NO TO HATTATSU
Online ISSN : 1884-7668
Print ISSN : 0029-0831
ISSN-L : 0029-0831
Current issue
Displaying 1-12 of 12 articles from this issue
Editorial
Review
  • Yasutoshi Koga
    2022 Volume 54 Issue 6 Pages 401-406
    Published: 2022
    Released on J-STAGE: December 07, 2022
    JOURNAL FREE ACCESS

      The development of sensitive and specific biomarkers useful for diagnosing mitochondrial diseases has been an urgent issue for mitochondrial disease researchers around the world. We have done the metabolome analysis using cybrid model having an A3243G mutation from MELAS. To enable the measurement of serum GDF15 concentrations at medical institutions, we developed a new latex-enhanced turbidimetric immunoassay (LTIA) as an automated diagnostic indication test for mitochondrial disease. We also examined the equivalency of specificity and sensitivity in measuring serum GDF15 concentrations between a commercially available enzyme-linked immunosorbent assay (ELISA) kit and a novel LTIA device in patients with mitochondrial disease, disease controls, and healthy controls. The diagnostic biomarker GDF15 for mitochondrial disease was discovered and patented. We developed a new diagnostic device that can be mounted on a fully automatic analytical instrument, verified its equivalence with the ELISA system, and then conducted a clinical performance test. As a result, the LTIA system enabled rapid diagnosis of mitochondrial disease with a probability of 94% sensitivity and 91% specificity. The automated, high-throughput technology based on LTIA device has definite advantages over the ELISA kit in shorter processing time and lower estimated cost per sample measurement, which enable to make early diagnosis and treatment of mitochondrial disease. This discovery is a successful example of translational research and will revolutionize the diagnostic algorithms for mitochondrial disease in the world.

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Original Articles
  • Masataka Fukuoka, Yukitoshi Takahashi, Tokito Yamaguchi, Tetsuhiro Fuk ...
    2022 Volume 54 Issue 6 Pages 407-413
    Published: 2022
    Released on J-STAGE: December 07, 2022
    JOURNAL RESTRICTED ACCESS

      Objective: This study aimed to elucidate the clinical significance of Granzyme B (GrB) levelin cerebrospinal fluid (CSF) of patients with Rasmussen syndrome (RS). Methods: Patients with a diagnosis of RS based on Bien’s criteria and onset age younger than 50 years, who had measured CSF GrB levels were recruited. We examined the relationship of GrB with age at examination, SNPs of immunomodulatory genes [cytotoxic T lymphocyte-associated protein 4 (CTLA4) and programmed cell-death 1 (PDCD1)], clinical stage, seizure outcome and motor outcome. GrB levels of 38 patients with epilepsy presumably not associated with immunological etiology were used as disease controls. Results: Thirty-eight RS patients (73 specimens) comprising 15 males and 23 females were analyzed. CSF GrB levels in RS patients in the clinical stages 1-2 (less than 2 years from onset) were significantly higher than those of disease controls. Motor outcome was better in patients (3/6) with declining GrB level in the course of disease. No significant association was observed between GrB level and immunomodulatory therapy or SNPs of CTLA4 and PDCD1. Conclusions: CSF GrB level tends to be high in the early stage of RS (less than 2 years from onset), and is useful as a diagnostic marker.

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  • Kenji Sugai, Masako Aso, Satomi Ban, Natsuko Arai, Aki Maeda, Bunsei E ...
    2022 Volume 54 Issue 6 Pages 414-420
    Published: 2022
    Released on J-STAGE: December 07, 2022
    JOURNAL RESTRICTED ACCESS

      Objective: Sialorrhea and excess oral secretion are major problems in patients with severe motor and intellectual disabilities (SMID). These cause respiratory problems as well as sanitary problems, and lead to a severe burden on caregivers. However, there is no appropriate treatment to these conditions. Scopolia extract (SE) is usually used as a patent medicine to treat gastrointestinal disorders. It contains belladonna alkaloids which suppress the parasympathetic nerves and is expected to reduce saliva secretion. Methods: The caregivers (guardians, nurses and/or health care assistants) of the residents with SMID at our institution who suffered from above problems asked us to manage them. Following informed consent from the caregivers and later approval from the ethical committee for off-label use of SE for sialorrhea and excess oral secretion were obtained, up to 1.1-3.5 mg/kg (mean : 2.2 mg/kg) of SE was administered to the patients. SE was considered to be effective when sialorrhea nearly disappeared or when oral secretion decreased to less than half of that at the baseline level, and the efficacy was retrospectively surveyed. The impact of SE on nursing was surveyed on 27 nurses and healthcare assistants. Results: SE was administered to 47 patients and effective in 45 patients : 23/24 cases of sialorrhea and 22/23 cases of excess oral secretion. Adverse events occurred in six cases, including four cases of increased gastric residue and each one case of decreased bowel movement and sticky sputa, which was resolved by reducing or discontinuing SE. Constipation worsened in 10 cases but improved in four cases. SE was discontinued in six patients, including two patients with adverse events. Decreased sialorrhea and oral secretion led to a reduction in caregivers’ time and mental stress. In addition, it also improved the quality of life of both patients and caregivers. Conclusions: With regard to off-label use, SE is effective and applicable to the management of sialorrhea and respiratory problems due to excess oral secretion in patients with SMID.

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Case Reports
  • Shunsuke Takeuchi, Tatsuo Mori, Aya Goji, Toshiyuki Takahashi, Yoshihi ...
    2022 Volume 54 Issue 6 Pages 421-425
    Published: 2022
    Released on J-STAGE: December 07, 2022
    JOURNAL RESTRICTED ACCESS

      Myelin oligodendrocyte glycoprotein (MOG) antibody-positive disorders are generally considered to have a good response to steroids ; however, no treatment policy has been established for patients who do not respond to initial treatment or whose symptoms do not improve sufficiently. We report the case of a 12-year-old boy who experienced the onset of photophobia in the left eye, difficulty in moving facial muscles, and dysuria. Fluid-attenuated inversion recovery images of the brain showed multiple lesions in the cerebral cortex and subcortical white matter. Hence, we diagnosed acute disseminated encephalomyelitis. However, visual symptoms did not improve after 3 courses of methylprednisolone pulse (each course : 1 g/day for 3 days) and high-dose immunoglobulin (1 g/kg/dose) therapies. Subsequently, MOG antibodies were found in the serum and cerebrospinal fluid samples (serum titer, 1 : 2,048 ; cerebrospinal fluid titer, 1 : 64), and thus an anti-MOG antibody-related disease was confirmed. Plasmapheresis was performed thrice, followed by one course of methylprednisolone pulse therapy, following which the visual symptoms gradually improved. To prevent recurrence, this treatment was followed by oral prednisolone, which was gradually tapered over the next 7 months. In the 20 months since the onset of symptoms, the patient has exhibited no relapse. In MOG antibody-related disorders, visual symptoms are a common residual disability. In our patient, the improvement of visual symptoms was observed after plasmapheresis ; therefore, plasmapheresis should be considered while referring to the flicker value when the therapeutic effect of intravenous methylprednisolone is poor in patients with optic nerve inflammation.

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  • Masayoshi Hamaguchi, Hirofumi Kurata, Hiroe Ueno, Chizuru Ikeda, Hidek ...
    2022 Volume 54 Issue 6 Pages 426-430
    Published: 2022
    Released on J-STAGE: December 07, 2022
    JOURNAL RESTRICTED ACCESS

      The cytoplasmic FMR1 interacting protein 2 (CYFIP2) gene on 5q33.3 encodes CYFIP2, a component of the WASP-family verprolin-homologous protein (WAVE) regulatory complex. The WAVE regulatory complex plays an important role in actin dynamics. In 2018, whole-exome sequencing of children with severe forms of West syndrome and other developmental and epileptic encephalopathies (DEE) identified a group of patients with amino acid substitutions of CYFIP2 p.Arg87. Other variants of CYFIP2 identified in patients with West syndrome or other epilepsies have been linked to various degrees of neurological impairment, including intellectual disability. In the present case, the patient was a 9-year-old Japanese girl. At the age of 17 months, she experienced repeated episodes of seizure with behavioral arrest, followed by atonic and focal motor seizures. Although her seizures were refractory to several antiepileptic drugs, her epilepsy was controlled using zonisamide ; her facial expression improved, and an improvement in her quality of life was observed. She had long fingers accompanied by severe intellectual disability and autism spectrum disorder. She showed hypotonia and could walk at the age of 26 months. Whole-exome sequencing revealed a novel heterozygous missense mutation in CYFIP2 (NM_001037333.3 : c.344T>C : p.Leu115Pro) at the age of 7 years. Refractory epilepsy, severe intellectual disability with hypotonia, and long or tapered fingers may be indicative of the CYFIP2 mutation being the causative gene.

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  • Kyohei Sakaguchi, Takuya Hayashida, Kazuhiko Hashimoto, Daishi Inoue, ...
    2022 Volume 54 Issue 6 Pages 431-436
    Published: 2022
    Released on J-STAGE: December 07, 2022
    JOURNAL RESTRICTED ACCESS

      Infantile neuroaxonal dystrophy (INAD) is a rare neurodegenerative disorder characterized by infantile-onset rapidly progressive psychomotor regression and hypotonia that eventually results in spasticity and dementia. It is also known that glutamate receptor (GluR) antibodies lead to autoimmune encephalitis and encephalopathy, thereby acting as a biomarker of cognitive dysfunction. We report the case of a one-year-old girl who showed psychomotor regression and hypotonia following a minor viral infection. Brain magnetic resonance imaging displayed cerebellar atrophy without signal abnormality. We suspected autoimmune encephalitis and cerebellitis because of elevated anti-GluRs antibody titers in serum and cerebrospinal fluid, for which she was given immunoglobulins and corticosteroids, which were ineffective. Later, whole-exome sequencing detected a new homozygous splice-donor site variant (NM_003560.4 : c.797+1 G>C) in the PLA2G6, which was suggestive of INAD. Since the antibody titers increased over time without response to immunotherapy, we presumed that the GluR antibodies in this case were secondary to the synapse breakage during the neurodegenerative process. Therefore, the production of GluR antibodies is not limited to only autoimmune encephalitis or encephalopathy but can also occur in neurodegenerative disease, which should be considered during the diagnostic process.

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  • Saki Oguro, Takayuki Mori, Yu Kakimoto, Akira Takenaka, Konomi Shimoda ...
    2022 Volume 54 Issue 6 Pages 437-442
    Published: 2022
    Released on J-STAGE: December 07, 2022
    JOURNAL RESTRICTED ACCESS

      Constructional apraxia (CA) is caused by lesions in the bilateral parietal lobes as well as those in the frontal lobe due to frontotemporal dementia. However, there have been no reports of a pediatric case of CA resulting from frontal lobe lesions. We report a case wherein CA developed in a 9-year-old boy with acute disseminated encephalomyelitis (ADEM) and a right frontal lobe lesion. The patient presented to the hospital with complaints of fatigue and back and neck pain. Brain MRI revealed a white matter lesion in the right frontal lobe. Serum anti-myelin oligodendrocyte glycoprotein antibodies were detected. He was diagnosed with ADEM, and was treated with an initial course of pulse intravenous methylprednisolone, which improved the symptoms. However, CA was revealed by evaluation of higher brain dysfunction. Therefore, he received a second course of pulse intravenous methylprednisolone, and subsequently recovered from CA. Higher brain dysfunction is not listed as a main clinical manifestation of pediatric ADEM ; nonetheless, its evaluation led to a better clinical decision in this case. The assessment of higher brain dysfunction could be useful in making an appropriate treatment plan for pediatric central nervous system diseases.

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  • Yuichi Tateishi, Nobutsune Ishikawa, Yoshiyuki Kobayashi, Kanako Takeu ...
    2022 Volume 54 Issue 6 Pages 443-447
    Published: 2022
    Released on J-STAGE: December 07, 2022
    JOURNAL RESTRICTED ACCESS

      Myasthenia gravis (MG), an autoimmune disease of the neuromuscular junction, have an increased risk for complicating autoimmune thyroid diseases (AITD) such as Basedow disease (BD). We herein report a case of MG complicated by BD, treated with mechanical ventilation (MV). A 5-year-old boy with bilateral ptosis and diplopia was diagnosed with BD associated with MG by blood test and edrophonium test (day 0). He had received thiamazole, and thereafter BD symptoms improved. MG symptom was ocular manifestation, and evoked electromyography revealed no waning ; therefore, we initiated pyridostigmine therapy on day 4. However, ocular manifestation did not improve, concurrent with bulbar palsy symptoms appearing. Therefore, prednisolone (PSL) was initiated on day 21, while he suffered from aspiration-induced respiratory failure eventually requiring MV on day 22. He had received intravenous methyl-PSL pulse therapy and immunoglobulin therapy, subsequently, he could successfully wean from MV. Afterward, tacrolimus was added on day 28. Combining the therapy of PSL and tacrolimus successfully improved his symptoms. Oral intake was resumed on day 49, while ocular manifestation was almost completely resolved on day 57. He was finally discharged on day 81. Reports show that 6.0% of patients with BD are accompanied by MG. MG concomitant with AITD presents with milder symptoms than those in MG alone. However, some studies report there is no difference in the frequency of occurrence of MG crisis. Complications of AITD such as BD should be considered in cases of MG. Patients with AITD associated with MG show a mild course ; however, a severe presentation is possible, as observed in this case. It is necessary to pay attention to changes in symptoms and select an appropriate treatment.

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