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Immediately after the initial methionine codon, the PABPN1 gene encodes a stretch of 10 alanines, 1 glycine, and 2 alanines. Oculopharyngeal muscular dystrophy (OPMD) is caused by the expansion of the first 10 alanine stretches. The only exception is the missense mutation of glycine at the 12th residue into alanine, which elongates the stretch to 13 alanines by connecting the first and second stretch with the addition of one alanine in between, indicating that the expansion or elongation of the alanine stretch results in OPMD. We report a 77-year-old man with the novel missense mutation c.34G > T (p.Gly12Trp) in PABPN1 gene whose clinicopathological findings were compatible with OPMD. He presented with slowly progressive bilateral ptosis, dysphagia, and symmetrical proximal dominant muscle weakness. Magnetic resonance imaging revealed selective fat replacement of the tongue, bilateral adductor magnus, and soleus muscles. Immunohistochemistry studies of the muscle biopsy sample revealed PABPN1-posibive aggregates in the myonuclei which have been reported to be specific to OPMD. This is the first OPMD case caused by neither the expansion nor the elongation of alanine stretch. The present case suggests that OPMD may be caused not only by triplet repeats but also by point mutations.

The pathologies of oculopharyngeal muscular dystrophy (OPMD) and oculopharyngodistal myopathy (OPDM) are indistinguishable. We found that p62-positive intra-nuclear inclusions (INIs) in myonuclei (myo-INIs) were significantly more frequent in OPMD (11.4 ± 4.1%, range 5.0– 17.5%) than in OPDM and other rimmed vacuolar myopathies (RVMs) (1–2% on average, range 0.0–3.5%, p

Oculopharyngodistal myopathy (OPDM) is caused by the expansion of CGG repeats in NOTCH2NLC (OPDM_NOTCH2NLC) GIPC1 (OPDM_GIPC1), or LRP12 (OPDM_LRP12). Neuronal intranuclear inclusion disease (NIID) is clinically distinct from OPDM but is also caused by the expansion of CGG repeats in NOTCH2NLC, which may be an indicator of intranuclear inclusion in skin biopsy. We investigated the presence of intranuclear inclusions in skin biopsies from patients with OPDM and muscle diseases with a similar pathology to evaluate whether they will have similar diagnostic findings on skin biopsy.We analysed the frequency of p62-positive intranuclear inclusions in sweat gland cells, adipocytes and fibroblasts in skin biopsy samples from patients with OPDM (OPDM_NOTCH2NLC [n = 2], OPDM_GIPC1 [n = 6] and OPDM_LRP12 [n = 3]), NIID (n = 1), OPMD (n = 1), IBM (n = 4) and GNE myopathy (n = 2).The p62-postive intranuclear inclusions were observed in all three cell types in both patients with OPDM_NOTCH2NLC and a patient with NIID, in at least one cell type in all six patients with OPDM_GIPC1, and all in three cell types in one of the three patients with OPDM_LRP12. These findings were not observed in patients with OPMD, IBM or GNE myopathy.Intranuclear inclusions in skin biopsy samples are not specific to NIID and are found in all three types of genetically confirmed OPDM, suggesting that the underlying mechanism of OPDM may be similar to NIID, regardless of causative genes.

Background Cerebral arterial air embolism is often associated with an invasive iatrogenic etiology and a high rate of convulsive seizures. There are only a few descriptions of electroencephalogram findings in convulsive seizures due to cerebral arterial air embolism of noniatrogenic etiology. Herein, we describe the case of a patient with lung cancer and convulsive seizures with abnormalities detected on electroencephalogram caused by cerebral arterial air embolism of noniatrogenic etiology. Case presentation A 55-year-old Japanese man underwent radiotherapy and chemotherapy for cancer in the hilum of the left lung that was diagnosed after hemoptysis. One year after the diagnosis, he developed fever and chest pain that required hospitalization. At admission, he was in shock, and chest computed tomography revealed invasion of the left atrium and left main bronchus by the hilar cancer. Chest and abdominal computed tomography revealed small low-density areas within the tumor and around the intestinal membrane, which were interpreted as the presence of air due to invasion of the lung cancer. He was diagnosed with septic shock due to necrotic infection secondary to cancer invasion into the left atrium. The following day, he complained of difficulty in speaking and weakness in the left side of his body. A head computed tomography scan revealed multiple small low-density areas in the right cortex and bilateral subcortex, which were interpreted as air emboli. On day 3, he experienced generalized tonic–clonic seizures for approximately 1 minute, followed by myoclonus-like convulsions in the left lower limb and a right-sided gaze. The electroencephalogram findings after the convulsive seizures revealed partial epilepsy-like waves with intermittent spikes in the bilateral cerebral hemispheres and a diffuse slow wave in the left frontal lobe. He recovered from sepsis without recurrence of convulsive seizures; however, he died of hemoptysis on day 50 after discharge. Conclusions Electroencephalogram findings of focal spike activities and diffuse slow waves were detected in early seizures due to cerebral arterial air embolism of noniatrogenic etiology associated with lung cancer. Additional case descriptions are warranted to establish patterns in electroencephalogram findings specific to cerebral arterial air embolism.

We report a 62-year-old female with rheumatoid meningitis. She presented with mental disorder, loss of consciousness, generalized seizures, and cognitive impairment. Brain MRI demonstrated high intensity lesions and abnormal enhancement along the left frontal and parietal sulci. Her serum and cerebrospinal fluid were positive for anti-cyclic citrullinated peptides (CCP) antibody, and the antibody index of cerebrospinal fluid anti-CCP antibody increased, which led us to suspect rheumatoid meningitis. Her symptoms improved immediately by methylpredonisolone pulse therapy and anti-CCP antibody turned negative in cerebrospinal fluid. However, she revealed arthritis with the reduction of betamethasone and was diagnosed as rheumatoid arthritis. We suggest that the elevation of antibody index of cerebrospinal fluid anti-CCP antibody is useful in the diagnosis of rheumatoid meningitis preceding neurological symptoms without arthritis, and anti-CCP antibody in cerebrospinal fluid may be helpful as the evaluation of the treatment.

A 45-year-old man suffered multiple cerebral infarctions in the vertebrobasilar artery territory, followed by second stroke against conservative treatment. Radiological examinations revealed intra-arterial defect in left persistent 1st intersegmental artery (PFIA) at C1 level, suggesting mural thrombus, and mechanical compression of left PFIA at the level with head rotation to the right clearly revealed by reconstructed 3-dimensional radiological images, but no findings of atlantoaxial instability. One month after the second stroke, posterior fixation was performed. Postoperative course was uneventful without subsequent stroke for 24 months. This unique case demonstrated that PFIA might associate with cerebral stroke as a clinical condition of bow hunter's stroke even in middle age. Reconstructed 3-dimensional radiological images might be useful for clear demonstration of the pathophysiology in this complex clinical entity.

Background Hypereosinophilia (HE) is caused by various conditions, including solid and hematologic tumors. Nonetheless, there exist no reports on cerebral infarctions caused by HE associated with lung cancer metastasis to the bone marrow. Case presentation We report a case of a 67-year-old man with multiple cerebral infarctions associated with HE. His white blood cell and eosinophil counts were 38,900/μL and 13,600/μL, respectively, at 4 weeks before admission. During treatment for HE, he presented with dysarthria and walking difficulties. Magnetic resonance imaging of the brain showed multiple small infarcts in regions such as the bilateral cortex, watershed area, and cerebellum. Chest computed tomography showed small nodes in the lung and enlargement of the left hilar lymph nodes. Bronchoscopic biopsy did not reveal a tumor; however, bone marrow biopsy showed infiltration of tumor cells. We considered a diagnosis of lung cancer metastasizing to the bone marrow, which induced HE and later caused cerebral infarctions. Conclusions This case report demonstrates that metastatic cancer in the bone marrow can induce HE, which can consequently cause multiple cerebral infarctions. Clinicians should consider HE as a cause of multiple cerebral infarctions in patients with cancer.

Ischemic stroke is one of the most common neurological diseases. However, the impact of ischemic stroke on human cerebral tissue remains largely unknown due to a lack of ischemic human brain samples. In this study, we applied cerebral organoids derived from human induced pluripotent stem cells to evaluate the effect of oxygen-glucose deprivation/reoxygenation (OGD/R). Pathway analysis showed the relationships between vitamin digestion and absorption, fat digestion and absorption, peroxisome proliferator-activated receptor (PPAR) signaling pathway, and complement and coagulation cascades. Combinational verification with transcriptome and gene expression analysis of different cell types revealed fatty acids-related PPAR signaling pathway and pyruvate kinase isoform M2 (PKM2) as key markers of neuronal cells in response to OGD/R. These findings suggest that, although there remain some limitations to be improved, our ischemic stroke model using human cerebral organoids would be a potentially useful tool when combined with other conventional two-dimensional (2D) mono-culture systems.

Human brain organoids provide us the means to investigate human brain development and neurological diseases, and single-cell RNA-sequencing (scRNA-seq) technologies allow us to identify homologous cell types and the molecular heterogeneity between individual cells. Previously established human brain organoids of brainstem (hBSOs) and midbrain (hMBOs) were analyzed by scRNA-seq, but the difference in cellular composition between these organoids remains unclear. Here, we integrated and compared the single-cell transcriptome of hBSOs and hMBOs. Our analysis demonstrated that the hBSOs and hMBOs contain some unique cell types, including inflammatory and mesenchymal cells. Further comparison of the hBSOs and hMBOs with publicly available scRNA-seq dataset of human fetal midbrain (hMB) showed high similarity in their neuronal components. These results provide new insights into human brain organoid technologies.

This study aimed to evaluate genotype-phenotype correlations of Parkinson’s disease (PD) patients with phospholipase A2 group V (PLA2G6) variants. We analyzed the DNA of 798 patients with PD, including 78 PD patients reported previously, and 336 in-house controls. We screened the exons and exon-intron boundaries of PLA2G6 using the Ion Torrent system and Sanger method. We identified 21 patients with 18 rare variants, such that 1, 9, and 11 patients were homozygous, heterozygous, and compound heterozygous, respectively, with respect to PLA2G6 variants. The allele frequency was approximately equal between patients with familial PD and those with sporadic PD. The PLA2G6 variants detected frequently were identified in the early-onset sporadic PD group. Patients who were homozygous for a variant showed more severe symptoms than those who were heterozygous for the variant. The most common variant was p.R635Q in our cohort, which was considered a risk variant for PD. Thus, the variants of PLA2G6 may play a role in familial PD and early-onset sporadic PD.

Background: Freezing of gait (FOG) has been linked to increased numbers of steps taken while walking. We tested the hypothesis that an increased number of steps associated with FOG might predict the exacerbation of the severity of Parkinson’s disease (PD). Methods: We prospectively studied 26 patients. Clinical assessments were performed and balance was evaluated in 30 patients with Hoehn-Yahr stage III PD 6 years previously. Gait parameters were analyzed with the use of an originally designed, suddenly narrowed path. PD-related independent variables, balance investigation-related variables, and gait-independent-related variables were analyzed by multiple logistic regression analysis. Results: The Hoehn-Yahr stage increased in 14 patients and was unchanged in 12 patients. The 36-item Short-Form Health Survey score (OR 1.079, p = 0.041, 95% CI 1.003–1.161) and the number of steps on the suddenly narrow path (OR 1.605, p = 0.047, 95% CI 1.006–2.56) were related to an increase in the Hoehn-Yahr stage. The number of steps was significantly higher on the suddenly narrowed path (11.3 ± 3.6) than on a straightly narrowed path (10.1 ± 3.2) at the time of final follow-up in the 26 patients (p < 0.001). Conclusions: An increased number of steps associated with FOG, which was elicited by the suddenly narrowed path, might be one predictor of an upgrade of stage in patients with Hoehn-Yahr stage III PD.

SummaryThe brainstem controls heartbeat, blood pressure and respiration, which are life-sustaining functions, therefore, disorders of the brainstem can be lethal. Brain organoids derived from human pluripotent stem cells recapitulate the course of human brain development and are expected to be useful for medical research on central nervous system disorders. However, existing organoid models have limitations, hampering the elucidation of diseases affecting specific components of the brain. Here, we developed a method to generate human brainstem organoids (hBSOs), containing neural crest stem cells as well as midbrain/hindbrain progenitors, noradrenergic and cholinergic neurons, and dopaminergic neurons, demonstrated by specific electrophysiological signatures. Single-cell RNA sequence analysis, together with proteomics and electrophysiology, revealed that the cellular population in these organoids was similar to that of the human brainstem and neural crest, which raises the possibility of making use of hBSOs in grafting for transplantation, efficient drug screenings and modeling the neural crest diseases.

Antibodies to glycine receptors were associated with synchronized myoclonus in both legs and the myoclonus derived from not only the brainstem but also the spine.

Importance Repeat expansion of CGG in LRP12 has been identified as the causative variation of oculopharyngodistal myopathy (OPDM). However, to our knowledge, the clinicopathologic features of OPDM with CGG repeat expansion in LRP12 (hereafter referred to as OPDM_LRP12) remain unknown. Objective To identify and characterize the clinicopathologic features of patients with OPDM_LRP12. Design, setting, and participants This case series included 208 patients with a clinical or clinicopathologic diagnosis of oculopharyngeal muscular dystrophy (OPDM) from January 1, 1978, to December 31, 2020. Patients with GCN repeat expansions in PABPN1 were excluded from the study. Repeat expansions of CGG in LRP12 were screened by repeat primed polymerase chain reaction and/or Southern blot. Main outcomes and measures Clinical information, muscle imaging data obtained by either computed tomography or magnetic resonance imaging, and muscle pathologic characteristics. Results Sixty-five Japanese patients with OPDM (40 men [62%]; mean [SD] age at onset, 41.0 [10.1] years) from 59 families with CGG repeat expansions in LRP12 were identified. This represents the most common OPDM subtype among all patients in Japan with genetically diagnosed OPDM. The expansions ranged from 85 to 289 repeats. A negative correlation was observed between the repeat size and the age at onset (r2 = 0.188, P = .001). The most common initial symptoms were ptosis and muscle weakness, present in 24 patients (37%). Limb muscle weakness was predominantly distal in 53 of 64 patients (83%), but 2 of 64 patients (3%) had predominantly proximal muscle weakness. Ptosis was observed in 62 of 64 patients (97%), and dysphagia or dysarthria was observed in 63 of 64 patients (98%). A total of 21 of 64 patients (33%) had asymmetric muscle weakness. Aspiration pneumonia was seen in 11 of 64 patients (17%), and 5 of 64 patients (8%) required mechanical ventilation. Seven of 64 patients (11%) developed cardiac abnormalities, and 5 of 64 patients (8%) developed neurologic abnormalities. Asymmetric muscle involvement was detected on computed tomography scans in 6 of 27 patients (22%) and on magnetic resonance imaging scans in 4 of 15 patients (27%), with the soleus and the medial head of the gastrocnemius being the worst affected. All 42 muscle biopsy samples showed rimmed vacuoles. Intranuclear tubulofilamentous inclusions were observed in only 1 of 5 patients. Conclusions and relevance This study suggests that OPDM_LRP12 is the most frequent OPDM subtype in Japan and is characterized by oculopharyngeal weakness, distal myopathy that especially affects the soleus and gastrocnemius muscles, and rimmed vacuoles in muscle biopsy.

Danon disease, primary lysosome-associated membrane protein-2 (LAMP-2) deficiency, is characterized clinically by cardiomyopathy, myopathy and intellectual disability in boys. Because Danon disease is inherited in an X-linked dominant fashion, males are more severely affected than females, who usually have only cardiomyopathy without myopathy or intellectual disability; moreover, the onset of symptoms in females is usually in adulthood. We describe a girl with Danon disease who presented with hypertrophic cardiomyopathy and Wolff-Parkinson-White (WPW) syndrome at 12 years of age. Subsequently, she showed signs of mild learning disability and intellectual disability on psychological examinations. She had a de novo novel mutation in the LAMP-2 gene and harbored an identical c.749C > A (p.Ser250X) variant, resulting in a stop codon in exon 6. She showed decreased, but not completely absent LAMP-2 expression on immunohistochemical and Western blot analyses of a skeletal muscle biopsy specimen, which has been suggested to be caused by a 50% reduction in LAMP-2 expression (LAMP-2 haploinsufficiency) in female patients with Danon disease caused by a heterozygous null mutation. To our knowledge, our patient is one of the youngest female patients to have been given a diagnosis of Danon disease. In addition, this is the first documented case in a girl that was clearly associated with intellectual disability, which is very rare in females with Danon disease. Our findings suggest that studies of female patients with Danon disease can extend our understanding of the clinical features of this rare disease.

OBJECTIVE The provisional diagnosis of progressive supranuclear palsy (PSP) depends on a combination of typical clinical features and specific MRI findings, such as atrophy of the tegmentum in the midbrain. Atrophy of the superior cerebellar peduncle (SCP) distinguishes PSP from other types of parkinsonism. Histological factors affect the conventional fluid-attenuated inversion recovery (FLAIR) signals, such as the extent of neuronal loss and gliosis. METHODS We investigated patients with PSP to verify the percentage of patients with various PSP phenotypes presenting a high signal intensity in the SCP. Three interviewers, who were not informed about the clinical data, visually inspected the presence or absence of a high signal intensity in the SCP on the FLAIR images. We measured the pixel value in the SCP of each patient. Clinical characteristics were evaluated using the Mann-Whitney test, followed by the χ2 test. RESULTS Ten of the 51 patients with PSP showed a high signal intensity in the SCP on FLAIR MRI. Higher pixel values were observed within the SCP of patients with a high signal intensity in the SCP than in patients without a high signal intensity (p < 0.001). The sensitivity and specificity of the high signal intensity in the SCP of patients with PSP was 19.6% and 100%, respectively. This finding was more frequently observed in patients with PSP with Richardson's syndrome (PSP-RS) (25.7%) than other phenotypes (6.2%). CONCLUSION The high signal intensity in the SCP on FLAIR MRI might be an effective diagnostic tool for PSP-RS.

We describe two patients with Parkinson’s disease who presented with accidental hypothermia and review seven patients to delineate the characteristics of hypothermia. All cases of hypothermia occurred in the winter. As clinical symptoms preceding the onset of hypothermia, deterioration of bradykinesia or limb coldness was evident. Most cases of hypothermia were accompanied by impaired consciousness and deterioration of parkinsonian features. After warming the body, the hypothermia improved in a relatively short period. Levodopa, dopamine agonists or anticholinergic agents were given to five patients, three patients and three patients, respectively. Bradykinesia developed in most patients a short time before the onset of hypothermia. In various neurological diseases, deterioration of the disease can occur on the background of metabolic/electrolyte disturbance. However, the fact that the bradykinesia developed a short time prior to the onset of hypothermia warrants close observation for signs of temperature dysregulation in patients with substantial neurologic deterioration, especially in the winter.

We hypothesized that the unusual and painful abdominal contractions in two of our patients with Parkinson disease (PD) were linked to abdominal muscle hypertrophy. The abdominal pain was aggravated by sitting, standing, or walking, and was characterized by a powerful pulling sensation associated with palpable contractions of the rectus abdominis. When the pain decreased, the camptocormia abated. The thickness of the rectus abdominis and the relative muscle thickness ratio were greater in the two patients with abdominal contractions than in the control patients with PD without abdominal contractions. Palpable painful abdominal contractions could be associated with the presence of hypertrophy of the rectus abdominis visible on CT scan. The abdominal muscle contractions probably contribute to the development a stooped posture.

Danon disease, an X-linked dominant cardioskeletal myopathy, is caused by primary deficiency of lysosome-associated membrane protein-2 (LAMP-2). To clarify the clinicopathological features and management, we performed the first nationwide, questionnaire-based survey on Danon disease in Japan. A total of 39 patients (17 males, 22 females) from 20 families were identified in the analysis. All patients had cardiomyopathy. Of the 21 patients who died, 20 (95%) died of cardiac failure or sudden cardiac arrest. Most patients had hypertrophic cardiomyopathy. Wolf&ndash, Parkinson&ndash, White syndrome was present at a comparatively high incidence (54% in males, 22% in females). Only one female patient received a heart transplant, which is the most effective therapy. Histopathologically, all male patients showed autophagic vacuoles with sarcolemmal features in muscle. Half of the probands showed de novo mutations. Male patients showed completely absent LAMP-2 expression in muscle. In contrast, female patients showed decreased LAMP-2 expression, which is suggested to reflect LAMP-2 haploinsufficiency due to a heterozygous null mutation. In conclusion, Danon disease is an extremely rare muscular disorder in Japan. Cardiomyopathy is the most significant prognostic factor and the main cause of death. Our findings suggest that the present survey can extend our understanding of the clinical features of this rare disease.

Objective: Myotonic dystrophy type 1 (DM1) is a rare autosomal dominant disorder with highly variable phenotypic expression. Some patients have diabetes mellitus, dyslipidemia, and/or arrhythmias, which are risk factors for stroke. However, the mechanism of stroke is poorly understood in patients with DM1. We studied the characteristics of risk-factor profiles for stroke associated with DM1. Patients and methods: We studied 77 patients with DM1 (45 men and 32 women) on the basis of the patients’ clinical histories and laboratory and genetic examination results. Results: The analysis showed that 26 patients (34%) had dyslipidemia, and 16 (21%) had diabetes. Arrhythmias were diagnosed in 46 patients (61%), including 11 (14%) with atrial fibrillation and 9 (12%) with conduction defects. Echocardiographic abnormalities were found in 28 patients (37%). Eight patients (11%) met the criteria for metabolic syndrome. We identified 2 patients (2.6%) with ischemic stroke caused by cardiogenic embolism among 77 patients with DM1. One had paroxysmal atrial fibrillation and sick sinus syndrome, and the other had cardiac dysfunction with an ejection-fraction of 35% and dyslipidemia. Both patients had highly expanded numbers of CTG repeats (1000 and 1500). Conclusion: To our knowledge, this is the first study to report a comprehensive analysis of risk-factor profiles for stroke in patients with DM1. Stroke is a relatively rare, but severe complication of DM1. Our results indicate that it is important to manage risk factors for stroke, especially cardiac involvement and arrhythmias.

Sporadic Inclusion Body Myositis (sIBM) is a refractory myositis developing in the elderly. Recently, anti-cytosolic 5'-nucleotidase 1A (cN1A) antibodies were reported to be present specifically in sIBM. To assess the clinicopathological features and usefulness of anti-cN1A positivity in muscle specimens, we evaluated a group of Japanese patients with sIBM. Among Japanese patients with myositis who underwent a muscle biopsy from 1991 through 2014 in our hospital, we identified cases of sIBM that met the European Neuromuscular Center (ENMC) criteria. We then analyzed clinical course, pathological findings, and treatment response. Of 282 patients with myositis, 35 (12%) were given a diagnosis of sIBM (24 men and 11 women). The median age at onset was 67 ± 7 (55-81) years, and that at diagnosis was 70 ± 7 years. Remarkably, 5 (14%) patients concurrently had hepatitis C virus (HCV) infection and 4 (11%) had heart disease. Pathologically, we found rimmed vacuoles in 32 (91%) patients and anti-cN1A positivity in perinuclear regions and rimmed vacuoles in 31 (89%) patients. Remarkably, anti-cN1A antibody positivity was significantly higher in sIBM than in polymyositis (30%), dermatomyositis (10%), and morphologically normal cases (0%), suggesting its high specificity for sIBM. Twelve (34%) patients received immunosuppressants, 8 (23%) received prednisone, and 5 (14%) received intravenous immunoglobulins (IVIg). Clinical symptoms transiently improved in 5 patients given prednisone and in 4 patients given IVIg, but these treatments failed to be radical therapies. In our study of Japanese patients with sIBM, anti-cN1A antibody positivity in muscle specimens was highly sensitive and specific pathologically. Therefore, the expression of anticN1A antibody may be greatly useful for the diagnosis of sIBM. Although the concurrent presence of HCV infection and heart disease was notable, other epidemiological characteristics were consistent with the results of previous studies.

Recently, we studied fallers and non-fallers with Hoehn-Yahr stage III Parkinson’s disease (PD) using a path that suddenly narrowed, which we originally designed and produced. A risk of future falls was suggested to be related to slow gait with freezing (SGF) elicited by a fear of falling before arrival at a narrowed entrance or while walking on a narrow path, as well as to the Unified Parkinson’s Disease Rating Scale part II score, associated with SGF. In the same study, we had faller patients walk on a path that narrowed in a straight-line fashion to determine whether SGF could be improved. In one patient, who showed a unique paradoxical gait, SGF resolved. We describe this patient in the hope that our experience will provide potential clues to effective ways to prevent future falls in patients with Hoehn-Yahr stage III PD. To prevent gait instability elicited by fear of falling in patients with Hoehn-Yahr stage III PD, it might be useful to remove narrowed entrances.