Clinicopathological Reclassification of Idiopathic Inflammatory Myopathy to Match the Serological Results of Myositis-Specific Antibodies

Background@#and Purpose Advances in serological tests are transforming the classification of idiopathic inflammatory myopathy (IIM). The new criteria suggested by the 119th European Neuromuscular Center international workshop divide IIM cases into four main diseases according to clinical and pathological findings, adding immune-mediated necrotizing myositis and nonspecific myositis to the classic categories of polymyositis and dermatomyositis. @*Methods@#Seventy one cases of IIM with sufficient available clinical and pathological data were reviewed to be reclassified according to the new criteria. @*Results@#Most of the cases previously classified as polymyositis (77.8%, 35/45) were reclassified as immune-mediated necrotizing myopathy. The results of myositis-specific antibodies matched well with the new clinicopathological classification. @*Conclusions@#This new clinicopathological classification for IIM in combination with serological test results could be applied to our previous case series. Adoption of the new criteria will lead to a better understanding of the disease and hence new therapeutic insights.

Atypical Presentation of Elsberg Syndrome Caused by Herpes Simplex Virus Type 2 Infection

Elsberg syndrome is a rare disease of lumbosacral myeloradiculitis, mostly caused by herpes simplex virus type 2 (HSV-2). It frequently has concomitant myelitis, and immunocompromised patients can be fatal with ascending myelitis. Since anti-viral agents might lead to good recovery, clinicians need to be suspicious for conditions of cauda equina syndrome. Detection of viral DNA from cerebrospinal fluid ensures the diagnosis. We report a case of Elsberg syndrome caused by HSV-2 and are to delineate the clinical and radiologic spectrum.

A Case of Inclusion Body Myositis with Clinical, Pathological and Serological Consideration

Inclusion body myositis is a rare condition of idiopathic inflammatory myopathy. Prior criteria for the diagnosis of inclusion body myositis essentially required pathological features of rimmed vacuoles, tubulofilamentous inclusions, and amyloid deposits. However, recently developed new diagnostic criteria emphasize clinical characteristics including weakness of finger flexors and knee extensors. In addition, a serological evaluation of anti-cN1A antibody is helpful for the diagnosis. We report a case of inclusion body myositis with clinical, pathological, and serological consideration.

Muscle and Nerve Biopsy in Various Neuromuscular Disorders / 대한신경근육질환학회지

Muscle and nerve biopsy may be vital diagnostic tools in various neuromuscular disorders. Since these procedures are invasive, it matters to decide when to perform a biopsy, which muscle or nerve to be selected, and how to interpret the pathologies. This review addresses the indications, methods of biopsies, and also significant pathological findings frequently encountered in muscle and nerve pathology.

Multicenter Targeted Population Screening of Late Onset Pompe Disease in Unspecified Myopathy Patients in Korea

Background@#Pompe disease is a rare autosomal recessive disorder caused by the deficiency of a lysosomal enzyme, acid alpha-glucosidase (GAA). Early diagnosis and initiation of treatment with enzyme replacement therapy have remarkable effects on the prognosis of Pompe disease. We performed the expanded screening for late onset Pompe disease (LOPD) at eight centers in Korea. @*Methods@#From September 1, 2015, GAA activity were measured from both dried blood spot (DBS) and mixed leukocyte for 188 available patients. For 12 patients with low GAA activity, we performed Sanger sequencing of GAA gene. @*Results@#Among 188 patients, 115 were males. The mean of age of symptom onset and diagnosis were 34.3 years and 41.6 years. Among 12 patients with decreased GAA activity, two patients were confirmed to have LOPD with genetic test (c.1316T>A [p.M439K] + c.2015G>A [p.R672Q], c.1857C>G [p.S619R] + c.546G>C [leaky splicing]). Other two patients had homozygous G576S and E689K mutation, known as pseudodeficiency allele. @*Conclusions@#This study is expanded study of LOPD screening for targeted Korean population. We found two patients with LOPD, and the detection rate of LOPD is 1.06%. With application of modified GAA cutoff value (0.4), which was previously reported, there were no false positive results of GAA activity test using DBS. Therefore, it could be an appropriate screening test for LOPD in especially East-Asian population, in which pseudodeficiency allele is frequent.

Multicenter Targeted Population Screening of Late Onset Pompe Disease in Unspecified Myopathy Patients in Korea

Background@#Pompe disease is a rare autosomal recessive disorder caused by the deficiency of a lysosomal enzyme, acid alpha-glucosidase (GAA). Early diagnosis and initiation of treatment with enzyme replacement therapy have remarkable effects on the prognosis of Pompe disease. We performed the expanded screening for late onset Pompe disease (LOPD) at eight centers in Korea. @*Methods@#From September 1, 2015, GAA activity were measured from both dried blood spot (DBS) and mixed leukocyte for 188 available patients. For 12 patients with low GAA activity, we performed Sanger sequencing of GAA gene. @*Results@#Among 188 patients, 115 were males. The mean of age of symptom onset and diagnosis were 34.3 years and 41.6 years. Among 12 patients with decreased GAA activity, two patients were confirmed to have LOPD with genetic test (c.1316T>A [p.M439K] + c.2015G>A [p.R672Q], c.1857C>G [p.S619R] + c.546G>C [leaky splicing]). Other two patients had homozygous G576S and E689K mutation, known as pseudodeficiency allele. @*Conclusions@#This study is expanded study of LOPD screening for targeted Korean population. We found two patients with LOPD, and the detection rate of LOPD is 1.06%. With application of modified GAA cutoff value (0.4), which was previously reported, there were no false positive results of GAA activity test using DBS. Therefore, it could be an appropriate screening test for LOPD in especially East-Asian population, in which pseudodeficiency allele is frequent.

Diagnostic Approaches to Various Muscle Diseases Based on Muscle Pathology

Muscle pathology can give much information to reach the diagnosis of neuromuscular disorders. Major pathological changes occurred in skeletal muscles include muscle fiber atrophy/hypertrophy, necrosis/regeneration, inflammation, myofibrillar disorganization, abnormal inclusions, and disruptions in cellular organelles. Physicians should be able to understand what each of these findings indicates. However, these are not always specific to a certain disease, and instead most of them are commonly found in many of muscle diseases. Thus, muscle pathological findings should be carefully interpreted under the given clinical settings.

Hereditary Myopathy with Early Respiratory Failure with a Heterozygous TTN Gene Missense Mutation

Hereditary myopathy with early respiratory failure (HMERF) is characterized by early respiratory insufficiency which is inappropriate to the degree of limb muscle weakness. Recently, mutation in TTN gene was found in HMERF patients with the aid of gene sequencing. We describe the first case presenting with distal leg weakness and early respiratory failure confirmed by TTN gene mutation in Korea.

RbAp48 expression and neuronal damage in the gerbil hippocampus following 5 min of transient ischemia / 한국실험동물학회지

Histone-binding protein RbAp48 has been known to be involved in histone acetylation, and epigenetic alterations of histone modifications are closely associated with the pathogenesis of ischemic reperfusion injury. In the current study, we investigated chronological change of RbAp48 expression in the hippocampus following 5 min of transient ischemia in gerbils. RbAp48 expression was examined 1, 2, 5, and 10 days after transient ischemia using immunohistochemistry. In sham operated gerbils, RbAp48 immunoreactivity was strong in pyramidal and non-pyramidal cells in the hippocampus. After transient ischemia, RbAp48 immunoreactivity was changed in the cornu ammonis 1 subfield (CA1), not in CA2/3. RbAp48 immunoreactivity in CA1 pyramidal neurons was gradually decreased and not detected at 5 and 10 days after ischemia. RbAp48 immunoreactivity in non-pyramidal cells was maintained until 2 days post-ischemia and significantly increased from 5 days post-ischemia. Double immunohistofluorescence staining revealed that RbAp48 immunoreactive non-pyramidal cells were astrocytes. At 5 days post-ischemia, death of pyramidal neurons occurred only in the CA1. These results showed that RbAp48 immunoreactivity was distinctively altered in pyramidal neurons and astrocytes in the hippocampal CA1 following 5 mins of transient ischemia. Ischemia-induced change in RbAp48 expression may be closely associated with neuronal death and astrocyte activation following 5 min of transient ischemia.

Efficacy and safety of tocilizumab in Korean patients with active rheumatoid arthritis

BACKGROUND/AIMS@#To investigate the efficacy and safety of tocilizumab (TCZ) humanized anti-interleukin-6 receptor monoclonal antibody, in Korean patients with active rheumatoid arthritis (RA) refractory to conventional disease modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX)@*METHODS@#The main study was a 24-week, randomized, double-blind, controlled trial that was followed by a 48-week, open-labeled, extension phase. TCZ (8 mg/kg) or placebo was intravenously administered every 4 weeks.@*RESULTS@#Those treated with TCZ showed more favorable outcomes in terms of 20% according to the American College of Rheumatology response criteria (ACR20) and ACR50 responses, individual parameters of ACR core set, disease activity score in 28 joints (DAS28) remission, and European League Against Rheumatism (EULAR) response at week 24. These improvements were maintained or increased during the extension period. DAS28 remission at week 72 was associated with EULAR good response at week 12. The patients who experienced any adverse event (AE) were more frequent in the TCZ group compared to the placebo group. Most AEs were mild or moderate in intensity, although TCZ therapy had possible AEs including serious infection, abnormal liver function, and atherogenic lipid profile.@*CONCLUSIONS@#TCZ infusion add-on is highly efficacious and well-tolerated in Korean patients with active RA refractory to conventional DMARDs including MTX. EULAR good response at week 12 could predict DAS28 remission at week 72.

Progression of GNE Myopathy Based on the Patient-Reported Outcome

BACKGROUND AND PURPOSE: GNE myopathy is a rare progressive myopathy caused by biallelic mutations in the GNE gene, and frequently accompanied by rimmed vacuoles in muscle pathology. The initial symptom of foot drop or hip-girdle weakness eventually spreads to all limbs over a period of decades. Recent advances in pathophysiologic research have facilitated therapeutic trials aimed at resolving the core biochemical defect. However, there remains unsettled heterogeneity in its natural course, which confounds the analysis of therapeutic outcomes. We performed the first large-scale study of Korean patients with GNE myopathy. METHODS: We gathered the genetic and clinical profiles of 44 Korean patients with genetically confirmed GNE myopathy. The clinical progression was estimated retrospectively based on a patient-reported questionnaire on the status of the functional joint sets and daily activities. RESULTS: The wrist and neck were the last joints to lose antigravity functionality irrespective of whether the weakness started from the ankle or hip. Two-thirds of the patients could walk either independently or with an aid. The order of losing daily activities could be sorted from standing to eating. Patients with limb-girdle phenotype showed an earlier age at onset than those with foot-drop onset. Patients with biallelic kinase domain mutations tended to progress more rapidly than those with epimerase and kinase domain mutations. CONCLUSIONS: The reported data can guide the clinical management of GNE myopathy, as well as provide perspective to help the development of clinical trials.

Clinical Reasoning: A 34-Year-Old Woman with Foot Drop

No abstract available.

Age-dependent changes of p53 and p63 immunoreactivities in the mouse hippocampus / 한국실험동물학회지

P53 and its family member p63 play important roles in cellular senescence and organismal aging. In this study, p53 and p63 immunoreactivity were examined in the hippocampus of young, adult and aged mice by using immunohistochemistry. In addition, neuronal distribution and degeneration was examined by NeuN immunohistochemistry and fluoro-Jade B fluorescence staining. Strong p53 immunoreactivity was mainly expressed in pyramidal and granule cells of the hippocampus in young mice. p53 immunoreactivity in the pyramidal and granule cells was significantly reduced in the adult mice. In the aged mice, p53 immunoreactivity in the pyramidal and granule cells was more significantly decreased. p63 immunoreactivity was strong in the pyramidal and granule cells in the young mice. p63 immunoreactivity in these cells was apparently and gradually decreased with age, showing that p63 immunoreactivity in the aged granule cells was hardly shown. However, numbers of pyramidal neurons and granule cells were not significantly decreased in the aged mice with normal aging. Taken together, this study indicates that there are no degenerative neurons in the hippocampus during normal aging, showing that p53 and p63 immunoreactivity in hippocampal neurons was progressively reduced during normal aging, which might be closely related to the normal aging processes.

Rapid onset of efficacy predicts response to therapy with certolizumab plus methotrexate in patients with active rheumatoid arthritis

BACKGROUND/AIMS: The objective of this study was to determine the efficacy and safety of add-on therapy with certolizumab pegol (CZP) in active rheumatoid arthritis (RA) patients of a single ethnicity. METHODS: In this 24-week, phase 3, randomized, double-blind, placebo-controlled trial, eligible patients (n = 127) were randomized 2:1 to subcutaneous CZP + methotrexate (MTX; 400 mg at week 0, 2, and 4 followed by 200 mg every 2 weeks) or placebo + MTX. RESULTS: At week 24, the American College of Rheumatology criteria for 20% (ACR20) response rate was significantly greater with CZP + MTX than with placebo (66.7% vs. 27.5%, p < 0.001). Differences in ACR20 response rates for CZP vs. placebo were significant from week 1 (p < 0.05) and remained significant through week 24. The CZP group reported significant improvement in physical function and disability compared to the placebo group (p < 0.001) at week 24, as assessed by Korean Health Assessment Questionnaire-Disability Index (KHAQ-DI). Post hoc analysis indicated that the proportion of patients who had ACR70 responses, Disease Activity Score 28 (DAS28) low disease activity, and DAS28 remission at week 24 was greater in CZP + MTX-treated patients who achieved a decrease in DAS28 ≥ 1.2 (43.8%) at week 4 than in nonresponders. Among 18 (22.2%) and 14 patients (35.0%) in CZP and placebo groups who had latent tuberculosis (TB), none developed active TB. Most adverse events were mild or moderate. CONCLUSIONS: CZP treatment combined with MTX in active RA patients with moderate to severe disease activity and an inadequate response to MTX resulted in rapid onset of efficacy, which is associated with better clinical outcome at week 24 and has an acceptable safety profile, especially in an intermediate TB-burden population.

Vasculitic Neuropathy in Cutaneous Polyarteritis Nodosa

No abstract available.

A Family of Bethlem Myopathy Caused by a Heterozygous COL6A1 Mutation

Collagen-VI-related myopathies are caused by mutations in the COL6A1, COL6A2, and COL6A3 and are known to have a wide phenotypic spectrum, including Bethlem myopathy, Ullrich congenital muscular dystrophy, intermediate phenotype, and limb-girdle muscular dystrophy. These patients present with joint hyperextensibility and/or contractures as well as skin changes and muscle weakness, and so clinicians need to notice those extramuscular symptoms in order to achieve a correct diagnosis. We describe the clinical, pathological, and radiological features in a family with Bethlem myopathy caused by a COL6A1 mutation.

Narcolepsy Followed by Intractable Vomiting Caused by Recurrent Brain Involvement in Neuromyelitis Optica Spectrum Disorder

We report a 26 year-old female who initially presented with hypersomnia and visual disturbance with preceding upper respiratory infection. She was diagnosed as neuromyelitis optica spectrum disorder (NMOSD) with the presence of anti-AQP4 antibody. Eight months later, she experienced nausea and vomiting refractory to conventional therapies, which was proved correlated with a lesion of area postrema on brain magnetic resonance imaging. These might be significant clinical manifestations in NMOSD and may widen the clinical spectrum of the disease.

Cap Myopathy With a Heterozygous TPM3 Missense Mutation

Cap myopathy is pathologically characterized by cap structures comprising well-demarcated areas under the sarcolemma and containing deranged myofibrils and scattered Z-disks. Clinically it presents with slowly progressive muscle weakness, myopathic face, and frequent respiratory insufficiency. Four genes have been reported to be associated with the disease: TPM2, TPM3, ACTA1, and NEB. Here we describe that a patient presenting with mild limb weakness with facial affection showed cap structures on muscle pathology and carried a heterozygous TPM3 mutation.

Clinical and Pathological Features of Korean Patients with DNM2-Related Centronuclear Myopathy

BACKGROUND AND PURPOSE: Centronuclear myopathy (CNM) is characterized by the presence of central nuclei within a large number of muscle fibers. Mutations of the dynamin 2 gene (DNM2) are common causes of autosomal dominant or sporadic CNM. The aim of this study was to characterize the clinical and pathological features of CNM relative to the presence of DNM2 mutations. METHODS: Six patients with clinical and pathological features of CNM were recruited. Detailed clinical and pathological findings were analyzed according to the presence of DNM2 mutations. RESULTS: We detected DNM2 mutations in four of the six sporadic CNM patients, and identified the following distinct clinical and pathological features in those patients with DNM2 mutations: preferential involvement of the distal lower limbs, typical nuclear centralization, and radially distributed sarcoplasmic strands in muscle pathology. In contrast, those without DNM2 mutations exhibited rather diffuse muscular involvement, and nuclear internalization and myofibrillar disorganization were more pronounced features of their muscle pathology. CONCLUSIONS: These findings suggest the presence of specific features in Korean CNM patients. A detailed clinical and pathological examination of CNM patients would be helpful for molecular genetic analyses of this condition.

Mutation analysis of SPAST, ATL1, and REEP1 in Korean Patients with Hereditary Spastic Paraplegia

BACKGROUND AND PURPOSE: Hereditary spastic paraplegia (HSP) is a genetically heterogeneous group of neurodegenerative disorders that are characterized by progressive spasticity and weakness of the lower limbs. Mutations in the spastin gene (SPAST) are the most common causes of HSP, accounting for 40-67% of autosomal dominant HSP (AD-HSP) and 12-18% of sporadic cases. Mutations in the atlastin-1 gene (ATL1) and receptor expression-enhancing protein 1 gene (REEP1) are the second and third most common causes of AD-HSP, respectively. METHODS: Direct sequence analysis was used to screen mutations in SPAST, ATL1, and REEP1 in 27 unrelated Korean patients with pure and complicated HSP. Multiplex ligation-dependent probe amplification was also performed to detect copy-number variations of the three genes. RESULTS: Ten different SPAST mutations were identified in 11 probands, of which the following 6 were novel: c.760A>T, c.131C>A, c.1351_1353delAGA, c.376_377dupTA, c.1114A>G, and c.1372A>C. Most patients with SPAST mutations had AD-HSP (10/11, 91%), and the frequency of SPAST mutations accounted for 66.7% (10/15) of the AD-HSP patients. No significant correlation was found between the presence of the SPAST mutation and any of the various clinical parameters of pure HSP. No ATL1 and REEP1 mutations were detected. CONCLUSIONS: We conclude that SPAST mutations are responsible for most Korean cases of genetically confirmed AD-HSP. Our observation of the absence of ATL1 and REEP1 mutations needs to be confirmed in larger series.