BACKGROUND Mucopolysaccharidosis typeⅥ(MPSⅥ)is a chronic,progressive,inherited disease with multiorgan involvement and a restricted life expectancy.AIM To investigate the epidemiological,clinical,and genetic charact...BACKGROUND Mucopolysaccharidosis typeⅥ(MPSⅥ)is a chronic,progressive,inherited disease with multiorgan involvement and a restricted life expectancy.AIM To investigate the epidemiological,clinical,and genetic characteristics of patients with mucopolysaccharidosis type 6 and their outcomes using the Russian Federation's national registry,as per the Russian registry,and compare them with previously published data.METHODS In a retrospective cohort study,clinical,laboratory data,molecular genetic analysis results,and enzyme replacement therapy(ERT)data were extracted and analyzed from the Russian MPSⅥregistry for 53 patients,comprising 26 males(49.1%)and 27 females(50.9%).RESULTS The median age of first symptoms was 2 years,ranging from the first months of life to 20 years.A positive family history of MPSⅥwas reported in 19/53(35.8%)patients,a negative family history in 24(45.3%),and missing information in 10(18.9%).The main features of the disease were hepatomegaly(n=23;60.5%),splenomegaly(n=15,39.5%),involvement of otolaryngological organs(n=24/33;72.7%),umbilical and inguinal hernia(n=19/36;52.8%),heart involvement(n=26/32;81.3%)with valve involvement(n=25/26;96.2%)and linear growth delay(n=30/39,76.9%).Two patients(3.8%)died.The most common variants identified in the ARSB gene were c.454C>T and c.194C>T.At the time of data collection,ERT had ever received 48/53(90.5%)patients.CONCLUSION No correlation was observed between the age of onset of the first symptoms,the severity of clinical manifestations,enzyme activity,or nucleotide variants in the ARSB gene.展开更多
BACKGROUND Rett syndrome is a monogenic X-linked dominant condition that affects 1/(10000-15000)girls due to de novo mutations in the methyl-CpG binding protein 2(MECP2)gene mapped to chromosome Xq28.The disease-causi...BACKGROUND Rett syndrome is a monogenic X-linked dominant condition that affects 1/(10000-15000)girls due to de novo mutations in the methyl-CpG binding protein 2(MECP2)gene mapped to chromosome Xq28.The disease-causing gene was identified as a mutation in the MECP2 gene,which is found in approximately 80%of patients diagnosed with Rett syndrome.Although chromosomal changes resulting in del(15)(q11q13)are usually associated with Angelman and Prader-Willi syndrome,very few cases,if any,of Rett syndrome with terminal 15q22-qter deletion have been published in English literature.CASE SUMMARY In this study,we report an unusual and rare clinical presentation of Rett syndrome in a 12-year-old Sudanese girl.The patient was brought in by her parents,complaining of gradual onset of abnormal walking,abnormal hand movement,loss of speech,and mental retardation for ten years.There was no reported history of convulsions or loss of consciousness.Clinical examination revealed microcephaly with no other apparent dysmorphic features,intact cranial nerves,and abnormal gait.She showed repetitive and stereotyped behaviors,including hand flapping,stimming,and chest pounding,which were concomitant with autism spectrum disorder.Magnetic resonance imaging and electroencephalography investigations were normal,and cytogenetic analysis showed 46,XX,del(15)(q22qter).Further molecular analysis using whole sequencing of MECP2 revealed an alteration cytosine>thymine at nucleotide 401,leading to phenylalanine replacing a serine at amino acid position 134.CONCLUSION This case,the first reported instance of Rett syndrome in Sudan,is of significant interest.The patient carries both the MECP2 gene mutation and the chromosome 15q22-qter deletion,which may explain the autistic behavior with atypical presentation of Rett syndrome.This report expands the genetic diversity of Rett syndrome,demonstrating how co-occurring 15q22-qter deletions can reshape MECP2-associated phenotypes in Rett syndrome.展开更多
BACKGROUND Mucopolysaccharidosis type Ⅱ(MPS Ⅱ)is a chronic inherited disease with multiorgan involvement,a progressive course,and restricted life expectancy.AIM To evaluate the predictors of fatal outcomes in MPS Ⅱ...BACKGROUND Mucopolysaccharidosis type Ⅱ(MPS Ⅱ)is a chronic inherited disease with multiorgan involvement,a progressive course,and restricted life expectancy.AIM To evaluate the predictors of fatal outcomes in MPS Ⅱ patients.METHODS In the retrospective cohort study,the clinical,laboratory data and enzyme replacement therapy(ERT)(84.2%)of about 160 patients were extracted and analyzed from the Russian MPS Ⅱ registry,with death as a primary outcome.We compared patients who died(n=20;12.5%)with severe form(n=13;68.4%)and attenuated form(n=6,31.6%)to 140 alive patients.RESULTS Fatal outcomes occurred in 5%,35%,20%,and 40%of patients before 10,10-14,15-19,and≥20 years.The most common causes of death were cardiovascular(29.4%),respiratory failure(17.6%),including pneumonia(17.6%),and their associations(17.6%)and MPS Ⅱ progression(11.8%).Acute or chronic respiratory failure was in 53%.Died patients had higher birth weight,higher age of diagnosis,and start of ERT.Hydrocephalus,hydrocephalus bypass surgery,epilepsy,difficulty swallowing,and impaired movement after 12 years of age were significantly more common in the deceased patients.Cox regression analysis has revealed the following time-dependent covariates of the lethal outcome:1^(st)-year psychomotor development delay,delayed mental and speech development,hydrocephalus,swallow disorders,impossible walking at age>12 years,respiratory disorders,tracheostomy,neuronopathic form.CONCLUSION Increased birth weight,delayed diagnosis and the start of ERT,and development of neuronopathic form with impossible walking after 12 years were the main predictors of the fatal outcome.展开更多
BACKGROUND Early diagnosis of left ventricular diastolic dysfunction(LVDD)is essential for preventing heart failure.B-type natriuretic peptide(BNP)is a viable marker for predicting LVDD,as elevated BNP levels have bee...BACKGROUND Early diagnosis of left ventricular diastolic dysfunction(LVDD)is essential for preventing heart failure.B-type natriuretic peptide(BNP)is a viable marker for predicting LVDD,as elevated BNP levels have been associated with worsening LVDD in patients with diabetes over time.However,the utility of BNP as a diagnostic marker in diabetes is controversial,as BNP levels are often low in overweight individuals.AIM To examine the effectiveness of BNP levels and fragmented QRS(fQRS)on electrocardiography for diagnosing LVDD in patients with type 2 diabetes.METHODS This retrospective cohort study included 303 patients with type 2 diabetes(67.4±12.3 years old)with preserved ejection fraction(EF)≥50%admitted to Toyama University Hospital for glycemic management and comorbidity evaluation between November 2017 and April 2021.All participants underwent plasma BNP measurement,electrocardiography,and echocardiography.Cardiologists who were blinded to the BNP results assessed the electrocardiograms and echocardiograms.Subgroup analyses were conducted for overweight individuals.RESULTS Receiver operating characteristic(ROC)curve analysis determined optimal BNP cut-off values of 34.8 pg/mL and 7.2 pg/mL for diagnosing LVDD in non-overweight[area under the ROC curve(AUC):0.70]and overweight(AUC:0.55)groups,respectively(P=0.040).In the overweight subgroup,fQRS showed greater diagnostic accuracy for LVDD(AUC:0.67),indicating moderate diagnostic utility compared with the low performance of the BNP cutoff of 35 pg/mL(AUC:0.52)(P=0.010).Multivariate analyses confirmed that fQRS was superior to BNP for LVDD diagnosis regardless of the patient’s weight.CONCLUSION A BNP level≥35 pg/mL in non-overweight individuals may be a reliable LVDD marker.Additionally,fQRS was more effective than BNP in diagnosing LVDD irrespective of the patient’s weight.fQRS can complement BNP in the early detection of LVDD,especially in overweight patients,potentially improving early detection and mitigating progression to heart failure with preserved EF in patients with type 2 diabetes.展开更多
Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A;p. Ala632Thr) in a 7-year-old boy exhibi...Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A;p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca2+ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^(−/−) OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^(−/−) OPCs in vitro and myelination in Tmem63a^(−/−) mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca^(2+) influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.展开更多
The Association of Chinese Geneticists in America （ACGA） and the Hong Kong Society of Medical Genetics （HKSMG） held their first joint Conference on Genetic and Genomic Medicine in Hong Kong from June 9-11 in 2008 ...The Association of Chinese Geneticists in America （ACGA） and the Hong Kong Society of Medical Genetics （HKSMG） held their first joint Conference on Genetic and Genomic Medicine in Hong Kong from June 9-11 in 2008 at the Cheung Kung Hai Conference Center, William MW Mong Block, Li Ka Shing Faculty of Medicine, the University of Hong Kong. Other co-organizers included the University of Hong Kong and Chinese Society of Medical Genetics. A satellite conference ＂ACGA-WZMC International Symposium of Genetics and Translational Medicine＂, co-organized with Wenzhou Medical College and Chinese Society of Medical Genetics, was held from June 12-14, 2008 at Wenzhou, Zhejiang Province of China.展开更多
In Indonesia,undervirilisation in 46,XY males is the most common form of difference of sex development(DSD).This can include hypospadias(misplacement of the urethra),micropenis,bifid scrotum,and undescended testis[1]....In Indonesia,undervirilisation in 46,XY males is the most common form of difference of sex development(DSD).This can include hypospadias(misplacement of the urethra),micropenis,bifid scrotum,and undescended testis[1].Undervirilisation or 46,XY DSD can be associated with a number of congenital syndromes,including Smith-Lemli-Opitz Syndrome(OMIM 602858),caused by an inborn error of cholesterol synthesis,and characterised by growth delay,intellectual disability,microcephaly,distinctive facial features,cleft palate,limb anomalies,and hypospadias[2]or Opitz syndrome(also known as Opitz G/BBB syndrome).Opitz syndrome can be caused by variants in the X-linked midline 1(MID1)gene(Type I)or in an autosomal dominant manner by monoallelic variants in sperm antigen with calponin homology and coiled-coil domains 1-like(SPECC1L)on chromosome 22q11.2(Type II)[3].Opitz syndrome is characterised by hypospadias,hypertelorism,cleft lip/palate,and heart defects[4].The prevalence of X-linked Opitz syndrome is estimated to be from 1 in 50000 to 1 in 100000 males[5].Recognition of a syndrome informs appropriate clinical management and patient care.Therefore,although these syndromes are rare,hypospadias may be diagnosed before the emergence of other comorbidities meaning that it is crucial for clinicians to perform a thorough clinical evaluation with syndromic causes in mind.展开更多
This editorial assesses the advancements in neuronavigation enhanced repetitive transcranial magnetic stimulation for depressive disorder and schizophrenia treatment.Conventional repetitive transcranial magnetic stimu...This editorial assesses the advancements in neuronavigation enhanced repetitive transcranial magnetic stimulation for depressive disorder and schizophrenia treatment.Conventional repetitive transcranial magnetic stimulation faces challenges due to the intricacies of brain anatomy and patient variability.Neuronavigation offers innovative solutions by integrating neuroimaging with three-dimensional localization to pinpoint brain regions and refine therapeutic targeting.This systematic review of recent literature underscores the enhanced efficacy of neuronavigation in improving treatment outcomes for these disorders.This editorial highlights the pivotal role of neuronavigation in advancing psychiatric care.展开更多
Dear Editor,Persistent Mullerian duct syndrome(PMDS;Online Mendelian Inheritance in Man[OMIM]:#261550)is a rare autosomal recessive inherent difference in sex development in males with Mullerian duct derivatives,inclu...Dear Editor,Persistent Mullerian duct syndrome(PMDS;Online Mendelian Inheritance in Man[OMIM]:#261550)is a rare autosomal recessive inherent difference in sex development in males with Mullerian duct derivatives,including the uterus,fallopian tubes,and upper part of the vagina.'Approximately 88%of PMDS patients were found to have biallelic variants in the anti-Mullerian hormone(AMH;OMIM:*600957)or AMH type 2 receptor(AMHR2;OMIM:*600956)genes,and the rest were referred as idiopathic.I The serum AMH levels are usually very low or undetectable in PMDS patients with AMH gene mutations but normal or elevated in those with AMHR2 gene mutations.Here,an adult Chinese patient with PMDS carrying biallelic variants of the AMH gene was reported to have unexpectedly normal serum AMH level.Please refer to Supplementary Information of Patient and Methods for methodologies.展开更多
Genomic mosaicism describes the phenomenon where some but not all cells within a tissue harbor unique genetic mutations.Traditionally,research focused on the impact of genomic mosaicism on clinical phenotype—motivate...Genomic mosaicism describes the phenomenon where some but not all cells within a tissue harbor unique genetic mutations.Traditionally,research focused on the impact of genomic mosaicism on clinical phenotype—motivated by its involvement in cancers and overgrowth syndromes.More recently,we increasingly shifted towards the plethora of neutral mosaic variants that can act as recorders of cellular lineage and environmental exposures.Here,we summarize the current state of the field of genomic mosaicism research with a special emphasis on our current understanding of this phenomenon in brain development and homeostasis.Although the field of genomic mosaicism has a rich history,technological advances in the last decade have changed our approaches and greatly improved our knowledge.We will provide current definitions and an overview of contemporary detection approaches for genomic mosaicism.Finally,we will discuss the impact and utility of genomic mosaicism.展开更多
Aminoglycosides(Am An) are widely used for their great efficiency against gram-negative bacterial infections. However, they can also induce ototoxic hearing loss, which has affected millions of people around the world...Aminoglycosides(Am An) are widely used for their great efficiency against gram-negative bacterial infections. However, they can also induce ototoxic hearing loss, which has affected millions of people around the world. As previously reported, individuals bearing mitochondrial DNA mutations in the 12 S rRNA gene, such as m.1555A>G and m.1494C>T, are more prone to Am An-induced ototoxicity. These mutations cause human mitochondrial ribosomes to more closely resemble bacterial ribosomes and enable a stronger aminoglycoside interaction. Consequently,exposure to Am An can induce or worsen hearing loss in these individuals. Furthermore, a wide range of severity and penetrance of hearing loss was observed among families carrying these mutations. Studies have revealed that these mitochondria mutations are the primary molecular mechanism of genetic susceptibility to Am An ototoxicity, though nuclear modifier genes and mitochondrial haplotypes are known to modulate the phenotypic manifestation.展开更多
Klinefelter syndrome （KS） （47, XXY） is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. Most men with KS go through life without knowing the diagnosis, as on...Klinefelter syndrome （KS） （47, XXY） is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. Most men with KS go through life without knowing the diagnosis, as only 25% are diagnosed and only a few of these before puberty. Apart from hypogonadism and azoospermia, most men with KS suffer from some degree of learning disability and may have various kinds of psychiatric problems. The effects of long-term hypogonadism may be difficult to discern from the gene dose effect of the extra X-chromosome. Whatever the cause, alterations in body composition, with more fat and less muscle mass and diminished bone mineral mass, as well as increased risk of metabolic consequences, such as type 2 diabetes and the metabolic syndrome are all common in KS. These findings should be a concern as they are not simply laboratory findings; epidemiological studies in KS populations show an increased risk of beth hospitalization and death from various diseases. Testosterone treatment should be offered to KS patients from early puberty, to secure a proper masculine development, nonetheless the evidence is weak or nonexisting, since no randomized controlled trials have ever been published. Here, we will review the current knowledge of hypogonadism in KS and the rationale for testosterone treatment and try to give our best recommendations for surveillance of this rather common, but often ignored, syndrome.展开更多
AIM： To evaluate the effect of single nucleotide poly- morphisms of interleukin （IL）-28B, rs12979860 on progression and treatment response in chronic hepatitis C. METHODS： Patients （n = 64; 37 men, 27 women; mean...AIM： To evaluate the effect of single nucleotide poly- morphisms of interleukin （IL）-28B, rs12979860 on progression and treatment response in chronic hepatitis C. METHODS： Patients （n = 64; 37 men, 27 women; mean age, 44 ＋ 12 years） with chronic hepatitis C, genotype 1, received treatment with peg-interferon plus ribavirin. Genotyping of rs12979860 was per- formed on peripheral blood DNA. Histopathological assessment of necroinflammatory grade and fibrosis stage were scored using the METAVIR system on a liver biopsy sample before treatment. Serum viral load, ami- notransferase activity, and insulin level were measured. Insulin resistance index, body mass index, waist/hip ratio, percentage of body fat and fibrosis progression rate were calculated. Applied dose of interferon and ribavirin, platelet and neutrophil count and hemoglobin level were measured. RESULTS： A sustained virological response （SVR） was significantly associated with IL28B polymorphism （CC vs -l-r allele： odds ratio （OR）, 25; CC vs CT allele： OR, 5.4）, inflammation activity （G 〈 1 vs G 〉 1： OR, 3.9）, fibrosis （F 〈 1 vs F 〉 1： OR, 5.9）, platelet count （〉 200 × 109/L vs 〈 200 ×109/L： OR, 4.7; OR in patients with genotype CT： 12.8）, fatty liver （absence vs presence of steatosis： OR, 4.8）, insulin resistance index （〈 2.5 vs 〉 2.5： OR, 3.9）, and baseline HCV viral load （〈 106 IU/mL vs 〉 106 IU/mL： OR, 3.0）. There was no association with age, sex, aminotransferases activity, body mass index, waist/hip ratio, or percentage body fat. There was borderline significance （P = 0.064） of increased fibrosis in patients with the I-I allele, and no differences in the insulin resistance index between groups of patients with CC, CT and -IF alleles （P = 0.12）. Spearman＇s rank correlation coefficient between insulin resistance and stage of fibrosis and body mass index was r = 0.618 and r = 0.605, respectively （P 〈 0.001）. Significant dif- ferences were found in the insulin resistance index （P = 0.01） between patients with and without steatosis. Patients with the C-I- allele and absence of a SVR had a higher incidence of requiring threshold dose reduction of interferon （P = 0.07）. CONCLUSION： IL28B variation is the strongest host factor not related to insulin resistance that determines outcome of antiviral therapy. Baseline platelet count predicts the outcome of antiviral therapy in CT allele patients.展开更多
Identification of carriers of fragile X syndrome(FXS) with the subsequent prenatal diagnosis and knowledge of FXS-associated genetic profiles are essential for intervention in specific populations. We report the resul...Identification of carriers of fragile X syndrome(FXS) with the subsequent prenatal diagnosis and knowledge of FXS-associated genetic profiles are essential for intervention in specific populations. We report the results of carrier screening of 39,458 East Asian adult women and prenatal diagnosis from 87 FXS carriers.The prevalence of FXS carriers and full mutation fetuses was estimated to be 1/581 and 1/3124 in East Asian populations, respectively. We confirmed the validity of the current threshold of CGG trinucleotide repeats for FMR1 categorization;the integral risks of full mutation expansion were approximately 6.0%,43.8%, and 100% for premutation alleles with 55—74, 75—89, and ≥ 90 CGG repeats, respectively. The protective effect of AGG(adenine-guanine-guanine nucleotides) interruption in East Asian populations was validated, which is important in protecting premutation alleles with 75—89 CGG repeats from full mutation expansion. Finally, family history was shown not an effective indicator for FXS carrier screening in East Asian populations, and population-based screening was more cost-effective. This study provides an insight into the largest carrier screening and prenatal diagnosis for FXS in East Asian populations to date. The FXSassociated genetic profiles of East Asian populations are delineated, and population-based carrier screening is shown to be promising for FXS intervention.展开更多
Inflammatory bowel disease (IBD), which comprises ulcerative colitis and Crohn’s disease, is characterized by inflammation of the gastrointestinal tract. The trefoil factors 1, 2, and 3 (TFF1-3) are a fami...Inflammatory bowel disease (IBD), which comprises ulcerative colitis and Crohn’s disease, is characterized by inflammation of the gastrointestinal tract. The trefoil factors 1, 2, and 3 (TFF1-3) are a family of peptides that play important roles in the protection and repair of epithelial surfaces, including the gastrointestinal tract. TFFs may be involved in IBD pathogenesis and are a potential treatment option. In the present review, we describe the TFF family and their potential role in IBD by summarizing the current knowledge of their expression, possible function and pharmacological role in IBD.展开更多
The underlying pathophysiology of liver dysfunction in urea cycle disorders(UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle(UC) intermediates are toxic for hepatocyte mitocho...The underlying pathophysiology of liver dysfunction in urea cycle disorders(UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle(UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients suffering from UCDs. Owing to our routine clinical practice to screen for iron overload in severely ill neonates, with the focus on the newborns suffering from acute liver failure, we report a case of citrullinemia with neonatal liver failure and high blood parameters of iron overload. We hypothesize that the key is in the decreased-deficient fumaric acid production in the course of UC in UCDs that causes several sequentially intertwined metabolic disturbances with final result of liver iron overload. The presented hypothesis could be easily tested by examining the patients suffering from UCDs, for liver iron overload. This could be easily performed in countries with a high population and comprehensive national register for inborn errors of metabolism. Conclusion: Providing the hypothesis is correct, neonatal liver damage in patients having UCD can be prevented by the supplementation of pregnant women with fumaric or succinic acid, prepared in the form of iron supplementation pills. After birth, liverdamage in patients having UCDs can be prevented by supplementation of these patients with zinc fumarate or zinc succinylate, as well.展开更多
Klinefelter syndrome （KS） is the set of symptoms that result from the presence of an extra X chromosome in males. Postnatal population-based KS screening will enable timely diagnosis of this common chromosomal disea...Klinefelter syndrome （KS） is the set of symptoms that result from the presence of an extra X chromosome in males. Postnatal population-based KS screening will enable timely diagnosis of this common chromosomal disease, providing the opportunity for early intervention and therapy at the time point when they are most effective and may prevent later symptoms or complications. Therefore, through this study, we introduced a simple high-resolution melting （HRM） assay for KS screening and evaluated its clinical sensitivity and specificity in three medical centers using 1373 clinical blood samples. The HRM assay utilized a single primer pair to simultaneously amplify specific regions in zinc finger protein, X-linked （ZFX） and zinc finger protein, Y-linked （ZFY）. In cases of KS, the ratios of ZFX/ZFYare altered compared to those in normal males. As a result, the specific melting profiles differ and can be differentiated during data analysis. This HRM assay displayed high analytical specificity over a wide range of template DNA amounts （5 ng-50 ng） and reproducibility, high resolution for detecting KS mosaicism, and high clinical sensitivity （100%） and specificity （98.1%）. Moreover, the HRM assay was rapid （2 h per run）, inexpensive （0.2 USD per sample）, easy to perform and automatic, and compatible with both whole blood samples and dried blood spots. Therefore, this HRM assay is an ideal postnatal population-based KS screening tool that can be used for different age groups.展开更多
BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)encompasses a group of autosomal recessive disorders with high morbidity and mortality.Variants in the gene encoding tight junction protein-2(TJP2)have bee...BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)encompasses a group of autosomal recessive disorders with high morbidity and mortality.Variants in the gene encoding tight junction protein-2(TJP2)have been linked to PFIC type 4(PFIC4),which predominantly presents in childhood.However,there are only limited data from adults with TJP2-related PFIC4.We report a family with an autosomal recessive disorder with a novel variant in the TJP2 gene in adults with very variable expression of PFIC4.CASE SUMMARY The index patient presented at 19 years old with liver cirrhosis and variceal bleeding and was treated with endoscopic banding and beta-blockers.In 2018,he developed primary liver cancer that was treated with radiofrequency ablation followed by liver transplantation in 2019.Genetic testing revealed a novel homozygous TJP2 variant causing PFIC4(TJP2([NM_004817.3]:c.[3334C>T];[3334C>T])).The consanguineous family consists of the father and mother(both heterozygous)and their 12 children,of which five carry the variant in a homozygous state;however,these five siblings have highly variable expression of PFIC4.Two homozygous brothers had cirrhosis and portal hypertension at diagnosis at the ages of 19 and 36.Two other homozygous brothers,age 23 and 19,and the homozygous sister,age 21,have elevated liver enzymes but presently no cirrhosis,which may suggest an age-dependent penetrance.In addition,five sisters had severe and mild intrahepatic cholestasis of pregnancy and carry the TJP2 variant in a homozygous and heterozygous state,respectively.CONCLUSION This novel TJP2 variant is associated with PFIC4 causing severe liver disease with cirrhosis and primary liver cancer in adolescents/adults.展开更多
Viruses commonly create favorable cellular conditions for their survival through multiple mechanisms. Micro RNAs(mi RNAs), which function as post-transcriptional regulators, are utilized by human cytomegalovirus(HCMV)...Viruses commonly create favorable cellular conditions for their survival through multiple mechanisms. Micro RNAs(mi RNAs), which function as post-transcriptional regulators, are utilized by human cytomegalovirus(HCMV) in its infection and pathogenesis. In the present study, the DNA replication inhibitor Geminin(GMNN) was identified to be a direct target of hcmv-mi R-US5-1. Overexpression of hcmv-mi R-US5-1 could block the accumulation of GMNN during HCMV infection, and the decrease of GMNN expression caused by hcmv-mi R-US5-1 or GMNN specific si RNA reduced HCMV DNA copies in U373 cells. Meanwhile, ectopic expression of hcmv-mi R-US5-1 and consequent lower expression of GMNN influenced host cell cycle and proliferation. These results imply that hcmv-mi R-US5-1 may affect viral replication and host cellular environment by regulating expression kinetics of GMNN during HCMV infection.展开更多
AIM: To investigate the relation of the response to Helicobacter pylori eradication therapy to the depth of tumor invasion and chromosome abnormalities in patients with mucosaassociated lymphoid tissue (MALT) lymphoma...AIM: To investigate the relation of the response to Helicobacter pylori eradication therapy to the depth of tumor invasion and chromosome abnormalities in patients with mucosaassociated lymphoid tissue (MALT) lymphoma and to determine the clinical value of aneuploidy.METHODS: We studied 13 patients with localized gastric MALT lymphoma of stage E1. Before eradication therapy,the depth of tumor invasion was assessed by endoscopic ultrasonography in 8 patients and by endoscopic examination and gastrointestinal series in the remaining patients. To detect chromosomal abnormalities, paraffin-embedded tissue sections of diagnostic biopsy specimens underwent tissuefluorescence in situ hybridization (FISH), using chromosomespecific α-satellite DNA probes for chromosomes 3,7,12,and 18 and YAC clones for t(11;18)(q21;q21).RESULTS: Seven of the 13 patients had complete regression(CR) in response to H pylori eradication therapy. No patient with CR had submucosal tumor invasion. Trisomy 18 was seen in 1 patient with CR, and both trisomies 12 and 18 were present in another patient with CR. All patients with no response or progressive disease had deep submucosal tumor invasion and showed t(11;18)(q21;q21) or trisomy 3. Trisomy 7 was not detected in this series of patients.CONCLUSION: The depth of tumor invasion is an accurate predictor of the response of stage E1 MALT lymphoma to H pylori eradication therapy and is closely associated with the presence of chromosomal abnormalities. Trisomy 3 may predict the aggressive development of MALT lymphoma.展开更多
文摘BACKGROUND Mucopolysaccharidosis typeⅥ(MPSⅥ)is a chronic,progressive,inherited disease with multiorgan involvement and a restricted life expectancy.AIM To investigate the epidemiological,clinical,and genetic characteristics of patients with mucopolysaccharidosis type 6 and their outcomes using the Russian Federation's national registry,as per the Russian registry,and compare them with previously published data.METHODS In a retrospective cohort study,clinical,laboratory data,molecular genetic analysis results,and enzyme replacement therapy(ERT)data were extracted and analyzed from the Russian MPSⅥregistry for 53 patients,comprising 26 males(49.1%)and 27 females(50.9%).RESULTS The median age of first symptoms was 2 years,ranging from the first months of life to 20 years.A positive family history of MPSⅥwas reported in 19/53(35.8%)patients,a negative family history in 24(45.3%),and missing information in 10(18.9%).The main features of the disease were hepatomegaly(n=23;60.5%),splenomegaly(n=15,39.5%),involvement of otolaryngological organs(n=24/33;72.7%),umbilical and inguinal hernia(n=19/36;52.8%),heart involvement(n=26/32;81.3%)with valve involvement(n=25/26;96.2%)and linear growth delay(n=30/39,76.9%).Two patients(3.8%)died.The most common variants identified in the ARSB gene were c.454C>T and c.194C>T.At the time of data collection,ERT had ever received 48/53(90.5%)patients.CONCLUSION No correlation was observed between the age of onset of the first symptoms,the severity of clinical manifestations,enzyme activity,or nucleotide variants in the ARSB gene.
文摘BACKGROUND Rett syndrome is a monogenic X-linked dominant condition that affects 1/(10000-15000)girls due to de novo mutations in the methyl-CpG binding protein 2(MECP2)gene mapped to chromosome Xq28.The disease-causing gene was identified as a mutation in the MECP2 gene,which is found in approximately 80%of patients diagnosed with Rett syndrome.Although chromosomal changes resulting in del(15)(q11q13)are usually associated with Angelman and Prader-Willi syndrome,very few cases,if any,of Rett syndrome with terminal 15q22-qter deletion have been published in English literature.CASE SUMMARY In this study,we report an unusual and rare clinical presentation of Rett syndrome in a 12-year-old Sudanese girl.The patient was brought in by her parents,complaining of gradual onset of abnormal walking,abnormal hand movement,loss of speech,and mental retardation for ten years.There was no reported history of convulsions or loss of consciousness.Clinical examination revealed microcephaly with no other apparent dysmorphic features,intact cranial nerves,and abnormal gait.She showed repetitive and stereotyped behaviors,including hand flapping,stimming,and chest pounding,which were concomitant with autism spectrum disorder.Magnetic resonance imaging and electroencephalography investigations were normal,and cytogenetic analysis showed 46,XX,del(15)(q22qter).Further molecular analysis using whole sequencing of MECP2 revealed an alteration cytosine>thymine at nucleotide 401,leading to phenylalanine replacing a serine at amino acid position 134.CONCLUSION This case,the first reported instance of Rett syndrome in Sudan,is of significant interest.The patient carries both the MECP2 gene mutation and the chromosome 15q22-qter deletion,which may explain the autistic behavior with atypical presentation of Rett syndrome.This report expands the genetic diversity of Rett syndrome,demonstrating how co-occurring 15q22-qter deletions can reshape MECP2-associated phenotypes in Rett syndrome.
文摘BACKGROUND Mucopolysaccharidosis type Ⅱ(MPS Ⅱ)is a chronic inherited disease with multiorgan involvement,a progressive course,and restricted life expectancy.AIM To evaluate the predictors of fatal outcomes in MPS Ⅱ patients.METHODS In the retrospective cohort study,the clinical,laboratory data and enzyme replacement therapy(ERT)(84.2%)of about 160 patients were extracted and analyzed from the Russian MPS Ⅱ registry,with death as a primary outcome.We compared patients who died(n=20;12.5%)with severe form(n=13;68.4%)and attenuated form(n=6,31.6%)to 140 alive patients.RESULTS Fatal outcomes occurred in 5%,35%,20%,and 40%of patients before 10,10-14,15-19,and≥20 years.The most common causes of death were cardiovascular(29.4%),respiratory failure(17.6%),including pneumonia(17.6%),and their associations(17.6%)and MPS Ⅱ progression(11.8%).Acute or chronic respiratory failure was in 53%.Died patients had higher birth weight,higher age of diagnosis,and start of ERT.Hydrocephalus,hydrocephalus bypass surgery,epilepsy,difficulty swallowing,and impaired movement after 12 years of age were significantly more common in the deceased patients.Cox regression analysis has revealed the following time-dependent covariates of the lethal outcome:1^(st)-year psychomotor development delay,delayed mental and speech development,hydrocephalus,swallow disorders,impossible walking at age>12 years,respiratory disorders,tracheostomy,neuronopathic form.CONCLUSION Increased birth weight,delayed diagnosis and the start of ERT,and development of neuronopathic form with impossible walking after 12 years were the main predictors of the fatal outcome.
基金Supported by the JSPS KAKENHI,No.JP21K10300 and No.JP24K02714.
文摘BACKGROUND Early diagnosis of left ventricular diastolic dysfunction(LVDD)is essential for preventing heart failure.B-type natriuretic peptide(BNP)is a viable marker for predicting LVDD,as elevated BNP levels have been associated with worsening LVDD in patients with diabetes over time.However,the utility of BNP as a diagnostic marker in diabetes is controversial,as BNP levels are often low in overweight individuals.AIM To examine the effectiveness of BNP levels and fragmented QRS(fQRS)on electrocardiography for diagnosing LVDD in patients with type 2 diabetes.METHODS This retrospective cohort study included 303 patients with type 2 diabetes(67.4±12.3 years old)with preserved ejection fraction(EF)≥50%admitted to Toyama University Hospital for glycemic management and comorbidity evaluation between November 2017 and April 2021.All participants underwent plasma BNP measurement,electrocardiography,and echocardiography.Cardiologists who were blinded to the BNP results assessed the electrocardiograms and echocardiograms.Subgroup analyses were conducted for overweight individuals.RESULTS Receiver operating characteristic(ROC)curve analysis determined optimal BNP cut-off values of 34.8 pg/mL and 7.2 pg/mL for diagnosing LVDD in non-overweight[area under the ROC curve(AUC):0.70]and overweight(AUC:0.55)groups,respectively(P=0.040).In the overweight subgroup,fQRS showed greater diagnostic accuracy for LVDD(AUC:0.67),indicating moderate diagnostic utility compared with the low performance of the BNP cutoff of 35 pg/mL(AUC:0.52)(P=0.010).Multivariate analyses confirmed that fQRS was superior to BNP for LVDD diagnosis regardless of the patient’s weight.CONCLUSION A BNP level≥35 pg/mL in non-overweight individuals may be a reliable LVDD marker.Additionally,fQRS was more effective than BNP in diagnosing LVDD irrespective of the patient’s weight.fQRS can complement BNP in the early detection of LVDD,especially in overweight patients,potentially improving early detection and mitigating progression to heart failure with preserved EF in patients with type 2 diabetes.
基金supported by grants from the National Key R&D Program of China(2019YFA0801603)the Guangdong High Level Innovation Research Institute(2021B0909050004)+2 种基金the National Natural Science Foundation of China(32330044,32170951,82201615,and 82101393)the Natural Science Foundation of Jiangsu Province(BK20201255 and BK20210008)the Fundamental Research Funds for the Central Universities(021414380533).
文摘Accurate timing of myelination is crucial for the proper functioning of the central nervous system. Here, we identified a de novo heterozygous mutation in TMEM63A (c.1894G>A;p. Ala632Thr) in a 7-year-old boy exhibiting hypomyelination. A Ca2+ influx assay suggested that this is a loss-of-function mutation. To explore how TMEM63A deficiency causes hypomyelination, we generated Tmem63a knockout mice. Genetic deletion of TMEM63A resulted in hypomyelination at postnatal day 14 (P14) arising from impaired differentiation of oligodendrocyte precursor cells (OPCs). Notably, the myelin dysplasia was transient, returning to normal levels by P28. Primary cultures of Tmem63a^(−/−) OPCs presented delayed differentiation. Lentivirus-based expression of TMEM63A but not TMEM63A_A632T rescued the differentiation of Tmem63a^(−/−) OPCs in vitro and myelination in Tmem63a^(−/−) mice. These data thus support the conclusion that the mutation in TMEM63A is the pathogenesis of the hypomyelination in the patient. Our study further demonstrated that TMEM63A-mediated Ca^(2+) influx plays critical roles in the early development of myelin and oligodendrocyte differentiation.
文摘The Association of Chinese Geneticists in America （ACGA） and the Hong Kong Society of Medical Genetics （HKSMG） held their first joint Conference on Genetic and Genomic Medicine in Hong Kong from June 9-11 in 2008 at the Cheung Kung Hai Conference Center, William MW Mong Block, Li Ka Shing Faculty of Medicine, the University of Hong Kong. Other co-organizers included the University of Hong Kong and Chinese Society of Medical Genetics. A satellite conference ＂ACGA-WZMC International Symposium of Genetics and Translational Medicine＂, co-organized with Wenzhou Medical College and Chinese Society of Medical Genetics, was held from June 12-14, 2008 at Wenzhou, Zhejiang Province of China.
基金Diponegoro University WCRU grant(No.118-03/UN7.6.1/PP/2021).
文摘In Indonesia,undervirilisation in 46,XY males is the most common form of difference of sex development(DSD).This can include hypospadias(misplacement of the urethra),micropenis,bifid scrotum,and undescended testis[1].Undervirilisation or 46,XY DSD can be associated with a number of congenital syndromes,including Smith-Lemli-Opitz Syndrome(OMIM 602858),caused by an inborn error of cholesterol synthesis,and characterised by growth delay,intellectual disability,microcephaly,distinctive facial features,cleft palate,limb anomalies,and hypospadias[2]or Opitz syndrome(also known as Opitz G/BBB syndrome).Opitz syndrome can be caused by variants in the X-linked midline 1(MID1)gene(Type I)or in an autosomal dominant manner by monoallelic variants in sperm antigen with calponin homology and coiled-coil domains 1-like(SPECC1L)on chromosome 22q11.2(Type II)[3].Opitz syndrome is characterised by hypospadias,hypertelorism,cleft lip/palate,and heart defects[4].The prevalence of X-linked Opitz syndrome is estimated to be from 1 in 50000 to 1 in 100000 males[5].Recognition of a syndrome informs appropriate clinical management and patient care.Therefore,although these syndromes are rare,hypospadias may be diagnosed before the emergence of other comorbidities meaning that it is crucial for clinicians to perform a thorough clinical evaluation with syndromic causes in mind.
基金Supported by The National Natural Science Foundation of China,No.82271949The Youth Project of General Items for Shaanxi Natural Science Foundation,No.2022JQ-908The Key Research and Development Program of Shaanxi Province,No.2023-YBSF-444.
文摘This editorial assesses the advancements in neuronavigation enhanced repetitive transcranial magnetic stimulation for depressive disorder and schizophrenia treatment.Conventional repetitive transcranial magnetic stimulation faces challenges due to the intricacies of brain anatomy and patient variability.Neuronavigation offers innovative solutions by integrating neuroimaging with three-dimensional localization to pinpoint brain regions and refine therapeutic targeting.This systematic review of recent literature underscores the enhanced efficacy of neuronavigation in improving treatment outcomes for these disorders.This editorial highlights the pivotal role of neuronavigation in advancing psychiatric care.
基金supported by grant from the Natural Science Foundation of Liaoning Province(No.2022 MS 208)the 345 Talent of Shengjing Hospital of China Medical University(No.M1395)the General Project of Shengjing Hospital of China Medical University(No.2023-M 1643).
文摘Dear Editor,Persistent Mullerian duct syndrome(PMDS;Online Mendelian Inheritance in Man[OMIM]:#261550)is a rare autosomal recessive inherent difference in sex development in males with Mullerian duct derivatives,including the uterus,fallopian tubes,and upper part of the vagina.'Approximately 88%of PMDS patients were found to have biallelic variants in the anti-Mullerian hormone(AMH;OMIM:*600957)or AMH type 2 receptor(AMHR2;OMIM:*600956)genes,and the rest were referred as idiopathic.I The serum AMH levels are usually very low or undetectable in PMDS patients with AMH gene mutations but normal or elevated in those with AMHR2 gene mutations.Here,an adult Chinese patient with PMDS carrying biallelic variants of the AMH gene was reported to have unexpectedly normal serum AMH level.Please refer to Supplementary Information of Patient and Methods for methodologies.
基金support from the Boettcher Foundation and the National Institutes of Health(1K99HD111686).
文摘Genomic mosaicism describes the phenomenon where some but not all cells within a tissue harbor unique genetic mutations.Traditionally,research focused on the impact of genomic mosaicism on clinical phenotype—motivated by its involvement in cancers and overgrowth syndromes.More recently,we increasingly shifted towards the plethora of neutral mosaic variants that can act as recorders of cellular lineage and environmental exposures.Here,we summarize the current state of the field of genomic mosaicism research with a special emphasis on our current understanding of this phenomenon in brain development and homeostasis.Although the field of genomic mosaicism has a rich history,technological advances in the last decade have changed our approaches and greatly improved our knowledge.We will provide current definitions and an overview of contemporary detection approaches for genomic mosaicism.Finally,we will discuss the impact and utility of genomic mosaicism.
基金supported by the project from National Basic Research Priorities Program of China (2014CB541702)National Natural Science Foundation of China (31671305)
文摘Aminoglycosides(Am An) are widely used for their great efficiency against gram-negative bacterial infections. However, they can also induce ototoxic hearing loss, which has affected millions of people around the world. As previously reported, individuals bearing mitochondrial DNA mutations in the 12 S rRNA gene, such as m.1555A>G and m.1494C>T, are more prone to Am An-induced ototoxicity. These mutations cause human mitochondrial ribosomes to more closely resemble bacterial ribosomes and enable a stronger aminoglycoside interaction. Consequently,exposure to Am An can induce or worsen hearing loss in these individuals. Furthermore, a wide range of severity and penetrance of hearing loss was observed among families carrying these mutations. Studies have revealed that these mitochondria mutations are the primary molecular mechanism of genetic susceptibility to Am An ototoxicity, though nuclear modifier genes and mitochondrial haplotypes are known to modulate the phenotypic manifestation.
文摘Klinefelter syndrome （KS） （47, XXY） is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. Most men with KS go through life without knowing the diagnosis, as only 25% are diagnosed and only a few of these before puberty. Apart from hypogonadism and azoospermia, most men with KS suffer from some degree of learning disability and may have various kinds of psychiatric problems. The effects of long-term hypogonadism may be difficult to discern from the gene dose effect of the extra X-chromosome. Whatever the cause, alterations in body composition, with more fat and less muscle mass and diminished bone mineral mass, as well as increased risk of metabolic consequences, such as type 2 diabetes and the metabolic syndrome are all common in KS. These findings should be a concern as they are not simply laboratory findings; epidemiological studies in KS populations show an increased risk of beth hospitalization and death from various diseases. Testosterone treatment should be offered to KS patients from early puberty, to secure a proper masculine development, nonetheless the evidence is weak or nonexisting, since no randomized controlled trials have ever been published. Here, we will review the current knowledge of hypogonadism in KS and the rationale for testosterone treatment and try to give our best recommendations for surveillance of this rather common, but often ignored, syndrome.
文摘AIM： To evaluate the effect of single nucleotide poly- morphisms of interleukin （IL）-28B, rs12979860 on progression and treatment response in chronic hepatitis C. METHODS： Patients （n = 64; 37 men, 27 women; mean age, 44 ＋ 12 years） with chronic hepatitis C, genotype 1, received treatment with peg-interferon plus ribavirin. Genotyping of rs12979860 was per- formed on peripheral blood DNA. Histopathological assessment of necroinflammatory grade and fibrosis stage were scored using the METAVIR system on a liver biopsy sample before treatment. Serum viral load, ami- notransferase activity, and insulin level were measured. Insulin resistance index, body mass index, waist/hip ratio, percentage of body fat and fibrosis progression rate were calculated. Applied dose of interferon and ribavirin, platelet and neutrophil count and hemoglobin level were measured. RESULTS： A sustained virological response （SVR） was significantly associated with IL28B polymorphism （CC vs -l-r allele： odds ratio （OR）, 25; CC vs CT allele： OR, 5.4）, inflammation activity （G 〈 1 vs G 〉 1： OR, 3.9）, fibrosis （F 〈 1 vs F 〉 1： OR, 5.9）, platelet count （〉 200 × 109/L vs 〈 200 ×109/L： OR, 4.7; OR in patients with genotype CT： 12.8）, fatty liver （absence vs presence of steatosis： OR, 4.8）, insulin resistance index （〈 2.5 vs 〉 2.5： OR, 3.9）, and baseline HCV viral load （〈 106 IU/mL vs 〉 106 IU/mL： OR, 3.0）. There was no association with age, sex, aminotransferases activity, body mass index, waist/hip ratio, or percentage body fat. There was borderline significance （P = 0.064） of increased fibrosis in patients with the I-I allele, and no differences in the insulin resistance index between groups of patients with CC, CT and -IF alleles （P = 0.12）. Spearman＇s rank correlation coefficient between insulin resistance and stage of fibrosis and body mass index was r = 0.618 and r = 0.605, respectively （P 〈 0.001）. Significant dif- ferences were found in the insulin resistance index （P = 0.01） between patients with and without steatosis. Patients with the C-I- allele and absence of a SVR had a higher incidence of requiring threshold dose reduction of interferon （P = 0.07）. CONCLUSION： IL28B variation is the strongest host factor not related to insulin resistance that determines outcome of antiviral therapy. Baseline platelet count predicts the outcome of antiviral therapy in CT allele patients.
基金supported by the National Natural Science Foundation of China(82071662,to Q.G.)。
文摘Identification of carriers of fragile X syndrome(FXS) with the subsequent prenatal diagnosis and knowledge of FXS-associated genetic profiles are essential for intervention in specific populations. We report the results of carrier screening of 39,458 East Asian adult women and prenatal diagnosis from 87 FXS carriers.The prevalence of FXS carriers and full mutation fetuses was estimated to be 1/581 and 1/3124 in East Asian populations, respectively. We confirmed the validity of the current threshold of CGG trinucleotide repeats for FMR1 categorization;the integral risks of full mutation expansion were approximately 6.0%,43.8%, and 100% for premutation alleles with 55—74, 75—89, and ≥ 90 CGG repeats, respectively. The protective effect of AGG(adenine-guanine-guanine nucleotides) interruption in East Asian populations was validated, which is important in protecting premutation alleles with 75—89 CGG repeats from full mutation expansion. Finally, family history was shown not an effective indicator for FXS carrier screening in East Asian populations, and population-based screening was more cost-effective. This study provides an insight into the largest carrier screening and prenatal diagnosis for FXS in East Asian populations to date. The FXSassociated genetic profiles of East Asian populations are delineated, and population-based carrier screening is shown to be promising for FXS intervention.
文摘Inflammatory bowel disease (IBD), which comprises ulcerative colitis and Crohn’s disease, is characterized by inflammation of the gastrointestinal tract. The trefoil factors 1, 2, and 3 (TFF1-3) are a family of peptides that play important roles in the protection and repair of epithelial surfaces, including the gastrointestinal tract. TFFs may be involved in IBD pathogenesis and are a potential treatment option. In the present review, we describe the TFF family and their potential role in IBD by summarizing the current knowledge of their expression, possible function and pharmacological role in IBD.
文摘The underlying pathophysiology of liver dysfunction in urea cycle disorders(UCDs) is still largely elusive. There is some evidence that the accumulation of urea cycle(UC) intermediates are toxic for hepatocyte mitochondria. It is possible that liver injury is directly caused by the toxicity of ammonia. The rarity of UCDs, the lack of checking of iron level in these patients, superficial knowledge of UC and an underestimation of the metabolic role of fumaric acid, are the main reasons that are responsible for the incomprehension of the mechanism of liver injury in patients suffering from UCDs. Owing to our routine clinical practice to screen for iron overload in severely ill neonates, with the focus on the newborns suffering from acute liver failure, we report a case of citrullinemia with neonatal liver failure and high blood parameters of iron overload. We hypothesize that the key is in the decreased-deficient fumaric acid production in the course of UC in UCDs that causes several sequentially intertwined metabolic disturbances with final result of liver iron overload. The presented hypothesis could be easily tested by examining the patients suffering from UCDs, for liver iron overload. This could be easily performed in countries with a high population and comprehensive national register for inborn errors of metabolism. Conclusion: Providing the hypothesis is correct, neonatal liver damage in patients having UCD can be prevented by the supplementation of pregnant women with fumaric or succinic acid, prepared in the form of iron supplementation pills. After birth, liverdamage in patients having UCDs can be prevented by supplementation of these patients with zinc fumarate or zinc succinylate, as well.
文摘Klinefelter syndrome （KS） is the set of symptoms that result from the presence of an extra X chromosome in males. Postnatal population-based KS screening will enable timely diagnosis of this common chromosomal disease, providing the opportunity for early intervention and therapy at the time point when they are most effective and may prevent later symptoms or complications. Therefore, through this study, we introduced a simple high-resolution melting （HRM） assay for KS screening and evaluated its clinical sensitivity and specificity in three medical centers using 1373 clinical blood samples. The HRM assay utilized a single primer pair to simultaneously amplify specific regions in zinc finger protein, X-linked （ZFX） and zinc finger protein, Y-linked （ZFY）. In cases of KS, the ratios of ZFX/ZFYare altered compared to those in normal males. As a result, the specific melting profiles differ and can be differentiated during data analysis. This HRM assay displayed high analytical specificity over a wide range of template DNA amounts （5 ng-50 ng） and reproducibility, high resolution for detecting KS mosaicism, and high clinical sensitivity （100%） and specificity （98.1%）. Moreover, the HRM assay was rapid （2 h per run）, inexpensive （0.2 USD per sample）, easy to perform and automatic, and compatible with both whole blood samples and dried blood spots. Therefore, this HRM assay is an ideal postnatal population-based KS screening tool that can be used for different age groups.
基金Supported by Sanming Project of Medicine in Shenzhen of China,No.SZSM201612074
文摘BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)encompasses a group of autosomal recessive disorders with high morbidity and mortality.Variants in the gene encoding tight junction protein-2(TJP2)have been linked to PFIC type 4(PFIC4),which predominantly presents in childhood.However,there are only limited data from adults with TJP2-related PFIC4.We report a family with an autosomal recessive disorder with a novel variant in the TJP2 gene in adults with very variable expression of PFIC4.CASE SUMMARY The index patient presented at 19 years old with liver cirrhosis and variceal bleeding and was treated with endoscopic banding and beta-blockers.In 2018,he developed primary liver cancer that was treated with radiofrequency ablation followed by liver transplantation in 2019.Genetic testing revealed a novel homozygous TJP2 variant causing PFIC4(TJP2([NM_004817.3]:c.[3334C>T];[3334C>T])).The consanguineous family consists of the father and mother(both heterozygous)and their 12 children,of which five carry the variant in a homozygous state;however,these five siblings have highly variable expression of PFIC4.Two homozygous brothers had cirrhosis and portal hypertension at diagnosis at the ages of 19 and 36.Two other homozygous brothers,age 23 and 19,and the homozygous sister,age 21,have elevated liver enzymes but presently no cirrhosis,which may suggest an age-dependent penetrance.In addition,five sisters had severe and mild intrahepatic cholestasis of pregnancy and carry the TJP2 variant in a homozygous and heterozygous state,respectively.CONCLUSION This novel TJP2 variant is associated with PFIC4 causing severe liver disease with cirrhosis and primary liver cancer in adolescents/adults.
基金supported by the National Natural Science Foundation of China (81371788 and 81171580)the Specialized Research Fund for the Doctoral Program of Higher Education (20112104110012)the Outstanding Scientific Fund of Shengjing Hospital
文摘Viruses commonly create favorable cellular conditions for their survival through multiple mechanisms. Micro RNAs(mi RNAs), which function as post-transcriptional regulators, are utilized by human cytomegalovirus(HCMV) in its infection and pathogenesis. In the present study, the DNA replication inhibitor Geminin(GMNN) was identified to be a direct target of hcmv-mi R-US5-1. Overexpression of hcmv-mi R-US5-1 could block the accumulation of GMNN during HCMV infection, and the decrease of GMNN expression caused by hcmv-mi R-US5-1 or GMNN specific si RNA reduced HCMV DNA copies in U373 cells. Meanwhile, ectopic expression of hcmv-mi R-US5-1 and consequent lower expression of GMNN influenced host cell cycle and proliferation. These results imply that hcmv-mi R-US5-1 may affect viral replication and host cellular environment by regulating expression kinetics of GMNN during HCMV infection.
文摘AIM: To investigate the relation of the response to Helicobacter pylori eradication therapy to the depth of tumor invasion and chromosome abnormalities in patients with mucosaassociated lymphoid tissue (MALT) lymphoma and to determine the clinical value of aneuploidy.METHODS: We studied 13 patients with localized gastric MALT lymphoma of stage E1. Before eradication therapy,the depth of tumor invasion was assessed by endoscopic ultrasonography in 8 patients and by endoscopic examination and gastrointestinal series in the remaining patients. To detect chromosomal abnormalities, paraffin-embedded tissue sections of diagnostic biopsy specimens underwent tissuefluorescence in situ hybridization (FISH), using chromosomespecific α-satellite DNA probes for chromosomes 3,7,12,and 18 and YAC clones for t(11;18)(q21;q21).RESULTS: Seven of the 13 patients had complete regression(CR) in response to H pylori eradication therapy. No patient with CR had submucosal tumor invasion. Trisomy 18 was seen in 1 patient with CR, and both trisomies 12 and 18 were present in another patient with CR. All patients with no response or progressive disease had deep submucosal tumor invasion and showed t(11;18)(q21;q21) or trisomy 3. Trisomy 7 was not detected in this series of patients.CONCLUSION: The depth of tumor invasion is an accurate predictor of the response of stage E1 MALT lymphoma to H pylori eradication therapy and is closely associated with the presence of chromosomal abnormalities. Trisomy 3 may predict the aggressive development of MALT lymphoma.
