Recurrent embolic stroke associated with adenomyosis: A single case report and literature review.

INTRODUCTION: Uterine adenomyosis is a benign disorder in which endometrial glands and stroma are present within the myometrium. There have been several case reports of cerebral infarction associated with adenomyosis, but their clinical characteristics, optimal treatment, and prognosis have not been systematically reviewed. METHODS: A case of cerebral infarction with adenomyosis is reported, and a comprehensive systematic literature search using the PubMed database was conducted. RESULTS: A 42-year-old woman, previously diagnosed with adenomyosis, developed multiple cerebral infarctions during menstruation. Her CA125 level was 293 U/mL, and treatment with edoxaban 30 mg was started. Seven days after hospital discharge, she had her subsequent menstrual period and then developed a recurrent stroke. Her CA125 level was 743 U/mL on readmission. A hysterectomy was performed, and the patient has had no further stroke recurrence. A systematic review identified 19 cases with cerebral infarction associated with adenomyosis, including the present case. The patients' clinical characteristics included young age (44.7 ± 6.2 years), stroke development during menstruation (85%), multiple infarctions affecting ≥ 3 vessel territories (39%), and high levels of CA125 and D-dimer (810.6 ± 888.4 U/mL, and 10.3 ± 18.6 µg/mL, respectively). Antithrombotic therapy was given to 14 patients, but recurrent stroke occurred in 5 (36%) patients. Hysterectomy was conducted in 5 and 4 patients with initial and recurrent stokes, respectively, and there were no further recurrences thereafter. CONCLUSION: Cerebral infarction associated with adenomyosis has specific clinical characteristics. Antithrombotic therapy was insufficient, and hysterectomy should particularly be considered in cases of recurrent stroke.

Chédiak-Higashi syndrome presenting as a hereditary spastic paraplegia.

Hereditary spastic paraplegias (HSPs) comprise a group of neurodegenerative disorders characterized by weakness and leg spasticity. LYST is responsible for Chédiak-Higashi syndrome (CHS), which exhibits partial oculocutaneous albinism, primary immunodeficiency, and bleeding tendency in childhood. Although neurological symptoms of CHS also appear in adulthood, a phenotype of spastic paraplegia has rarely been reported in CHS. In this study, we investigated LYST mutations in 387 HSP patients through the Japan Spastic Paraplegia Research Consortium to clarify the frequency of LYST mutations in HSP, finding six adult patients with LYST mutations in four HSP families. They exhibited intellectual disability, cerebellar ataxia, neuropathy, and pyramidal signs. Meanwhile, only 15 patients with CHS in childhood have been revealed in a decade by a nationwide survey in Japan. Thus, LYST mutations might indicate a HSP phenotype in a considerable number of adult patients with CHS.

RFC1 repeat expansion in Japanese patients with late-onset cerebellar ataxia.

Recently, the expansion of an intronic AAGGG repeat in the replication factor C subunit 1 (RFC1) gene was reported to cause cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). In Europeans, the expansion accounted for 22% of sporadic patients with late-onset ataxia. We genotyped 37 Japanese patients comprising 25 familial (autosomal recessive or undecided transmission) and 12 sporadic ones with late-onset ataxia. We found intronic repeat expansions in RFC1 in three (12%) of the familial patients and one (8.5%) of the sporadic ones. Although our cohort study was small, the disease frequency in Japanese patients with CANVAS might be lower than that in European ones. In addition, we found biallelic ACAGG repeat expansion in one patient, indicating ACAGG repeat expansion might cause CANVAS. Clinically, we found one patient with sleep apnea syndrome, which has not been reported previously. Thus, this study might expand the clinical and genetic spectrum of CANVAS.

Sympathetic outflow to skin predicts central autonomic dysfunction in multiple system atrophy.

BACKGROUND: To find out the physiological method for evaluating the severity of central autonomic dysfunction, we performed detailed evaluation of cutaneous vasomotor neural function in a comparatively large sample of multiple system atrophy (MSA). METHODS: We evaluated cutaneous vasomotor neural function in 24 MSA patients. Skin sympathetic nerve activity (SSNA) and sympathetic skin response (SSR) and skin blood flow (skin vasomotor reflex [SVR]) were recorded at rest, as well as reflex changes after electrical stimulation. The parameters investigated were SSNA frequency at rest, reflex latency and amplitude of SSNA reflex bursts, absolute decrease and percent reduction of SVR, recovery time, and spontaneous SVR and SSR frequency. RESULTS: There were negative correlations between resting SSNA and disease duration or the SCOPA-AUT score, but these were not significant. SSNA reflex latency displayed significant positive correlations with disease duration and SCOPA-AUT score (p < 0.001 and p < 0.01, respectively). In all five patients who underwent the same examination twice, SSNA reflex latency was significantly longer at the second examination than at the first examination (p < 0.005). A significant positive correlation was identified between recovery time of skin blood flow and SCOPA-AUT score or reflex latency (p < 0.05). Significant correlations were not observed between SCOPA-AUT score or disease duration and other parameters. CONCLUSIONS: These results suggest that some MSA patients with a comparatively short duration of disease potentially have impaired thermoregulatory function. Measurement of sympathetic outflow to the skin is potentially a useful tool for predicting the severity of central autonomic dysfunction in MSA.

Pathological findings in a patient with non-dystrophic myotonia with a mutation of the SCN4A gene; a case report.

BACKGROUND: Non-dystrophic myotonias (NDMs) are skeletal muscle disorders involving myotonia distinct from myotonic dystrophy. It has been reported that the muscle pathology is usually normal or comprises mild myopathic changes in NDMs. We describe various pathological findings mimicking those of myotonic dystrophy (DM) in biopsied muscle specimens from a patient with NDMs with a long disease duration. CASE PRESENTATION: A 66-year-old Japanease man presented eye closure myotonia, percussion myotonia and grip myotonia together with the warm-up phenomenon and cold aggravation from early childhood. On genetic analysis, a heterozygous mutation of the SCN4A gene (c.2065 C > T, p.L689F), with no mutation of the CLCN1, DMPK, or ZNF9/CNBP gene, was detected. He was diagnosed as having NDMs. A biopsy of the biceps brachii muscle showed increasing fiber size variation, internal nuclei, chained nuclei, necrotic fibers, fiber splitting, endomysial fibrosis, pyknotic nuclear clumps and disorganized intermyofibrillar networks. Sarcoplasmic masses, tubular aggregates and ragged-red fibers were absent. CONCLUSION: It is noteworthy that the present study revealed various pathological findings resembling those seen in DM, although the pathology is usually normal or mild in NDMs. The pathological similarities may be due to muscular modification with long-standing myotonia or excessive muscle contraction based on abnormal channel activity.

Novel GARS mutation presenting as autosomal dominant intermediate Charcot-Marie-Tooth disease.

We report the first family with a glycyl-tRNA synthetase (GARS) mutation with autosomal dominant intermediate Charcot-Marie-Tooth disease (DI-CMT). The proband and the proband's father presented with gait disturbance and hand weakness. Both patients displayed moderately decreased conduction velocities (MNCV) (ranging from 29.2 to 37.8 m/s). A sural nerve biopsy of the father revealed evidence of both axonal loss and demyelination. On exome sequencing, in both the proband and his father, we identified a novel missense mutation (c.643G > C, p.Asp215His) in the GARS gene in a heterozygous state, which is considered to be pathogenic for this DI-CMT family. The present study broadens current knowledge about intermediate CMT and the phenotypic spectrum of defects associated with GARS.

Vasomotor regulation in patients with multiple system atrophy.

To investigate the vasomotor regulation in multiple system atrophy (MSA), we simultaneously recorded muscle sympathetic nerve activity (MSNA), heart rate, and blood pressure in 14 MSA patients without syncope and 18 healthy subjects. Resting MSNA bursts were significantly less frequent in MSA patients than healthy subjects (p < 0.001), while the increase of MSNA bursts with head-up tilt was significantly greater in MSA patients (p < 0.01). In patients with MSA, orthostatic hypotension may be prevented by an augmented MSNA response.

Clinicopathological features of adult-onset neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a slowly progressive neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the central and peripheral nervous system, and also in the visceral organs. NIID has been considered to be a heterogeneous disease because of the highly variable clinical manifestations, and ante-mortem diagnosis has been difficult. However, since we reported the usefulness of skin biopsy for the diagnosis of NIID, the number of NIID diagnoses has increased, in particular adult-onset NIID. In this study, we studied 57 cases of adult-onset NIID and described their clinical and pathological features. We analysed both NIID cases diagnosed by post-mortem dissection and by ante-mortem skin biopsy based on the presence of characteristic eosinophilic, hyaline and ubiquitin-positive intanuclear inclusion: 38 sporadic cases and 19 familial cases, from six families. In the sporadic NIID cases with onset age from 51 to 76, dementia was the most prominent initial symptom (94.7%) as designated 'dementia dominant group', followed by miosis, ataxia and unconsciousness. Muscle weakness and sensory disturbance were also observed. It was observed that, in familial NIID cases with onset age less than 40 years, muscle weakness was seen most frequently (100%), as designated 'limb weakness group', followed by sensory disturbance, miosis, bladder dysfunction, and dementia. In familial cases with more than 40 years of onset age, dementia was most prominent (100%). Elevated cerebrospinal fluid protein and abnormal nerve conduction were frequently observed in both sporadic and familial NIID cases. Head magnetic resonance imaging showed high intensity signal in corticomedullary junction in diffusion-weighted image in both sporadic and familial NIID cases, a strong clue to the diagnosis. All of the dementia dominant cases presented with this type of leukoencephalopathy on head magnetic resonance imaging. Both sporadic and familial NIID cases presented with a decline in Mini-Mental State Examination and Frontal Assessment Battery scores. Based on these clinicopathological features, we proposed a diagnosis flow chart of adult-onset NIID. Our study suggested that the prevalence rate of adult-onset NIID may be higher than previously thought, and that NIID may be underdiagnosed. We should take NIID into account for differential diagnosis of leukoencephalopathy and neuropathy.

Changes in sympathetic thermoregulatory function with aging.

We recorded skin sympathetic nerve activity (SSNA), SSR, and SVR in 30 subjects. SSNA and SVR showed a slight decrease and spontaneous changes in resting SSR were significantly less frequent in older subjects compared with younger subjects (p < 0.05). There was no significant relationship between age and the reflex latency or amplitude of SSNA, SSR, and SVR in response to electrical stimulation.

Ubiquitin ligase CHIP suppresses cancer stem cell properties in a population of breast cancer cells.

Cancer stem cells (CSCs) have several distinctive characteristics, including high metastatic potential, tumor-initiating potential, and properties that resemble normal stem cells such as self-renewal, differentiation, and drug efflux. Because of these characteristics, CSC is regarded to be responsible for cancer progression and patient prognosis. In our previous study, we showed that a ubiquitin E3 ligase carboxyl terminus of Hsc70-interacting protein (CHIP) suppressed breast cancer malignancy. Moreover, a recent clinical study reported that CHIP expression levels were associated with favorable prognostic parameters of patients with breast cancer. Here we show that CHIP suppresses CSC properties in a population of breast cancer cells. CHIP depletion resulted in an increased proportion of CSCs among breast cancers when using several assays to assess CSC properties. From our results, we propose that inhibition of CSC properties may be one of the functions of CHIP as a suppressor of cancer progression.

Case report: Atypical case of autoimmune glial fibrillary acidic protein astrocytopathy following COVID-19 vaccination refractory to immunosuppressive treatments.

A 54-year-old Japanese man presented with headache and fever the day after SARS-CoV-2 vaccination. He became deeply unconscious within a week. Brain MRI showed periventricular linear enhancements and a few spotty lesions in the cerebral white matter. Cerebrospinal fluid (CSF) testing showed mild pleocytosis. He was treated with intravenous methylprednisolone and plasma exchange. However, the white matter lesions enlarged to involve the brainstem and cerebellum, and long cord spinal lesions appeared. Anti-glial fibrillary acidic protein (GFAP) antibody was positive in the CSF and serum, and he was therefore diagnosed as autoimmune GFAP-astrocytopathy (GFAP-A). In addition, high-dose immunoglobulin therapy was administered twice, but his symptoms did not improve; the white matter lesions enlarged further, and modified Rankin Scale score increased to 5. A brain biopsy specimen showed infiltration of macrophages and CD4 + lymphocytes together with neuron and oligodendrocytic injuries and glial scar. Although GFAP-A generally responds well to steroids, the present case developed GFAP-A following SARS-CoV-2 vaccination, with refractory to intensive immunosuppressive therapy and atypical pathologic findings of infiltration of CD4 + lymphocytes and demyelination.

[A case of ataxic gait disturbance due to 1-bromopropane neurotoxicity].

A 55-year-old man presented a slowly progressive sensory disorder, predominantly in both lower limbs, and gait disturbance. Neurological examinations revealed abnormal sensation and spasticity in both lower limbs, and a wide-based gait. Although examination revealed mild hyperchloremia and decreased motor conduction velocity in the peroneal nerve, head and whole spine MRI, and spinal fluid examination were normal. His job history revealed he had been engaged in metal cleaning work using 1-bromopropane (1-BP) for three years. His serum bromide concentration was increased to 175.6 mg/l (standard value: 5 or less), so we diagnosed him as having 1-BP neurotoxicity. The serum bromide concentration decreased after avoidance of exposure to 1-BP, but the gait disturbance remained. It was considered that we should obtain a detailed job history and measure the serum bromide concentration in patients with a sensory disorder in the extremities and gait disturbance of unknown origin.

Novel nucleolar pathway connecting intracellular energy status with p53 activation.

In response to a shortage of intracellular energy, mammalian cells reduce energy consumption and induce cell cycle arrest, both of which contribute to cell survival. Here we report that a novel nucleolar pathway involving the energy-dependent nucleolar silencing complex (eNoSC) and Myb-binding protein 1a (MYBBP1A) is implicated in these processes. Namely, in response to glucose starvation, eNoSC suppresses rRNA transcription, which results in a reduction in nucleolar RNA content. As a consequence, MYBBP1A, which is anchored to the nucleolus via RNA, translocates from the nucleolus to the nucleoplasm. The translocated MYBBP1A induces acetylation and accumulation of p53 by enhancing the interaction between p300 and p53, which eventually leads to the cell cycle arrest (or apoptosis). Taken together, our results indicate that the nucleolus works as a sensor that transduces the intracellular energy status into the cell cycle machinery.

Novel SLC9A6 Variation in Female Carriers With Intellectual Disability and Atypical Parkinsonism.

BACKGROUND AND OBJECTIVES: Variations in SLC9A6 cause the X-linked neurologic disorder Christianson syndrome in males. Meanwhile, female carriers with SLC9A6 variations may remain asymptomatic or develop intellectual disability, behavioral problems, and psychiatric illnesses. Only a few female carriers have been reported to have associated atypical parkinsonism in late life. METHODS: We present a Japanese family with a novel SLC9A6 variation identified by quad whole-exome sequencing analysis and a reverse phenotyping strategy. The molecular and cellular impacts of the W89R variation in vitro were examined. RESULTS: The missense variation (c.265T>C, p.Trp89Arg) in SLC9A6 cosegregated with atypical parkinsonism and intellectual disability in female carriers of this family. The female carriers in this family presented with bradykinesia, rigidity, and tremor, predominately on the right side. We found that the W89R variation changed membrane traffic of NHE6-harboring vesicles, indicating potential involvement in the disease pathogenesis. DISCUSSION: This study might have revealed an example of a monogenic origin of atypical parkinsonism in females with SLC9A6 variations and draw attention to this understudied female-specific phenotype in clinical practice.

Estrogen and antiestrogens alter breast cancer invasiveness by modulating the transforming growth factor-ß signaling pathway.

In the later stages of breast cancer, estrogen receptor (ER)α-negative cancers typically have higher histological grades than ERα-positive cancers, and transforming growth factor (TGF)-ß promotes invasion and metastasis. Our previous study indicated that ERα inhibited TGF-ß signaling by inducing the degradation of Smad in an estrogen-dependent manner. In the present study, we report that the suppressive effects of ERα and estrogen on tumor progression are mediated by inhibiting TGF-ß signaling. Furthermore, we investigated the effects of antiestrogens such as ICI182,780 (ICI) or tamoxifen (TAM) on TGF-ß signaling and breast cancer invasiveness. The levels of total Smad and pSmad were reduced by estrogen, whereas ICI slightly increased them, and TAM had no effect. To investigate the effect of antiestrogens on breast cancer invasiveness, we generated highly migratory and invasive MCF-7-M5 cells. The migration and invasion of these cells were suppressed by the inhibitor of TGF-ß receptor kinase, SB-505124, and estrogen. However, antiestrogens did not suppress the migration and invasion of these cells. In addition, we screened TGF-ß target genes whose expression was reduced by estrogen treatment and identified four genes associated with breast cancer invasiveness and poor prognosis. The expression of these genes was not decreased by antiestrogens. These observations provide a new insight into estrogen function and the mechanisms underlying estrogen-mediated suppression of tumor progression.

Critical role of the nucleolus in activation of the p53-dependent postmitotic checkpoint.

Cells eventually exit from mitosis during sustained arrest at the spindle checkpoint, without sister chromatid separation and cytokinesis. The resulting tetraploid cells are arrested in the subsequent G1 phase in a p53-dependent manner by the regulatory function of the postmitotic G1 checkpoint. Here we report how the nucleolus plays a critical role in activation of the postmitotic G1 checkpoint. During mitosis, the nucleolus is disrupted and many nucleolar proteins are translocated from the nucleolus into the cytoplasm. Among the nucleolar factors, Myb-binding protein 1a (MYBBP1A) induces the acetylation and accumulation of p53 by enhancing the interaction between p300 and p53 during prolonged mitosis. MYBBP1A-dependent p53 activation is essential for the postmitotic G1 checkpoint. Thus, our results demonstrate a novel nucleolar function that monitors the prolongation of mitosis and converts its signal into activation of the checkpoint machinery.

[A patient with recurrent multiloculated hydrocephalus after Cryptococcal ventriculitis].

We report here a rare case of adult-onset multiloculated hydrocephalus (MLH) after Cryptococcal meningitis. A 63-year-old man had Cryptococcal ventriculitis in 2011, and he recovered with treatment of antimycotic drugs. However, he was admitted again because of disorientation and amnesia, and brain MRI showed dilation of the inferior horn of the left lateral ventricle. He underwent a ventriculoperitoneal shunt (VPS) for noncommunicating hydrocephalus in 2019, and the disorientation and amnesia improved. One year after the VPS, he was admitted because of urinary dysfunction and gait disturbance. Brain MRI showed dilation of the bilateral anterior horns of the lateral ventricles. He underwent an additional VPS into the space in 2020, and urinary dysfunction and gait disturbance improved. This case was supposed that the symptom in agreement with the dilated ventricle by MLH was shown.