X-linked Myotubular Myopathy Manifesting Carrier with Central and Peripheral Nervous System Involvement.

X-linked myotubular myopathy (XLMTM) is a rare genetic disorder caused by X-linked mutations in the MTM1 gene. Although heterozygous females are typically asymptomatic, affected cases have recently been reported. We herein report a case of XLMTM manifesting carrier of the pathogenic c.206dupG mutation in MTM1 with uncommon extramuscular symptoms. She developed gaze nystagmus and cognitive impairment in addition to muscle weakness. Electrophysiological studies and brain magnetic resonance imaging indicated the involvement of the central and peripheral nervous systems. XLMTM manifesting carriers may have a wider spectrum of clinical phenotypes than currently assumed. Appropriate follow-up of extramuscular and conventional muscular manifestations is important in such cases.

A Case of a Patient with Calpainopathy Carrying Compound Heterozygous Mutations of a de novo Pathogenic Variant of c.1333G>A and a Novel Variant of c.1331C>T in CAPN3.

Calpainopathy is primarily an autosomal recessive inherited myopathy; however, dominantly inherited cases with a pathogenic variant of c.1333G>A have been reported. A 13-year-old Japanese girl presented with toe walking and elevated serum creatine kinase levels. Genetic panel testing revealed compound heterozygosity for c.1333G>A and a novel variant of c.1331C>T in CAPN3, leading to a diagnosis of calpainopathy. A genetic analysis of her parents revealed the possibility that c.1333G>A was de novo. In this patient, the onset age was earlier than that of the reported autosomal dominant cases, suggesting the influence of the novel variant in the contralateral allele.

Characteristics of the muscle involvement along the disease progression in a large cohort of oculopharyngodistal myopathy compared to oculopharyngeal muscular dystrophy.

BACKGROUND AND OBJECTIVES: Oculopharyngodistal myopathy (OPDM) is an autosomal dominant myopathy clinically characterized by distal muscle weakness. Even though the identification of four causative genes, LRP12, GIPC1, NOTCH2NLC and RILPL1, it is unclear whether the myopathy progressed similarly among OPDM subtypes. We aimed to establish diagnostic clues in muscle imaging of OPDM in comparison with clinicopathologically similar oculopharyngeal muscular dystrophy (OPMD). METHODS: Axial muscle CT and/or T1-weighted MRI data from 54 genetically confirmed patients with OPDM (OPDM_LRP12; n = 43, OPDM_GIPC1; n = 6, OPDM_NOTCH2NLC; n = 5) and 57 with OPMD were evaluated. We scored the degree of fat infiltration in each muscle by modified Mercuri score and performed hierarchical clustering analyses to classify the patients and infer the pattern of involvement on progression. RESULTS: All OPDM subtypes showed a similar pattern of distribution in the affected muscles; soleus and medial gastrocnemius involved in the early stage, followed by tibialis anterior and extensor digitorum longus. For differentiating OPDM and OPMD, severely affected gluteus medius/minimus and adductor magnus was indicative of OPMD. DISCUSSION: We identified a diagnostic muscle involvement pattern in OPDM reflecting its natural history. The results of this study will help in the appropriate intervention based on the diagnosis of OPDM, including its stage.

CGG repeat expansion in LRP12 in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the degeneration of motor neurons. Although repeat expansion in C9orf72 is its most common cause, the pathogenesis of ALS isn't fully clear. In this study, we show that repeat expansion in LRP12, a causative variant of oculopharyngodistal myopathy type 1 (OPDM1), is a cause of ALS. We identify CGG repeat expansion in LRP12 in five families and two simplex individuals. These ALS individuals (LRP12-ALS) have 61-100 repeats, which contrasts with most OPDM individuals with repeat expansion in LRP12 (LRP12-OPDM), who have 100-200 repeats. Phosphorylated TDP-43 is present in the cytoplasm of iPS cell-derived motor neurons (iPSMNs) in LRP12-ALS, a finding that reproduces the pathological hallmark of ALS. RNA foci are more prominent in muscle and iPSMNs in LRP12-ALS than in LRP12-OPDM. Muscleblind-like 1 aggregates are observed only in OPDM muscle. In conclusion, CGG repeat expansions in LRP12 cause ALS and OPDM, depending on the length of the repeat. Our findings provide insight into the repeat length-dependent switching of phenotypes.

A Case of Oculopharyngeal Muscular Dystrophy Caused by a Novel PABPN1 c.34G > T (p.Gly12Trp) Point Mutation without Polyalanine Expansion.

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.

Embolic stroke induced by rotational persistent 1st intersegmental artery compression.

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.

Electromyography varies by stage in inclusion body myositis.

Introduction: Inclusion body myositis (IBM) is a chronic inflammatory muscle disease that is characterized by mixed myogenic and neurogenic electromyography (EMG) findings. We investigated the association between EMG findings and the IBM stage. Methods: We included consecutive patients diagnosed with IBM based on muscle biopsy and had needle EMG performed within 1 month of biopsy. Motor unit potential waveform (MUP) in EMG and pathological findings were compared between patients in early and late phases. Results: In total, 30 patients with biopsy-confirmed IBM and 254 muscles were included. The rate of abnormal discharge did not differ according to disease stage. There was a difference in the frequency of occurrence between myogenic suggestive MUP and neurogenic of biceps and flexor digitorum profundus in the late phase. Abnormal MUP was observed even in muscles without muscle weakness, and myogenic changes were predominant in biceps and gastrocnemius with muscle weakness. The biopsy findings on the contralateral side of the muscle where electromyography was performed revealed a tendency for muscles that exhibited myogenic origin to have more inflammatory cells and RV; however, the difference was not significant. Conclusion: The target muscles for EMG must be selected considering the disease stage as well. In the early stages of IBM, EMG results should be interpreted cautiously, as neurogenic suggestive pattern of MUP might also be exhibited. Contralateral electromyography findings may be helpful in selecting muscles for muscle biopsies, such as biceps and quadriceps.

Intranuclear inclusions in muscle biopsy can differentiate oculopharyngodistal myopathy and oculopharyngeal muscular dystrophy.

Oculopharyngodistal myopathy (OPDM) and oculopharyngeal muscular dystrophy (OPMD) are similar and even believed to be indistinguishable in terms of their myopathological features. To address the diagnostic gap, we evaluated the muscle biopsy samples for p62 expression by immunohistochemistry and compared the occurrence and the frequency of intranuclear inclusions among the individuals with OPDM (harboring CGG repeat expansion in LRP12 (n = 19), GIPC1 (n = 6), or NOTCH2NLC (n = 7)), OPMD (n = 15), and other rimmed vacuolar myopathies. We found that myonuclei with p62-positive intra-nuclear inclusions (myo-INIs) were significantly more frequent in OPMD (11.9 ± 1.1%, range 5.9-18.6%) than in OPDM and other rimmed vacuolar myopathies (RVMs) (0.9-1.5% on average, range 0.0-2.8%, p < 0.0001). In contrast, INIs in non-muscle cells such as blood vessels, peripheral nerve bundles, and muscle spindles (non-muscle-INIs) were present in OPDM, but absent in OPMD. These results indicate that OPMD can be differentiated from OPDM and other RVMs by the frequent presence of myo-INIs; and in OPDM, the presence of non-muscle-INIs in muscle pathology should be a diagnostic hallmark.

Pathological features of inflammatory myopathy as a manifestation of chronic graft-versus-host disease after allogeneic bone marrow transplantation.

Chronic graft-versus-host disease (cGVHD) is the most important complication resulting in the death of bone marrow transplantation (BMT) survivors. It is also a relatively rare cause of inflammatory myopathy (IM). We report the case of a 46-year-old woman who developed severe cGVHD-related IM after BMT for myelodysplastic syndrome. She presented with severe muscle pain and weakness with cGVHD-related symptoms in other organs. Myopathological analysis showed moderate cell infiltration with remarkable necrotic and regenerative fibers. Sarcoplasm and capillaries expressed C5b9 and myxovirus resistance protein 1. Non-necrotic fibers in perifascicular regions expressed MHC-II. Steroid therapy did not sufficiently control cGVHD-related IM, and the patient was concurrently treated with an immunosuppressant. Our findings show that IM is a key manifestation of cGVHD and that the expression of interferon-inducible proteins in muscle pathology is useful for identifying cGVHD-related IM.

Electroencephalographic findings after convulsive seizures due to cerebral arterial air embolism secondary to lung cancer: a case report.

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.

Intranuclear inclusions in skin biopsies are not limited to neuronal intranuclear inclusion disease but can also be seen in oculopharyngodistal myopathy.

AIMS: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Multiple cerebral infarctions associated with lung cancer-induced hypereosinophilia: a case report.

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.

Gene Expression Profiles of Human Cerebral Organoids Identify PPAR Pathway and PKM2 as Key Markers for Oxygen-Glucose Deprivation and Reoxygenation.

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.

Clinicopathologic Features of Oculopharyngodistal Myopathy With LRP12 CGG Repeat Expansions Compared With Other Oculopharyngodistal Myopathy Subtypes.

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.

PLA2G6 variants associated with the number of affected alleles in Parkinson's disease in Japan.

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.

[Elevation of cerebrospinal fluid anti-cyclic citrullinated peptides antibody index is useful for rheumatoid meningitis preceding neurological symptoms without arthritis: a case report].

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.

Brainstem Organoids From Human Pluripotent Stem Cells.

The brainstem is a posterior region of the brain, composed of three parts, midbrain, pons, and medulla oblongata. It is critical in controlling heartbeat, blood pressure, and respiration, all of which are life-sustaining functions, and therefore, damages to or disorders of the brainstem can be lethal. Brain organoids derived from human pluripotent stem cells (hPSCs) 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 are limited in the extent hPSCs recapitulate human brain development and hence are not able to fully elucidate the diseases affecting various components of the brain such as brainstem. Here, we developed a method to generate human brainstem organoids (hBSOs), containing midbrain/hindbrain progenitors, noradrenergic and cholinergic neurons, dopaminergic neurons, and neural crest lineage cells. Single-cell RNA sequence (scRNA-seq) analysis, together with evidence from proteomics and electrophysiology, revealed that the cellular population in these organoids was similar to that of the human brainstem, which raises the possibility of making use of hBSOs in investigating central nervous system disorders affecting brainstem and in efficient drug screenings.