Single-cell analyses reveal evolution mimicry during the specification of breast cancer subtype.

Background: The stem or progenitor antecedents confer developmental plasticity and unique cell identities to cancer cells via genetic and epigenetic programs. A comprehensive characterization and mapping of the cell-of-origin of breast cancer using novel technologies to unveil novel subtype-specific therapeutic targets is still absent. Methods: We integrated 195,144 high-quality cells from normal breast tissues and 406,501 high-quality cells from primary breast cancer samples to create a large-scale single-cell atlas of human normal and cancerous breasts. Potential heterogeneous origin of malignant cells was explored by contrasting cancer cells against reference normal epithelial cells. Multi-omics analyses and both in vitro and in vivo experiments were performed to screen and validate potential subtype-specific treatment targets. Novel biomarkers of identified immune and stromal cell subpopulations were validated by immunohistochemistry in our cohort. Results: Tumor stratification based on cancer cell-of-origin patterns correlated with clinical outcomes, genomic aberrations and diverse microenvironment constitutions. We found that the luminal progenitor (LP) subtype was robustly associated with poor prognosis, genomic instability and dysfunctional immune microenvironment. However, the LP subtype patients were sensitive to neoadjuvant chemotherapy (NAC), PARP inhibitors (PARPi) and immunotherapy. The LP subtype-specific target PLK1 was investigated by both in vitro and in vivo experiments. Besides, large-scale single-cell profiling of breast cancer inspired us to identify a range of clinically relevant immune and stromal cell subpopulations, including subsets of innate lymphoid cells (ILCs), macrophages and endothelial cells. Conclusion: The present single-cell study revealed the cellular repertoire and cell-of-origin patterns of breast cancer. Combining single-cell and bulk transcriptome data, we elucidated the evolution mimicry from normal to malignant subtypes and expounded the LP subtype with vital clinical implications. Novel immune and stromal cell subpopulations of breast cancer identified in our study could be potential therapeutic targets. Taken together, Our findings lay the foundation for the precise prognostic and therapeutic stratification of breast cancer.

Comprehensive single-cell and bulk RNA-seq analyses reveal a novel CD8+ T cell-associated prognostic signature in ovarian cancer.

CD8+ T cells play pivotal roles in combating intracellular pathogens and eliminating malignant cells in cancer. However, the prognostic role of CD8+ T cells in ovarian carcinoma is insufficiently exploited. Herein, through univariate Cox regression along with least absolute shrinkage and selection operator (LASSO) regression analyses, we developed a novel prognostic model based on CD8+ T cell markers identified by single-cell sequencing (scRNA-seq) analyses. Patient grouping by the median risk score reveals an excellent prognostic efficacy of this model in both training and validation cohorts. Of note, patients classified as low-risk group exhibit a dramatically improved prognosis. In addition, higher enrichment level of immune-related pathways and increased infiltration level of multiple immune cells are found in patients with lower risk score. Importantly, low-risk patients also exhibited higher response rate to immunotherapies. Summarily, this developed CD8+ T cell-associated prognostic model serves as an excellent predictor for clinical outcomes and aids in guiding therapeutic strategy choices for ovarian cancer patients.

Cancer-associated fibroblast-derived gene signature discriminates distinct prognoses by integrated single-cell and bulk RNA-seq analyses in breast cancer.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are one of the most predominant cellular subpopulations in the tumor stroma and play an integral role in cancer occurrence and progression. However, the prognostic role of CAFs in breast cancer remains poorly understood. METHODS: We identified a number of CAF-related biomarkers in breast cancer by combining single-cell and bulk RNA-seq analyses. Based on univariate Cox regression as well as Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis, a novel CAF-associated prognostic model was developed. Breast cancer patients were grouped according to the median risk score and further analyzed for outcome, clinical characteristic, pathway activity, genomic feature, immune landscape, and drug sensitivity. RESULTS: A total of 341 CAF-related biomarkers were identified from single-cell and bulk RNA-seq analyses. We eventually screened eight candidate prognostic genes, including CERCAM, EMP1, SDC1, PRKG1, XG, TNN, WLS, and PDLIM4, and constructed the novel CAF-related prognostic model. Grouped by the median risk score, high-risk patients showed a significantly worse prognosis and exhibited distinct pathway activities such as uncontrolled cell cycle progression, angiogenesis, and activation of glycolysis. In addition, the combined risk score and tumor mutation burden significantly improved the ability to predict patient prognosis. Importantly, patients in the high-risk group had a higher infiltration of M2 macrophages and a lower infiltration of CD8+ T cells and activated NK cells. Finally, we calculated the IC50 for a range of anticancer drugs and personalized the treatment regimen for each patient. CONCLUSION: Integrating single-cell and bulk RNA-seq analyses, we identified a list of compositive CAF-associated biomarkers and developed a novel CAF-related prognostic model for breast cancer. This robust CAF-derived gene signature acts as an excellent predictor of patient outcomes and treatment responses in breast cancer.

Integrative multi-omics analyses unravel the immunological implication and prognostic significance of CXCL12 in breast cancer.

Background: CXCL12 is a vital factor in physiological and pathological processes, by inducing migration of multiple cells. We aimed to comprehensively detect the role of CXCL12 in breast cancer, and explore novel CXCL12-related biomarkers through integrative multi-omics analyses to build a powerful prognostic model for breast cancer patients. Methods: Immunohistochemistry analysis of the tissue microarray was performed to evaluate the correlation between CXCL12 expression levels and breast cancer patient outcomes. Combined single-nucleus and spatial transcriptomics data was used to uncover the expression distribution of CXCL12 in breast cancer microenvironment. CXCL12-related genes were identified by WGCNA analysis. Univariate Cox and LASSO regression analyses were then conducted to screen prognostic genes from above CXCL12-related genes, followed by the construction of the CXCL12-related prognostic signature, identification of risk groups, and external validation of the prognostic signature. Analyses of biological function, mutation landscape, immune checkpoint genes and immune cells, were performed to further reveal the differences between high/low-risk groups. Paired single-cell RNA-seq and bulk RNA-seq were analyzed to further disclose the association between the risk score and the complex tumor immune microenvironment. To screen potential therapeutic agents for breast cancer patients, analyses of gene-drug correlation and sensitivity to immunotherapy were conducted. Results: High expression of CXCL12 was linked with a prolonged survival in breast cancer. A total of 402 genes were identified by WGCNA analysis and 11 genes, covering VAT1L, TMEM92, SDC1, RORB, PCSK9, NRN1, NACAD, JPH3, GJA1, BMP8B and ADAMTS2, were screened as the candidate prognostic genes. Next, the prognostic signature was built and validated using these genes to predict the outcomes of breast cancers. The high-risk group patients exhibited significantly inferior prognoses. The combination of the risk score and tumor mutational burden (TMB) had remarkably improved performance in predicting patient outcomes. Besides, high-risk group patients showed higher infiltration of M2-like macrophages. Finally, several potential anticancer drugs were identified. The high-risk group patients were more sensitive to immunotherapy but resistant to docetaxel. Conclusions: CXCL12 has important immunological implication and prognostic significance in breast cancer. The CXCL12-related prognostic model could well predict the prognosis and treatment response of breast cancers.

Single-cell analysis of white adipose tissue reveals the tumor-promoting adipocyte subtypes.

BACKGROUND: The tumor-adipose microenvironment (TAME) is characterized by the enrichment of adipocytes, and is considered a special ecosystem that supports cancer progression. However, the heterogeneity and diversity of adipocytes in TAME remains poorly understood. METHODS: We conducted a single-cell RNA sequencing analysis of adipocytes in mouse and human white adipose tissue (WAT). We analyzed several adipocyte subtypes to evaluate their relationship and potential as prognostic factors for overall survival (OS). The potential drugs are screened by using bioinformatics methods. The tumor-promoting effects of a typical adipocyte subtype in breast cancer are validated by performing in vitro functional assays and immunohistochemistry (IHC) in clinical samples. RESULTS: We profiled a comprehensive single-cell atlas of adipocyte in mouse and human WAT and described their characteristics, origins, development, functions and interactions with immune cells. Several cancer-associated adipocyte subtypes, namely DPP4+ adipocytes in visceral adipose and ADIPOQ+ adipocytes in subcutaneous adipose, are identified. We found that high levels of these subtypes are associated with unfavorable outcomes in four typical adipose-associated cancers. Some potential drugs including Trametinib, Selumetinib and Ulixertinib are discovered. Emphatically, knockdown of adiponectin receptor 1 (AdipoR1) and AdipoR2 impaired the proliferation and invasion of breast cancer cells. Patients with AdipoR2-high breast cancer display significantly shorter relapse-free survival (RFS) than those with AdipoR2-low breast cancer. CONCLUSION: Our results provide a novel understanding of TAME at the single-cell level. Based on our findings, several adipocyte subtypes have negative impact on prognosis. These cancer-associated adipocytes may serve as key prognostic predictor and potential targets for treatment in the future.

Identification of a centrosome-related prognostic signature for breast cancer.

Background: As the major microtubule organizing center in animal cells, the centrosome is implicated with human breast tumor in multiple ways, such as promotion of tumor cell immune evasion. Here, we aimed to detect the expression of centrosome-related genes (CRGs) in normal and malignant breast tissues, and construct a novel centrosome-related prognostic model to discover new biomarkers and screen drugs for breast cancer. Methods: We collected CRGs from the public databases and literature. The differentially expressed CRGs between normal and malignant breast tissues were identified by the DESeq2. Univariate Cox and LASSO regression analyses were conducted to screen candidate prognostic CRGs and develop a centrosome-related signature (CRS) to score breast cancer patients. We further manipulated and visualized data from TCGA, GEO, IMvigor210, TCIA and TIMER to explore the correlation between CRS and patient outcomes, clinical manifestations, mutational landscapes, tumor immune microenvironments, and responses to diverse therapies. Single cell analyses were performed to investigate the difference of immune cell landscape between high- and low-risk group patients. In addition, we constructed a nomogram to guide clinicians in precise treatment. Results: A total of 726 CRGs were collected from the public databases and literature. PSME2, MAPK10, EIF4EBP1 were screened as the prognostic genes in breast cancer. Next, we constructed a centrosome-related prognostic signature and validated its efficacy based on the genes for predicting the survival of breast cancer patients. The high-risk group patients had poor prognoses, the area under the ROC curve for 1-, 3-, and 5-year overall survival (OS) was 0.77, 0.67, and 0.65, respectively. The predictive capacity of CRS was validated by other datasets from GEO dataset. In addition, high-risk group patients exhibited elevated level of mutational landscapes and decreased level of immune infiltration, especially T and B lymphocytes. In terms of treatment responses, patients in the high-risk group were found to be resistant to immunotherapy but sensitive to chemotherapy. Moreover, we screened a series of candidate anticancer drugs with high sensitivity in the high-risk group. Conclusion: Our work exploited a centrosome-related prognostic signature and developed a predictive nomogram capable of accurately predicting breast cancer OS. The above discoveries provide deeper insights into the vital roles of the centrosome and contribute to the development of personalized treatment for breast cancer.

Dietary regulation in health and disease.

Nutriments have been deemed to impact all physiopathologic processes. Recent evidences in molecular medicine and clinical trials have demonstrated that adequate nutrition treatments are the golden criterion for extending healthspan and delaying ageing in various species such as yeast, drosophila, rodent, primate and human. It emerges to develop the precision-nutrition therapeutics to slow age-related biological processes and treat diverse diseases. However, the nutritive advantages frequently diversify among individuals as well as organs and tissues, which brings challenges in this field. In this review, we summarize the different forms of dietary interventions extensively prescribed for healthspan improvement and disease treatment in pre-clinical or clinical. We discuss the nutrient-mediated mechanisms including metabolic regulators, nutritive metabolism pathways, epigenetic mechanisms and circadian clocks. Comparably, we describe diet-responsive effectors by which dietary interventions influence the endocrinic, immunological, microbial and neural states responsible for improving health and preventing multiple diseases in humans. Furthermore, we expatiate diverse patterns of dietotheroapies, including different fasting, calorie-restricted diet, ketogenic diet, high-fibre diet, plants-based diet, protein restriction diet or diet with specific reduction in amino acids or microelements, potentially affecting the health and morbid states. Altogether, we emphasize the profound nutritional therapy, and highlight the crosstalk among explored mechanisms and critical factors to develop individualized therapeutic approaches and predictors.

Single-cell and spatially resolved analysis uncovers cell heterogeneity of breast cancer.

The heterogeneity and the complex cellular architecture have a crucial effect on breast cancer progression and response to treatment. However, deciphering the neoplastic subtypes and their spatial organization is still challenging. Here, we combine single-nucleus RNA sequencing (snRNA-seq) with a microarray-based spatial transcriptomics (ST) to identify cell populations and their spatial distribution in breast cancer tissues. Malignant cells are clustered into distinct subpopulations. These cell clusters not only have diverse features, origins and functions, but also emerge to the crosstalk within subtypes. Furthermore, we find that these subclusters are mapped in distinct tissue regions, where discrepant enrichment of stromal cell types are observed. We also inferred the abundance of these tumorous subpopulations by deconvolution of large breast cancer RNA-seq cohorts, revealing differential association with patient survival and therapeutic response. Our study provides a novel insight for the cellular architecture of breast cancer and potential therapeutic strategies.

Characteristics of Peripheral Lymphocyte Subsets in Patients With Acute-On-Chronic Liver Failure Associated With Hepatitis B.

Background and Aims: Acute-on-chronic liver failure (ACLF) is a rare, but dramatic clinical syndrome. There is substantial evidence suggesting that immunity-mediated inflammation plays an important role in HBV-ACLF. Our aim was to characterize the proportion and cell counts of peripheral blood lymphocyte subsets in acute-on-chronic liver failure patients caused by HBV infection. Methods: One hundred and seventeen patients were enrolled in this study, including those with HBV-related ACLF (HBV-ACLF; n = 70), and HBV related non-ACLF patients (HBV non-ACLF; n = 47). Demographics, clinical and laboratory data at hospital admission were retrospectively analyzed. The percentage and cell count of peripheral lymphocyte subsets were evaluated by flow cytometry. Comparison analysis was performed by t-test or non-parametric Mann-Whitney U-test. Actuarial probabilities of death were calculated by the Kaplan-Meier method. Results: Both circulating lymphocyte count and lymphocyte percentage were significantly reduced in patients with HBV-ACLF (P < 0.001). The CD8+ T cell, CD4+ T cell, and CD16+CD56+ NK cell counts were significantly decreased in HBV-ACLF. Consistently, flow cytometric analysis showed that CD8+ T cell counts were significantly decreased in non-survivors, while no significant differences were found in CD4+ T cell, CD19+ B cell, or CD56+CD16+ NK cell counts. Furthermore, the group with the lower CD8+ T cell count displayed a significantly higher mortality rate compared with the group with the higher CD8+ T cell count. Conclusions: The abnormal prevalence of lymphocyte subsets may be important in the pathogenesis of HBV-ACLF. The decrease in CD8+ T cell counts may be related to poor survival in HBV-ACLF patients.

Overview of bile acid signaling in the cardiovascular system.

Bile acids (BAs) are classically known to play a vital role in the metabolism of lipids and in absorption. It is now well established that BAs act as signaling molecules, activating different receptors (such as farnesoid X receptor, vitamin D receptor, Takeda G-protein-coupled receptor 5, sphingosine-1-phosphate, muscarinic receptors, and big potassium channels) and participating in the regulation of energy homeostasis and lipid and glucose metabolism. In addition, increased BAs can impair cardiovascular function in liver cirrhosis. Approximately 50% of patients with cirrhosis develop cirrhotic cardiomyopathy. Exposure to high concentrations of hydrophobic BAs has been shown to be related to adverse effects with respect to vascular tension, endothelial function, arrhythmias, coronary atherosclerotic heart disease, and heart failure. The BAs in the serum BA pool have relevant through their hydrophobicity, and the lipophilic BAs are more harmful to the heart. Interestingly, ursodeoxycholic acid is a hydrophilic BA, and it is used as a therapeutic drug to reverse and protect the harmful cardiac effects caused by hydrophobic elevated BAs. In order to elucidate the mechanism of BAs and cardiovascular function, abundant experiments have been conducted in vitro and in vivo. The aim of this review was to explore the mechanism of BAs in the cardiovascular system.

Effects of compound K, a metabolite of ginsenosides, on memory and cognitive dysfunction in db/db mice involve the inhibition of ER stress and the NLRP3 inflammasome pathway.

Accumulating clinical and epidemiological evidence indicates a close relationship between diabetes mellitus and dementia. The ginsenoside compound K (CK) has been reported to ameliorate diabetes mellitus and confer protection to the central nervous system. In this study, we investigated whether CK could improve memory impairment and cognitive dysfunction in diabetic db/db mice. Firstly, we found that CK treatments significantly improved behavioral impairment and cognitive dysfunction based on Morris water maze, Y-maze, and fear conditioning tests. Besides, CK decreased the fasting glucose level, increased lipid metabolism, and ameliorated glucose tolerance, insulin sensitivity, and dyslipidemia in diabetic db/db mice. In addition, CK treatments alleviated oxidative stress and inhibited the inflammatory response in hippocampal tissue. Further investigations showed that CK treatments inhibited the NLRP3 inflammasome pathway, as evidenced by the declined expression of TXNIP, NLRP3 inflammasomes, ASC, cleaved caspase-1, and mature IL-1ß in hippocampal tissues. Moreover, CK treatments alleviated ER stress via down-regulating the level of BiP, CHOP, p-PERK, p-IRE1α and ATF6 in the hippocampus of db/db mice. These results suggest that CK improves memory and cognitive dysfunction, possibly by ameliorating glucose tolerance, insulin sensitivity, and dyslipidemia, suppressing oxidative stress and inflammatory response and modulating the NLRP3 inflammasome pathway and ER stress.

Neferine alleviates memory and cognitive dysfunction in diabetic mice through modulation of the NLRP3 inflammasome pathway and alleviation of endoplasmic-reticulum stress.

Accumulating clinical and epidemiological evidence indicates a close relationship between diabetes mellitus and dysfunction in memory and cognition. Neferine (NE) is a unique bis-benzylisoquinoline alkaloid derived from the seed embryo of Nelumbo nucifera (Lotus), an herbal medicine with a long history of use in used in China. NE has been reported to ameliorate diabetes mellitus and exert considerable protective effects on the central nervous system. Thus, this study aimed to investigate the effects of NE on memory and cognitive dysfunction in db/db mouse model of diabetes. First, we found that NE treatments significantly ameliorated behavioral impairment and cognitive dysfunction in the Morris water maze, Y-maze, and fear conditioning test in db/db mice. Additionally, in these diabetic mice, NE decreased fasting glucose and insulin resistance while promoting lipid metabolism. Furthermore, NE treatments alleviated oxidative stress and inhibited inflammatory responses in the hippocampus. Further investigations showed that NE suppressed the NOD-like receptor protein 3 (NLRP3) inflammasome pathway via down-regulating the levels of thioredoxin-interacting protein (TXNIP), NLRP3 inflammasomes, apoptosis-associated speck-like protein containing a CARD (ASC), and mature interleukin-1ß (IL-1ß) in the hippocampus. Moreover, NE alleviated endoplasmic-reticulum (ER) stress via down-regulating the levels of immunoglobulin heavy-chain-binding protein (GRP78), C/EBP homologous protein (CHOP), proteins kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6) in the hippocampus. In conclusion, these results suggest that NE ameliorated memory and cognitive dysfunction, possibly through modulating the NLRP3 inflammasome pathways and alleviating ER stress.

[A clinical and genetic analysis of a child with supernumerary marker chromosome 15-caused mental retardation, intractable epilepsy, and central precocious puberty].

Supernumerary marker chromosome 15 is a rare chromosome abnormality. This paper reports the clinical diagnosis and treatment, as well as genetic defects, of a child with supernumerary marker chromosome 15. The patient was a 9.5-year-old girl who had mental and motor retardation since infancy, breast development at the age of 7 years, and seizures at the age of 8.5 years. Seizures occurred with various features and could not be controlled by a variety of antiepileptic drugs. No abnormalities were found by brain magnetic resonance imaging. Electroencephalogram showed frequent epileptiform discharges. G-banding karyotype analysis, fluorescence in situ hybridization, methylation-specific multiplex ligation-dependent probe amplification, and array comparative genomic hybridization identified a de novo 15q duplication in the patient. The maternal copy number increased in the 15q11-13 region. The form of genome rearrangement was 47,XX,+inv dup(15)(pter to q13:q13 to pter). The increased copy number in the 15q11-13 region is closely related to mental retardation, intractable epilepsy, and central precocious puberty. High-resolution karyotype analysis is recommended for children with unexplained mental retardation and epilepsy.

[Glucose transporter 1 deficiency syndrome: features of movement disorders, diagnosis and treatment].

OBJECTIVE: To investigate the clinical features, diagnosis and treatment of glucose transporter 1 deficiency syndrome (GLUT1-DS), as well as the diagnostic value of movement disorders. METHODS: The clinical data of four children with GLUT1-DS were collected, and their clinical features, treatment, and follow-up results were analyzed. RESULTS: There were two boys and two girls, with an age of onset of 2-15 months. Clinical manifestations included movement disorders, seizures, and developmental retardation. Seizures were the cause of the first consultation in all cases. The four children all had persistent ataxia, dystonia, and dysarthria; two had persistent tremor, two had paroxysmal limb paralysis, and two had eye movement disorders. Paroxysmal symptoms tended to occur in fatigue state. All four children had reductions in the level of cerebrospinal fluid glucose and its ratio to blood glucose, as well as SLC2A1 gene mutations. The four children were given a ketogenic diet, at a ketogenic ratio of 2:1 to 3:1, and achieved complete remission of paroxysmal symptoms within 5 weeks. CONCLUSIONS: GLUT1-DS should be considered for epileptic children with mental retardation and motor developmental delay complicated by various types of movement disorders. The ketogenic diet is effective at a ketogenic ratio of 2:1 to 3:1 for the treatment of GLUT1-DS.

[Clinical and molecular genetic study of nonketotic hyperglycinemia in a Chinese family].

Nonketotic hyperglycinemia (NKH) is a rare, inborn error of metabolism. In this case report, a Chinese male infant was diagnosed with NKH caused by GLDC gene mutation. The clinical characteristics and genetic diagnosis were reported. The infant presented with an onset of early metabolic encephalopathy and Ohtahara syndrome. Both blood and urinary levels of metabolites were in the normal range. Brain MRI images indicated a poor development of corpus callosum, and a burst suppression pattern was found in the EEG. Results of target gene sequencing technology combined with multiplex ligation-dependent probe amplification (MLPA) indicated a heterozygous missense mutation of c.1786 C>T (p.R596X) in maternal exon 15 and a loss of heterozygosity of 4-15 exon gross deletions in paternal GLDC gene. These definite pathogenic mutations confirmed the diagnosis of NKH. The infant's clinical condition was not improved after treatment with adreno-cortico-tropic-hormone, topiramate and dextromethorphan, and he finally died at 4 months of age. Patients with NKH often exhibit complicated clinical phenotypes and are lack of specific symptoms. NKH could be diagnosed by metabolic screening and molecular genetic analysis.

[Episodic central nervous system symptoms with reversible white matter involvement in Chinese patients with X-linked Charcot-Marie-Tooth disease and literatures review].

OBJECTIVE: To analyze the phenotype and genotype of CMTX1 patients with episodic transient reversible white matter involvement, and delineate the features of brain MRI in the episode and the possible mechanisms. METHOD: Three Chinese probands and their family members were sequenced in the coding regions of GJB1. With the other 16 reported CMTX1 patients with episodic transient reversible white matter involvement, the clinical feature of the episodic central nervous system symptoms and the genotypes were reviewed. RESULT: Missense mutations in GJB1 were identified in all 3 probands. In 19 patients with transient reversible white matter involvement, the episodes were manifested as weakness of the limbs, dysarthria, and dysphagia, without disturbance of consciousness or seizures. The episodes lasted for 13 hours (10 min-72 hours) with complete remission in all patients; There were multiple episodes in 9 patients. During the episode, brain MRI showed symmetrical high signals in T2 weighted, Flair and DWI images in periventricular white matter, with predominance in posterior region including splenium of corpus callosum. These changes in imaging were most prominent during or within 1 week after the clinical episode.Significant improvements occurred within 1 month, with complete remission within 4-6 months.No specific locations of mutant amino acids in GJB1 protein were found in these patients with episodic transient reversible white matter involvement. CONCLUSION: Episodic transient reversible white matter involvement may present in a small number of patients with CMTX1. Transient edema of oligodendrocytes due to the dysfunction of gap junction may be involved in the pathogenesis. There is no correlation between the location of the mutant amino acids in GJB1 and the occurrence of the episodes.

[Clinical and genetic study of twelve Chinese patients with Alexander disease].

OBJECTIVE: To delineate the phenotype and genotype characteristics in 12 Chinese children with Alexander disease (AD), which is helpful for the molecular diagnosis and genetic counseling in China. METHODS: Clinical diagnosis of AD was based on MRI criteria proposed by van der Knaarp in 2001. Included AD patients were followed up for 0.50 - 3.67 years. Mutations in GFAP were detected by DNA sequencing. RESULTS: The 12 cases of AD were clinically diagnosed. Age of first visit was 4.87 years (0.75 - 12.00 years), with 3 types of chief complaints: developmental delay in 3, recurrent seizures in 7, unable to walk after falling in 2. Average head circumference was 52.34 cm (44 - 58 cm), which larger than age-matched average by 6.45% (1.80% - 13.95%). On the first visit, scaling according to Gross motor functional classification system (GMFCS) was performed, with GMFCSI in 8, II in 3, V in 1. Mild to severe cognitive dysfunction were found in 8, and seizures in 11 cases. The 12 patients were followed up for 0.50 - 3.67 years, their motor and cognitive function remained stable. Episodic aggravations provoked by fever or falling were observed in 5 cases (41.67%). Heterozygous missense mutations of GFAP were detected in 12 patients. All mutations were de novo; 3 out of 10 mutations identified were novel. R79 and R239 were hot mutations, which was consistent with previous reports. Mutations were located in exon 1 in 8 cases. CONCLUSIONS: The phenotype in these patients is characterized by slower progression compared with reports from other population and high incidence of seizures. And episodic aggravations provoked by fever or falling were more common. The genotype characteristics are consistent with previous reports. The results of this research expanded the number of patients with Alexander disease found to have GFAP coding mutations in China.

[Emotional and behavioral comorbidities and the impact on the quality of life in epilepsy children].

OBJECTIVE: To find out the rate of comorbidities of depression, anxiety disorder and attention deficit hyperactivity disorder (ADHD) symptoms in children with epilepsy and to analyze the relevant affecting factors and impacts on quality of life. METHOD: Totally 142 children with various types of epilepsy underwent neuropsychological assessment with the Depression Self-rating Scale for Children, the Screen for Child Anxiety Related Emotional Disorders and the ADHD Rating Scale-IV, an 18-item parent-rated questionnaire based on the diagnostic criteria for ADHD, the quality of life was measured in 100 cases on antiepileptic medications by the Quality of Life in Epilepsy Inventory (QOLIE-31). The comorbidity rates were calculated using t-test, chi(2) test and multiple logistic analysis, the variables associated with psychiatric comorbidities were determined, and the impact on quality of life was analyzed. RESULT: (1) The total rate of emotional and behavioral comorbidities was 57.7% (82/142), the frequency of depressive disorder, anxiety disorder and ADHD was 14.8%, 44.4% and 17.6%, respectively. The suicidal ideation occasionally occurred in 5.6% of the cases and 0.7% of cases often had the ideation, but no suicidal action was found in any case. (2) Risk factors for the emotional and behavioral disorders: multiple logistic analysis indicated that age, gender and epilepsy illness-related variables were not relative to the comorbidities, P > 0.05, there were interactions among the disorders. (3) The impact on the quality of life: The emotional and behavioral conditions were associated with the low quality of life, which was significantly lower in epileptic children with co-morbid disorder compared to non-comorbidities epilepsy group. Especially negative impact on the total score of quality of life and four sub-items such as overall quality, emotional well-being, cognitive and social function, P < 0.001. There were also significant differences between the two groups in the other three sub-items including fear for seizure attack, energy/fatigue and medication effects (P < 0.05). CONCLUSIONS: The frequency of emotional and behavioral disorders including depress disorder, anxiety disorder and ADHD was considerably high in children with epilepsy. Age, gender and epilepsy illness-related variables are not associated with the emotional and behavioral comorbidities, which interfere with each other. Emotional and behavioral disorder is one of the negative factors to the quality of life in epileptic patients. Neuropsychological assessment and treatment are important for improvement of the quality of life in children with epilepsy.