Parkinsonism in spinocerebellar ataxia with axonal neuropathy caused by adult-onset COA7 variants: a case report.

BACKGROUND: Individuals with variants of cytochrome c oxidase assembly factor 7 (COA7), a mitochondrial functional-related gene, exhibit symptoms of spinocerebellar ataxia with axonal neuropathy before the age of 20. However, COA7 variants with parkinsonism or adult-onset type cases have not been described. CASE PRESENTATION: We report the case of a patient who developed cerebellar symptoms and slowly progressive sensory and motor neuropathy in the extremities, similar to Charcot-Marie-Tooth disease, at age 30, followed by parkinsonism at age 58. Exome analysis revealed COA7 missense mutation in homozygotes (NM_023077.2:c.17A > G, NP_075565.2: p.Asp6Gly). Dopamine transporter single-photon emission computed tomography using a 123I-Ioflupane revealed clear hypo-accumulation in the bilateral striatum. However, 123I-metaiodobenzylguanidine myocardial scintigraphy showed normal sympathetic nerve function. Levodopa administration improved parkinsonism in this patient. CONCLUSIONS: COA7 gene variants may have caused parkinsonism in this case because mitochondrial function-related genes, such as parkin and PINK1, are known causative genes in some familial Parkinson's diseases.

Cynomolgus macaque model of neuronal ceroid lipofuscinosis type 2 disease.

Neuronal ceroid lipofuscinoses (NCLs) are autosomal-recessive fatal neurodegenerative diseases that occur in children and young adults, with symptoms including ataxia, seizures and visual impairment. We report the discovery of cynomolgus macaques carrying the CLN2/TPP1 variant and our analysis of whether the macaques could be a new non-human primate model for NCL type 2 (CLN2) disease. Three cynomolgus macaques presented progressive neuronal clinical symptoms such as limb tremors and gait disturbance after about 2 years of age. Morphological analyses using brain MRI at the endpoint of approximately 3 years of age revealed marked cerebellar and cerebral atrophy of the gray matter, with sulcus dilation, gyrus thinning, and ventricular enlargement. Histopathological analyses of three affected macaques revealed severe neuronal loss and degeneration in the cerebellar and cerebral cortices, accompanied by glial activation and/or changes in axonal morphology. Neurons observed throughout the central nervous system contained autofluorescent cytoplasmic pigments, which were identified as ceroid-lipofuscin based on staining properties, and the cerebral cortex examined by transmission electron microscopy had curvilinear profiles, the typical ultrastructural pattern of CLN2. These findings are commonly observed in all forms of NCL. DNA sequencing analysis identified a homozygous single-base deletion (c.42delC) of the CLN2/TPP1 gene, resulting in a frameshifted premature stop codon. Immunohistochemical analysis showed that tissue from the affected macaques lacked a detectable signal against TPP1, the product of the CLN2/TPP1 gene. Analysis for transmission of the CLN2/TPP1 mutated gene revealed that 47 (49.5%) and 48 (50.5%) of the 95 individuals genotyped in the CLN2-affected macaque family were heterozygous carriers and homozygous wild-type individuals, respectively. Thus, we identified cynomolgus macaques as a non-human primate model of CLN2 disease. The CLN2 macaques reported here could become a useful resource for research and the development of drugs and methods for treating CLN2 disease, which involves severe symptoms in humans.

Dentatorubropallidoluysian Atrophy with Prominent Autonomic Dysfunction.

We herein report a 45-year-old man with dentatorubropallidoluysian atrophy (DRPLA) who presented with mild dementia, ataxia, and involuntary movement and developed constipation, dysuria, and orthostatic hypotension. Thermography revealed an abnormal thermal response of the skin to cold stimulation. Skin temperature reflects the skin blood flow and is regulated by the sympathetic nervous system. Thermography is currently used to study diseases associated with vasomotor dysfunction of the skin. The thermography results suggested the possibility of autonomic dysfunction. Although little is known regarding autonomic dysfunction in DRPLA, this report demonstrates the importance of autonomic dysfunction in DRPLA.

Nonaneurysmal subarachnoid hemorrhage associated with COVID-19 infection: A case report.

Background: Most coronavirus disease 2019 (COVID-19)-related cerebrovascular disorders are ischemic while hemorrhagic disorders are rarely reported. Among these, subarachnoid hemorrhage (SAH) is very rarely reported and nonaneurysmal SAH has been reported in only about a dozen cases. Here, we report a case of nonaneurysmal SAH as the only clinical manifestation of COVID-19 infection. In addition, we reviewed and analyzed the literature data on cases of nonaneurysmal SAH caused by COVID-19 infection. Case Description: A 50-year-old woman presented to an emergency department with a sudden headache, right hemiparesis, and consciousness disturbance. At that time, no fever or respiratory failure was observed. Laboratory data were within normal values but the rapid antigen test for COVID-19 on admission was positive, resulting in a diagnosis of COVID-19 infection. Computed tomograms (CTs) showed bilateral convexal SAH with a hematoma but three-dimensional CT angiograms showed no obvious sources, such as a cerebral aneurysm. Therefore, the patient was diagnosed with nonaneurysmal SAH associated with COVID-19 infection. With conservative treatment, consciousness level and hemiparesis both improved gradually until transfer for continued rehabilitation. Approximately 12 weeks after onset, the patient was discharged with only mild cognitive impairment. During the entire course of the disease, the headache, hemiparesis, and mild cognitive impairment due to nonaneurysmal SAH with small hematoma were the only abnormalities experienced. Conclusion: Since COVID-19 infection can cause nonaneurysmal hemorrhaging, it should be considered (even in the absence of characteristic infectious or respiratory symptoms of COVID-19) when atypical hemorrhage distribution is seen as in our case.

Aplastic or twiglike middle cerebral artery with contralateral middle cerebral artery stenosis showing transient ischemic attack: illustrative case.

BACKGROUND: Aplastic or twiglike middle cerebral artery (Ap/T-MCA) is a rare anomaly characterized by a unilateral MCA occlusion with plexiform vessels that causes hemorrhagic and (less commonly) ischemic strokes. The reasons for this are rarely discussed, and thus optimal treatment for ischemic Ap/T-MCA remains controversial. Here, the authors report a case of Ap/T-MCA with transient ischemic attacks treated by bypass surgery and discuss the mechanism of ischemic development and treatment methods. OBSERVATIONS: A 62-year-old hypertensive man with transient, recurrent left hemiparesis visited the authors' hospital. Magnetic resonance angiography showed proximal occlusion of the right MCA and stenosis in the left MCA. Digital subtraction angiography revealed occlusion of the right MCA and abnormal vascular networks, leading to a diagnosis of Ap/T-MCA with contralateral MCA stenosis. Antiplatelet therapy with aspirin was insufficient, and a superficial temporal artery-MCA bypass was performed. There were no ischemic or hemorrhagic events postoperatively. LESSONS: Atherosclerosis seems to have a significant impact on the development of ischemic stroke in patients with Ap/T-MCA, and the presence of coexisting atherosclerotic stenotic vascular lesions outside the Ap/T-MCA site is substantial in its development. Bypass surgery is a promising treatment option for ischemic Ap/T-MCA.

Tuberculous meningitis with good outcome following appropriate timing of ventriculoperitoneal shunting for hydrocephalus.

BACKGROUND: Tuberculous meningitis is often associated with hydrocephalus. However, the appropriate timing for shunt placement to treat hydrocephalus remains controversial. CASE PRESENTATION: A 43-year-old man presented with high fever and disturbance of consciousness. Cerebrospinal fluid (CSF) findings showed pleocytosis, increased protein levels, and hypoglycemia with an elevated pressure of 30 cm H2O. Brain magnetic resonance imaging revealed cerebral infarctions and hydrocephalus resulting in suspicion of tuberculous meningitis. A few days after admission, external ventricular drainage was carried out for acute hydrocephalus. Four antitubercular drugs (isoniazid, rifampicin, pyrazinamide, and ethambutol) as well as dexamethasone sodium phosphate were given. The CSF polymerase chain reaction test for tuberculosis was found to be positive 2 weeks later. Once CSF protein levels improved, a ventriculoperitoneal shunting operation was undertaken. CONCLUSIONS: When tuberculous meningitis is suspected, treatment with antitubercular drugs should be initiated prior to definitive diagnosis, and a shunt surgery should be carried out in a timely manner.

Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis.

OBJECTIVE: To evaluate the efficacy and safety of perampanel in patients with sporadic amyotrophic lateral sclerosis (SALS). METHODS: This randomized, double-blind, placebo-controlled, multicenter, phase 2 clinical study was conducted at 12 sites. Patients with probable or definite ALS as defined by revised El Escorial criteria were enrolled. Sixty-six patients were randomly assigned (1:1:1) to receive placebo, 4 mg perampanel, or 8 mg perampanel daily for 48 weeks. Adverse events (AEs) were recorded throughout the trial period. The primary efficacy outcome was the change in Amyotrophic Lateral Sclerosis Rating Scale-Revised (ALSFRS-R) score after 48 weeks of treatment. RESULTS: One patient withdrew before starting the treatment. Of 65 patients included, 18 of 22 patients randomized to placebo (82%), 14 of 22 patients randomized to 4 mg perampanel (64%), and 7 of 21 patients randomized to 8 mg perampanel (33%) completed the trial. There was a significant difference in the change of ALSFRS-R scores [- 8.4 (95% CI - 13.9 to - 2.9); p = 0.015] between the placebo and the perampanel 8 mg group, primarily due to worsening of the bulbar subscore in the perampanel 8 mg group. Serious AEs were more frequent in the perampanel 8 mg group than in the placebo group (p = 0.0483). CONCLUSIONS: Perampanel was associated with a significant decline in ALSFRS-R score and was linked to worsening of the bulbar subscore in the 8 mg group.

Cybernic treatment with wearable cyborg Hybrid Assistive Limb (HAL) improves ambulatory function in patients with slowly progressive rare neuromuscular diseases: a multicentre, randomised, controlled crossover trial for efficacy and safety (NCY-3001).

BACKGROUND: Rare neuromuscular diseases such as spinal muscular atrophy, spinal bulbar muscular atrophy, muscular dystrophy, Charcot-Marie-Tooth disease, distal myopathy, sporadic inclusion body myositis, congenital myopathy, and amyotrophic lateral sclerosis lead to incurable amyotrophy and consequent loss of ambulation. Thus far, no therapeutic approaches have been successful in recovering the ambulatory ability. Thus, the aim of this trial was to evaluate the efficacy and safety of cybernic treatment with a wearable cyborg Hybrid Assistive Limb (HAL, Lower Limb Type) in improving the ambulatory function in those patients. RESULTS: We conducted an open-label, randomised, controlled crossover trial to test HAL at nine hospitals between March 6, 2013 and August 8, 2014. Eligible patients were older than 18 years and had a diagnosis of neuromuscular disease as specified above. They were unable to walk for 10 m independently and had neither respiratory failure nor rapid deterioration in gait. The primary endpoint was the distance passed during a two-minute walk test (2MWT). The secondary endpoints were walking speed, cadence, and step length during the 10-m walk test (10MWT), muscle strength by manual muscle testing (MMT), and a series of functional measures. Adverse events and failures/problems/errors with HAL were also evaluated. Thirty patients were randomly assigned to groups A or B, with each group of 15 receiving both treatments in a crossover design. The efficacy of a 40-min walking program performed nine times was compared between HAL plus a hoist and a hoist only. The final analysis included 13 and 11 patients in groups A and B, respectively. Cybernic treatment with HAL resulted in a 10.066% significantly improved distance in 2MWT (95% confidence interval, 0.667-19.464; p = 0.0369) compared with the hoist only treatment. Among the secondary endpoints, the total scores of MMT and cadence at 10MWT were the only ones that showed significant improvement. The only adverse effects were slight to mild myalgia, back pain, and contact skin troubles, which were easily remedied. CONCLUSIONS: HAL is a new treatment device for walking exercise, proven to be more effective than the conventional method in patients with incurable neuromuscular diseases. TRIAL REGISTRATION: JMACTR, JMA-IIA00156.

Comprehensive characterization of migration profiles of murine cerebral cortical neurons during development using FlashTag labeling.

In the mammalian cerebral neocortex, different regions have different cytoarchitecture, neuronal birthdates, and functions. In most regions, neuronal migratory profiles are speculated similar based on observations using thymidine analogs. Few reports have investigated regional migratory differences from mitosis at the ventricular surface. In this study, we applied FlashTag technology, in which dyes are injected intraventricularly, to describe migratory profiles. We revealed a mediolateral regional difference in the migratory profiles of neurons that is dependent on developmental stage; for example, neurons labeled at embryonic day 12.5-15.5 reached their destination earlier dorsomedially than dorsolaterally, even where there were underlying ventricular surfaces, reflecting sojourning below the subplate. This difference was hardly recapitulated by thymidine analogs, which visualize neurogenic gradients, suggesting a biological significance different from the neurogenic gradient. These observations advance our understanding of cortical development and the power of FlashTag in studying migration and are thus resources for future neurodevelopmental studies.

CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome.

Fragile X-related tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease caused by CGG triplet repeat expansions in FMR1, which elicit repeat-associated non-AUG (RAN) translation and produce the toxic protein FMRpolyG. We show that FMRpolyG interacts with pathogenic CGG repeat-derived RNA G-quadruplexes (CGG-G4RNA), propagates cell to cell, and induces neuronal dysfunction. The FMRpolyG polyglycine domain has a prion-like property, preferentially binding to CGG-G4RNA. Treatment with 5-aminolevulinic acid, which is metabolized to protoporphyrin IX, inhibited RAN translation of FMRpolyG and CGG-G4RNA-induced FMRpolyG aggregation, ameliorating aberrant synaptic plasticity and behavior in FXTAS model mice. Thus, we present a novel therapeutic strategy to target G4RNA prionoids.

Normocalcemic Primary Hyperparathyroidism Presenting with Muscle Weakness and Body Pain.

We herein report a 39-year-old woman who had aggravated body pain, waddling gait, and fatigability for the past 2 years. A neurological examination showed hyperreflexia and proximal muscle weakness. The serum calcium level was normal (10.1 mg/dL). However, serum alkaline phosphatase (3,855 IU/I) and parathyroid hormone (1,008 pg/mL) levels were remarkably high. Cervical ultrasonography revealed parathyroid goiter. The patient was diagnosed with hyperparathyroidism. Her muscle weakness and pain improved within three months after parathyroidectomy. Our findings suggest that clinicians should consider hyperparathyroidism as a differential diagnosis in patients with proximal muscle weakness, even if the serum calcium level is normal.

Use of the Illumina EPIC methylation array for epigenomic research in the crab-eating macaque (Macaca fascicularis).

BACKGROUND: Commercially available Illumina DNA methylation arrays (HumanMethylation 27K, HumanMethylation450, and MethylationEPIC BeadChip) can be used for comprehensive DNA methylation analyses of not only the human genome but also other mammalian genomes, ranging from those of nonhuman primates to those of rodents. However, practical application of the EPIC array to the crab-eating macaque has not been reported. METHODS: Through bioinformatic analyses involving cross-species comparison and consideration of probe performance, we selected array probes that can be reliably used for the crab-eating macaque genome. A DNA methylation assay using an EPIC array was performed on genomic DNA extracted from the brains of five crab-eating macaques. The obtained DNA methylation data were compared with a publicly available dataset. RESULTS: Among the 865 918 probes in the EPIC array, a total of 183 509 probes (21.2%) were selected as high-confidence array probes in the crab-eating macaque. Subsequent comparisons revealed that the data from these probes showed good concordance with other DNA methylation datasets of the crab-eating macaque. CONCLUSION: The selected high-confidence array probes would be useful for high-throughput DNA methylation assays of the crab-eating macaque.

Familial cerebral cavernous malformation presenting with epilepsy caused by mutation in the CCM2 gene: A case report.

RATIONALE: Cerebral cavernous malformation (CCM) of the familial type is caused by abnormalities in the CCM1, CCM2, and CCM3 genes. These 3 proteins forming a complex associate with the maintenance of vascular endothelial cell-cell junctions. Dysfunction of these proteins results in the development of hemangiomas and abnormal intercellular junctions. PATIENT CONCERNS: We report a 68-year-old man with familial cerebral cavernous malformation with initial presentation as convulsions at an advanced age. Brain magnetic resonance imaging revealed multiple cavernous hemangiomas in the right occipital lobe. The convulsions were considered to be induced by hemorrhage from cavernous hemangioma in the right occipital lobe. DIAGNOSES: Genetic screening of the CCM1, CCM2, and CCM3 genes revealed a novel mutation in the CCM2 gene (exon4 c: 359 T>A, p: V120D). No abnormalities were found in CCM1 or CCM3. Therefore, we diagnosed the patient with familial CCM caused by a CCM2 mutation. INTERVENTIONS: This patient was treated with the administration of levetiracetam at a dosage of 1000 mg/day. OUTCOMES: No seizures have been observed since the antiepileptic drug was administered. We performed brain magnetic resonance imaging (MRI) regularly to follow-up on appearance of new cerebral hemorrhages and cavernous hemangiomas. LESSONS: This report reviews cases of familial cerebral cavernous malformations caused by abnormalities in the CCM2 gene. This mutation site mediates interactions with CCM1 and CCM3. The mutation occurs in the phosphotyrosine binding (PTB) site, which is considered functionally important to CCM2.

Familial Mediterranean Fever Is Important in the Differential Diagnosis of Recurrent Aseptic Meningitis in Japan.

Familial Mediterranean fever (FMF) is an autoinflammatory disease characterized by a recurrent fever and multiple serositis. In the present report, we discuss the case of a 42-year-old man diagnosed with FMF accompanied by recurrent aseptic meningitis (RAM). The patient experienced RAM at intervals of several years without any serositis or synovitis. We detected Mediterranean fever (MEFV) gene mutations (E148Q homozygotes) and diagnosed FMF in perfect accordance with clinical diagnostic criteria. FMF, in which RAM is a major symptom, has also been described in previous reports. Therefore, FMF should be considered in the differential diagnosis of causative diseases for RAM.

Probable progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome with immunosuppressant dose reduction following lung transplantation: a case report and literature review.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rapidly developing demyelinating disease in the cerebral white matter and is often caused by JC polyomavirus (JCV). PML after lung transplantation is rare and has a poor prognosis, with no established therapies. Reducing the patient's immunosuppressant doses, thereby restoring immunity, could be used to treat PML. However, some patients develop immune reconstitution inflammatory syndrome (IRIS) with this treatment, an immune-induced inflammatory response to JCV that results in serious neuronal damage. We herein report a case of a 60-year-old female who suffered from PML 5 years after lung transplantation, had worsened brain lesions thought to be related to PML-IRIS at the time of immunosuppressant reduction, and missed treatment opportunities. CASE PRESENTATION: A 60-year-old female developed PML 5 years after lung transplantation. Fluid-attenuated inversion recovery and diffusion-weighted brain magnetic resonance imaging (MRI) revealed multiple high-signal lesions, mainly in the cerebral white matter. Polymerase chain reaction found 0.32 million copies/mL of JCV in the cerebrospinal fluid. Thus, she was given a diagnosis of PML. Mycophenolate mofetil and tacrolimus dosages were reduced, and CD4-positive cell counts and the blood concentration of each immunosuppressant were monitored. Mefloquine was also orally administered at a daily dose of 275 mg for 3 days and was then administered at a dose of 275 mg per week. Although the patient's CD4-positive cell counts increased and her immune system recovered, her symptoms and brain MRI findings worsened. We suspected PML progression or a transition to PML-IRIS. Steroid pulse therapy to suppress the inflammatory lesions was not possible but was retrospectively indicated. The patient rapidly began to exhibit akinetic mutism and died 4 months after the onset of neurologic symptoms. CONCLUSIONS: When neurologic symptoms and abnormal brain MRI findings are noted during immune recovery, it is often difficult to distinguish between progressed PML and PML-IRIS. However, the pathogenesis of brain lesions usually involves inflammation and immune-reactive mechanisms for JCV. Steroid pulse therapy, which can reduce inflammation, should thus be administered in organ transplantation cases with differential diagnoses including PML-IRIS.

GDF-15, a mitochondrial disease biomarker, is associated with the severity of multiple sclerosis.

GDF-15, a member of the transforming growth factor beta superfamily, regulates inflammatory and apoptotic pathways in various diseases, such as heart failure, kidney dysfunction, and cancer. We aimed to clarify potentially confounding variables affecting GDF-15 and demonstrate its utility as a mitochondrial biomarker using serum samples from 15 patients with mitochondrial diseases (MD), 15 patients with limbic encephalitis (LE), 10 patients with multiple sclerosis/neuromyelitis optica spectrum disorders (MS/NMOSD), and 19 patients with amyotrophic lateral sclerosis (ALS). GDF-15 and FGF-21 were significantly elevated in MD. GDF-15 and FGF-21 showed a good correlation in MD but not in LE, MS, and ALS. GDF-15 was potentially influenced by age in LE, MS/NMOSD, and ALS but not in MD. FGF-21 was not correlated with age in MS/NMOSD, ALS, LE, and MD. GDF-15 was not correlated with clinical features in LE or BMI or body weight in ALS. GDF-15 positively correlated with the Expanded Disability Status Scale (EDSS) in MS/NMOSD, while EDSS showed no correlation with age. In conclusion, the results revealed that GDF-15 may be influenced by EDSS in MS/NMOPSD and by age in LE, MS/NMOSD, and ALS but not in MD. Mitochondrial damage in MS/NMOSD is a potentially confounding variable affecting GDF-15.