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We herein report a novel de novo KCNH5 variant in a patient with refractory epileptic encephalopathy. The patient exhibited seizures at 1 year and 7 months old, which gradually worsened, leading to a bedridden status. Brain magnetic resonance imaging (MRI) showed cerebral atrophy and cerebellar hypoplasia. A trio whole-exome sequence analysis identified a de novo heterozygous c.640A>C, p.Lys214Gln variant in KCNH5 that was predicted to be deleterious. Recent studies have linked KCNH5 to various epileptic encephalopathies, with many patients showing normal MRI findings. The present case expands the clinical spectrum of the disease, as it is characterized by severe neurological prognosis, cerebral atrophy, and cerebellar hypoplasia.
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Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by various combinations of autonomic failure, parkinsonism, and cerebellar ataxia. To elucidate variants associated with MSA, we have been conducting short-read-based whole-genome sequence analysis. In the process of the association studies, we initially focused on GBA1, a previously proposed susceptibility gene for MSA, to evaluate whether GBA1 variants can be efficiently identified despite its extraordinarily high homology with its pseudogene, GBA1LP. To accomplish this, we conducted a short-read whole-genome sequence analysis with alignment to GRCh38 as well as Sanger sequence analysis and compared the results. We identified five variants with inconsistencies between the two pipelines, of which three variants (p.L483P, p.A495P-p.V499V, p.L483_M489delinsW) were the results of misalignment due to minor alleles in GBA1P1 registered in GRCh38. The miscalling events in these variants were resolved by alignment to GRCh37 as the reference genome, where the major alleles are registered. In addition, a structural variant was not properly identified either by short-read or by Sanger sequence analyses. Having accomplished correct variant calling, we identified three variants pathogenic for Gaucher disease (p.S310G, p.L483P, and p.L483_M489delinsW). Of these variants, the allele frequency of p.L483P (0.003) in the MSA cases was higher than that (0.0011) in controls. The meta-analysis incorporating a previous report demonstrated a significant association of p.L483P with MSA with an odds ratio of 2.92 (95% CI; 1.08 - 7.90, p = 0.0353).
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Background: Idiopathic basal ganglia calcification (IBGC), also known as Farh's disease, is a rare neurodegenerative disorder characterized by calcification of the basal ganglia and other brain regions. This disease usually occurs in middle-aged patients and presents with various neurological and psychiatric symptoms. The exact prevalence is unknown; however, population genomic data analysis suggests a prevalence of at least 4.5/10,000 to 3.3/1000, indicating that the disease is more common than previously thought and remains underdiagnosed. Case Presentation: We report the case of a middle-aged Japanese man who attempted suicide twice because of obsessive-compulsive ideation caused by trivial triggers. The patient's psychiatric symptoms resolved relatively quickly after hospitalization, and imaging and genetic testing led to a diagnosis of IBGC. Conclusion: This case report illustrates the importance of including IBGC in the differential diagnosis of psychiatric symptoms that initially develop in middle-aged patients.
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Síncope , Humanos , Síncope/etiologia , Síncope/diagnóstico , Masculino , Proteína de Replicação C/genética , Recidiva , Feminino , AdultoRESUMO
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.
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Objective: This study aimed to determine the maximum safe dose of intranasal insulin administration during cardiac surgery. Methods: This open-label, Phase 1, single-center, dose-escalation clinical trial recruited patients scheduled to undergo elective cardiac surgery or major vascular surgery requiring cardiopulmonary bypass between February and September 2021. They were grouped into 5 dose-escalation cohorts and administered 0, 40, 80, 160, and 240 IU insulin (n = 6 in each group) via a metered nasal dispenser after the induction of general anesthesia. Blood samples were collected at 10-minute intervals for the first 60 minutes and at 30-minute intervals thereafter. Hypoglycemia was defined as a blood glucose level <70 mg/dL. Patient recruitment was terminated after hypoglycemia was observed in 2 patients in any of the groups. Results: In total, 27 of 29 enrolled patients were administered intranasal insulin or saline. Hypoglycemia was not observed after the administration of intranasal insulin in the 0, 40, 80, or 160 IU groups; however, it was observed in 2 of 3 patients in the 240 IU group. The serum insulin concentration was elevated in the 160-IU group, but the C-peptide concentration was not elevated in any of the groups. Conclusions: The administration of up to 160 IU intranasal insulin did not induce clinically significant hypoglycemia. However, 160 IU intranasal insulin should be administered cautiously because insulin can enter the systemic circulation in a dose-dependent manner.
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Post-transplant lymphoproliferative disorders (PTLDs) are lymphoproliferative diseases that occur after solid organ transplantation or hematopoietic stem cell transplantation (HSCT). The development of PTLD is often associated with reactivation of Epstein-Barr virus (EBV). A 26-year-old woman with a history of HSCT and total-body irradiation developed spinal cord hemorrhage from a radiation-induced cavernous hemangioma (RICH) shortly after the development of classical Hodgkin lymphoma PTLD with EBV reactivation. Although little is known about the factors leading to hemorrhagic events from spinal cord RICH, we suspect that EBV reactivation may have been a factor contributing to the hemorrhage in the present case.
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OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a devastating, incurable neurodegenerative disease. A subset of ALS patients manifests with early-onset and complex clinical phenotypes. We aimed to elucidate the genetic basis of these cases to enhance our understanding of disease etiology and facilitate the development of targeted therapies. METHODS: Our research commenced with an in-depth genetic and biochemical investigation of two specific families, each with a member diagnosed with early-onset ALS (onset age of <40 years). This involved whole-exome sequencing, trio analysis, protein structure analysis, and sphingolipid measurements. Subsequently, we expanded our analysis to 62 probands with early-onset ALS and further included 440 patients with adult-onset ALS and 1163 healthy controls to assess the prevalence of identified genetic variants. RESULTS: We identified heterozygous variants in the serine palmitoyltransferase long chain base subunit 2 (SPTLC2) gene in patients with early-onset ALS. These variants, located in a region closely adjacent to ORMDL3, bear similarities to SPTLC1 variants previously implicated in early-onset ALS. Patients with ALS carrying these SPTLC2 variants displayed elevated plasma ceramide levels, indicative of increased serine palmitoyltransferase (SPT) activity leading to sphingolipid overproduction. INTERPRETATION: Our study revealed novel SPTLC2 variants in patients with early-onset ALS exhibiting frontotemporal dementia. The combination of genetic evidence and the observed elevation in plasma ceramide levels establishes a crucial link between dysregulated sphingolipid metabolism and ALS pathogenesis. These findings expand our understanding of ALS's genetic diversity and highlight the distinct roles of gene defects within SPT subunits in its development.
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Esclerose Lateral Amiotrófica , Demência Frontotemporal , Doenças Neurodegenerativas , Adulto , Humanos , Demência Frontotemporal/genética , Esclerose Lateral Amiotrófica/genética , Serina C-Palmitoiltransferase/genética , Esfingolipídeos , CeramidasRESUMO
Adrenomyeloneuropathy (AMN)/adrenoleukodystrophy (ALD) is an X-linked genetic disorder caused by pathogenic variants in ABCD1. We treated a 54-year-old man with slowly progressive spastic paraparesis with later development of the cerebral form. A pathogenic splice-site variant of ABCD1 (c.1489-1G>A, p.Val497Alafs*51) and elevated levels of very long-chain fatty acids were found, leading to the diagnosis of AMN. Detailed ABCD1 mRNA expression analyses revealed decreased levels of ABCD1 mRNA accompanied by deletion of the first 31 bp in exon 6. The altered mRNA transcriptional patterns associated with splice site variants are diverse and may provide important insights into ALD pathogenesis.
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Adrenoleucodistrofia , Masculino , Humanos , Pessoa de Meia-Idade , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/diagnóstico , Adrenoleucodistrofia/metabolismo , Linhagem , RNA Mensageiro/genética , Membro 1 da Subfamília D de Transportadores de Cassetes de Ligação de ATP/genéticaRESUMO
Neuronal ceroid lipofuscinosis type 2 (CLN2) is an autosomal recessive lysosomal disease caused by decreased activity of the enzyme tripeptidyl peptidase 1 (TPP1) due to pathogenic variants in the TPP1 gene. Cerliponase alfa, a recombinant proenzyme form of TPP1, has shown efficacy in preventing motor and language function decline in early-stage CLN2. However, the safety and effects of this therapy in advanced-stage CLN2 are unclear. We herein report a case of intraventricular cerliponase alfa treatment for over a year in a patient with advanced-stage CLN2. The results suggest the safety and potential efficacy of treatment at an advanced stage of CLN2.
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PURPOSE: Perioperative shivering is common and can occur as a result of hypothermia or changes in the threshold of thermoregulation. Droperidol usage for anesthesia is currently limited to its sedative and antiemetic effects. We investigated the effects of high and low doses of droperidol on the shivering threshold in rabbits. METHODS: Forty-two male Japanese white rabbits were anesthetized with isoflurane and randomly assigned to the control, high-dose, or low-dose group. Rabbits in the high-dose group received a 5 mg/kg droperidol bolus followed by continuous infusion at 5 mg/kg/h, those in the low-dose group received a 0.5 mg/kg droperidol bolus, and those in the control group received the same volume of saline as the high-dose group. Body temperature was reduced at a rate of 2-3 °C/h, and the shivering threshold was defined as the subject's core temperature (°C) at the onset of shivering. RESULTS: The shivering thresholds in the control, high-dose, and low-dose groups were 38.1 °C ± 1.1 °C, 36.7 °C ± 1.2 °C, and 36.9 °C ± 1.0 °C, respectively. The shivering thresholds were significantly lower in the high-dose and low-dose groups than in the control group (P < 0.01). The thresholds were comparable between the high-dose and low-dose groups. CONCLUSIONS: Droperidol in high and low doses effectively reduced the shivering threshold in rabbits. Droperidol has been used in low doses as an antiemetic. Low doses of droperidol can reduce the incidence of shivering perioperatively and during the induction of therapeutic hypothermia.
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Hipotermia , Isoflurano , Animais , Coelhos , Masculino , Estremecimento/fisiologia , Droperidol/farmacologia , Temperatura Corporal/fisiologia , Isoflurano/farmacologia , Hipotermia/tratamento farmacológicoRESUMO
To elucidate the molecular basis of multiple system atrophy (MSA), a neurodegenerative disease, we conducted a genome-wide association study (GWAS) in a Japanese MSA case/control series followed by replication studies in Japanese, Korean, Chinese, European and North American samples. In the GWAS stage rs2303744 on chromosome 19 showed a suggestive association ( P = 6.5 × 10 -7 ) that was replicated in additional Japanese samples ( P = 2.9 × 10 -6 . OR = 1.58; 95% confidence interval, 1.30 to 1.91), and then confirmed as highly significant in a meta-analysis of East Asian population data ( P = 5.0 × 10 -15 . Odds ratio= 1.49; 95% CI 1.35 to 1.72). The association of rs2303744 with MSA remained significant in combined European/North American samples ( P =0.023. Odds ratio=1.14; 95% CI 1.02 to 1.28) despite allele frequencies being quite different between these populations. rs2303744 leads to an amino acid substitution in PLA2G4C that encodes the cPLA2γ lysophospholipase/transacylase. The cPLA2γ-Ile143 isoform encoded by the MSA risk allele has significantly decreased transacylase activity compared with the alternate cPLA2γ-Val143 isoform that may perturb membrane phospholipids and α-synuclein biology.
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Protein misfolding is a major factor of neurodegenerative diseases. Post-mitotic neurons are highly susceptible to protein aggregates that are not diluted by mitosis. Therefore, post-mitotic cells may have a specific protein quality control system. Here, we show that LONRF2 is a bona fide protein quality control ubiquitin ligase induced in post-mitotic senescent cells. Under unperturbed conditions, LONRF2 is predominantly expressed in neurons. LONRF2 binds and ubiquitylates abnormally structured TDP-43 and hnRNP M1 and artificially misfolded proteins. Lonrf2-/- mice exhibit age-dependent TDP-43-mediated motor neuron (MN) degeneration and cerebellar ataxia. Mouse induced pluripotent stem cell-derived MNs lacking LONRF2 showed reduced survival, shortening of neurites and accumulation of pTDP-43 and G3BP1 after long-term culture. The shortening of neurites in MNs from patients with amyotrophic lateral sclerosis is rescued by ectopic expression of LONRF2. Our findings reveal that LONRF2 is a protein quality control ligase whose loss may contribute to MN degeneration and motor deficits.
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Neurônios Motores , Ubiquitina , Camundongos , Animais , Neurônios Motores/metabolismo , Ubiquitina/metabolismo , Ligases/metabolismo , DNA Helicases/metabolismo , Proteínas de Ligação a Poli-ADP-Ribose/metabolismo , RNA Helicases/metabolismo , Proteínas com Motivo de Reconhecimento de RNA/metabolismo , Proteínas de Ligação a DNA/genéticaRESUMO
OBJECTIVE: Lactoferrin is an iron-binding glycoprotein. Enteral lactoferrin attenuates myocardial ischemia-reperfusion (IR) injury, but the underlying mechanism remains unknown. The aim of this study was to investigate protein kinase A (PKA) signaling pathway activation and levels of serum glucagonlike peptide-1 (GLP-1), secreted by intestinal endocrine L cells, and adiponectin, secreted by adipose tissue, after enteral lactoferrin administration. METHODS: Hearts (N = 32) were excised from Wistar rats and perfused using a Langendorff system. To assess the role of the PKA pathway in the cardioprotective effects of lactoferrin, an inhibitor of PKA (H89) was applied before no-flow ischemia. Rats were randomly divided into four groups: control, lactoferrin (LF), control+H89, and LF+H89. The control and control+H89 groups were administered normal saline by gavage, and the LF and L +H89 groups were administered bovine lactoferrin (1000 mg/kg) by gavage 15 min before intraperitoneal pentobarbital injection. Muscle sampling was performed at the end of reperfusion. When rats were sacrificed, blood was sampled to measure hormone levels. The primary outcome was maximum left ventricular pressure derivative (LV dP/dt max) 15 min after reperfusion. RESULTS: LV dP/dt max at 10 and 15 min after reperfusion was significantly higher in the LF group than in the control group (P < 0.05), and the effect was diminished by H89. The PKA pathway was significantly activated in the LF group. Enteral lactoferrin increased serum GLP-1 but not serum adiponectin levels. CONCLUSIONS: Enteral lactoferrin induces cardioprotective effects against myocardial IR injury via the PKA signaling pathway and increases serum GLP-1 levels.
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Lactoferrina , Traumatismo por Reperfusão Miocárdica , Ratos , Animais , Ratos Wistar , Lactoferrina/farmacologia , Lactoferrina/uso terapêutico , Adiponectina , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Transdução de Sinais , Proteínas Quinases Dependentes de AMP Cíclico , Miocárdio/metabolismo , CoraçãoRESUMO
RATIONALE: Gorham-Stout disease (GSD) is a rare disease that causes massive osteolysis and proliferation of abnormal lymphangiomatous tissues. Patients with GSD often experience pain associated with bone fractures and chylothorax. However, bleeding caused by abnormal lymphangiomatous tissue or hematological dysfunction rarely occurs. PATIENT CONCERNS: A 22-year-old female patient with GSD presented with severe left hip and lower limb pain. The GSD had disappeared her right pelvic bone and femur, but no abnormalities were found in the bones at the site of the pain. DIAGNOSES: The patient presented with a chylothorax and cerebrospinal fluid leakage. She was treated with sirolimus and an epidural blood patch, and her symptoms resolved. Computed tomography and magnetic resonance imaging revealed an epidural hematoma extending from L3 to the caudal region, and blood results revealed a consumption coagulopathy. INTERVENTIONS: We presumed that the hematoma caused pain and prescribed pregabalin and morphine. The pain gradually subsided. OUTCOMES: An unexpected liver subcapsular hemorrhage occurred 4 months later, and the patient went into hemorrhagic shock. Transcatheter arterial embolization was promptly performed, and the patient recovered. LESSONS: GSD infrequently causes bleeding related to abnormal lymphangiomatous tissues and coagulopathy, yet it can lead to serious events if it occurs.
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Quilotórax , Hematoma Epidural Craniano , Hematoma Epidural Espinal , Osteólise Essencial , Humanos , Feminino , Adulto Jovem , Adulto , Quilotórax/etiologia , Osteólise Essencial/complicações , Dor/complicações , Hematoma Epidural Craniano/complicações , Fígado/patologia , Hemorragia/terapia , Hemorragia/complicações , Hematoma Epidural Espinal/complicações , Perna (Membro)RESUMO
OBJECTIVE: Adrenoleukodystrophy (ALD) has a poor prognosis when it progresses to the cerebral form (CALD). The aim of this study is to investigate whether cerebrospinal fluid (CSF) neurofilament light chain (cNfL) is a sensitive biomarker for detecting CALD and assessing response to hematopoietic stem cell transplantation (HSCT). METHODS: We conducted a cross-sectional study of 41 male ALD patients. The cNfL levels in patients with the cerebral form of ALD (CALD) or the cerebello-brainstem form of ALD were compared with those in patients with adrenomyeloneuropathy (AMN). The correlation between cNfL levels and MRI-based Loes severity scores was investigated. A longitudinal analysis was performed on patients who underwent multiple CSF examinations. RESULTS: The cNfL levels in 22 patients with CALD were significantly higher than those in 14 patients with AMN (median, 5545 vs. 1490 pg/mL; p < 0.001). The cutoff cNfL level of 1930 pg/mL showed good sensitivity (95.5%) and specificity (85.7%) for distinguishing CALD from AMN. The cNfL levels were positively correlated with Loes scores (p < 0.001). The cNfL levels in three AMN patients who later converted to CALD increased above the cutoff level during the conversion period, while the cNfL levels in four patients who remained in AMN were consistently below the cutoff. In 10 ALD patients who underwent HSCT, their cNfL levels decreased 3-24 months after HSCT. Two patients whose cNfL increased after HSCT showed deterioration in cognitive functions. INTERPRETATION: The cNfL level is useful for evaluating the disease activities of ALD and the response to HSCT.
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Adrenoleucodistrofia , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Adrenoleucodistrofia/diagnóstico , Estudos Transversais , Filamentos Intermediários , BiomarcadoresRESUMO
Background: Functionally impaired variants of COQ2, encoding an enzyme in biosynthesis of coenzyme Q10 (CoQ10), were found in familial multiple system atrophy (MSA) and V393A in COQ2 is associated with sporadic MSA. Furthermore, reduced levels of CoQ10 have been demonstrated in MSA patients. Methods: This study was a multicentre, randomised, double-blinded, placebo-controlled phase 2 trial. Patients with MSA were randomly assigned (1:1) to either ubiquinol (1500 mg/day) or placebo. The primary efficacy outcome was the change in the unified multiple system atrophy rating scale (UMSARS) part 2 at 48 weeks. Efficacy was assessed in all patients who completed at least one efficacy assessment (full analysis set). Safety analyses included patients who completed at least one dose of investigational drug. This trial is registered with UMIN-CTR (UMIN000031771), where the drug name of MSA-01 was used to designate ubiquinol. Findings: Between June 26, 2018, and May 27, 2019, 139 patients were enrolled and randomly assigned to the ubiquinol group (n = 69) or the placebo group (n = 70). A total of 131 patients were included in the full analysis set (63 in the ubiquinol group; 68 in the placebo group). This study met the primary efficacy outcome (least square mean difference in UMSARS part 2 score (-1.7 [95% CI, -3.2 to -0.2]; P = 0.023)). The ubiquinol group also showed better secondary efficacy outcomes (Barthel index, Scale for the Assessment and Rating of Ataxia, and time required to walk 10 m). Rates of adverse events potentially related to the investigational drug were comparable between ubiquinol (n = 15 [23.8%]) and placebo (n = 21 [30.9%]). Interpretation: High-dose ubiquinol was well-tolerated and led to a significantly smaller decline of UMSARS part 2 score compared with placebo. Funding: Japan Agency for Medical Research and Development.
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AIM: Hereditary neuropathy with liability to pressure palsies (HNPP) is a peripheral neuropathy with autosomal dominant inheritance. Diagnosis can be made from the characteristic abnormalities determined by nerve conduction studies (NCS), including subclinical deficits at physiological compression sites. Heterozygous deletion of the chromosome 17p11.2-p12 region including the peripheral myelin protein 22 gene (PMP22) is the cause in the majority of cases. However, the loss of function of PMP22 due to frameshift-causing insertion/deletion, missense, nonsense, or splice-site disrupting variants cause HNPP in some patients. We report a case of a patient diagnosed with HNPP on the basis of clinical features and the results of NCS. No deletions of PMP22 were detected by fluorescence in situ hybridization. METHODS: We performed direct nucleotide sequence analysis and identified a heterozygous variant, c.78 + 3G > T, in PMP22. Since this variant is located outside the canonical splice site at the exon 2-intron 2 junction, we investigated whether the variant causes aberrant splicing and leads to the skipping of exon 2 of PMP22 by in vitro minigene splicing assay. RESULTS: We demonstrated that the c.78 + 3G > T variant causes the skipping of exon 2 and leads to loss of function of the mutant allele. CONCLUSION: Searching for sequence variants located outside the canonical splice sites should also be considered even when deletion of PMP22 is not found in a patient with a clinical diagnosis suggesting HNPP.