Hematopoietic Prostaglandin D Synthase Is Increased in Mast Cells and Pericytes in Autopsy Myocardial Specimens from Patients with Duchenne Muscular Dystrophy.

The leading cause of death for patients with Duchenne muscular dystrophy (DMD), a progressive muscle disease, is heart failure. Prostaglandin (PG) D2, a physiologically active fatty acid, is synthesized from the precursor PGH2 by hematopoietic prostaglandin D synthase (HPGDS). Using a DMD animal model (mdx mice), we previously found that HPGDS expression is increased not only in injured muscle but also in the heart. Moreover, HPGDS inhibitors can slow the progression of muscle injury and cardiomyopathy. However, the location of HPGDS in the heart is still unknown. Thus, this study investigated HPGDS expression in autopsy myocardial samples from DMD patients. We confirmed the presence of fibrosis, a characteristic phenotype of DMD, in the autopsy myocardial sections. Additionally, HPGDS was expressed in mast cells, pericytes, and myeloid cells of the myocardial specimens but not in the myocardium. Compared with the non-DMD group, the DMD group showed increased HPGDS expression in mast cells and pericytes. Our findings confirm the possibility of using HPGDS inhibitor therapy to suppress PGD2 production to treat skeletal muscle disorders and cardiomyopathy. It thus provides significant insights for developing therapeutic drugs for DMD.

Spinal muscular atrophy type 2 patient who survived 61 years: an autopsy case report.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by progressive muscle weakness due to degeneration of lower motor neurons in the anterior horn of the spinal cord. We analyzed autopsy findings of a male patient with SMA type 2 who survived until 61 years of age. Genetic analysis revealed a homozygous deletion of the survival motor neuron (SMN) gene 1 (SMN1) exon 7, confirming the diagnosis of SMA. Results of further analyses indicated that the patient had two copies of the genuine SMN gene 2 (SMN2) and one copy of a hybrid gene containing SMN2 exon 7 and SMN1 exon 8. Pathological examination revealed moderate neuronal loss of the anterior horn and appearance of heterotopic neurons in the lateral funiculus, whereas a few achromatic neurons were notably localized in the anterior horn of the lumbar segment. Microdysgenesis as a consequence of migration disturbance was found in the white matter of the frontal lobe, postulating the possibility of the maldevelopment of the nervous system.

[Progressive multifocal leukoencephalopathy in a patient with rheumatoid arthritis under salazosulfapyridine treatment].

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection caused by JC virus (JCV) activation. We report an 85-years old man who had been diagnosed to have rheumatoid arthritis (RA) 1.5 years prior to diagnosis of PML, and had been treated with salazosulfapyridine (SASP). He developed weakness of the left upper limb, which progressed gradually for two months. A neurological examination on admission revealed severe palsy of the left upper limb without sensory disturbance, cognitive decline or gait disturbance. Brain MRI revealed white matter lesions in the right frontal lobe around the precentral gyrus. Cerebrospinal fluid (CSF) examination and peripheral lymphocyte counts were normal. HIV was ruled out serologically. There were no findings suggestive of malignancy. We suspected PML and stopped SASP. JCV-DNA was detected in CSF. There were enlarged nuclei positive with VP-1 immunostaining in the brain biopsy materials. Thus, the diagnosis of PML was definitive. Paralysis of the left upper limb began to improve one week after discontinuing SASP. Treatment with mefloquine and mirtazapine was initiated, but he developed severe interstitial pneumonia, which might be caused by mefloquine. Therefore, he underwent rehabilitation without medication. JCV-DNA became undetectable and white matter lesions decreased 6 months later. Paralysis improved and he had no problem with activities of daily living a year later. The risk factor for PML has changed over the last decade, and drugs such as biologics became significant risk factors for patients with autoimmune diseases. There are reports suggesting that systemic lupus erythematosus (SLE) and RA themselves might be independent risk factors for PML. Although there is no previous report of SASP inducing PML, SASP might be the culprit in our case. However, there is another possibility that SAPS and RA worked synergistically for the onset of PML.

Pembrolizumab-Induced Meningoencephalitis: A Brain Autopsy Case.

Encephalitis is very rare, but often fatal immune-related adverse event (irAE) of immune checkpoint inhibitors (ICIs). A 65-year-old Japanese woman was admitted to our hospital because of general fatigue, chillness and high-grade fever for 4 days, 8 months after the initiation of the first-line pembrolizumab monotherapy for metastatic pulmonary adenocarcinoma. On the hospital day 3, she suddenly presented delirium and uncontrollable impaired consciousness. Although the magnetic resonance imaging (MRI) did not suggest a diagnosis of encephalitis and meningitis, the spinal fluid showed abnormally elevated levels of protein (317.6 mg/L) and cell count (197 cells/µL) with increased mononuclear cells (93%). An empirical and intravenous administration of acyclovir in doses of 10 mg/kg body weight every 8 h and steroid pulse therapy in dose of 1 g/body/day from the hospital day 5 until her death failed to improve her conditions. She died on the hospital day 8. The postmortem autopsy showed viable cancer cells in the metastatic tumor in the left occipital lobe and in the spinal fluids. However, many inflammatory cells infiltration in the meninges and perivascular cuffing were prominent especially in the brain stem and medial part of the temporal lobe. Infiltrating lymphocytes in the meninges and parenchyma of the brain stem were mainly composed of cluster of differentiation (CD)8-positive lymphocytes. For irAE encephalitis, early recognition of early signs and symptoms and subsequent early therapeutic intervention are necessary. It is important for oncologists to keep in mind of the possible adverse effects of immunotherapies on the nervous system.

Clinical phenotypes of spinal muscular atrophy patients with hybrid SMN gene.

BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by homozygous deletion of SMN1 exons 7 and 8. However, exon 8 is retained in some cases, where SMN2 exon 7 recombines with SMN1 exon 8, forming a hybrid SMN gene. It remains unknown how the hybrid SMN gene contribute to the SMA phenotype. METHOD: We analyzed 515 patients with clinical suspicion for SMA. SMN1 exons 7 and 8 deletion was detected by PCR followed by enzyme digestion. Hybrid SMN genes were further analyzed by nucleotide sequencing. SMN2 copy number was determined by real-time PCR. RESULTS: SMN1 exon 7 was deleted in 228 out of 515 patients, and SMN1 exon 8 was also deleted in 204 out of the 228 patients. The remaining 24 patients were judged to carry a hybrid SMN gene. In the patients with SMN1 exon 7 deletion, the frequency of the severe phenotype was significantly lower in the patients with hybrid SMN gene than in the patients without hybrid SMN gene. However, as for the distribution of SMN2 exon 7 copy number among the clinical phenotypes, there was no significant difference between both groups of SMA patients with or without hybrid SMN gene. CONCLUSION: Hybrid SMN genes are not rare in Japanese SMA patients, and it appears to be associated with a less severe phenotype. The phenotype of patients with hybrid SMN gene was determined by the copy number of SMN2 exon 7, as similarly for the patients without hybrid SMN gene.

ADSSL1 myopathy is the most common nemaline myopathy in Japan with variable clinical features.

OBJECTIVE: To elucidate the prevalence of Japanese ADSSL1 myopathy and determine the clinicopathologic features of the disease. METHODS: We searched for ADSSL1 variants in myopathic patients from January 1978 to March 2019 in our repository and assessed the clinicopathologic features of patients with variants. RESULTS: We identified 63 patients from 59 families with biallelic variants of ADSSL1. Among the 7 distinct variants identified, c.781G>A and c.919delA accounted for 53.2% and 40.5% of alleles, respectively, suggesting the presence of common founders, while the other 5 were novel. Most of the identified patients displayed more variable muscle symptoms, including symptoms in the proximal and/or distal leg muscles, tongue, masseter, diaphragm, and paraspinal muscles, in adolescence than previously reported patients. Dysphagia with masticatory dysfunction developed in 26 out of 63 patients; hypertrophic cardiomyopathy developed in 12 out of 48 patients; and restrictive ventilatory insufficiency developed in 26 out of 34 patients in later stages. Radiologically, fat infiltration into the periphery of vastus lateralis, gastrocnemius, and soleus muscles was observed in all patients. Pathologically, nemaline bodies in addition to increased lipid droplets and myofibrillar disorganization were commonly observed in all patients, suggesting that the disease may be classified as nemaline myopathy. This finding revealed that ADSSL1 myopathy is the most frequent among all genetically diagnosable nemaline myopathies in our center. CONCLUSIONS: ADSSL1 myopathy is characterized by more variable manifestations than previously reported. It is the most common among all genetically diagnosable nemaline myopathies in our center, although mildly increased lipid droplets are also constantly observed features.

A clinicopathological study of ALS with L126S mutation in the SOD1 gene presenting with isolated inferior olivary hypertrophy.

We report an autopsy case of amyotrophic lateral sclerosis with L126S mutation in the superoxide dismutase 1 (SOD1) gene (SOD1). The patient was a 69-year-old Japanese man without relevant family history, who initially presented with slow progressive muscle weakness of the lower extremities without upper motor neuron signs, and died of respiratory failure 6 years after the onset. Neuropathological examination revealed a loss of lower motor neurons and degeneration of Clarke's column commensurate with that of the posterior spinocerebellar tract and the middle root zone of the posterior column. The primary motor area was minimally affected. Characteristic SOD1-immunopositive neuronal intracytoplasmic inclusions, mixed with neurofilament accumulation, were present in the affected areas. Isolated inferior olivary hypertrophy was observed, but did not involve the contralateral dentate nucleus, or the ipsilateral red nucleus and central tegmental tract, where no neuronal inclusions were found. In combination with data from a previous autopsy case, this study suggests that the L126S mutation may cause focal neuronal degeneration in the brainstem.

Bile acid abnormality induced by intestinal dysbiosis might explain lipid metabolism in Parkinson's disease.

Intestinal dysbiosis refers to an imbalance in the intestinal flora. The concept of small intestinal bacterial overgrowth (SIBO), a condition of abnormal proliferation of the small intestine microbiota, has been proposed as a form of small intestine dysbiosis. In Parkinson's disease patients, weight loss and metabolic disorders such as lipid abnormalities are frequently encountered. This was a prospective investigation of the presence of SIBO using the lactulose breath test, Parkinson's disease symptoms, medications, abdominal symptoms, and blood data involving 39 Parkinson's disease patients. Of the 39 patients, 19 were positive for SIBO, 16 were negative, and 4 were equivocal. SIBO-positive patients had a significantly smaller dopaminergic drug load (dopamine replacement of Parkinson's disease drug potency) (P = 0.009) and significantly lower serum triglyceride (TG) (P = 0.024) and total bilirubin (P = 0.019) levels. No relationship was seen between the presence or absence of SIBO and motor or abdominal symptoms. The following hypothesis was developed with regard to the possibility that intestinal bacterial overgrowth has various effects that are exhibited via bile acid metabolism in Parkinson's disease patients. Serum bilirubin levels become higher as bilirubin metabolism declines with decreases in the intestinal bacteria. At the same time, bile acid is broken down due to increased intestinal bacteria, and lipid absorption decreases. This induces low serum TG levels and leads to weight loss. By a similar mechanism, there is less absorption of vitamin D as bile acid levels decrease, leading to osteoporosis and fractures. The possibility that some of the non-motor manifestations accompanying Parkinson's disease are caused by intestinal dysbiosis needs to be considered.

Increased number of mitochondria in capillaries distributed in stroke-like lesions of two patients with MELAS.

We investigated two autopsy cases of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) using immunohistochemical staining with an anti-mitochondrial antibody against translocase of the outer membrane 20 (TOMM20). In case 1, the patient was a 42-year-old man with a disease duration of 53 days, and in case 2, the patient was a 62-year-old woman with a disease duration of 27 months. In both the cases autopsy revealed moderate atrophy of the cerebrum and cerebellum and multifocal necrotizing lesions, irrespective of the vascular territory. Case 1 showed multiple areas with total necrosis in the cortex, accompanied by increases in number of protoplasmic astrocytes and acidophilic neurons as well as axonal swelling, suggestive of acute or subacute stage stroke-like lesions (SLLs). In case 2, most of the SLLs displayed laminar spongy change in a rarefied cortex, and were considered to be at the chronic stage. In both the cases, capillary proliferation was noted within the SLLs, particularly in the acute phase. Endothelial cells of proliferating capillaries were strongly positive for TOMM20. In the cortex outside the SLLs, microvessels displayed only a fine granular immunoreactivity, as is seen in the controls. Although smooth muscle cells and endothelial cells in pial arteries and arterioles were also strongly positive for TOMM20, the territories of the affected pial arteries and arterioles did not correlate with the distribution of the SLLs. Although MELAS is characterized by recurrent stroke-like episodes (SLEs), the pathogenetic relationship between SLEs and mitochondrial angiopathy remains unknown. An aberrant increase of mitochondria in the capillary endothelial cells of SLLs may disturb endothelial function, thus playing a role in the formation or development of SLLs.

Microvascular disturbance with decreased pericyte coverage is prominent in the ventral horn of patients with amyotrophic lateral sclerosis.

In amyotrophic lateral sclerosis (ALS) there is emerging evidence for vasculature disturbance. The aim of this study was to investigate the area of predominant vasculature disturbance in ALS. We used immunohistochemistry to quantitatively evaluate the microvascular density (MVD) and pericyte coverage (PC) in the lumbar spinal cord of 25 ALS patients and six controls. In controls, MVD was almost equal in the ventral horn (VH) and dorsal horn (DH). In the VH of ALS, MVD was significantly increased, and PC was significantly decreased compared with the DH in ALS and the VH in controls (p < 0.001), possibly reflecting that PC is an essential requirement for the vasculature in the VH. We then found a significant relationship between the severity of aberrant angiogenesis and the use of artificial respiratory support (ARS). In conclusion, vasculature disturbance is observed in all ALS patients including patients with ARS. Therefore, breakdown of the blood-spinal cord barrier due to aberrant angiogenesis with decreased PC may be responsible for the predominant neuronal death in the VH in ALS.

Adult-onset multiple acyl CoA dehydrogenation deficiency associated with an abnormal isoenzyme pattern of serum lactate dehydrogenase.

We report a case of a 37 year-old male with multiple acyl-CoA dehydrogenation deficiency (MADD). The patient had suffered from exercise intolerance in his hip and thigh muscles for one year. Then, restriction of carbohydrates for a diet made his symptoms rapidly deteriorate. Blood test revealed compound heterozygosity for two novel missense mutations in the electron transfer flavoprotein dehydrogenase gene (ETFDH), and an abnormal LDH isoenzyme pattern: LDH-1 (60.0%) and LDH-2 (26.0%) predominated with abnormally elevated LDH-1/LDH-2 ratio (2.3), compared with muscle-derived LDH-5 (4.0%). Oral riboflavin treatment significantly improved his exercise intolerance and the LDH profile: LDH-1 (34.4%), LDH-2 (34.9%), LDH-5 (6.9%) and LDH-1/LDH-2 ratio (1.0). The abnormal LDH isoenzyme pattern may be one feature of adult-onset MADD selectively affecting type I muscle fibers with relatively high LDH-1 content.