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autosomal recessive cerebellar ataxia with spasticity due to a rare mutation in GBA2 gene in a large consanguineous Saudi family

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Genes & Diseases 2021年第1期8卷 110-114页

作者： Hussein Algahtani Bader Shirah Ikram Ullah Mohammad H.Al-Qahtani Angham Abdulrahman Abdulkareem Muhammad Imran Naseer King Abdulaziz Medical City King Saud bin Abdulaziz University for Health SciencesJeddahSaudi Arabia King Abdullah International Medical Research Center King Saud bin Abdulaziz University for Health SciencesJeddahSaudi Arabia Sulaiman Bin Abdullah Aba Al-Khail Centre for Interdisciplinary Research in Basic Sciences International Islamic UniversityIslamabadPakistan Center of Excellence in Genomic Medicine Research King Abdulaziz UniversityJeddahSaudi Arabia Department of Medical Laboratory Technology Faculty of Applied Medical SciencesKing Abdulaziz UniversityJeddahSaudi Arabia

The nonlysosomal glucosylceramidase b2(GBA2)gene encode an enzyme that catalyzes the hydrolysis of glucosylceramide to glucose and *** in the GBA2 gene have been reported to cause hereditary spastic paraplegia,autosomal recessive cerebellar ataxia with spasticity,and Marinescu-Sjogren-Like *** this study,we report the clinical features and genetic diagnosis of autosomal recessive cerebellar ataxia with spasticity due to a rare mutation in GBA2 gene in a large consanguineous Saudi *** included a large consanguineous Saudi family with a presumptive clinical diagnosis of ataxia at King Abdulaziz Medical City in Jeddah,Saudi *** family included six affected individuals and four unaffected in addition to the *** exome sequencing(WES)was performed for the probandⅣ-5,and Sanger sequencing was used to confirm the variant in other family *** study was performed using DNA from the parents and siblings of the *** analysis identified a homozygous variant c.2618G>A,p.(Arg873His)in GBA2 *** homozygous variant was identified in affected members of the family while the parents and the other four siblings were heterozygous carriers of the *** sibling was not available for genetic *** variant identified in our patients is classified as pathogenic considering the current evidence of the *** recessive cerebellar ataxia with spasticity is an extremely rare genetic disorder with very few cases reported in the *** conclude that the c.2617G>A mutation in GBA2 gene causes the loss of function with abolishment of the enzymatic activity that causes the *** report adds further evidence to support the pathogenicity of this *** patients had the classical clinical phenotype of cerebellar ataxia and spasticity consistent with previous reports in the literature.

关键词： Ataxia with spasticity autosomal recessive GBA2 Novel mutation Saudi Arabia

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autosomal recessive hereditary auditory neuropathy

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中华耳科学杂志 2003年第1期1卷 8-13,18页

作者：王秋菊顾瑞曹菊阳 Yu Liming GUO WEIWEI YU Ning ZHOU Na Han Dongyi YANG Weiyan Department of Otorhinolaryngology Head and Neck Surgery China PLA Otolaryngology Institute China PLA General Hospital 28 Fuxing Road Beijing 100853 China

Objectives: Auditory neuropathy (AN) is a sensorineural hearing disorder characterized by absent or abnormal auditory brainstem responses (ABRs) and normal cochlear outer hair cell function as measured by otoacoustic emissions (OAEs). Many risk factors are thought to be involved in its etiology and pathophysiology. Three Chinese pedigrees with familial AN are presented herein to demonstrate involvement of genetic factors in AN etiology. Methods: Probands of the above - mentioned pedigrees, who had been diagnosed with AN, were evaluated and followed up in the Department of Otolaryngology Head and Neck Surgery, China PLA General Hospital. Their family members were studied and the pedigree diagrams were established. History of illness, physical examination,pure tone audiometry, acoustic reflex, ABRs and transient evoked and distortion- product otoacoustic emissions (TEOAEs and DPOAEs) were obtained from members of these families. DPOAE changes under the influence of contralateral sound stimuli were observed by presenting a set of continuous white noise to the non - recording ear to exam the function of auditory efferent system. Some subjects received vestibular caloric test, computed tomography (CT)scan of the temporal bone and electrocardiography (ECG) to exclude other possible neuropathy disorders. Results: In most affected subjects, hearing loss of various degrees and speech discrimination difficulties started at 10 to16 years of age. Their audiological evaluation showed absence of acoustic reflex and ABRs. As expected in AN, these subjects exhibited near normal cochlear outer hair cell function as shown in TEOAE & DPOAE recordings. Pure- tone audiometry revealed hearing loss ranging from mild to severe in these patients. autosomal recessive inheritance patterns were observed in the three families. In Pedigree Ⅰ and Ⅱ, two affected brothers were found respectively, while in pedigree Ⅲ, 2 sisters were affected. All the patients were otherwise normal without evidence

关键词： auditory neuropathy inheritance pattern autosomal recessive audiology candidate genes screening otology

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Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease

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World Journal of Nephrology 2017年第4期6卷 188-200页

作者： William E Sweeney Philip Frost Ellis D Avner Children’s Research Institute Children’s Hospital Health System of Wisconsin and the Medical College of WisconsinMedical College of Wisconsin Calesca Pharmaceuticals Inc.

AIMTo investigate the therapeutic potential of tesevatinib （TSV）, a unique multi-kinase inhibitor currently in Phase Ⅱ clinical trials for autosomal dominant polycystic kidney disease （ADPKD）, in well-defined rodent models of autosomal recessive polycystic kidney disease （ARPKD）. METHODSWe administered TSV in daily doses of 7.5 and 15 mg/kg per day by I.P. to the well characterized bpk model of polycystic kidney disease starting at postnatal day（PN） 4 through PN21 to assess efficacy and toxicity in neonatal mice during postnatal development and still undergoing renal maturation. We administered TSV by oral gavage in the same doses to the orthologous PCK model （from PN30 to PN90） to assess effcacy and toxicity in animals where developmental processes are complete. The following parameters were assessed： Body weight, total kidney weight; kidney weight to body weight ratios; and morphometric determination of a cystic index and a measure of hepatic disease. Renal function was assessed by： Serum BUN; creatinine; and a 12 h urinary concentrating ability. Validation of reported targets including the level of angiogenesis and inhibition of angiogenesis （active VEGFR2/KDR） was assessed by Western *** study demonstrates that：（1） in vivo pharmacological inhibition of multiple kinase cascades with TSV reduced phosphorylation of key mediators of cystogenesis： EGFR, ErbB2, c-Src and KDR; and （2） this reduction of kinase activity resulted in signifcant reduction of renal and biliary disease in both bpk and PCK models of ARPKD. The amelioration of disease by TSV was not associated with any apparent *** data supports the hypothesis that this multi-kinase inhibitor TSV may provide an effective clinical therapy for human ARPKD.

关键词： autosomal recessive autosomal dominant Polycystic kidney disease Therapy Kinase inhibition Multi-kinase inhibitor Phosphorylation Renal cysts Biliary G-protein coupled receptor

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Mutations of the AAAS gene in an Indian family with Allgrove's syndrome

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World Journal of Gastroenterology 2006年第29期12卷 4764-4766页

作者： Ashis Mukhopadhya Sumita Danda Angela Huebner Ashok Chacko Department of Gastrointestinal Sciences Christian Medical College VelloreIndia Children's Hospital Technical University Dresden Germany

The triple A or AIIgrove＇s syndrome is an autosomal recessive disorder characterized by the triad of achalasia cardia, alacrima and ACTH resistant adrenocortical insufficiency. Mutations of the Achalasia-AddisonianismAlacrima-Syndrome （AAAS） gene on chromosome 12q13 are associated with this syndrome. We report an Indian family where two siblings were homozygous for a known mutation of the AAAS gene and presented with the classical triad of symptoms. The mother and the brother were heterozygous and asymptomatic. The affected siblings had iron deficiency anemia and the younger sister had pes cavus and palmoplantar keratosis. Neurological symptoms were absent in both affected children. Recognition of this syndrome can lead to early treatment of adrenal insufficency and genetic counselling.

关键词： Allgrove's syndrome Triple A syndrome autosomal recessive Genetic mutation India

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Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia

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Translational Neurodegeneration 2019年第1期8卷 230-242页

作者： Qiao Wei Hai-Lin Dong Li-Ying Pan Cong-Xin Chen Yang-Tian Yan Rou-Min Wang Hong-Fu Li Zhi-Jun Liu Qing-Qing Tao Zhi-Ying Wu Department of Neurology and Research Center of Neurology in Second Affiliated Hospital and Key Laboratory of Medical Neurobiology of Zhejiang ProvinceZhejiang University School of Medicine88 Jiefang RoadHangzhou 310009China Longyan First Hospital Fujian Medical UniversityLongyanChina Department of Neurology and Institute of Neurology Huashan HospitalShanghai Medical CollegeFudan UniversityShanghaiChina Joint Institute for Genetics and Genome Medicine between Zhejiang University and University of Toronto Zhejiang UniversityHangzhouChina

Background:Although many causative genes of hereditary spastic paraplegia(HSP)have been uncovered in recent years,there are still approximately 50% of HSP patients without genetically diagnosis,especially in autosomal recessive(AR)HSP *** studies have been performed to determine the genetic spectrum and clinical profiles of recessive HSP patients in the Chinese ***:In this study,we investigated 24 Chinese index AR/sporadic patients by targeted next-generation sequencing(NGS),Sanger sequencing and multiplex ligation-dependent probe amplification(MLPA).Further functional studies were performed to identify pathogenicity of those uncertain significance ***:We identified 11 mutations in HSP related genes including 7 novel mutations,including two(p.V1979_L1980delinsX,p.F2343 fs)in SPG11,two(p.T55 M,p.S308 T)in AP5Z1,one(p.S242N)in ALDH18A1,one(p.D597fs)in GBA2,and one(p.Q486X)in ATP13A2 in 8 index patients and their family *** in ALDH18A1,AP5Z1,CAPN1 and ATP13A2 genes were firstly reported in the Chinese ***,the clinical phenotypes of the patients carrying mutations were described in *** mutation(p.S242 N)in ALDH18A1 decreased enzyme activity of P5CS and mutations(p.T55 M,p.S308 T)in AP5Z1 induced lysosomal ***:Our results expanded the genetic spectrum and clinical profiles of AR-HSP patients and further demonstrated the efficiency and reliability of targeted NGS diagnosing suspected HSP patients.

关键词： Hereditary spastic paraplegia autosomal recessive Targeted next-generation sequencing Chinese Genetic spectrum Phenotype

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Whole-genome amplification/preimplantation genetic testing for propionic acidemia of successful pregnancy in an obligate carrier Mexican couple:A case report

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World Journal of Clinical Cases 2021年第29期9卷 8797-8803页

作者： Adina Neumann Miguel Angel Alcantara-Ortigoza Ariadna González-del Angel Nestor Alejandro Zarate Díaz Javier Sam Santana Leonardo M Porchia Esther López-Bayghen Laboratorio de Investigación y Diagnóstico Molecular IngenesMexico City 05320Mexico Laboratorio de Biología Molecular Subdirección de Investigación MédicaInstituto Nacional de PediatríaMexico City 04530Mexico DNA-GEN S.C.Centro de Alta Especialidad en Genética Humana Mexico City 14070Mexico Investigación Clínica IngenesPuebla 72820Mexico Departamento de Toxicología Centro de Investigación y de Estudios Avanzados del Instituto Politécnico NacionalMexico City 07360Mexico

BACKGROUND Identifying a potential single monogenetic disorder in healthy couples is costly due to the Assisted Reproduction facilities'current methodology for screening,which focuses on the detecting multiple genetic disorders at ***,we report the successful application of a low-cost and fast preimplantation genetic testing for monogenic/single gene defects(PGT-M)approach for detecting propionic acidemia(PA)in embryos obtained from a confirmed heterozygous propionyl-CoA carboxylase alpha subunit(PCCA)*** SUMMARY A fertile 32-years old Mexican couple with denied consanguinity sought antenatal genetic *** were suspected obligate PA carriers due to a previous deceased PA male newborn with an unknown PCCA/propionyl-CoA carboxylase beta subunit(PCCB)***-Generation Sequencing revealed a heterozygous genotype for a pathogenic PCCA variant(c.2041-1G>T,ClinVar:RCV-000802701.1;dbSNP:rs1367867218)in both *** couple requested in vitro fertilization(IVF)and PGT-M for *** IVF,12 oocytes were collected and fertilized,of which two resulted in high-quality *** biopsies and Whole Genome Amplification by a fragmentation/amplification-based method were performed and revealed that the two embryos were *** polymerase chain reaction and further Sanger sequencing of the exon-intron borders revealed a wild-type PCCA male embryo and a heterozygous c.2041-1G>T female *** embryos were transferred,resulting in a clinical pregnancy and the delivery of a healthy male newborn(38 wk,weight:4080 g,length:49 cm,APGAR 9/9).The absence of PA was confirmed by expanded newborn *** We show that using PGT-M with Whole Genome Amplification templates,coupled with IVF,can reduce the transmission of a pathogenic variant of the PCCA gene.

关键词： Propionic acidemia autosomal recessive Propionyl-CoA carboxylase alpha subunit(PCCA)gene Preimplantation genetic testing Next-generation sequencing Embryo transfer

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3M syndrome patient with a novel mutation:A case rep

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World Journal of Clinical Cases 2024年第8期12卷 1454-1460页

作者： Ming-Ran Luo Si-Ming Dai Yin Li Qian Wang Hao Liu Peng Gao Jia-Yun Liu Jian Chen Shu-Jie Zhao Guo-Yong Yin Department of Orthopedics The First Affiliated Hospital of Nanjing Medical UniversityNanjing 210029Jiangsu ProvinceChina

BACKGROUND A rare autosomal recessive genetic disorder,3M syndrome,is characterized by severe intrauterine and postnatal growth *** with 3M syndrome typically exhibit short stature,facial deformities,long tubular bones,and high vertebral bodies but generally lack mental abnormalities or other organ *** genes associated with 3M syndrome include CUL7,OBSL1 and *** clinical and molecular characteristics of patient with 3M syn-drome are unique and serve as important diagnostic *** SUMMARY In this case,the patient displayed square shoulders,scoliosis,long slender tubular bones,and normal neurological ***,the patient did not exhibit the typical dysmorphic facial features,relative macrocephaly,or growth retardation commonly observed in individuals with 3M *** exon sequencing revealed a novel heterozygous c.56681+1G>C(Splice-3)variant and a previously reported nonsense heterozygous c.3341G>A(***1114Ter)variant of ***,it is important to note that the clinical features of 3M syndrome may not always be observable,and genetic confirmation is often ***,the identification of the c.5683+1G>C variant in OBSL1 is notewor-thy because it has not been previously reported in public *** Our study identified a new variant(c.5683+1G>C)of OBSL1 that contributes to expanding the molecular profile of 3M syndrome.

关键词： 3M syndrome CUL7 OBSL1 CCDC8 autosomal recessive Case report

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Methylmalonic Acidemia: An Unusual Cause of Chronic Renal Disease in Adults

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Open Journal of Nephrology 2024年第3期14卷 334-339页

作者： Kamel El Reshaid Abdulrahman Al Kanderi Department of Medicine Faculty of Medicine Kuwait University Kuwait City Kuwait Department of Nephrology Al-Jahra Hospital Ministry of Health Kuwait City Kuwait

Background: Methylmalonic aciduria (MMA) is a genetic disorder of aminoacid metabolism, due to mutations in methylmalonyl-CoA mutase, which leads to the accumulation of methylmalonic acid in body fluids. Patients typically present at the age of 1 month to 1 year with dehydration, renal impairment as well as neurologic manifestations viz. seizure, encephalopathy, strokes and disease in the globus pallidi. The case: a 26-year-old man presented with severe acute on top of chronic renal disease with serum creatinine at 590 umol/L and bilateral 8 cm kidneys with thin and echogenic cortex. He had: (a) hypernatremic dehydration, metabolic acidosis and high ammonia level with (b) a history of multiple similar attacks since the age of 8 months. Diagnosis of MMA was confirmed by high serum and urine enzymatic levels as well as genetic testing. His initial management included support with replacements of fluids, electrolytes, and bicarbonates as well as intravenous dextrose, vitamin B12 and broad-spectrum antibiotic (Meropenem) for his chest infection. Subsequently, he received 1) CARBAGLU (carglumic acid) for 7 days to lower his ammonia level to Conclusion: Untreated homozygous MMA variants, can achieve adulthood with significant renal disease yet their morbidity and mortality can be ameliorated with diet and specific therapy.

关键词： Methylmalonic Acidemia Kidney Failure Metabolic Acidosis autosomal recessive Amino Acid Disorder Kreps Cycle Hyperammonia Vitamin 12 Carnitine

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Parkin gene mutations in younger onset Parkinson's disease

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中国临床神经科学 2000年第Z1期8卷 25-页

作者： Piu Chan Hua Bai Rong Chen J Willian Langston Department of Neurology Xuanwu Hospital of the Capital University of Medical Sciences Beijing 100053 China The Parkinson's Institute 1170 Morse Avenue Sunnyvale California 94089 USA Department of Neurology Xuanwu Hospital of the Capital University of Medical Sciences Beijing 100053 China The Parkinson's Institute 1170 Morse Avenue Sunnyvale California 94089 USA The Parkinson's Institute 1170 Morse Avenue Sunnyvale California 94089 USA

Objective': To screen for exonic and point mutations in the Parkin gene in both Chinese and American Caucasian younger onset Parkinson's disease (YOPD) ***: Recently, the autosomal recessive juvenile parkinsonism (ARJP) gene was first mapped to chromosome 6q25.2-27 and was late cloned and designated as Parkin. A wide variety of mutations, including homozygous exonic deletions and point mutations,have been found in at least more than 50 ARJP families of Japanese, European and Jewish origins. However, the distribution of Parkin gene mutations is not known in the Chinese and American Caucasians, It is also not clear how frequent the Parkin gene mutations occur in YOPD patients. Method and Material: Twenty-one Chinese subjects were selected from 121 Chinese PD inpatients who were admitted to the Xuanwu Hospital in Beijing between August of 1998 and April of 1999 and had an onset before age 51. Thirty-eight American subjects were PD patients with an onset before age 41 from the Tissue Bank of the Parkinson′s Institute at California. Homozygous exonic deletion and point mutations in all 12 exons of the Parkin gene were screened using PCR, SSCP and direct sequencing methods. Mutations identified by sequencing were further confirmed by restriction enzyme digestion. Results: Five different types of homozygous deletion mutations (exons 1, 4, 6, 7 and 12) were found in 7 out of 21 Chinese cases but none of the 37 American Caucasian patients in all 12 exons of Parkin gene. One novel and four polymorphic mutationswere found in the American Caucasian YOPD ***: our results suggest that homozygous exonic deletions in the Parkin gene may account for a significant amount of YOPD in the Chinese but not in the American Caucasian YOPD.

关键词： Parkin gene point mutations autosomal recessive restriction enzyme direct sequencing Xuanwu Hospital

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Lafora progressive myoclonus epilepsy: NHLRC1 mutations affect glycogen metabolism

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世界最新医学信息文摘 2015年第5期 6-6页

作者： Philippe Couarch Santiago Vernia Isabelle Gourfinkel-An Ga tan Lesca Svetlana Gataullina Estelle Fedirko Oriane Trouillard Christel Depienne Olivier Dulac Dominique Steschenko Eric Leguern Pascual Sanz Stéphanie Baulac

Lafora disease is a fatal autosomal recessive formof progressive myoclonus epilepsy. Patients manifest myoclonus and tonic–clonic seizures, visual hallucinations, intellectual, and progressive neurologic deterioration beginning in *** two genes known to be involved in Lafora disease are EPM2 A and NHLRC1(EPM2B). The EPM2 A gene encodes laforin,a dual-specificity protein phosphatase, and the NHLRC1 gene encodes malin, an E3-ubiquitin ligase. The two proteins interact with each other and, as a complex, are thought to regulate glycogen synthesis. Here, we report three Lafora families with two novel pathogenic mutations(C46Y and L261P) and two recurrent mutations(P69A and D146N) in NHLRC1. Investigation of their functional consequences in cultured mammalian cells revealed that malin C46 Y, malin P69 A, malin D146 N, and malin L261 P mutants failed to downregulate the level of R5/PTG, a regulatory subunit of protein phosphatase 1 involved in glycogen synthesis. Abnormal accumulation of intracellular glycogen was observed with all malin mutants, reminiscent of the polyglucosan inclusions(Lafora bodies) present in patients with Lafora disease.

关键词： Epilepsy Mendelian disorder Genetics autosomal recessive

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