CBS) is a typical phenotype of corticobasal degeneration (CBD). However, autopsy series have shown that many CBS cases emerge from various types of non-CBD pathology. We report a 73-year-old Korean man who was clinically diagnosed with CBS whose underlying pathology was Alzheimer's disease (AD) at autopsy (CBS-AD). This case suggests that early developing memory impairment and myoclonus, severe temporoparietal atrophy, and visual hallucinations may support a more specific prediction of CBS-AD.

Dual adeno-associated virus (AAV) technology was developed in 2000 to double the packaging capacity of the AAV vector. The proof of principle has been demonstrated in various mouse models. Yet, pivotal evidence is lacking in large animal models of human diseases. Here we report expression of a 7-kb canine ΔH2–R15 mini-dystrophin gene using a pair of dual AAV vectors in the canine model of Duchenne muscular dystrophy (DMD). The ΔH2–R15 minigene is by far the most potent synthetic dystrophin gene engineered for DMD gene therapy. We packaged minigene dual vectors in Y731F tyrosine-modified AAV-9 and delivered to the extensor carpi ulnaris muscle of a 12-month-old affected dog at the dose of 2 × 10(13) viral genome particles/vector/muscle. Widespread mini-dystrophin expression was observed 2 months after gene transfer. The missing dystrophin-associated glycoprotein complex was restored. Treatment also reduced muscle degeneration and fibrosis and improved myofiber size distribution. Importantly, dual AAV therapy greatly protected the muscle from eccentric contraction-induced force loss. Our data provide the first clear evidence that dual AAV therapy can be translated to a diseased large mammal. Further development of dual AAV technology may lead to effective therapies for DMD and many other diseases in human patients.

The aim of this study was to elucidate correlations among clinical, genetic, and magnetic resonance imaging (MRI) data of muscles in myotonic dystrophy type 1 (DM1). We retrospectively reviewed the medical records and images of nineteen patients with DM1 from different families. We retrieved the genetic data (CTG repeats) and the clinical data, which included disease duration, creatine kinase level, sum score of manual muscle testing, modified Medical Research Council sum score, and the six-minute walk test results (6MWT). The correlation analyses showed a statistically significant correlation between the modified Medical Research Council sum score and CTG repeat numbers. Among the lower extremity muscles, 6MWT correlated most with the sum of the ankle plantar-flexors (the soleus, medial, and lateral gastrocnemius muscles). Compared to the other plantar-flexor muscles, the soleus muscle presented the highest correlation with the 6MWT. Additionally, our results showed that the CTG repeat numbers did not correlate with the 6MWT. However, it correlated with the modified Medical Research Council sum score. The ankle plantar-flexor muscles were the most severely affected muscles revealed in the whole body MRI, and presented statistically significant correlation with the 6MWT. Among the plantar-flexor muscles, the soleus muscle most influenced the 6MWT.

Nemaline myopathy (NM), the most common of the congenital myopathies, is caused by various genetic mutations. In this study, we attempted to identify the causative mutations of NM and to reveal any specific genotype-phenotype relationship in Korean patients with this disease. We investigated the clinical features and genotypes in 15 pathologically diagnosed NM patients, using whole exome sequencing (WES) combined with targeted sequencing and array-based comparative genomic hybridization. This strategy revealed pathogenic causative mutations in seven patients (46.7%), among whom mutations in the nebulin gene (NEB) were the most frequent (5 patients, 33.3%). Copy number variation (CNV) abnormality in NEB was not observed in any of our patients. In those with NEB-associated NM, the clinical spectrum was highly variable regardless of the mutation type. However, the majority of patients showing anterior lower leg weakness were associated with mutations located between NEB exons 166 and 177. We concluded that the combination of WES and targeted Sanger sequencing is an effective strategy for analyzing genotypes in patients with NM, and that CNV in NEB may not be a frequent cause of this disease among Koreans.

Duchenne muscular dystrophy is a progressive and lethal X-linked recessive neuromuscular disease caused by mutations in the dystrophin gene. It has a high rate of diagnostic delay; early diagnosis and treatment are often not possible due to delayed recognition of muscle weakness and lack of effective treatments. Current treatments based on genetic therapy can improve clinical results, but treatment must begin as early as possible before significant muscle damage. Therefore, early diagnosis and rehabilitation of Duchenne muscular dystrophy are needed before symptom aggravation. Creatine kinase is a diagnostic marker of neuromuscular disorders. Herein, the authors report a case of an infant patient with Duchenne muscular dystrophy with a highly elevated creatine kinase level but no obvious symptoms of muscle weakness. The patient was diagnosed with Duchenne muscular dystrophy via next-generation sequencing and chromosomal microarray analysis to identify possible inherited metabolic and neuromuscular diseases related to profound hyperCKemia. The patient is enrolled in a rehabilitation program and awaits the approval of the genetic treatment in Korea. This is the first report of an infantile presymptomatic Duchenne muscular dystrophy diagnosis using next-generation sequencing and chromosomal microarray analysis.

It has been proposed that susceptibility-weighted imaging is a sensitive magnetic resonance imaging (MRI) technique for identifying white matter (WM) pathologic changes involving demyelination and iron accumulation. We identified the tree silhouette-like configuration with a paramagnetic phase shift in the frontal subcortical WM lesions of 4 patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia who underwent 3T MRI. According to our postmortem 7T MRI and histologic correlation study to investigate the origin of the susceptibility-related phase contrast, changes in the subcortical WM architecture and central WM loss with the relative preservation of iron-rich U-fibers may contribute to the paramagnetic susceptibility.

Episodic ataxia (EA) is a rare neurological condition characterized by recurrent spells of truncal ataxia and incoordination. Five genes (KCNA1, CACNA1A, CACNB4, SLC1A3, and UBR4) have been linked to EA. Despite extensive efforts to genetically diagnose EA, many patients remain still undiagnosed. Whole-exome sequencing was carried out in 39 Korean patients with EA to identify pathogenic mutations of the five known EA genes. We also evaluated 40 candidate genes that cause EA as a secondary phenotype or cerebellar ataxia. Eighteen patients (46%) revealed genetic information useful for establishing a molecular diagnosis of EA. In 11 patients, 16 pathogenic mutations were detected in three EA genes. These included nine mutations in CACNA1A, three in SLC1A3, and four in UBR4. Three patients had mutations in two genes, either CACNA1A and SLC1A3 or CACNA1A and UBR4, suggesting that SLC1A3 and UBR4 may act as genetic modifiers with synergic effects on the abnormal presynaptic activity caused by CACNA1A mutations. In seven patients with negative results for screening of EA genes, potential pathogenic mutations were identified in the candidate genes ATP1A2, SCN1A, TTBK2, TGM6, FGF14, and KCND3. This study demonstrates the genetic heterogeneity of Korean EA, and indicates that whole-exome sequencing may be useful for molecular genetic diagnosis of EA.

Folic acid, a water soluble B vitamin, plays an important role in cellular metabolic activities, such as functioning as a cofactor in one-carbon metabolism for DNA and RNA synthesis as well as nucleotide and amino acid biosynthesis in the body. A lack of dietary folic acid can lead to folic acid deficiency and result in several health problems, including macrocytic anemia, elevated plasma homocysteine, cardiovascular disease, birth defects, carcinogenesis, muscle weakness, and walking difficulty. However, the effect of folic acid deficiency on skeletal muscle development and its molecular mechanisms are unknown. We, therefore, investigated the effect of folic acid deficiency on myogenesis in skeletal muscle cells and found that folic acid deficiency induced proliferation inhibition and cell cycle breaking as well as cellular senescence in C2C12 myoblasts, implying that folic acid deficiency influences skeletal muscle development. Folic acid deficiency also inhibited differentiation of C2C12 myoblasts and induced deregulation of the cell cycle exit and many cell cycle regulatory genes. It inhibited expression of muscle-specific marker MyHC as well as myogenic regulatory factor (myogenin). Moreover, immunocytochemistry and Western blot analyses revealed that DNA damage was more increased in folic acid-deficient medium-treated differentiating C2C12 cells. Furthermore, we found that folic acid resupplementation reverses the effect on the cell cycle and senescence in folic acid-deficient C2C12 myoblasts but does not reverse the differentiation of C2C12 cells. Altogether, the study results suggest that folic acid is necessary for normal development of skeletal muscle cells.

We performed targeted population screening of late onset Pompe disease (LOPD) in unspecified myopathy patients, because early diagnosis is difficult due to its heterogeneous clinical features. We prospectively enrolled 90 unrelated myopathic patients who had one or more signs out of five LOPD-like clinical findings (proximal weakness, axial weakness, lingual weakness, respiratory difficulty, idiopathic hyperCKemia). Acid alpha glucosidase activity was evaluated with dried blood spot and mixed leukocyte simultaneously. For a final diagnosis of LOPD, 16 patients with decreased enzyme activity were genotyped by GAA molecular analysis. We found two patients with LOPD (2.2%), and the remaining 14 patients had at least one G576S or E689K mutation, known as the pseudodeficiency allele. Acid alpha glucosidase activity of LOPD patients was significantly lower than that of patients with at least one pseudodeficiency allele (p = 0.017). This study is the first LOPD screening study for targeted Korean population, and more generally, an Asian population. Our findings suggest that for diagnosis of LOPD in Asian population, modified cutoff value of acid alpha glucosidase activity with dry blood spot considering that of patients having heterozygote pathogenic variants or pseudodeficiency alleles may reduce time and cost requirements and increase the comfort of patients.

Episodic ataxia type 6 (EA6) is caused by mutations in SLC1A3 that encodes excitatory amino acid transporter 1 (EAAT1), a glial glutamate transporter. EAAT1 regulates the extent and durations of glutamate-mediated signal by the clearance of glutamate after synaptic release. In addition, EAAT1 also has an anion channel activity that prevents additional glutamate release. We identified a missense mutation in SLC1A3 in a family with EA. The proband exhibited typical EA2-like symptoms such as recurrent ataxia, slurred speech with a duration of several hours, interictal nystagmus and response to acetazolamide, but had late-onset age of sixth decade. Whole-exome sequencing detected a heterozygous c.1177G>A mutation in SLC1A3. This mutation predicted a substitution of isoleucine for a highly conserved valine residue in the seventh transmembrane domain of EAAT1. The mutation was not present in 100 controls, a large panel of in-house genome data and various mutation databases. Most functional prediction scores revealed to be deleterious. Same heterozygous mutation was identified in one clinically affected family member and two asymptomatic members. Our data expand the mutation spectrum of SLC1A3 and the clinical phenotype of EA6.

Mutations in human PAX6 gene are associated with various congenital eye malformations including aniridia, foveal hypoplasia, and congenital nystagmus. These various phenotypes may depend on the mutation spectrums that can affect DNA-binding affinity, although this hypothesis is debatable. We screened PAX6 mutations in two unrelated patients with congenital nystagmus, and measured DNA-binding affinity through isothermal titration calorimetry (ITC). To elucidate phenotypic differences according to DNA-binding affinity, we also compared DNA-binding affinity among the previously reported PAX6 missense mutations within the linker region between two subdomains of the paired domain (PD). We identified two novel mutations of PAX6 gene: c.214 G > T (p.Gly72Cys) and c.249_250delinsCGC (p.Val84Alafs*8). Both were located within the linker region between the two subdomains of the PD. ITC measurement revealed that the mutation p.Val84Alafs*8 had no DNA-binding affinity, while the p.Gly72Cys mutation showed a decreased binding affinity (Kd = 0.58 μM) by approximately 1.4 times compared to the wild type-PAX6 (Kd = 0.41 μM). We also found that there was no close relationship between DNA-binding affinity and phenotypic differences. Our results suggest that the DNA-binding affinity alone might be insufficient to determine PAX6-related phenotypes, and that other modifier genes or environmental factors might affect phenotypes of the PAX6 gene.

FHL1-related myopathies are clinically heterogeneous, involving skeletal and cardiac muscles. Overlapping clinical features include joint contractures, rigid spine, scapuloperoneal weakness and cardiac diseases. Histopathologically, reducing bodies are the most characteristic finding, but not present in all FHL1-related cases. Non-specific dystrophic pathology without reducing body is usual in the forms of X-linked myopathy with postural muscle atrophy, Emery-Dreifuss muscular dystrophy and isolated hypertrophic cardiomyopathy. Here, we describe a patient with mild weakness with ankle contracture. We finally concluded he has a FHL1-related myopathy at an extreme end of phenotypic spectrum of FHL1 myopathy, which one might miss to recognize as a form of myopathy. The genetic variant was detected by whole exome sequencing, and its pathogenicity was clearly confirmed with pathological and biochemical studies. This is the first FHL1 case with a mildest phenotype backed by biochemical/genetic evidence. This report will help clinicians hesitating to further evaluate mild cases to better correlate the genotype to the phenotype.

Background & objective Although iron accumulation is thought to be associated with neurodegenerative processes, the timing of putaminal iron deposition during the disease course of multiple system atrophy (MSA) remains unclear. We sought to investigate the temporal pattern of iron deposition in the putamen of MSA patients by calculating the conditional probabilities (CPs) of multimodal MRI changes. Methods We simultaneously measured putaminal R2*, volume and MD values of 39 probable MSA patients and 22 control subjects. The presence of significant MRI changes was defined as higher R2* and MD values, or lower volumes than cut-off values derived from mean values in control putamen. The CPs of R2* changes without MD or volume changes were then compared with those of MD or volume changes without R2* changes. Results Regardless of the cut-off values, the CPs of R2* increments without MD or volume changes were significantly lower than those for MD or volume changes without R2* increments. The associations of R2* with volume and MD values appeared in non-linear exponential and quadratic patterns, respectively. Conclusions Our findings suggest that putaminal iron accumulation would occur under volume atrophy or MD increments. Thus, iron deposition in the putamen of MSA patients is likely a secondary byproduct of neurodegeneration.

Hard coatings are required to have a long lifetime without performance degradation when used in tough working environments. In this study, quaternary Ti–Si–B–C coatings with various Si contents were synthesised at a relatively low temperature of 600°C by a plasma-enhanced chemical vapour deposition. Effect of the Si/(Si+B) ratio on the microstructure and mechanical properties of the Ti–Si–B–C coatings was systematically investigated. Instrumental analyses, such as EPMA, XRD, XPS and HR-TEM, revealed that the microstructure was changed from a huge crystalline structure with an hexagonal close-packed (HCP) (Ti,C)B2 phase into a nanocomposite structure that consists of nano-sized HCP (Ti,C)B2 crystallites and amorphous SiC/TiC phases by a percolation effect with the Si addition. As the Si content increased, hardness of the Ti–Si–B–C coatings varied from 18.8 to 35.6 GPa. In addition, the tribology and anti-oxidation properties of the Ti–Si–B–C coatings with the characteristic microstructural evolution were f...

Thiopurine-induced leukopenia is a relatively common adverse event related to thiopurine medication in Korean pediatric Crohn's disease. In addition to the mutations of TPMT gene, the NUDT15 c.415CT variant was recently identified to have a strong association with thiopurine-induced early leukopenia. We conducted this study to define the incidence of azathioprine (AZA)-related leukopenia and to determine the incidence and characteristics of their genetic variants in Korean pediatric Crohn's disease patients.Patients diagnosed with pediatric Crohn's disease who had used AZA for more than 3 months were recruited. The dose and duration of medication and data regarding adverse events including leukopenia were collected. TPMT and NUDT15 gene sequencing was performed for patients who had experienced AZA-induced leukopenia.A total of 81 patients had used AZA as a maintenance therapy of Crohn's disease. The mean dose of AZA was 1.88±0.39 mg/kg/day. Nine patients (11.1%) experienced AZA-induced leukopenia, and eight patients (9.9%) experienced AZA-induced early leukopenia. Among the eight early leukopenia patients, six patients (75.0%) harbored the NUDT15 c.415CT variant and one patient (12.5%) had the TPMT c.719AG (TPMT*3C) variant. All the three patients with NUDT15 c.415CT homozygous variant suffered from alopecia totalis, and two of them experienced severe systemic infection. Three patients with the NUDT15 heterozygous variant are currently treated with AZA at a dose of 0.76 mg/kg/day.Mutations of the NUDT15 and TPMT gene accounted for ∼88% of cases with thiopurine-induced early leukopenia. Extensive hair loss was a recognizable early symptom in patients with the homozygous NUDT15 c.415CT variant. Sequencing of the NUDT15 genes can guide the clinicians before thiopurine medication. An alternative immunosuppressive medication is recommended for patients with homozygous NUDT15 c.415CT variant. For those with the heterozygous variant, half the usual dose of AZA can achieve efficacy comparable to that for wild-type patients.

Electrodiagnostic studies can obtain information 2 or 3 weeks after an acute nerve injury. Previous studies have shown increased glucose metabolism in denervated muscles 1 week after injury using 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) positron emission tomography (PET). Therefore, this study aimed to evaluate the changes in glucose metabolism in denervated muscles using serial monitoring by [(18)F]FDG PET scans.Denervation was induced in eight male Sprague-Dawley rats (aged 7 weeks old) weighing 200-250 g. The right legs of the rats were denervated by resecting the sciatic nerve in the thigh after the initial skin incision. Two rats were sacrificed 1 and 10 weeks after denervation. Skeletal muscles (gastrocnemius and tibialis anterior) were excised from both the right and left legs of the rats. Staining with hematoxylin and eosin, glucose transporter (GLUT)-1, GLUT-4, and hexokinase II was undertaken. PET/computed tomography (CT) scans were performed on the six remaining rats a total of five times at 1, 2, 5, 8, and 10 weeks after denervation. Regions of interest were drawn on integrated PET/CT images to measure the degree of [(18)F]FDG uptake in the right and left lower leg muscles. Target-to-background ratios (TBRs) were calculated by dividing the FDG uptake of the lower leg muscles by that of the upper leg muscles.The TBRs of the denervated muscles were higher than those of the control muscles at both 1 (6.84 ± 1.98 vs. 1.18 ± 0.11, p = 0.009) and 2 (4.10 ± 2.05 vs. 1.86 ± 0.73, p = 0.0374) weeks after denervation. After 5 (2.18 ± 0.78 vs. 1.35 ± 0.47, p = 0.1489), 8 (1.76 ± 0.18 vs. 1.69 ± 0.18, p = 0.5127), and 10 (1.76 ± 0.52 vs. 1.56 ± 0.37, p = 0.5637) weeks, the difference in the TBRs between the denervated and controls became non-significant.[(18)F]FDG PET can visualize increased glucose metabolism in a denervated muscle early as 1 week after injury. Therefore, PET could be adopted as a noninvasive imaging modality for acute nerve injuries. In addition, [(18)F]FDG PET may help to understand the role of the nervous system in the control of peripheral tissues.

Cr–Ni–N coatings, the Ni content of which was altered from 0 to 6·3 at-%, were deposited by a hybrid coating system consisting of high power impulse magnetron sputtering and radio frequency magnetron sputtering. The effects of Ni addition to Cr-N coatings on the microstructure and mechanical properties of the coatings were investigated in this study. The instrumental analysis revealed that the Ni element was incorporated into Cr-N crystals as solid solutions, while excess Ni was precipitated as nanocrystalline phases at the Cr-N grain boundaries. The toughness of the Cr–Ni–N coatings was significantly improved with Ni content increased. In addition, the hardness of the coatings slightly increased from 30·4 to 32·6 GPa due to the grain refinement effect and solid solution hardening. From the tribological tests, the highest wear resistance was obtained from the sample having a Ni content of 2·7 at-%.

We investigate the genotype and phenotype spectrum of FRMD7-associated infantile nystagmus syndrome in Korean probands.A total of 37 patients with infantile nystagmus syndrome were recruited prospectively for genetic analysis. We performed polymerase chain reaction (PCR)-based direct sequencing and haplotype analysis for FRMD7. Detailed ophthalmic examinations and eye movement recordings were compared between FRMD7 and non-FRMD7 groups.In 13 (35%) of 37 patients, five different mutations of FRMD7 were detected: start codon mutation c.1AG, splice site mutation c.162+6TC, and three missense mutations (c.575AC, c.722AG, and c.875TC). The latter mutation was identified in seven unrelated patients, and always was accompanied with two single nucleotide polymorphisms of exon 12 (rs6637934, rs5977623). Compared to non-FRMD7 groups, a cup-to-disc ratio was significantly decreased in FRMD7 groups (P0.001), and a disc-macula distance to disc diameter ratio markedly increased in the FRMD7 group (P = 0.015). Most patients in the FRMD7 group had at least two types of the nystagmus waveforms, and the most common type was unidirectional jerk nystagmus (75%), such as pure jerk and jerk with extended foveation, followed by pendular (25%), bidirectional jerk (19%), and dual jerk (6%) nystagmus. No significant differences were observed between FRMD7 and non-FRMD7 groups in terms of the nystagmus waveform, presence of periodic alternating nystagmus, and mean foveation time.We identified five FRMD7 mutations in 35% of our infantile nystagmus syndrome cohort, expanding its mutational spectrum. The missense mutation c.875TC may be a common mutation arisen from the founder effect in Korea. Optic nerve dysplasia associated with FRMD7 mutations suggests that the abnormal development of afferent visual systems may affect neural circuitry within the oculomotor system.

Heart disease is a major health threat for Duchenne/Becker muscular dystrophy patients and carriers. Expression of a 6-8 kb mini-dystrophin gene in the heart holds promise to change the disease course dramatically. However, the mini-dystrophin gene cannot be easily studied with adeno-associated virus (AAV) gene delivery because the size of the minigene exceeds AAV packaging capacity. Cardiac protection of the ΔH2-R19 minigene was previously studied using the cardiac-specific transgenic approach. Although this minigene fully normalized skeletal muscle force, it only partially corrected electrocardiogram and heart hemodynamics in dystrophin-null mdx mice that had moderate cardiomyopathy. This study evaluated the ΔH2-R15 minigene using the same transgenic approach in mdx mice that had more severe cardiomyopathy. In contrast to the ΔH2-R19 minigene, the ΔH2-R15 minigene carries dystrophin spectrin-like repeats 16 to 19 (R16-19), a region that has been suggested to protect the heart in clinical studies. Cardiac expression of the ΔH2-R15 minigene normalized all aberrant electrocardiogram changes and improved hemodynamics. Importantly, it corrected the end-diastolic volume, an important diastolic parameter not rescued by ΔH2-R19 mini-dystrophin. It is concluded that that ΔH2-R15 mini-dystrophin is a superior candidate gene for heart protection. This finding has important implications in the design of the mini/micro-dystrophin gene for Duchenne cardiomyopathy therapy.

The ultimate goal of muscular dystrophy gene therapy is to treat all muscles in the body. Global gene delivery was demonstrated in dystrophic mice more than a decade ago using adeno-associated virus (AAV). However, translation to affected large mammals has been challenging. The only reported attempt was performed in newborn Duchenne muscular dystrophy (DMD) dogs. Unfortunately, AAV injection resulted in growth delay, muscle atrophy and contracture. Here we report safe and bodywide AAV delivery in juvenile DMD dogs. Three ∼2-m-old affected dogs received intravenous injection of a tyrosine-engineered AAV-9 reporter or micro-dystrophin (μDys) vector at the doses of 1.92-6.24 × 10(14) viral genome particles/kg under transient or sustained immune suppression. DMD dogs tolerated injection well and their growth was not altered. Hematology and blood biochemistry were unremarkable. No adverse reactions were observed. Widespread muscle transduction was seen in skeletal muscle, the diaphragm and heart for at least 4 months (the end of the study). Nominal expression was detected in internal organs. Improvement in muscle histology was observed in μDys-treated dogs. In summary, systemic AAV gene transfer is safe and efficient in young adult dystrophic large mammals. This may translate to bodywide gene therapy in pediatric patients in the future.

A 63-year-old man presented with a 1.5-year history of progressive personality changes. Clinical evaluations revealed severe frontal dysfunction and bilateral frontal atrophy/glucose hypometabolism. He was diagnosed as probable behavioral variant frontotemporal dementia. He continued to decline, and died at the age of 66. At autopsy, numerous tau-positive gilial threads and coiled bodies were observed in the white matter. Tau-positive astrocytic plaques and neuronal cytoplasmic inclusions were also seen in cerebral cortices, which were compatible with corticobasal degeneration. J Korean Neurol Assoc 33(3):178-182, 2015

Eun-Joo Kim, MD, Eun-Hye Oh, MD, Ki-Tae Kim, MD, Yoori Jung, MD, Jeong Hee Lee, MD, Jae-Hyeok Lee, MD, Young Min Lee, MD, Seong-Jang Kim, MD, Jin-Hong-Shin, MD, Myung-Jun Shin, MD, Myung Jun Lee, MD, Jae Woo Ahn, MD, Suk Sung, MD, Kyung-Un Choi, MD, Dae Soo Jung, MD, William W. Seeley, MD, Gi Yeong Huh, MD Departments of Neurology, Pathology, Psychiatry, Nuclear Medicine, Rehabilitation Medicine, Anatomy, and Forensic Medicine, Pusan National University School of Medicine, Yangsan, Korea Memory and Aging Center, University of California San Francisco, CA, USA

Episodic ataxia type 2 (EA2) is characterized by recurrent attacks of vertigo and ataxia lasting hours triggered by emotional stress or exercise. Although interictal horizontal gaze-evoked nystagmus and rebound nystagmus are commonly observed in patients with EA2, the nystagmus has been rarely reported during the vertigo attack. To better describe exercise-induced nystagmus in EA2, four affected members from three generations of a Korean family with EA2 received full neurological and neuro-otological evaluations. Vertigo was provoked in the proband with running for 10 min to record eye movements during the vertigo attack. We performed a polymerase chain reaction-based direct sequence analysis of all coding regions of CACNA1A in all participants. The four affected members had a history of exertional vertigo, imbalance, childhood epilepsy, headache, and paresthesia. The provocation induced severe vertigo and imbalance lasting several hours, and oculography documented pure downbeat nystagmus during the attack. Genetic analyses identified a nonsense mutation in exon 23 which has been registered in dbSNP as a pathogenic allele (c.3832C>T, p.R1278X) in all the affected members. Ictal downbeat nystagmus in the studied family indicates cerebellar dysfunction during the vertigo attack in EA2. In patients with episodic vertigo and ataxia, the observation of exercise-induced nystagmus would provide a clue for EA2.