The effect of 20-minute mindful breathing exercise on psychological well-being in epilepsy: A pilot randomized controlled trial.

INTRODUCTION: Depression and anxiety are prevalent in epilepsy patients, but psychiatric or psychological services may not be accessible to all patients. This study aimed to determine the effectiveness of the 20-minute mindful breathing on the psychological well-being of PWE using an instructional video. METHOD: This was a pilot, assessor-blinded, randomized controlled trial. The intervention group received a guided video and was briefed to perform the exercise twice a week for two weeks while the waitlist control group only received the video upon completion of the study. The subjects were assessed at three-time points (T0: Baseline, T1: 2 weeks after the intervention, T2: 4 weeks after intervention), using the Neurological Disorders Depression Index (NDDI-E), General Anxiety Disorder (GAD-7), Quality of Life in Epilepsy Inventory (QOLIE-31) and Mindfulness Attention Awareness Scale (MAAS). RESULTS: Twenty patients were recruited, with 10 in the intervention and waitlist-control groups. Compared with the waitlist-control group, participants in the intervention group showed significant improvement in NDDI-E at T1 (p = 0.022) but not at T2 (p = 0.056) and greater improvement in GAD-7 at T1 and T2 but not statistically significant. The QOLIE-31 overall score in the intervention group has significantly improved at T1 (p = 0.036) and T2 (p = 0.031) compared to the waitlist-control group. For MAAS, the intervention group also had an increased score at T2 (p = 0.025). CONCLUSION: The 20-minute mindfulness breathing exercise has an immediate effect in improving depression and quality of life among people with epilepsy.

Feasibility of psychological screening in a tertiary epilepsy clinic.

OBJECTIVE: People with epilepsy (PWE) have a high prevalence of developing depression and anxiety. The objective is to determine the feasibility of brief screening tools to screen for depression and anxiety in epilepsy, and the predictive factors. METHOD: This is a cross-sectional study in the neurology clinic in a tertiary teaching hospital in Kuala Lumpur. The screening tools used were the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) and the General Anxiety Disorder Form (GAD-7). RESULTS: Five hundred and eighty-five patients were recruited in this study, and 50.8% of them were male, predominantly Chinese (46.7%), with a mean age of seizure onset of 21.8 ± 16.1 years. The majority had focal seizures (75.0%), and 41.9% had seizure remission. There were 15.5% who scored ≥15 in the NDDI-E, and 17.0% had moderate or severe anxiety (scored ≥10 in the GAD-7). In a regression model to predict the NDDI-E score, the age of seizure onset recorded a higher beta value (ß = -0.265, p =< 0.001), followed by the duration of epilepsy (ß = -0.213, p =< 0.001), use of levetiracetam (LEV) (ß = 0.147, p = 0.002), clonazepam (CLZ) (ß = 0.127, p = 0.011), and lamotrigine (LTG) (ß = 0.125, p = 0.011), number of current antiseizure medications (ß = -0.124, p = 0.049), seizure remission for ≥1 year (ß = -0.108, p = 0.011), and female (ß = 0.082, p = 0.049). For the GAD-7 score, the predictors included current age (ß = -0.152, p = 0.001), the use of LEV (ß = 0.122, p = 0.011), Indian ethnicity (ß = 0.114, p = 0.006), and the use of carbamazepine (ß = -0.090, p = 0.043). CONCLUSION: Implementation of simple psychological screening using self-administered questionnaires was feasible in a busy tertiary epilepsy clinic.

Caregiver burden for adults with epilepsy in Malaysian families: A qualitative study.

BACKGROUND: Caregivers of adults with epilepsy (AWE) play an important role in the healthcare pathway of AWE and are described as the "co-client." Being caregivers can be stressful and the negative impacts might accumulate over time, affecting their quality of life and well-being. OBJECTIVES: This qualitative study aimed to explore the lived experience of caregivers of AWE in Malaysian families and understand their caregiving challenges. Individual semi-structured interviews were held with 12 primary caregivers of AWE. Interpretative Phenomenological Approach (IPA) was used. The interview transcripts were analyzed using NVivo12 software. RESULTS: Primary caregivers of AWE were parents or siblings, with ages ranging from 56 to 80 years old and years of caregiving from 24 to 40 years. Most AWE (58%) were intellectually disabled and fully dependent on ADL needs. Two categories of themes emerged, including four themes on caregiver burden, i.e., physical, emotional, and social burdens, and challenges in future planning of care, and two themes on coping strategies (problem- or emotional-focused). In future planning of care, most caregivers especially parents carried a burden of responsibility and were reluctant to depend on others or institutional services. CONCLUSION: The caregiving burden among caregivers for adult AWE was not confined to current burdens only but also challenges in future planning. A better understanding of the caregiving burden for AWE and coping strategies is needed to provide tailored psychoeducation or psychosocial intervention to support this population.

Case report: A Chinese patient with spinocerebellar ataxia finally confirmed as Gerstmann-Sträussler-Scheinker syndrome with P102L mutation.

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a rare genetic prion disease caused by a mutation in the prion protein (PRNP) gene. It is typically characterized by progressive cerebellar ataxia and slowly progressive dementia. We present a case study of the GSS from China in which a 45-year-old male with a progressive gait and balance disorder developed cerebellar ataxia onset but was misdiagnosed as spinocerebellar ataxia (SCA) for 2 years. The patient's clinical, electrophysiological, and radiological data were retrospectively analyzed. Examination revealed ataxia, dysarthria, muscle weakness, areflexia in lower limbs, including a pyramidal sign, whereas cognitive decline was insignificant. His late mother had a similar unsteady gait. An electroencephalogram (EEG) showed normal findings, and 14-3-3 protein was negative. A brain MRI was performed for global brain atrophy and ventricular enlargement. Positron emission tomography-computed tomography (PET-CT) (18F-fluoro-2-deoxy-d-glucose, FDG) images showed mild to moderate decreased glucose metabolism in the left superior parietal lobe and left middle temporal lobe. According to genetic testing, his younger brother also had the P102L variant in the PRNP gene. This single case adds to the clinical and genetic phenotypes of GSS.

High-risk screening of late-onset Pompe disease: A different early portrait in China.

Introduction: The lack of knowledge regarding the differences between Chinese and other ethnicities in the early manifestation of late-onset Pompe disease (LOPD) prohibits the development of an effective screening strategy. We conducted a multicenter screening study to determine LOPD prevalence in high-risk populations and define the early manifestation of LOPD in China. Methods: Between August 2020 and April 2021, the participants were prospectively identified through medical examination at 20 centers from inpatient departments and outpatient neuromuscular clinics in China. The inclusion criteria were as follows: (1) age ≥ 1 year and (2) either one of the following conditions: (a) persistent hyperCKemia, (b) muscle weakness of the axial and/or limb-girdle muscles, or (c) unexplained restrictive respiratory insufficiency (RI). Enzymatic activity of acid α-glucosidase (GAA) was measured in a dried blood spot (DBS) using a tandem mass spectrometry (MS/MS) assay. Next-generation sequencing (NGS) was used to evaluate all samples with decreased GAA activity, searching for GAA mutations and pseudodeficiency alleles. Results: Among the 492 cases, 26 positive samples (5.3%) were detected in the DBS test. Molecular studies confirmed a diagnosis of LOPD in eight cases (1.6%). Using MS/MS assay, GAA activities in individuals with pseudodeficiency could be distinguished from those in patients with LOPD. The median interval from the onset of symptoms to diagnosis was 5 years. All patients also showed RI, with a mean forced vital capacity (FVC) of 48%, in addition to axial/proximal muscle weakness. The creatine kinase (CK) level ranged from normal to no more than 5-fold the upper normal limit (UNL). LOPD with isolated hyperCKemia was not identified. Conclusion: Less frequent hyperCKemia and predominant RI depict a different early portrait of adult Chinese patients with LOPD. A modified high-risk screening strategy should be proposed for the early diagnosis of Chinese patients with LOPD.

Liposomal PHD2 Inhibitors and the Enhanced Efficacy in Stabilizing HIF-1α.

Prolyl hydroxylase domain-containing protein 2 (PHD2) inhibition, which stabilizes hypoxia-inducible factor (HIF)-1α and thus triggers adaptation responses to hypoxia in cells, has become an important therapeutic target. Despite the proven high potency, small-molecule PHD2 inhibitors such as IOX2 may require a nanoformulation for favorable biodistribution to reduce off-target toxicity. A liposome formulation for improving the pharmacokinetics of an encapsulated drug while allowing a targeted delivery is a viable option. This study aimed to develop an efficient loading method that can encapsulate IOX2 and other PHD2 inhibitors with similar pharmacophore features in nanosized liposomes. Driven by a transmembrane calcium acetate gradient, a nearly 100% remote loading efficiency of IOX2 into liposomes was achieved with an optimized extraliposomal solution. The electron microscopy imaging revealed that IOX2 formed nanoprecipitates inside the liposome's interior compartments after loading. For drug efficacy, liposomal IOX2 outperformed the free drug in inducing the HIF-1α levels in cell experiments, especially when using a targeting ligand. This method also enabled two clinically used inhibitors-vadadustat and roxadustat-to be loaded into liposomes with a high encapsulation efficiency, indicating its generality to load other heterocyclic glycinamide PHD2 inhibitors. We believe that the liposome formulation of PHD2 inhibitors, particularly in conjunction with active targeting, would have therapeutic potential for treating more specifically localized disease lesions.

Key Characteristics of Nitrous Oxide-Induced Neurological Disorders and Differences Between Populations.

Background: Nitrous oxide (N2O), commonly known as laughing gas, is inhaled recreationally because it produces the feelings of euphoria and freedom from pain. The risk of neurological dysfunction secondary to N2O abuse and its clinical diagnosis are, however, not yet sufficiently recognized, especially in China. Here, we have summarized the key clinical characteristics of N2O-induced neurological disorders. Materials and Methods: We recruited 20 patients with N2O-induced neurological disorders and analyzed their clinical features, laboratory data, magnetic resonance imaging and electromyography. We also carried out a literature review and compared 99 previously reported patients with our case series to confirm our results. Subgroup analysis was performed to explore the difference in demographical and clinical characteristics of N2O abuse between Asian and non-Asian patients. Results: The most common initial symptoms of N2O-induced neurological disorders were weakness and/or paresthesia. Most patients presented with myelopathy and/or peripheral neuropathy. The most commonly involved segment of the spinal cord was the cervical spinal cord, extending over 4-6 vertebral levels, but more than half of the patients with myelopathy had no sensory change at the corresponding spinal level. Homocysteine was found to be the most sensitive and practical indicator for diagnosis. Subgroup analysis showed that the Asian patients (median: 22.0 years old, Q1-Q3:19.0-26.0 years old) with N2O abuse were younger than non-Asian patients [26.0 (22.3-31.0) years old, P = 2.8 × 10-4]. The incidence of myelopathy combined with peripheral neuropathy was significantly higher in Asian patients than in non-Asian patients, who had myelopathy or peripheral neuropathy (P = 2 × 10-5). Conclusions: Key clinical characteristics of N2O abuse are longitudinally extensive cervical myelopathy and peripheral neuropathy. Recognition of these traits in young people in the age group of 20-30 years will provide important guidance for accurate diagnosis of neurological disease associated with N2O abuse. The clinical manifestations differ in Asian patients and non-Asian patients.

Immune cell shuttle for precise delivery of nanotherapeutics for heart disease and cancer.

The delivery of therapeutics through the circulatory system is one of the least arduous and less invasive interventions; however, this approach is hampered by low vascular density or permeability. In this study, by exploiting the ability of monocytes to actively penetrate into diseased sites, we designed aptamer-based lipid nanovectors that actively bind onto the surface of monocytes and are released upon reaching the diseased sites. Our method was thoroughly assessed through treating two of the top causes of death in the world, cardiac ischemia-reperfusion injury and pancreatic ductal adenocarcinoma with or without liver metastasis, and showed a significant increase in survival and healing with no toxicity to the liver and kidneys in either case, indicating the success and ubiquity of our platform. We believe that this system provides a new therapeutic method, which can potentially be adapted to treat a myriad of diseases that involve monocyte recruitment in their pathophysiology.

Polyglucosan body myopathy 1 may cause cognitive impairment: a case report from China.

BACKGROUND: Polyglucosan body myopathy 1 (PGBM1) is a type of glycogen storage disease that can cause skeletal muscle myopathy and cardiomyopathy with or without immunodeficiency due to a pathogenic mutation in the RBCK1 gene. PGBM1 has been reported in only 14 European and American families, and no cognitive impairment phenotype was reported. Its prevalence in Asia is unknown. CASE PRESENTATION: We report a Chinese boy with teenage onset of skeletal muscle myopathy and mild cognitive impairment. Whole-exome sequencing analysis identified a homozygous missense mutation in RBCK1 (c.1411G > A:p.Glu471Lys). A muscle biopsy indicated the accumulation of periodic acid-Schiff-positive material, which could be ubiquitinated by immunohistochemistry with an anti-ubiquitin antibody. In skeletal muscle tissue, HOIL-1 and HOIP protein levels were lower than those in the control, confirming the phenotype of an RBCK1 mutation. MRI revealed abnormal cerebral white matter signals. Immune system and cardiac examination found no abnormalities. The patient was diagnosed with PGBM1 with no effective treatment. CONCLUSIONS: This case from China with a novel homozygous missense mutation in RBCK1 extends the phenotypic spectrum and geographical distribution of PGBM 1, which may cause cerebral white matter changes and cognitive impairment.

Identification of TYW3/CRYZ and FGD4 as susceptibility genes for amyotrophic lateral sclerosis.

OBJECTIVE: A 2-stage genome-wide association was conducted to explore the genetic etiology of amyotrophic lateral sclerosis (ALS) in the Chinese Han population. METHODS: Totally, 700 cases and 4,027 controls were genotyped in the discovery stage using Illumina Human660W-Quad BeadChips. Top associated single nucleotide polymorphisms from the discovery stage were then genotyped in an independent cohort with 884 cases and 5,329 controls. Combined analysis was conducted by combining all samples from the 2 stages. RESULTS: Two novel loci, 1p31 and 12p11, showed strong associations with ALS. These novel loci explained 2.2% of overall variance in disease risk. Expression quantitative trait loci searches identified TYW/CRYZ and FGD4 as risk genes at 1p13 and 12p11, respectively. CONCLUSIONS: This study identifies novel susceptibility genes for ALS. Identification of TYW3/CRYZ in the current study supports the notion that insulin resistance may be involved in ALS pathogenesis, whereas FGD4 suggests an association with Charcot-Marie-Tooth disease.

The study of Wilson disease in pregnancy management.

INTRODUCTION: Pregnancy management in women with Wilson disease (WD) remains an important clinical problem. This research was conducted to investigate how to avoid worsening of WD symptoms during pregnancy and increase pregnancy success in women with WD by identifying the best pregnancy management approaches in these patients. PATIENTS AND METHODS: The clinical data of 117 pregnancies among 75 women with WD were retrospectively analyzed. Related information of the fetus was also recorded and analyzed. At the same time, regression analysis was performed for data of 22 pregnant women without WD, as normal controls. RESULTS: Of a total of 117 pregnancies among the 75 women with WD and 31 pregnancies among the 22 control womenincluded in this study, there were 108 successful pregnancies and 9 spontaneous abortions. Among the 108 successful pregnancies, 97 women a history of copper chelation therapy before pregnancy; all 97 women stopped anti-copper therapy during pregnancy. The nine women with spontaneous abortion had no pre-pregnancy history of copper displacement therapy. The incidence of lower limb edema was higher in the WD group than in normal controls (P = 0.036). Compared with the control group, there was a higher proportion in the WD group of male infants (P = 0.022) and lower average infant birth weight (t = 3.514, P = 0.001). CONCLUSION: It is relatively safe for women with WD patients to become pregnant. The best management method for pregnancy in women with WD may be intensive pre-pregnancy copper chelation therapy and no anti-copper treatment during pregnancy.

Long-term outcomes of a patient with late-onset multiple acyl-CoA dehydrogenase deficiency caused by novel mutations in ETFDH: A case report.

RATIONALE: Late-onset multiple acyl-coenzyme A dehydrogenase deficiency (MADD) mainly affects the neck extensor muscle group, which has been confirmed by novel mutations in electron-transferring-flavoprotein dehydrogenase (ETFDH). So far, a few cases have been reported with long-term follow-up. Here we report a case of late-onset MADD where the patient was followed up for 8 years during which time he underwent 2 muscle biopsies and 2 pathological examinations and his symptoms were significantly alleviated after appropriate treatments. PATIENT CONCERNS: In September 2009, a 16-year-old male patient was hospitalized due to gradually increasing difficulty in raising his head and weakness in limb muscles over a 6-month period. During the physical examination, the patient's neck extensor muscle strength was grade III-IV. His proximal limb muscle strength was grade IV, and his distal muscle strength was normal. His blood creatine kinase (CK) was 783 U/L. DIAGNOSIS: Muscle biopsy revealed a large number of vacuolar fibers, which were mainly type I fibers. These findings were consistent with the diagnosis of lipid storage myopathy (LSM). ETFDH gene test detected C.736G > A at exon 7 and C.920C > G at exon 8. INTERVENTIONS: Coenzyme Q10 treatment was administered. The first coenzyme Q10 40 mg tid was treated for three months, with the change of coenzyme Q10 20 mg tid for 6 months, followed by the change of coenzyme Q10 10 mg tid for long-term use. OUTCOMES: The patient's condition significantly improved after 3 months. At 7th year follow-up the patient's blood CK was normal, and a second muscle biopsy revealed no muscle vacuolar fibers and no increase in lipid droplets. Subsequently, the patient was withdrawn from the coenzyme Q10 treatment, and the condition of the patient remained normal. LESSONS: Muscle biopsy was the main method used to determine LSM. Treatment with riboflavin should be started when the diagnosis of LSM is definitive. Furthermore, ETFDH gene tests should be performed for further classification. Moreover, coenzyme Q10 may be another effective drug for MADD.

Sex Differences in Clinical Characteristics and Brain MRI Change in Patients With Wilson's Disease in a Chinese Population.

Background: Wilson's disease (WD) is an inborn copper metabolism disease. Sex differences in clinical features of WD patients have been reported; however, the effect of sex on brain MRI is still unclear, especially for Chinese WD patients. Therefore, we aimed to examine sex differences in clinical correlates and brain MRI changes in WD patients in a Chinese Han population. Methods: 535 WD patients were enrolled and underwent MRI scanning. These patients were subdivided by the clinical symptoms, Kayser-Fleischer (K-F) rings, laboratory tests and sex. The mean age of onset and diagnosis, disease latency, localization of brain MRI lesions, and the level of copper metabolism were compared between male and female patients. Results: The neuropsychiatric form (452 and 84.5%) was the most common subtype. Compared to female patients, male patients had a higher percentage in three clinical forms: neuropsychiatric form (263 and 58.2%), hepatic form (41 and 59.4%), and presymptomatic form (10 and 71.4%). In the neuropsychiatric form, male patients had the earlier age of onset and definitive diagnosis, and shorter time of disease latency than female patients. Putamen was the most common site for lesions in brain MRI of three groups. In the hepatic form, more male patients showed the ventricular widening than female patients (14/41 vs. 3/28; p < 0.05). The level of serum ceruloplasmin and copper of WD patients with neuropsychiatric form was higher than that of male patients with hepatic or presymptomatic form. In women, however, patients of presymptomatic form have the highest level of the ceruloplasmin, and the level of serum copper in hepatic patients was highest. Conclusion: Our findings suggest sex differences in the percentage of three clinical forms. Meanwhile, the mean age of onset and diagnosis of female was higher than male, also happened in the disease latency. Only in the hepatic form, there was a sex difference in the ventricular widening.

[Analysis of a cerebrotendinous xanthomatosis case with mental retardation as the initial symptom].

OBJECTIVE: To analyze a case of cerebrotendinous xanthomatosis (CTX) with mental retardation as the initial neurological symptom. METHODS: Medical imaging, histopathological assay and genetic testing were carried out to analyze the patient. RESULTS: Neurological manifestations of the 27-year-old male patient were initiated by mental retardation and subsequently memory lapses, ataxia, spastic paraplegia and fuzzy language. Other symptoms included cataract, xanthomatosis in Achilles tendon, kidney stones and high arches. The total bile acid in serum has risen to 14.7 umol/L. There were symmetrical abnormal signals in bilateral cerebellar dentate nuclei, hypointensities on T1WI and DWI and mixed signals on T2WI. Cholesterol crystallization and cholesterol granulomatous inflammation were found upon pathological examination of the Achilles tendon. The patient was found to have carried a compound heterozygous mutation of the CTX gene, which consisted of two novel mutations including c.379C>T (p.Arg127Trp) in exon 2 and c.1174G>A (p.Glu392Lys) in exon 6 of the CYP27A1 gene. CONCLUSION: Clinicians should be alert to cerebrotendinous xanthomatosis when the patient has mental retardation caused by genetic and metabolic factors beginning at a young age, particularly accompanied with tendinous xanthomatosis and cataracts. CTX can be readily diagnosed by histopathological assay and sequencing of the CYP27A1 gene.

Susceptibility-Weighted Imaging Manifestations in the Brain of Wilson's Disease Patients.

PURPOSE: It is well known that patients with Wilson's disease (WD) suffer copper metabolism disorder. However, recent studies point to an additional iron metabolism disorder in WD patients. The purpose of our study was to examine susceptibility-weighted imaging (SWI) manifestations of WD in the brains of WD patients. METHODS: A total of 33 patients with WD and 18 normal controls underwent conventional MRI (Magnetic resonance imaging) and SWI. The phase values were measured on SWI-filtered phase images of the bilateral head of the caudate nuclei, globus pallidus, putamen, thalamus, substantia nigra, and red nucleus. Student's t-tests were used to compare the phase values between WD groups and normal controls. RESULTS: The mean phase values for the bilateral head of the caudate nuclei, globus pallidus, putamen, thalamus, substantia nigra, and red nucleus were significantly lower than those in the control group (P < 0.001), and bilateral putamen was most strongly affected. CONCLUSIONS: There is paramagnetic mineralization deposition in brain gray nuclei of WD patients and SWI is an effective method to evaluate these structures.

[Clinical and genetic study of Wilson's disease in affected twins and siblings].

OBJECTIVE: To study the clinical and genetic characteristics of twins and siblings affected with Wilson's disease (WD). METHODS: Clinical data and blood samples were collected from the subjects after informed consent was obtained. Genomic DNA was extracted and potential mutations in the exons in ATP7B gene were detected with PCR-DNA sequencing. Short tandem repeat (STR) genotyping was performed to determine the zygosity of the twins. RESULTS: The 5 pairs of twins have all met the diagnostic criteria for WD. STR genotyping has confirmed that 4 pairs were monozygotic twins. 3 pairs of twins had an onset with liver symptoms, the other 2 had an onset with brain symptoms. ATP7B gene mutations were detected in 4 pairs of twins, which have all located in exons 8 and 13. A heterozygous p.R778W mutation in exon 8 and homozygous p.P992L mutation in exon 13 were detected in all patients from one family, whose parents have carried a heterozygous p.R778W mutation and p.P992L heterozygous mutation, respectively, which suggested loss of heterozygosity (LOH). In one family, no mutation was detected in all exons of the ATP7B gene in the patients and their parents. For a triplet, one female was with definite WD and brain symptoms at the onset, one male had subclinical type with WD, whilst another female was completely normal. The triplets and their mother have all carried a p.P992L heterozygous mutation . CONCLUSION: Above results have confirmed an important role for genetic factors in the pathogenesis of WD. In addition to point mutations, LOH is also involved in the pathogenesis for WD.

[Wilson's disease in decision-making functions of Iowa gambling task].

OBJECTIVE: To explore the presence of impaired decision-making functions of Wilson's disease patients in Iowa gambling task (IGT) and its association with basal ganglia damage. METHODS: Thirty-two IGT patients with WD (WD group) and 29 healthy people (control group) were recruited from the same period. And two options of high and low rewards were selected. Before the start of experiment, a basal figure of 2000 yuan was shown on computer display and they were prompted to win more money as much as possible. The general trend was observed with or without social learning effects. RESULTS: With the increased number of cards selected, the number of favorable and unfavorable selections shifted from negative to positive and gradually rose in the control group. However, such a pattern was absent in the WD group. The WD patients in the IGT group in Trial4 and Trial5 were significantly lower than the controls (P = 0.009 and P = 0.020). CONCLUSION: The WD IGT patients have significant impairments of policy-making functions due to the damage of basal ganglia. And the effects of copper metabolism on cerebral cortex should be further studied in WD patients.