Soluble form of the APP fragment, sAPPß, positively regulates tau secretion.

Extracellular tau has been highlighted in the pathogenesis of Alzheimer disease (AD), which is the most common neurodegenerative disease. Pathological analyses as well as model animal studies suggest that amyloid-ß peptide (Aß) deposition facilitates the spreading of tau aggregation pathology via extracellular tau. However, the precise mechanism of tau secretion remains unknown. Here, we show that the overexpression of amyloid precursor protein (APP) enhances the secretion of tau phosphorylated at threonine 181 in mouse neuroblastoma Neuro2a cells. Moreover, we found that soluble amyloid precursor protein ß (sAPPß), which is generated by ß-site APP cleaving enzyme 1 (BACE1), mediates tau secretion. Our results demonstrate that BACE1-mediated cleavage of APP plays pathological roles in AD pathogenesis by not only Aß production, but by the spreading of tau aggregation pathology via sAPPß in AD patients.

Idiopathic rapid eye movement sleep behavior disorder in Japan: An observational study.

INTRODUCTION: Idiopathic rapid eye movement sleep behavior disorder (iRBD) is one of the most specific prodromal symptoms of synucleinopathies, including Parkinson's disease (PD) and multiple system atrophy. The Japan Parkinson's Progression Markers Initiative (J-PPMI) was a prospective cohort study conducted in Japanese patients with iRBD to investigate biomarkers for prodromal synucleinopathies. We carried out an initial assessment of the J-PPMI study to reveal the factors correlated with dopamine transporter single-photon emission computed tomography (DaT) and 123I-meta-iodobenzylguanidine (MIBG) myocardial scintigraphy. METHODS: This cross-sectional study was conducted in 108 patients with iRBD, selected from the J-PPMI study. We divided the patients into four groups based on the MIBG and DaT results. We also recorded the patients' demographics and clinical data. Following PD probability calculation, we examined the biomarkers associated with DaT and MIBG. RESULTS: Ninety-five of the enrolled patients (88%) met the diagnostic criteria for prodromal PD based on the probability score. Only five patients had normal MIBG and DaT. We identified 29 cases with decreased DaT and MIBG, all of whom met the above diagnostic criteria. Both DaT and MIBG were significantly correlated with the Japanese version of the Montreal Cognitive Assessment (MoCA-J) score. CONCLUSION: Both DaT and MIBG are important biomarkers for confirming synucleinopathies and/or staging disease progression. Although 95% of iRBD patients were consistent with the body-first subtype concept, alpha-synuclein pathologies of iRBD might have widespread systemic involvement rather than being confined to the lower brainstem, particularly in patients with reduced MoCA-J scores.

Parcellation of the murine cortical hindlimb area is demonstrated by its subcortical connectivity and cytoarchitecture.

Although corticospinal neurons are known to be distributed in both the primary motor and somatosensory cortices (S1), details of the projection pattern of their fibers to the lumbar cord gray matter remain largely uncharacterized, especially in rodents. We previously investigated the cortical area projecting to the gray matter of the fourth lumbar cord segment (L4) (L4 Cx) in mice. In the present study, we injected an anterograde tracer into multiple sites to cover the entire L4 Cx. We found that (1) the rostromedial part of the L4 Cx projects to the intermediate and ventral zones of the lumbar cord gray matter, (2) the lateral part projects to the medial dorsal horn, and (3) the caudal part projects to the lateral dorsal horn. We also found that the border between the rostromedial and caudolateral parts corresponds to the border between the agranular and granular cortex. Analysis of the somatotopic patterns formed by the cortical projection cells and the primary sensory neurons innervating the skin of the hindlimb and its related area suggests that the lateral part corresponds to the S1 hindlimb area and the caudal part to the S1 trunk area. Examination of thalamic innervation by the L4 Cx revealed that the caudolateral L4 Cx focally projects to the ventrobasal complex (VB) and the posterior complex (PO), while the medial L4 Cx widely projects to the PO but little to the VB. These findings suggest that the L4 Cx is parceled into subregions defined by the cytoarchitecture and subcortical projection.

Treatment Satisfaction With Current Medications for Chronic Constipation: An Internet Survey of Japanese Patients.

GOALS: This survey aims to determine relevant patient characteristics, treatment satisfaction, and bothersome symptoms in Japanese patients with chronic constipation (CC) treated at medical institutions. BACKGROUND: Epidemiological surveys of Japanese patients with CC are limited. STUDY: This internet survey, conducted in 2017, included 500 adults (selected from 589 respondents to match age composition ratio in Japan) who experienced constipation-like symptoms for ≥6 months, were treated at medical institutions for symptoms, and were taking any prescribed medication. RESULTS: Of 500 patients, 65.6% were female and 62.6% had experienced constipation for >10 years. Abdominal bloating, infrequent bowel movement, hard consistency of stool, and difficulty of defecation were the most frequently reported and most bothersome symptoms in males and females. Overall, 29% of patients were satisfied with treatment (36% of males, 26% of females); the individual major CC symptom with the highest level of treatment satisfaction was infrequent bowel movement (31% of total, 45% of males, 26% of females). The level of treatment satisfaction for most individual major CC symptoms was lower in females than in males, and overall treatment satisfaction by therapeutic categories ranged from 16% to 46%. Mean overall treatment satisfaction, as well as mean treatment satisfaction for each major symptom, decreased with increasing number of treatments. CONCLUSIONS: The survey results suggest that conventional treatment options were not effective enough to improve bothersome symptoms or treatment satisfaction. Treatment selection that is tailored to individual symptoms and takes patient characteristics into consideration may be key to improving patients' treatment satisfaction.

Diagnostic Values of Venous Peak Lactate, Lactate-to-pyruvate Ratio, and Fold Increase in Lactate from Baseline in Aerobic Exercise Tests in Patients with Mitochondrial Diseases.

Objective Although aerobic exercise tests on cycle ergometry have long been used for initial assessments of cases of suspected mitochondrial disease, the test parameters in patients with final diagnoses of other diseases via the widely used 15 W for 15 minutes exercise protocol have not been fully characterized. Methods We retrospectively reviewed all patients who underwent the test at our institution. We classified the patients with genetic diagnoses or those who met previously reported clinical criteria as having mitochondrial diseases and those with a final diagnosis of another disease as having other diseases. Results were available from 6 patients with mitochondrial disease and 15 with other diseases. Results During the test, elevated venous peak lactate above the upper normal limit of healthy controls at rest [19.2 mg/dL (2.13 mM)] was observed in 3 patients with mitochondrial diseases (50.0%) and 5 with other diseases (33.3%). In the group of patients with elevated venous peak lactate, a lactate-to-pyruvate ratio of >20 was observed in all 3 patients with mitochondrial disease but in only 1 of the 5 with other diseases. More than a 2-fold increase in venous lactate from baseline was observed in 4 patients with mitochondrial disease (66.7%) and 1 with another disease (6.7%). Conclusion Elevated venous peak lactate levels were observed in patients with final diagnoses of other diseases, even under a low 15-minute workload at 15 W. The lactate-to-pyruvate ratio and increase in lactate level from baseline may add diagnostic value to venous peak lactate levels alone.

[Multicenter Evaluation of Cine Angiography and Digital Subtraction Angiography Dose Rate for Various Angiography Programs: Comparison with Fluoroscopic Dose Rate].

We conducted a nationwide multicenter survey of various interventional radiology (IVR) procedures. Data were collected from 385 X-ray systems in 126 institutions, including 432 cine programs and 380 digital subtraction angiography (DSA) programs for diagnostic catheterization, percutaneous coronary intervention (PCI), ablation, transcatheter aortic valve implantation (TAVI), neurologic IVR, thorax IVR, abdominal IVR, and endovascular therapy (EVT). Fluoroscopic and cine dose rates were 10.1 mGy/min and 110.7 mGy/min, respectively, whereas for DSA programs, the median fluoroscopic and DSA dose rates were 8.0 mGy/min and 224.8 mGy/min, respectively. The DSA dose rate was more than twice the cine dose rate. The largest difference between dose rates was for diagnostic catheterization, which had a cine dose rate of 142.6 mGy/min and a fluoroscopic dose rate of 12.6 mGy/min (by a factor of 12.5), followed by EVT, which had a DSA dose rate of 216.0 mGy/min and a fluoroscopic dose rate of 7.7 mGy/min (by a factor of 29.6). The smallest difference between dose rates was for TAVI, which had a cine dose rate of 96.8 mGy/min and a fluoroscopic dose rate of 12.0 mGy/min (by a factor of 8.9), followed by neurologic IVR, which had a DSA dose rate of 227.9 mGy/min and a fluoroscopic dose rate of 9.6 mGy/min (by a factor of 22.6). Compared with the fluoroscopic dose rates, the cine dose rates were 9-13 times higher and the DSA dose rates were 22-30 times higher; the DSA dose rates were more than double the cine dose rates.

Cerebellar Ataxia as a Common Clinical Presentation Associated with DNMT1 p.Y511H and a Review of the Literature.

The phenotypes of patients with disease-associated variants in DNMT1 have been classified into two syndromes: hereditary sensory and autonomic neuropathy type 1E (HSAN1E, MIM614116, https://www.omim.org/ ) and autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN, MIM604121). The amino acid codon 511 is a hotspot, and p.Y511C is the most frequently observed disease-associated variant among those in HSAN1E patients, whereas there have been only a few reports on patients with p.Y511H. In this study, we report on the cases of a kindred carrying the DNMT1 variant NM_001130823.2:c.1531 T > C (p.Y511H) presenting with the ADCA-DN phenotype. The review of the literature further revealed that later ages at onset and the presence of cerebellar ataxia are the main characteristics of patients carrying the DNMT1 p.Y511H as compared with those carrying DNMT1 p.Y511C. Although HSAN1E and ADCA-DN are proposed to be called DNMT1-complex disorders owing to their overlapping symptoms, this finding suggests a distinct genotype-phenotype correlation regarding the DNMT1 p.Y511H and p.Y511C variants.

Inference of Regulatory System for TAG Biosynthesis in Lipomyces starkeyi.

Improving the bioproduction ability of efficient host microorganisms is a central aim in bioengineering. To control biosynthesis in living cells, the regulatory system of the whole biosynthetic pathway should be clearly understood. In this study, we applied our network modeling method to infer the regulatory system for triacylglyceride (TAG) biosynthesis in Lipomyces starkeyi, using factor analyses and structural equation modeling to construct a regulatory network model. By factor analysis, we classified 89 TAG biosynthesis-related genes into nine groups, which were considered different regulatory sub-systems. We constructed two different types of regulatory models. One is the regulatory model for oil productivity, and the other is the whole regulatory model for TAG biosynthesis. From the inferred oil productivity regulatory model, the well characterized genes DGA1 and ACL1 were detected as regulatory factors. Furthermore, we also found unknown feedback controls in oil productivity regulation. These regulation models suggest that the regulatory factor induction targets should be selected carefully. Within the whole regulatory model of TAG biosynthesis, some genes were detected as not related to TAG biosynthesis regulation. Using network modeling, we reveal that the regulatory system is helpful for the new era of bioengineering.

Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy.

Accumulated experience supports the efficacy of allogenic haematopoietic stem cell transplantation in arresting the progression of childhood-onset cerebral form of adrenoleukodystrophy in early stages. For adulthood-onset cerebral form of adrenoleukodystrophy, however, there have been only a few reports on haematopoietic stem cell transplantation and the clinical efficacy and safety of that for adulthood-onset cerebral form of adrenoleukodystrophy remain to be established. To evaluate the clinical efficacy and safety of haematopoietic stem cell transplantation, we conducted haematopoietic stem cell transplantation on 12 patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy in a single-institution-based prospective study. Through careful prospective follow-up of 45 male adrenoleukodystrophy patients, we aimed to enrol patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy at early stages. Indications for haematopoietic stem cell transplantation included cerebral form of adrenoleukodystrophy or cerebello-brainstem form of adrenoleukodystrophy with Loes scores up to 13, the presence of progressively enlarging white matter lesions and/or lesions with gadolinium enhancement on brain MRI. Clinical outcomes of haematopoietic stem cell transplantation were evaluated by the survival rate as well as by serial evaluation of clinical rating scale scores and neurological and MRI findings. Clinical courses of eight patients who did not undergo haematopoietic stem cell transplantation were also evaluated for comparison of the survival rate. All the patients who underwent haematopoietic stem cell transplantation survived to date with a median follow-up period of 28.6 months (4.2-125.3 months) without fatality. Neurological findings attributable to cerebral/cerebellar/brainstem lesions became stable or partially improved in all the patients. Gadolinium-enhanced brain lesions disappeared or became obscure within 3.5 months and the white matter lesions of MRI became stable or small. The median Loes scores before haematopoietic stem cell transplantation and at the last follow-up visit were 6.0 and 5.25, respectively. Of the eight patients who did not undergo haematopoietic stem cell transplantation, six patients died 69.1 months (median period; range 16.0-104.1 months) after the onset of the cerebral/cerebellar/brainstem lesions, confirming that the survival probability was significantly higher in patients with haematopoietic stem cell transplantation compared with that in patients without haematopoietic stem cell transplantation (P = 0.0089). The present study showed that haematopoietic stem cell transplantation was conducted safely and arrested the inflammatory demyelination in all the patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy when haematopoietic stem cell transplantation was conducted in the early stages. Further studies are warranted to optimize the procedures of haematopoietic stem cell transplantation for adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy.

[Multicenter Survey on Radiation Dose of Cardiac Intervention].

We conducted a nationwide survey of multiple institutions and collected data of various interventional procedures in the field of cardiology. Included in the analysis were 126 institutions, 381 X-ray systems, and 805 protocols. The dose values were compared with the Japanese diagnostic reference levels (DRLs) 2015. Fluoroscopy time, air kerma at the patient entrance reference point (Ka, r), and air kerma-area product (PKA ) were analyzed for various interventional procedures in 5,734 cardiology patients. The fluoroscopic dose rate (FDR) for pulmonary vein isolation (PVI) was less than half that of the 75th percentile of the Japanese DRLs 2015. The 75th percentiles of fluoroscopy time, Ka, r, and PKA for the respective interventional procedures were as follows: 11.0 min, 735 mGy, and 64 Gyï½¥cm2 for diagnostic coronary angiography (CA); 13.2 min, 839 mGy, and 75 Gyï½¥cm2 for CA + left ventriculography; 34.4 min, 1,810 mGy, and 148 Gyï½¥cm2 for percutaneous coronary intervention (PCI) excluding chronic total occlusion; 80.1 min, 4,338 mGy, and 312 Gyï½¥cm2 for PCI for chronic total occlusion; 74.4 min, 833 mGy, and 90 Gyï½¥cm2 for PVI; and 34.0 min, 795 mGy, and 94 Gyï½¥cm2 for transcatheter aortic valve implantation, respectively. In assessing dose values in interventional radiology, the difficulty of the technique needs to be considered, and the DRL values for FDR, fluoroscopic time, Ka, r, and PKA for each interventional procedure are considered necessary when reassessing or updating DRLs.

Selective impairment of On-reading (Chinese-style pronunciation) in alexia with agraphia for kanji due to subcortical hemorrhage in the left posterior middle temporal gyrus.

We report a patient with alexia with agraphia for kanji after hemorrhage in the left posterior middle temporal gyrus. The results of single-character kanji reading and two-character on- (Chinese-style pronunciation), kun- (native Japanese pronunciation), and Jukujikun (irregular kun-) reading word tests revealed that the patient could not read kanji characters with on-reading but read the characters with kun-reading. We consider that this on-reading alexia was caused by disconnection between the posterior inferior temporal cortex (orthographic lexicon) and the posterior superior temporal gyrus (phonological lexicon), and preserved kun- and Jukujikun-reading was realized by bypassing the orthography-to-phonology route by the semantic route.

[A cross-sectional analysis of the health-related quality of life and work productivity in Japanese subjects with self-reported chronic constipation using the National Health and Wellness Survey 2017].

BACKGROUND: Chronic constipation (CC) is associated with lower health-related quality of life (HR-QoL) and work productivity in Western countries;however, limited data in Japanese subjects are available. METHODS: This retrospective, cross-sectional analysis used the data from the National Health and Wellness Survey (NHWS), a web-based questionnaire survey conducted in 2017 for the Japanese general population. Subjects were allocated to the self-reported CC group when they answered "yes" to the question "Did you have chronic constipation in the past 12 months?". Other subjects were allocated to the non-CC group. Self-reported CC population was sub-categorized as per the abdominal symptoms. The HR-QoL was assessed using the Medical Outcomes Study 12-Item Short-Form Health Survey version 2 using the Mental Component Summary (MCS), Physical Component Summary (PCS), and Role/Social Component Summary (RCS) scores (3-component method). Work productivity was assessed using the Work Productivity and Activity Impairment:General Health version 2.0 for absenteeism, presenteeism, work productivity loss, and activity impairment. RESULTS: Of the 30001 respondents, 3373 had self-reported CC (895 with abdominal symptoms, 2478 without abdominal symptoms) and 26628 did not report CC. The differences in the summary scores [95% confidence interval (CI) ] adjusted for potential confounders between self-reported CC and non-CC (self-reported CC - non-CC) were -1.60 (-1.98, -1.22) in MCS, -0.78 (-1.19, -0.37) in PCS, and -2.09 (-2.57, -1.61) in RCS;the differences in the adjusted summary scores (95% CI) between self-reported CC with and without abdominal symptoms (self-reported CC with abdominal symptoms - without abdominal symptoms) were -0.95 (-1.77, -0.14) in MCS, -1.67 (-2.66, -0.68) in PCS, and -2.05 (-3.55, -0.55) in RCS. All the summary scores were lower in those with self-reported CC and abdominal symptoms than in those with self-reported CC without abdominal symptoms;all the adjusted differences between the summary scores were statistically significant. The adjusted risk ratio (95% CI) of each outcome of self-reported CC relative to non-CC was 1.34 (1.04, 1.73) in absenteeism, 1.21 (1.12, 1.31) in presenteeism, 1.20 (1.11, 1.29) in work productivity loss, and 1.21 (1.15, 1.27) in activity impairment. In terms of statistics, the risk of decreased work productivity for all the outcomes was significantly higher in those with than in those without self-reported CC, indicating decreased work productivity in those with self-reported CC. CONCLUSION: HR-QoL and work productivity were lower in those with self-reported CC than in those who did not report CC, suggesting that CC negatively affects the HR-QoL and work productivity.

A Novel de novo KIF1A Mutation in a Patient with Autism, Hyperactivity, Epilepsy, Sensory Disturbance, and Spastic Paraplegia.

Heterozygous mutations in KIF1A have been reported to cause syndromic intellectual disability or pure spastic paraplegia. However, their genotype-phenotype correlations have not been fully elucidated. We herein report a man with autism and hyperactivity along with sensory disturbance and spastic paraplegia, carrying a novel de novo mutation in KIF1A [c.37C>T (p.R13C)]. Autism and hyperactivity have only previously been reported in a patient with c.38 G>A (R13H) mutation. This case suggests that alterations in this arginine at codon 13 might lead to a common clinical spectrum and further expand the genetic and clinical spectra associated with KIF1A mutations.

Hypoglossal Nerve Palsy as a Cause of Severe Dysphagia along with the Oropharyngeal Stenosis due to Occipitocervical Kyphosis.

Hypoglossal nerve palsy (HNP) is a potential cause of dysphagia. A 66-year-old man presented to our hospital with dysphagia and neck pain. One year prior to his first visit, he had been diagnosed with upper cervical tuberculosis and had undergone posterior C1-2 fixation. The physical examination led to the diagnosis of dysphagia with HNP, and he had severe weight loss. Radiographic examination revealed that the O-C kyphosis had been exacerbated and that the deformity was likely the primary cause of HNP. To restore the swallowing function, O-C fusion surgery was performed. Postoperatively, the patient showed immediate improvement of dysphagia with gradual recovery of hypoglossal nerve function. In the last follow-up evaluation, swallowing function was confirmed with no signs of HNP. Our results indicate that HNP could be more prevalent in cases with severe cervical kyphosis, being underdiagnosed due to the more apparent signs of the oropharyngeal narrowing.

Mediolateral and dorsoventral projection patterns of cutaneous afferents within transverse planes of the mouse spinal dorsal horn.

The central projection patterns of cutaneous afferents from the forelimb and shoulder of mice were studied in the spinal dorsal horn after intracutaneous injection of AlexaFluor 488-conjugated and/or 594-conjugated cholera toxin subunit B (CTB). Based on their dermatomes, the following eight skin regions are thought to be innervated by spinal nerves from the sixth to eighth cervical spinal nerve roots: the dorsal surface of the shoulder, brachium, proximal forearm, distal forearm, hand, palmar surface of the second and third digits, and palm. The termination areas of afferents from the dorsal surface of the shoulder and forearm were narrow, distributed in a dorsoventral direction, and aligned in order from lateral to medial within the sixth to eighth cervical dorsal horns. By contrast, the termination areas of the palmar surface of the second and third digits largely overlapped. We also injected CTB into the dorsal surface of the hindlimb and pelvic regions. Skin regions there are thought to be innervated by nerves from the third to fifth lumbar spinal nerve roots. The observed projection patterns in the lumbar dorsal horn were similar to the cervical patterns. Injection of a mixture of CTB and wheat-germ agglutinin-conjugated horseradish peroxidase (WGA-HRP), which are thought to label Aß and Aδ/C fibers, respectively, showed segregated termination areas of CTB- and WGA-HRP-labeled afferents. Moreover, alignment of the termination areas was in the dorsoventral direction. These results suggest there is fine somatotopic (mediolateral axis) and modality-specific (dorsoventral axis) organization within the spinal dorsal horn.

Aphasic status epilepticus preceding tumefactive left hemisphere lesion in anti-MOG antibody associated disease.

INTRODUCTION: Anti-myelin oligodendrocyte glycoprotein (MOG) antibodies have recently been associated with epilepsy with FLAIR hyperintense cortical lesions on MRI. Association between anti-MOG antibodies and epilepsy without detectable structural brain lesion on MRI is unknown. CASE REPORT: A 48-year-old right-handed man with a four-and-a-half year history of anti-MOG antibody associated demyelinating disease presented with persistent global aphasia. Brain MRI showed no new lesion or cortical lesion in the left hemisphere. Electroencephalogram, magnetoencephalography, and brain perfusion single-photon emission computed tomography suggested epileptic foci in the left temporal and parietal lobes, and the patient's aphasia transiently responded to intravenous diazepam, compatible with aphasic status epilepticus. Cerebrospinal fluid showed mildly elevated cell count and positive oligoclonal bands. The patient only partially responded to antiepileptic drugs but responded to steroid pulse therapy. Six months later, the patient again exhibited global aphasia. Brain MRI showed tumefactive white matter lesion in the left temporo-parietal lobes. CONCLUSION: Autoimmune epilepsy without obvious causative lesion on MRI can be seen in the course of anti-MOG antibody associated demyelinating disease. The subsequent emergence of tumefactive lesion closely located to the epileptic foci may suggest some association between autoimmune epilepsy and demyelinating lesions.

[FAMILIAL OCCURRENCE OF SUMMER-TYPE HYPERSENSITIVITY PNEUMONITIS IN DEFECTIVE HOME].

A 53-year-old-woman presented our hospital with 1 month history of exertional dyspnea and mild fever. When examined, temperature was 37.2℃ and her respiratory rate of 22/min with an O2 saturation of 95% (02 4L/min), the rest of her vital signs were normal. The Chest X-ray was significant for ground-grass attenuation, and computed tomography showed diffuse nodular lesions bilaterally. She reported that the floorboard in the living room had been rotten last two months, and her husband was admitted to another hospital with similar symptoms the day before. We suspected that she and her husband have familial hypersensitivity pneumonitis although their children who live in the same house don't have any symptoms. After the admission, her respiratory status improved without treatment. The trans-bronchial lung biopsy specimens showed lymphocytic infiltration in alveolar area, and epithelioid cell granuloma consisted of CD68-positive macrophages. These findings corresponded to subacute hypersensitivity pneumonitis. The bronchoalveolar lavage revealed predominant lymphocytes of 92%, with a low CD4/8 ratio of 0.39. Serum anti-Trichosporon asahii antibodies were positive. With the result of positive environmental challenge test in her house, which showed elicited dyspnea and temperature increase up to 38℃ a few hours after she came back home, the patient was diagnosed as having summer-type hypersensitivity pneumonitis. Her husband was also diagnosed as the same disease, and symptoms improved with antigen avoidance and prednisolone. The patient was discharged to her relative's place for the moment of house repair. The patient's symptoms did not recur after her house was repaired.

Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy.

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.