Hirotaka Nakanishi

Impaired muscle uptake of creatine in spinal and bulbar muscular atrophy

The aim of this study was to explore the pathomechanism underlying the reduction of serum creatinine (Cr) concentrations in spinal and bulbar muscular atrophy (SBMA).

インターフェロンα治療中に発症し，脳に長大な錐体路病変をみとめたNMO（neuromyelitis optica）spectrum disorderの1例

A 65-year-old woman developed left optic neuritis during the course of peg-interferon alpha (PEG-IFN-α) and ribavirin combination therapy for chronic hepatitis C. Brain T(2)W-MRI disclosed hyperintense lesions in the corpus callosum and white matter. We diagnosed neuromyelitis optica spectrum disorder (NMOSD) on the basis of anti-aquaporin-4 antibody seropositivity. PEG-IFN-α was discontinued, and she received steroid pulse therapy (intravenous high dose methylprednisolone). Two weeks later she also developed right optic neuritis. Repetitive steroid pulse therapy improved the left optic neuritis, but the upper half of the visual field of the right eye remained impaired. One month later she presented with mild dysarthria and mild left hemiparesis. Brain MRI disclosed an extensive pyramidal tract lesion from the right corona radiata to the pedunculus cerebri. This cerebral pyramidal tract lesion is associated with NMOSD. Our case corresponds to the past reports of optic neuritis or multiple sclerosis-like disease triggered by IFN-α. IFN-α may trigger NMOSD via a biological effect characteristic of Type I IFNs, a group that includes IFN-α and IFN-β.

Genetic profile for suspected dysferlinopathy identified by targeted next-generation sequencing

Objective: To investigate the genetic causes of suspected dysferlinopathy and to reveal the genetic profile for myopathies with dysferlin deficiency. Methods: Using next-generation sequencing, we analyzed 42 myopathy-associated genes, including DYSF, in 64 patients who were clinically or pathologically suspected of having dysferlinopathy. Putative pathogenic mutations were confirmed by Sanger sequencing. In addition, copy-number variations in DYSF were investigated using multiplex ligation-dependent probe amplification. We also analyzed the genetic profile for 90 patients with myopathy with dysferlin deficiency, as indicated by muscle specimen immunohistochemistry, including patients from a previous cohort. Results: We identified putative pathogenic mutations in 38 patients (59% of all investigated patients). Twenty-three patients had DYSF mutations, including 6 novel mutations. The remaining 16 patients, including a single patient who also carried the DYSF mutation, harbored putative pathogenic mutations in other genes. The genetic profile for 90 patients with dysferlin deficiency revealed that 70% had DYSF mutations (n = 63), 10% had CAPN3 mutations (n = 9), 2% had CAV3 mutations (n = 2), 3% had mutations in other genes (in single patients), and 16% did not have any identified mutations (n = 14). Conclusions: This study clarified the heterogeneous genetic profile for myopathies with dysferlin deficiency. Our results demonstrate the importance of a comprehensive analysis of related genes in improving the genetic diagnosis of dysferlinopathy as one of the most common subtypes of limb-girdle muscular dystrophy. Unresolved diagnoses should be investigated using whole-genome or whole-exome sequencing.

Decreased Peak Expiratory Flow Associated with Muscle Fiber-Type Switching in Spinal and Bulbar Muscular Atrophy

The aim of this study was to characterize the respiratory function profile of subjects with spinal and bulbar muscular atrophy (SBMA), and to explore the underlying pathological mechanism by comparing the clinical and biochemical indices of this disease with those of amyotrophic lateral sclerosis (ALS). We enrolled male subjects with SBMA (n = 40) and ALS (n = 25) along with 15 healthy control subjects, and assessed their respiratory function, motor function, and muscle strength. Predicted values of peak expiratory flow (%PEF) and forced vital capacity were decreased in subjects with SBMA compared with controls. In SBMA, both values were strongly correlated with the trunk subscores of the motor function tests and showed deterioration relative to disease duration. Compared with activities of daily living (ADL)-matched ALS subjects, %PEF, tongue pressure, and grip power were substantially decreased in subjects with SBMA. Both immunofluorescence and RT-PCR demonstrated a selective decrease in the expression levels of the genes encoding the myosin heavy chains specific to fast-twitch fibers in SBMA subjects. The mRNA levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha and peroxisome proliferator-activated receptor delta were up-regulated in SBMA compared with ALS and controls. In conclusion, %PEF is a disease-specific respiratory marker for the severity and progression of SBMA. Explosive muscle strength, including %PEF, was selectively affected in subjects with SBMA and was associated with activation of the mitochondrial biogenesis-related molecular pathway in skeletal muscles.

HMGCR antibody-associated myopathy as a paraneoplastic manifestation of esophageal carcinoma

Immune-mediated myopathies with antibodies may be triggered by statin exposure, but some patients with these disorders are statin-naive; thus, there are probably other etiologies.1 Several malignant tumors, including esophageal squamous cell carcinoma (ESCC), overexpress 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) protein.2 To date, the relationship between anti-HMGCR antibody–associated myopathy (HMGCR-M) and malignancy remains unclear.3,4 Here, we report a case of HMGCR-M in a patient with ESCC and paraneoplastic syndrome.

Myotonia-like symptoms in a patient with spinal and bulbar muscular atrophy

We describe the case of a 33-year-old man with a 4-year history of worsening muscle stiffness and weakness in his right hand. He showed elevated serum creatine kinase levels at the onset of muscle stiffness that was characterized by delayed muscle relaxation after voluntary contraction. This symptom often occurred during cold exposure, and was partially attenuated by sodium channel blockade. Electrodiagnostic findings in repetitive nerve stimulation, short-exercise, and cooling tests were normal. Electromyography showed chronic denervation potentials in his cranial, cervical, thoracic, and lumbosacral myotomes without myotonic discharge. He exhibited facial and tongue fasciculations, hypernasality, gynecomastia, neurogenic changes in muscle biopsy, and increased serum testosterone levels. Spinal and bulbar muscular atrophy (SBMA) was diagnosed on the basis of the CAG trinucleotide expansion in the gene coding androgen receptor. A myotonia-like symptom without myotonic discharge may present as an early neurological sign of SBMA, which possibly reflects a sodium channel dysfunction in skeletal muscles.

Transforming growth factor-β signaling is upregulated in sporadic inclusion body myositis.

In this study we aimed to determine whether transforming growth factor‐β (TGF‐β) signaling is dysregulated in sporadic inclusion body myositis (sIBM) muscle samples.

Gene Expression Profile of Inflammatory Myopathy with Malignancy is Similar to that of Dermatomyositis rather than Polymyositis.

Objective An association has been reported between inflammatory myopathies (IMs), which include polymyositis (PM) and dermatomyositis (DM), and malignancy, and the concept of cancer-associated myositis (CAM) was recently proposed. We herein attempted to determine the features and etiologies of these myopathies. Methods We analyzed the gene expression levels via microarray and real-time quantitative reverse transcription polymerase chain reaction analyses to identify genes that were specifically upregulated or downregulated with suspected inflammatory involvement and verified the microarray data via an immunohistochemical (IHC) analysis in additional cases. Patients We selected 14 patients with the following conditions: PM without malignancy (n=3), DM without malignancy (n=3), CAM (n=3), and Controls (no pathological changes or malignancy; n=5). Results PM was distinct from DM and CAM in a clustering analysis and exhibited the highest numbers of overexpressed genes and specific pathologies in a gene ontology analysis. The IHC analysis confirmed the gene expression results. Conclusion PM is associated with severe inflammatory pathological findings, primarily in the cell-mediated immune system. DM and CAM exhibit similarities in the gene expression and IHC results, which suggest that humoral immunity is the main etiology for both myopathies, indicating the importance of cancer screening in patients with IMs, particularly DM.

[67Ga scintigraphy as a therapeutic marker for spinal cord and muscular sarcoidosis: A case report].

A 70-year-old woman was admitted to our hospital because of the right limb pain and gait disturbance. (67)Ga scintigraphy showed an increased uptake in the spinal cord, mediastinal lymph node and right tibialis anterior muscle. Based on the histopathological findings of epithelioid cell granuloma in endobronchial ultrasound-guided transbronchial needle aspiration of lymph node, she was diagnosed as having probable spinal cord/muscular sarcoidosis. After she was treated with oral prednisolone, her limb pain and gait disturbance improved. Furthermore, uptake in (67)Ga scintigraphy was reduced after the treatment. In conclusion, (67)Ga scintigraphy is useful not only for diagnosis, but also for estimating the efficiency of the treatment for sarcoidosis involving multiple organs such as the spinal cord and skeletal muscle.

A patient with Parkinson’s disease and dermatomyositis with serum anti-transcriptional intermediary factor 1-γ antibody

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