High Levels of Protein C Are Determinated by PROCR H3 in a Dutch Family.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2139-2139
Author(s):  
Maria Carolina Pintao ◽  
Sara Roshani ◽  
Marieke C.H. de Visser ◽  
Cris Tieken ◽  
Michael W.T. Tanck ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Candidate Genes ◽  
Protein C ◽  
Transmembrane Domain ◽  
Family Members ◽  
Endothelial Protein C Receptor ◽  
Lod Score ◽  
Chromosome 20 ◽  
The Family ◽  
The Mean

Abstract Abstract 2139 Poster Board II-116 The natural anticoagulant protein C (PC) circulates in blood at a concentration of about 60 nM. Inter-individual variations in the levels of PC are in part genetically determined, but which loci in the genome are involved is only partially known. In a recent study we identified a locus on chromosome 20 which was associated with high PC levels in a large pedigree from the GENES study (LOD score >5 at 55 cMorgan). Candidate genes related to the PC pathway under the LOD-1 region encoded FOXA2 (previously known as HNF3 beta, a nuclear factor regulating protein C gene transcription), thrombomodulin (THBD,which is key to activation of PC), and the endothelial protein C receptor (PROCR). Here we present data that pinpoint a SNP in PROCRas being responsible for the observed segregation of high PC levels. The pedigree has 218 members and was ascertained through a proband with a family history of venous thrombosis (VT). Classical genetic risk factors for thrombosis (i.e. PC-, PS-, antithrombin deficiency, factor V Leiden and prothrombin G20201A) were not present. Complete medical data, plasma measurements and DNA was available for 161 family members. The mean age was 47±15 (range 15-87) years. The mean PC plasma level was 116±25% (range 72-212). Four family members had experienced VT and 2 had had recurrence. These symptomatic members had normal to high PC levels (66, 82, 114 and 178%).Haplotypes (and genotypes) for PROCR were determined in the family members by TaqMan assay using tag SNPs (single nucleotide polymorphisms) and PROCR H3 was associated with the levels of PC in the family. Furthermore, the promoter, exons, and 3`UTR of the 3 candidate genes were sequenced in 13 individuals, 9 with high and 4 with normal plasma PC levels. Critical SNPs that were encountered during sequencing were genotyped in all family members, namely FOXA2 rs1055080 (3`UTR) and rs2277764 (promoter region). As those 2 SNPs were inherited together in the set of 13 patients and also in the LETS (data not shown), our further analysis used only rs1055080. Plasma soluble endothelial protein C receptor (sEPCR) and soluble thrombomodulin (sTM) levels were measured with an ELISA assay. PC and sEPCR and levels were compared between PROCR H3 and FOXA2 rs1055080 carriers and non carriers by Student's t-test. sTM was analyzed by Mann-Whitney test. Association between PC levels and sEPCR/sTM levels were evaluated using linear regression analysis. Afterwards associations were adjusted for the PROCR H3 and FOXA2 rs1055080 SNP separately to detect their possible confounding effect. DNA sequencing only yielded previously reported SNPs in FOXA2, THBD and PROCR. Only the above mentioned SNPs were associated with PC plasma levels. Linkage analysis for PC levels using the original markers (from Marshifield) and adding the new PROCR and FOXA2 SNPs did not change the LOD score. When the analysis was adjusted for the mentioned markers, the LOD score dropped below 2. sEPCR has a bimodal distribution; mean ± SD was 103±27 ng/ml for the first mode and 262±70 ng/ml for the second mode. Median (range) sTM was 1.2 ng/ml (0.1-4). Linkage analysis for sEPCR levels yielded a high LOD score (above 6) that was accentuated to above 8 when PROCR H3 was included as a marker. For sTM, the LOD score was low with every combination of markers. PC, sEPCR and sTM levels were compared between PROCR H3 carriers and non-carriers and both PC levels and sEPCR levels were influenced by this PROCR haplotype, but not sTM. In conclusion, chromosome 20 harbors a locus which influences PC levels and also the levels of sEPCR, but not the levels of sTM. A detailed analysis with SNPs in PROCR, THBD and FOXA2suggests that the so-called PROCR H3 is directly responsible for the increased PC and sEPCR levels in this family. PROCR H3 is known to represent a g.A6936G substitution leading to a p.Ser219Gly replacement in the transmembrane domain of EPCR. The Gly219 isoform is more sensitive to sheddases (such as the ADAM17 metalloprotease) and is associated with generation of truncated mRNA lacking the transmembrane domain. However, the exact mechanism by which EPCR and sEPCR levels influence the level of PC remains to be determined Disclosures: No relevant conflicts of interest to declare.

scholarly journals PDS Is a New Susceptibility Gene to Autoimmune Thyroid Diseases: Association and Linkage Study

2003 ◽  
Vol 88 (5) ◽  
pp. 2274-2280 ◽  
Author(s):  
Hassen Hadj Kacem ◽  
Ahmed Rebai ◽  
Noureddine Kaffel ◽  
Saber Masmoudi ◽  
Mohamed Abid ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Transmembrane Protein ◽  
Susceptibility Gene ◽  
Association Test ◽  
Lod Score ◽  
Autoimmune Thyroid ◽  
The Family ◽  
Family Based ◽  
Idiopathic Myxedema ◽  
Pds Gene

Autoimmune thyroid disease (AITD), including Graves’ disease (GD), Hashimoto thyroiditis (HT), and primary idiopathic myxedema, is caused by multiple genetic and environmental factors. Genes involved in immune response and/or thyroid physiology appear to influence susceptibility to disease. The PDS gene (7q31), responsible for Pendred syndrome (congenital sensorineural hearing loss and goiter), encodes a transmembrane protein known as pendrin. Pendrin is an apical porter of iodide in the thyroid. To evaluate the contribution of PDS gene in the genetic susceptibility of AITD, we examined four microsatellite markers in the gene region. Two hundred thirty-three unrelated patients (GD,141; HT, 54; primary idiopathic myxedema, 38), 15 multiplex AITD families (104 individuals/46 patients) and 154 normal controls were genotyped. Analysis of case-control data showed a significant association of D7S496 and D7S2459 with GD (P = 10−3) and HT (P = 1.07 10−24), respectively. The family-based association test showed significant association and linkage between AITDs and alleles 121 bp of D7S496 and 173 bp of D7S501. Results obtained by transmission disequilibrium test are in good agreement with those obtained by the family-based association test. Indeed, evidence for linkage and association of allele 121 bp of D7S496 with AITD was confirmed (P = 0.0114). Multipoint nonparametric linkage analysis using MERLIN showed intriguing evidence for linkage with marker D7S496 in families with only GD patients [Z = 2.12, LOD = 0.81, P = 0.026]. Single-point and multipoint parametric LOD score linkage analysis was also performed. Again, the highest multipoint parametric LOD score was found for marker D7S496 (LOD = 1.23; P = 0.0086) in families segregating for GD under a dominant model. This work suggests that the PDS gene should be considered a new susceptibility gene to AITDs with varying contributions in each pathology.

scholarly journals An exploratory study to estimate cost-effectiveness threshold value for life saving treatments in western Iran

2020 ◽  
Author(s):  
Najmeh Moradi ◽  
Abraha Woldemichael ◽  
Parisa Malekian ◽  
Delnia Moradi Rotavandi ◽  
Satar Rezaei
Keyword(s):  
Cost Effectiveness ◽  
Family Members ◽  
Threshold Value ◽  
Education Level ◽  
Monthly Income ◽  
Tobit Regression ◽  
Life Saving ◽  
Additional Qaly ◽  
The Family ◽  
The Mean

Abstract Background Cost-effectiveness analysis provides a crucial means for evidence-informed decision-making on resource allocation. This study aims to elicit individuals' willingness to pay (WTP) for one additional quality-adjusted life-year (QALY) gained from life-saving treatment and associated factors in Kermanshah city, western Iran. Methods We conducted a cross-sectional study on a total of 847 adults aged 18 years and above to elicit their WTP for one additional QALY gained by oneself and a family member using a hypothetical life-saving treatment. We used a multistage sampling technique to select the samples, and the Iranian version of EQ-5D-3L, and visual analogue scale (VAS) measures was used to obtain the participants’ health utility value. The Tobit regression model was used to identify the factors affecting WTP per QALY values. Results The mean WTP value and standard deviation (SD) was US$ 862 (3224) for the respondents and US$ 1355 (3993) for the family members. The mean utility values using EQ-5D-3L and VAS methods were 0.779 and 0.800, respectively. The WTP for the additional QALY gained by the individual participants using the EQ-5D-3L and VAS methods were respectively US$ 1202 and US$ 1101, while the estimated value of the family members was US$ 1355 (SD= 3993). The Tobit regression models indicated that monthly income, education level, sex, and birthplace were statistically significantly associated (p < 0.05) with both the WTP for the extra QALY values using the EQ-5D-3L and the VAS methods. Besides, education level and monthly income showed statistically significant relationships with the WTP for the additional QALY gained by the family members (p < 0.05). Conclusion Our findings indicated that the participants' WTP value of the additional QALY gained from the hypothetical life-saving treatment was in the rage of 0.20 to 0.24 of Iran’s gross domestic product (GDP) per capita, which is far lower than the World Health Organization (WHO) recommended CE threshold value of one. This wide gap reflects the challenges the health system is facing and requires further research for defining the most appropriate CE threshold at the local level.

scholarly journals An Exploratory Study to Estimate Cost-effectiveness Threshold Value for Life Saving Treatments in Western Iran

2020 ◽  
Author(s):  
Najmeh Moradi ◽  
Abraha Woldemichael ◽  
Parisa Malekian ◽  
Delnia Moradi Rotavandi ◽  
Satar Rezaei
Keyword(s):  
Cost Effectiveness ◽  
Family Members ◽  
Threshold Value ◽  
Education Level ◽  
Monthly Income ◽  
Tobit Regression ◽  
Life Saving ◽  
Additional Qaly ◽  
The Family ◽  
The Mean

Abstract Background: Cost-effectiveness analysis provides a crucial means for evidence-informed decision-making on resource allocation. This study aims to elicit individuals' willingness to pay (WTP) for one additional quality-adjusted life-year (QALY) gained from life-saving treatment and associated factors in Kermanshah city, western Iran.Methods: We conducted a cross-sectional study on a total of 847 adults aged 18 years and above to elicit their WTP for one additional QALY gained by oneself and a family member using a hypothetical life-saving treatment. We used a multistage sampling technique to select the samples, and the Iranian version of EQ-5D-3L, and visual analogue scale (VAS) measures was used to obtain the participants’ health utility value. The Tobit regression model was used to identify the factors affecting WTP per QALY values.Results: The mean WTP value and standard deviation (SD) was US$ 862 (3224) for the respondents and US$ 1355 (3993) for the family members. The mean utility values using EQ-5D-3L and VAS methods were 0.779 and 0.800, respectively. The WTP for the additional QALY gained by the individual participants using the EQ-5D-3L and VAS methods were respectively US$ 1202 and US$ 1101, while the estimated value of the family members was US$ 1355 (SD= 3993). The Tobit regression models indicated that monthly income, education level, sex, and birthplace were statistically significantly associated (p < 0.05) with both the WTP for the extra QALY values using the EQ-5D-3L and the VAS methods. Besides, education level and monthly income showed statistically significant relationships with the WTP for the additional QALY gained by the family members (p < 0.05). Conclusion: Our findings indicated that the participants' WTP value of the additional QALY gained from the hypothetical life-saving treatment was in the rage of 0.20 to 0.24 of Iran’s gross domestic product (GDP) per capita, which is far lower than the World Health Organization (WHO) recommended CE threshold value of one. This wide gap reflects the challenges the health system is facing and requires further research for defining the most appropriate CE threshold at the local level.

scholarly journals An exploratory study to estimate cost-effectiveness threshold value for life saving treatments in western Iran

2020 ◽  
Author(s):  
Najmeh Moradi ◽  
Abraha Woldemichael ◽  
Parisa Malekian ◽  
Delnia Moradi Rotavandi ◽  
Satar Rezaei
Keyword(s):  
Cost Effectiveness ◽  
Family Members ◽  
Threshold Value ◽  
Monthly Income ◽  
Tobit Regression ◽  
Western Iran ◽  
Life Saving ◽  
Additional Qaly ◽  
The Family ◽  
The Mean

Abstract Background: Cost-effectiveness analysis provides a crucial means for evidence-informed decision-making on resource allocation. This study aims to elicit individuals' willingness to pay (WTP) for one additional quality-adjusted life-year (QALY) gained from life-saving treatment and associated factors in Kermanshah city, western Iran.Methods: We conducted a cross-sectional study on a total of 847 adults aged 18 years and above to elicit their WTP for one additional QALY gained by oneself and a family member using a hypothetical life-saving treatment. We used a multistage sampling technique to select the samples, and the Iranian version of EQ-5D-3L, and visual analogue scale (VAS) measures was used to obtain the participants’ health utility value. The Tobit regression model was used to identify the factors affecting WTP per QALY values.Results: The mean WTP value and standard deviation (SD) was US$ 862 (3,224) for the respondents and US$ 1,355 (3,993) for the family members. The mean utility values using EQ-5D-3L and VAS methods were 0.779 and 0.800, respectively. Besides, Tthe WTP for the additional QALY gained by the individual participants using the EQ-5D-3L and VAS methods were respectively US$ 1,202 and US$ 1,101, while the estimated value of the family members was US$ 1,355 (SD= 3,993). The Tobit regression models indicated that monthly income, education level, sex, and birthplace were statistically significantly associated (p < 0.05) with both the WTP for the extra QALY values using the EQ-5D-3L and the VAS methods. Besides, eEducational level and monthly income also showed statistically significant relationships with the WTP for the additional QALY gained by the family members (p < 0.05). Conclusion: Our findings indicated that the participants' WTP value of the additional QALY gained from the hypothetical life-saving treatment was in the range of 0.20 to 0.24 of the Iran’s gross domestic product (GDP) per capita of Iran. This value, which is far lower than the World Health Organization (WHO) recommended CE threshold value of one. This wide gap reflects the challenges the health system is facing and requires further research for defining the most appropriate CE threshold at the local level.

Fluorescent PCR Based Gene Dose Assessment for Detection of Deletion Mutations in the FIX Gene Among Carriers of Hemophilia B.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3486-3486
Author(s):  
Eunice Sindhuvi Edison ◽  
G. Sankari Devi ◽  
G. Jayandharan ◽  
Shaji R Velayudhan ◽  
Auro Viswabandya ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Real Time ◽  
Real Time Pcr ◽  
Gene Dosage ◽  
Family Members ◽  
Peak Height ◽  
Hemophilia B ◽  
Carrier Status ◽  
Fluorescent Pcr ◽  
The Family

Abstract Abstract 3486 Poster Board III-423 Haemophilia B (HB), an X linked inherited disorder is caused by heterogeneous mutations in the F9 gene. Approximately 3% of hemophilia B patients have major deletions in the F9 gene. Gross and small deletions in the F9 gene in HB affected males are easily detected by PCR but detecting the carrier state of females in the family is challenging due to the presence of the normal allele. Different methods like linkage analysis, real time PCR and MLPA have been used to assess the carrier status in this situation. Linkage analysis is limited by the availability of informative markers and adequate number of family members. Real time PCR involves standardisation and preparation of calibration curves for each run. Although MLPA is a better alternative, it can be time consuming and involves multiple steps. We have therefore developed a fluorescent PCR based gene dosage approach which is simple, rapid and cost-effective for determining the carrier status of females in families with deletions in the F9 gene. 200ng of DNA extracted by standard protocols was used for amplification with primers designed to amplify a 160bp product from exon h in the F9 gene. One of the primers was fluorescently labelled. Amplification was carried out using these primers for 20 cycles only and the amplified product was subjected to capillary electrophoresis on an ABI 310 genetic analyser. A 230 bp fragment in the albumin gene was used as the control. Analysis was done using Genescan and Genotyper software. The ratio between the peak heights of the exon h in the F9 and control genes in the patient samples were normalised to a normal control. Five families with deletional HB were analysed (in toto deletion-1; Ex g-h – 1; Ex g-poly A-1; Ex h-poly A-2). The ratios in the probands and the family members are presented in the table. Out of eight females analysed, 6 were carriers and 2 were normal. The mean ratio in the carriers was 0.49±0.08 and 0.75±0.05 in the normal. Deletions are not uncommon in HB and deletions involving the exon g and h constitute a major group. Among 212 families with HB assessed at our centre, we have identified large deletions in 8 families (3.7%). It is interesting to note that all except one of these deletional mutations involved exon h. This method confirmed the presence of these deletions in the males and helped us to identify the carrier status of the females in the family. Identification of carrier status of females with deletions in F9 gene by gene dosage Subject ID Peak height of Exh in F9 Peak height of albumin Normalised Ratio Interpretation HB5 284 442 0.59 Carrier HB6 305 489 0.57 Carrier HB22 188 372 0.47 Carrier HB63 85 165 0.48 Carrier HB129 247 295 0.78 Normal HB238 94 326 0.4 Carrier HB280 372 679 0.77 Normal HB384 202 670 0.4 Carrier Disclosures: No relevant conflicts of interest to declare.

scholarly journals Candidate Gene Discovery Procedure after Follow-Up Confirmatory Analyses of Candidate Regions of Interests for Alzheimer’s Disease in the NIMH Sibling Dataset

2008 ◽  
Vol 24 (6) ◽  
pp. 293-309 ◽  
Author(s):  
Tesfaye M. Baye ◽  
Rodney T. Perry ◽  
Howard W. Wiener ◽  
Zuomin Chen ◽  
Lindy E. Harrell ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Disease Susceptibility ◽  
Lod Score ◽  
Str Markers ◽  
Simple Tandem Repeat ◽  
Original Genome ◽  
The Mean ◽  
Candidate Regions ◽  
Marker Distance

The objective of this research was to develop a procedure to identify candidate genes under linkage peaks confirmed in a follow-up of candidate regions of interests (CRIs) identified in our original genome scan in the NIMH Alzheimer’s diseases (AD) Initiative families (Blacker et al. [1]). There were six CRIs identified that met the threshold of multipoint lod score (MLS) of ≥ 2.0 from the original scan. The most significant peak (MLS = 7.7) was at 19q13, which was attributed toAPOE. The remaining CRIs with ‘suggestive’ evidence for linkage were identified at 9q22, 6q27, 14q22, 11q25, and 3p26. We have followed up and narrowed the 9q22 CRI signal using simple tandem repeat (STR) markers (Perry et al. [2]). In this confirmatory project, we have followed up the 6q27, 14q22, 11q25, and 3p26 CRIs with a total of 24 additional flanking STRs, reducing the mean interval marker distance (MID) in each CRI, and substantially increase in the information content (IC). The linkage signals at 6q27, 14q22 and 11q25 remain ‘suggestive’, indicating that these CRIs are promising and worthy of detailed fine mapping and assessment of candidate genes associated with AD.We have developed a bioinformatics approach for identifying candidate genes in these confirmed regions based on the Gene Ontology terms that are annotated and enriched among the systematic meta-analyzed genes, confirmed by at least three case-control samples, and cataloged in the “AlzGene database” as potential Alzheimer disease susceptibility genes (http://www.alzgene.org).

scholarly journals Depression, Anxiety, Stress, and Resiliency in Iranian Families with Autistic Children

2020 ◽  
Author(s):  
Maryam alsadat Hosseini ◽  
Fatemeh Shirzad ◽  
Masoud Ahmadzad-Asl ◽  
Fatemeh Hadi
Keyword(s):  
Mental Illness ◽  
Educational Level ◽  
Family Members ◽  
Severe Depression ◽  
Children With Autism ◽  
Family Resilience ◽  
Autistic Children ◽  
The Family ◽  
History Of ◽  
The Mean

Abstract Background Autism is a chronic, debilitating condition that begins in childhood and is associated with burnout and sometimes even depression and anxiety in families. The main objective of this study was to investigate the relationship between resilience and anxiety-depression-stress among families of children with autism in 2018. Materials and Methods In this cross-sectional study, after the Ethics Committee approval, according to the calculated sample size, 137 members of the families of children with autism were selected randomly. They were self-questioned themselves by family resilience scale, and also DASS-21 questionnaires, along with the checklist of variables such as number of family members, marital status, educational level, income, background of physical and mental disorders, age and sex. After data collection, they were entered into and analyzed by MS Excel and SPSS V.24 software. Results The mean age of the subjects was 40.67 years (± 9.12) with the range of 42 years. 80 persons (58.4%) were female and 57 (41.6%) were male, most of who had a bachelor's degree (51.7%), and generally were married (78.8%) (Living with family). They often had a history of chronic physical (84.7%) or mental illness (95.6%). The mean of the family resilience scores was 193 (± 25) and its range was 124. There was no significant correlation between age/gender and resilience, but depression, anxiety and stress were related to the level of resiliency. Regarding the rate of depression, 51.8% were normal, 10.2% had mild depression, 22.6% had moderate depression, 10.2% had severe depression and 5.1% had very severe depression; income and history of mental illness were significantly associated with depression. In addition, the level of anxiety was 46% normal, 8% mild, 17.5% moderate, 11.7% severe and 16.8% very severe. The number of family members, educational level, income, and history of mental illness had a significant effect on people's anxiety. Also, the stress status of the studied samples were 43.8%, 12.4%, 26.3%, 10.9% and 6.6% normal, mild, moderate, severe and very severe, respectively. The level of education, income, history of mental illness and gender were statistically significant with the level of stress among individuals. Conclusion Based on the results of this study, it is concluded that family resilience is a factor that directly correlates with the level of depression, anxiety and stress among the family members of the autistic children. It is therefore advisable to increase this ability of individuals in various ways, such as training, counseling, support groups, and etc.

A 23bp Insertion in the Endothelial Protein C Receptor (EPCR) Gene Impairs EPCR Function

2001 ◽  
Vol 86 (10) ◽  
pp. 945-948 ◽  
Author(s):  
Giuliana Merati ◽  
Patricia Liaw ◽  
Paolo Bucciarelli ◽  
Natalia Oganesyan ◽  
Dongfeng Qu ◽  
...  
Keyword(s):  
Protein C ◽  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Activated Protein C ◽  
Type I ◽  
Endothelial Protein C Receptor ◽  
Vein Thrombosis ◽  
Expression Studies ◽  
Deep Vein ◽  
Activation Capacity

SummaryEPCR is a type I transmembrane protein, highly expressed on the endothelium of large vessels, that binds protein C and augments its activation. In this study, a 23bp insertion in the EPCR gene was found in 4/198 survivors of myocardial infarction and 3/194 patients with deep vein thrombosis. The EPCR gene with the insertion predicts a protein that lacks part of the extracellular domain, the transmembrane domain and the cytoplasmic tail. Expression studies showed that the truncated protein is not localized on the cell surface, cannot be secreted in the culture medium, and does not bind activated protein C. Since protein C activation depends on the concentration of EPCR, patients with the EPCR insertion could have a diminished protein C activation capacity. Further clinical studies of adequate samples size are necessary to establish whether or not the EPCR insertion predisposes to the development of thrombotic events.

Molecular Characterization of a Prototype Family Harboring Two Genomic Instability Disorders: Ataxia Telangiectasia and Fanconi Anemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1680-1680
Author(s):  
Gunay Balta ◽  
Turkan Patiroglu ◽  
Fatma Gumruk ◽  
Ozden Sanal ◽  
Aytemiz Gurgey ◽  
...  
Keyword(s):  
Linkage Analysis ◽  
Genomic Instability ◽  
Fanconi Anemia ◽  
Ataxia Telangiectasia ◽  
Family Members ◽  
The Other ◽  
Intrauterine Death ◽  
Cousin Marriage ◽  
The Family ◽  
Atm Gene

Abstract Ataxia telangiectasia (AT) and Fanconi anemia (FA) are rare, clinically distinct autosomal recessive disorders characterized by genomic instability and predisposition to cancer. In recent years, it was demonstrated that ATM and FA genes function in parallel and interrelate in DNA damage response pathways to maintain genomic integrity and cell viability. To date, no case or a family with these two genomic instability disorders with proven genetic defects, clinical and laboratory features has been reported. In this study, we characterize the molecular pathologies of a prototype family exceptionally harboring both AT and FA patients. Among the 5 ofsprings of a consanguineous parents of first degree cousin marriage, 1 male was diagnosed as AT, 1 male and 1 female as FA, 1 male and 1 female appeared to have none of these two disorders. Family history revealed that a 1.5 years old female child was deceased, and the mother had 1 early abortion and 1 intrauterine death at the 8th months of pregnancy. During the follow up period of 5 years, the patient with AT and the male patient with FA were lost due to the complications of the related disorders. Linkage analysis of DNA samples of the family members for FA led to the assignment of the family to complementation group A. The mutation analysis of 43 exons of FANCA gene revealed novel homozygous co-deletions of 10 (1361–1370del) and 1 (1374delC) nucleotides at the 5′ end of exon 15 leading to 3 aminoacid deletions and frameshift. Screening of the family members for the mutation revealed that 2 FA patients were homozygous and the parents and the patient with AT were heterozygous for the mutation while other 2 siblings were non-carriers for FA. The mutation was not detected among 200 chromosomes from normal population. On the other hand, linkage analysis of the family for AT with the intra ATM gene microsatellite markers showed that AT patient was homozygous while other family members were heterozygous for the common haplotype observed in parents. In this patient, sequencing of the 62 coding exons of the ATM gene led to the identification of a homozygous C to T substitution (8977C>T) at exon 61. This alteration resulted in replacement of Arginin with termination at codon 2993 (R2993X) leading to 63 aminoacid truncation of the ATM protein. Consistent with the linkage results, all the other family members including 2 FA patients were heterozygous for the mutation. The results of this study showed that the state of homozygosity for AT with a coexistent heterozygosity for FA or homozygosity for FA with a coexistent heterozygosity for AT are compatible with life. This observation indicates that even in the presence of null mutations, such combinations do not alter phenotypic expression of the homozygous states of neither AT nor FA. However, in this family with 5 living siblings, absence of any case coinciding homozygous mutations for both disorders may indicate that such possibilities are not compatible with life. Even though there is no laboratory evidence due to absence of fetal study, presence of maternal history of an abortion and an intrauterine death may be considered as evidences in supporting assumption above.

scholarly journals Discrepancy in the perception of symptoms of cognitive decline between older adults and their family members: results of the Toyama dementia survey

BMC Neurology ◽  
2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Nobue Nakahori ◽  
Michikazu Sekine ◽  
Masaaki Yamada ◽  
Takashi Tatsuse ◽  
Hideki Kido ◽  
...  
Keyword(s):  
Older Adults ◽  
Cognitive Function ◽  
Cognitive Decline ◽  
Older Adult ◽  
Family Members ◽  
Kappa Statistic ◽  
The Family ◽  
Perception Gap ◽  
The Mean ◽  
Loss Of Appetite

Abstract Background Early consultation is important to delay the onset of dementia. The present study aimed to explore the reasons for delaying a consultation of dementia while focusing on the differences in the perception of cognitive decline between older adults and their family members. Methods A group of 663 older adults aged ≥65 years and living with family members in Toyama Prefecture was surveyed. The questionnaires included items that measured changes in cognitive function noticed by older adults and their family members, and the Revised Hasegawa Dementia Scale (HDS-R). The degrees of consistency on the perception of mental changes that accompanied cognitive decline were measured using the Kappa statistic. Results Both older adults and their family members were well aware of “forgetfulness” as a symptom of cognitive decline. Only the perception of “loss of appetite” at the late stage of cognitive decline was consistent between older adults and their family (κ = 0.707). When older adults often noticed their own forgetfulness, their mean HDS-R score was 22.7, whereas that of the family members was 14.7. The combinations of perception of forgetfulness by older adults and their family members, and the mean HDS-R scores were unaware/unaware (mean HDS-R score = 27.0), aware/unaware (mean HDS-R score = 24.9), aware/aware (mean HDS-R score = 15.5), and unaware/aware (mean HDS-R score = 13.0). Conclusions There were discrepancies in the perception of cognitive decline between older adults and their family members. Cognitive decline had progressed by the time that family members had noticed the symptom of forgetfulness in their older adult relatives. The perception gap regarding cognitive decline deters consultation of dementia.

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