Age Of Onset In Patients Research Articles

Generation of Aβ38 and Aβ42 Is Independently and Differentially Affected by Familial Alzheimer Disease-associated Presenilin Mutations and γ-Secretase Modulation

Alzheimer disease amyloid beta-peptide (Abeta) is generated via proteolytic processing of the beta-amyloid precursor protein by beta- and gamma-secretase. Gamma-secretase can be blocked by selective inhibitors but can also be modulated by a subset of non-steroidal anti-inflammatory drugs, including sulindac sulfide. These drugs selectively reduce the generation of the aggregation-prone 42-amino acid Abeta(42) and concomitantly increase the levels of the rather benign Abeta(38). Here we show that Abeta(42) and Abeta(38) generation occur independently from each other. The amount of Abeta(42) produced by cells expressing 10 different familial Alzheimer disease (FAD)-associated mutations in presenilin (PS) 1, the catalytic subunit of gamma-secretase, appeared to correlate with the respective age of onset in patients. However, Abeta(38) levels did not show a negative correlation with the age of onset. Modulation of gamma-secretase activity by sulindac sulfide reduced Abeta(42) in the case of wild type PS1 and two FAD-associated PS1 mutations (M146L and A285V). The remaining eight PS1 FAD mutants showed either no reduction of Abeta(42) or only rather subtle effects. Strikingly, even the mutations that showed no effect on Abeta(42) levels allowed a robust increase of Abeta(38) upon treatment with sulindac sulfide. Similar observations were made for fenofibrate, a compound known to increase Abeta(42) and to decrease Abeta(38). For mutants that predominantly produce Abeta(42), the ability of fenofibrate to further increase Abeta(42) levels became diminished, whereas Abeta(38) levels were altered to varying extents for all mutants analyzed. Thus, we conclude that Abeta(38) and Abeta(42) production do not depend on each other. Using an independent non-steroidal anti-inflammatory drug derivative, we obtained similar results for PS1 as well as for PS2. These in vitro results were confirmed by in vivo experiments in transgenic mice expressing the PS2 N141I FAD mutant. Our findings therefore have strong implications on the selection of transgenic mouse models used for screening of the Abeta(42)-lowering capacity of gamma-secretase modulators. Furthermore, human patients with certain PS mutations may not respond to gamma-secretase modulators.

Both Germ Line and Somatic Genetics of the p53 Pathway Affect Ovarian Cancer Incidence and Survival

Although p53 is one of the most studied genes/proteins in ovarian carcinomas, the predictive value of p53 alterations is still ambiguous. We performed analyses of the TP53 mutational status and its protein expression using immunohistochemistry. Moreover, the single nucleotide polymorphism SNP309 in the P2 promoter of the MDM2 gene was investigated. We correlated the results with age of onset and outcome from 107 patients with ovarian carcinoma. In our study, we identified a large group of patients with p53 overexpression despite having a wild-type gene (49% of all patients with wild-type TP53). This was associated with a significantly shortened overall survival time (P = 0.019). Patients with p53 alterations (especially those with overexpression of wild-type TP53) were also more refractory to chemotherapy compared with patients with normal p53 (P = 0.027). The G-allele of SNP309 is associated with an earlier age of onset in patients with estrogen receptor-overexpressing FIGO stage III disease (P = 0.048). In contrast, in patients with FIGO stage III disease, a weakened p53 pathway (either the G-allele of SNP309 or a TP53 mutation) was correlated with increased overall survival compared with patients whose tumors were wild-type for both TP53 and SNP309 (P = 0.0035). Our study provides evidence that both germ line and somatic alterations of the p53 pathway influence the incidence and survival of ovarian carcinoma, and it underscores the importance of assessing the functionality of p53 in order to predict the sensitivity of platinum-based chemotherapies and patient outcome.

Predictive factors for organic central precocious puberty and utility of simplified gonadotropin‐releasing hormone tests

The aim of the present study was to determine whether the clinical presentation of patients with central precocious puberty (CPP) permits differentiation between idiopathic and organic forms, and to examine whether luteinizing hormone (LH) determination in single blood sample after gonadotropin-releasing hormone (GnRH) administration is sufficient to diagnose CPP. Potential clinical and laboratory predictors for the presence of central nervous system (CNS) abnormalities were assessed. Sensitivities and specificities of LH and follicle-stimulating hormone (FSH) levels at 0, 15, 30, 60, 90 and 120 min were compared after GnRH stimulation. In 45 girls with signs of breast development, 26 were diagnosed as having CPP. The age of onset in patients with organic CPP was 4.75 +/- 2.01 years (range 1.2-7.1 years, median 5.0 years), whereas the age in patients with idiopathic CPP was 7.09 +/- 0.87 years (range 5.0-7.9 years, median 7.0 years). This parameter is the only one showing statistical significance. In addition, the specimen at 30 min after GnRH stimulation yielded highest sensitivity for the diagnosis of CPP. The earlier the onset of disease, the higher the possibility of presence of CNS lesion. According to the mean GnRH-stimulated LH levels and sensitivity at each time, a single blood sample obtained for LH determined after GnRH administration at 30 min can be used to diagnose CPP.

Benign infantile convulsions associated with mild gastroenteritis: A retrospective study of 39 cases including virological tests and efficacy of anticonvulsants

Benign convulsions associated with mild gastroenteritis (CwG) are a commonly observed disorder in Asia, especially in infants and seniors. Here, we describe a retrospective study about the clinical features of CwG in 62 children hospitalized at St. Mary’s Hospital (Kurume City, Japan) between January 1, 2000 and March 31, 2006, and further evaluate the efficacies of various anticonvulsant treatments for patients with CwG due to either rotavirus or norovirus. Causative diarrheal viruses were detected in 71% of the fecal specimens tested; 30 patients were positive for rotavirus, nine patients were positive for norovirus, two patients were positive for sapovirus, two patients were positive for adenovirus, and one patient was positive for coxackievirus A4. The age of onset for patients with norovirus-positive CwG (16.7 ± 2.7 months) was significantly lower than that of patients with rotavirus-positive CwG (23.0 ± 8.7 months). The duration of the seizures due to norovirus infection (11.8 ± 12.0 h) was significantly longer than that due to rotavirus infection (4.9 ± 5.7 h). There were no significant differences between the two groups with regard to the results of blood chemistry analysis, including the concentrations of serum electrolytes, blood glucose levels, and liver function tests. In this preliminary study, the duration of seizures in patients with CwG due to norovirus that was treated with carbamazepine was significantly shorter than the duration of seizures in the patients treated with another anticonvulsant (phenobarbital). Further randomized controlled studies are required to clarify the efficacies of the various anticonvulsants for patients with CwG.

Influence of MDM2 Single Nucleotide Polymorphism SNP309 on Disease Onset and Course in CLL.

Background: A SNP in the MDM2 promotor region (SNP309) has been shown to directly influence MDM2 transcript and protein levels with the subsequent attenuation of the p53 pathway. In addition, the GG and GT genotype have been linked to earlier age of onset in patients with different cancers. Because of the well documented prognostic role of p53 in patients with CLL and the potential involvement of MDM2 particularly in patients with trisomy 12, we studied the MDM2 SNP309 in patients with CLL.Methods: We developed a Denaturing High-Performance Liquid Chromatography (DHPLC) assay as a high-throughput approach to efficiently type this polymorphism.Results: We analysed 627 CLL patients and found a similar genotype distribution as described for a large German control population (CLL: GG 12,75%; GT 48.8%; TT 38.4% vs. control: GG 14.4%; GT 44.1%; TT 41.8%). There was an equal genotype distribution among women and men. We compared the median age at diagnosis of the different genotype groups in CLL patients and did not find differences (female: GG 62.3; GT 59.8 TT 60; male: GG 58; GT 56.2; TT 58) (figure 1). However as a hormone dependent difference for pre- and postmenopausal female patients with cancer has been described, we separated the patients according to age and found a overrepresentation of the GG phenotype in young female CLL patients (<51 years) (25% GG vs 11% GG; p=0.04). In contrast, for older, female patients with the GG genotype there was a trend towards delayed onset of CLL (Figure1).The overall survival among a subgroup of 483 patients was not influenced by the presence of a particular genotype (Median survival (months): GG 132.6; GT 134.1; TT 112.8). The mRNA expression levels of MDM2 and p53 were analysed by quantitative RT-PCR and correlated with the different genotypes.Conclusion: The approach described can be used to rapidly type the MDM2-SNP309. Based on this study a role for the MDM2 polymorphism on disease predisposition of CLL is unlikely. The role of hormone dependent differences according to genotype in female patients warrants further investigation. [Display omitted]

N-Acetyltransferase (NAT) 2 acetylator status and age of tumour onset in patients with sporadic and familial, microsatellite stable (MSS) colorectal cancer

N-Acetyltransferase (NAT) 2 is an important enzyme involved in the metabolism of different xenobiotics, including potential carcinogens. Allelic variants of the NAT2 gene are determined by a pattern of single nucleotide polymorphisms (SNPs) resulting in slow (SA), intermediate (IA) or rapid acetylator (RA) phenotypes and causing the individual differences in the NAT2 metabolic capacity. To clarify the potential modifying role of the NAT2 acetylator status in microsatellite stable (MSS) colorectal cancer (CRC), we studied 140 patients with sporadic CRC (group 1) and 69 patients with CRC who met at least one criterion of the revised Bethesda guidelines (group 2). We did not observe any significant difference in the NAT2 acetylator status frequency between patients in both groups and 100 healthy controls (P=0.486). Regardless of a younger median age of tumour onset (AO) of 41 years in group 2 patients compared to 64 years in group 1 patients, no significant difference in AO was found between RA and SA status patients in both groups. The median AO in group 1 was 65 years in patients with RA and 63 years with SA status (P=0.065). The median AO in group 2 was 40 years in patients with RA and 42 years with SA status (P=0.814). Multivariate Cox regression analysis revealed that neither the NAT2 acetylator status (P=0.064 and 0.810, respectively) nor the gender (P=0.165 and 0.918, respectively) was a risk factor for the AO in both groups. These data do not support the hypothesis that the NAT2 acetylatorship acts as a modifying factor on the AO in sporadic and familial, microsatellite stable CRC.

Influence of Heterozygosity for Parkin Mutation on Onset Age in Familial Parkinson Disease

The PARK2 gene at 6q26 encodes parkin, whose inactivation is implicated in an early-onset autosomal recessive form of Parkinson disease (PD). To evaluate the influence of heterozygosity for parkin mutation on onset age in a sample of families with at least 2 PD-affected members. Clinical and genetic study. Twenty collaborative clinical sites. Patients with familial PD collected in the GenePD study. Studied families were selected for (1) affected sibling pairs sharing 2 alleles identical by state at PARK2 (D6S305) or (2) 1 or more family members with onset age younger than 54 years, regardless of D6S305 status. At least 1 member from each of 183 families underwent comprehensive screening for deletion/insertion variants and point mutations in PARK2. Mutations in the parkin gene were screened by means of single-stranded conformation polymorphism and sequencing in all 12 coding exons and flanking intronic sequences for point mutations and duplex quantitative polymerase chain reaction in all exons for rearrangement, duplication, and deletion. Mutations were found in 23 families (12.6% of those screened). Among the mutation-positive families, 10 (43%) contained compound heterozygotes; 3 (13%), homozygotes; and 10 (43%), heterozygotes. The onset age in patients with parkin gene mutations ranged from 20 to 76 years. Patients with 1 parkin mutation had an 11.7-year age at onset than did patients with none (P = .04), and patients with 2 or more parkin mutations had a 13.2-year decrease in age at onset compared with patients with 1 mutation (P = .04). These data indicate that parkin mutations are not rare in multiply affected sibships, and that heterozygous mutation carrier status in PARK2 significantly influences age at onset of PD.

N-acetyltransferase (NAT) 2 acetylator status and age of onset in patients with hereditary nonpolyposis colorectal cancer (HNPCC)

N-acetyltransferase (NAT) 2 is an essential polymorphic enzyme involved in the metabolism of various xenobiotics, including potential carcinogens. The individual differences in the NAT2 metabolic capacity are caused by allelic variants of the NAT2 gene which are determined by a pattern of single nucleotide polymorphisms (SNPs) resulting in slow (SA), intermediate (IA) or rapid acetylator (RA) phenotypes. Highly penetrant germline mutations in mismatch repair (MMR) genes are the cause of the disease in hereditary nonpolyposis colorectal cancer (HNPCC). There is no strict correlation between the type of germline mutation in MMR genes and the HNPCC phenotype, but age of tumor onset (AO) in HNPCC has been associated at least in part with different variants in apoptosis-related genes. To clarify the potential modifying role of the NAT2 acetylator status in HNPCC, we performed a multicenter study in 226 individuals with colorectal cancer carrying exclusively pathogenic germline mutations in MSH2 or MLH1. We did not observe any significant difference in the NAT2 acetylator status frequency between HNPCC patients and 107 healthy controls ( P=0.156), and between MLH1 and MSH2 mutation carriers ( P=0.198). Multivariate Cox regression analysis revealed that male patients had a significantly increased risk to develop CRC compared to females during any interval ( P=0.043), while the NAT2 acetylator status ( P=0.447) and the mutated gene ( MLH1 or MSH2) ( P=0.236) were not risk factors for AO. The median AO in HNPCC patients was 39 years in patients with RA as well as with SA status ( P=0.347). In MLH1 mutation carriers, the median AO was 38 years in RA and 36 years in SA status patients ( P=0.901), whereas in MSH2 mutation carriers, the median AO was 39 years in RA and 42 years in SA status patients ( P=0.163). Log-rank test revealed a significantly lower age of CRC onset in male compared to female HNPCC patients ( P=0.0442). These data do not support the hypothesis that the NAT2 acetylatorship acts as a modifying factor on AO in HNPCC-associated CRC.

Association Between Tau H2 Haplotype and Age at Onset in Frontotemporal Dementia

The frontotemporal dementia (FTD) syndromes have been associated with the microtubule-associated tau protein since tau gene mutations have been demonstrated to be the cause of FTD and parkinsonism linked to chromosome 17. In cases of FTD without tau gene mutations, however, it is unclear whether genetic variability in the tau gene is associated with the development or modulation of FTD. To determine whether genetic variability in tau and apolipoprotein E (ApoE) modulates and contributes to the development of FTD. Design and Patients The distribution of tau gene haplotypes and the ApoE genotype were investigated in 86 patients with well-characterized FTD and 50 control subjects. No difference in the distribution of the tau H1 and H2 haplotypes between FTD cases and controls was observed, whereas the ApoE epsilon4 allele was more frequent in FTD cases. The presence of at least 1 tau H2 allele was found to be significantly associated with an earlier age of onset in patients with FTD. The association between the H2 allele and age at onset was not related to family history, clinical presentation, or ApoE genotype. These findings support a role of tau protein in modulating disease phenotype by influencing the age at onset in these FTD cases.

Genetic analysis of the glutathione s-transferase genes MGST1, GSTM3, GSTT1, and GSTM1 in patients with hereditary pancreatitis.

Specific mutations in the cationic trypsinogen gene ( PRSS1) are disease-causing in patients with hereditary pancreatitis, but the genetic background still remains mysterious in about 40% of patients with the disease. It has been suggested that oxidative stress contributes to pancreatic damage. The glutathione s-transferases (GSTs) represent major detoxification enzymes that protect cells from oxidative stress. In the present study we tested whether mutations in the MGST1 and GSTM3 genes or common deletions in the GSTT1 and GSTM1 genes are associated with hereditary pancreatitis. We analyzed the entire coding region of MGST1 and GSTM3 in 30 patients that were tested negative for PRSS1 mutations, and we studied 55 controls. For GSTT1 and GSTM1, we investigated 75 hereditary pancreatitis patients who had been tested negative for PRSS1 mutations, 135 hereditary pancreatitis patients with a PRSS1 mutation, and 183 controls. Patients were further subclassified with regard to age of onset of disease as a marker of severity. No mutation was found in the MGST1 gene. In the GSTM3 gene, we detected a homozygous 670G > A polymorphism (V224I) with similar frequencies in patients and controls. We found no difference in the frequencies of the GSTT1 and GSTM1 null genotypes between patients and controls, and we detected no differences in age of onset in patients with or without GSTT1 and GSTM1 deletions. We conclude that genetic alterations in the MGST1, GSTM3, GSTT1, and GSTM1 genes do not play a dominant role in hereditary pancreatitis.

Single nucleotide polymorphism (D68D, T to C) in the syntaxin 1A gene correlates to age at onset and insulin requirement in Type II diabetic patients.

Syntaxin 1A is a candidate gene for Type II (non-insulin-dependent) diabetes mellitus, because it plays an important role in insulin secretion from the islet beta cells. We aimed to scan this gene for mutations or genetic markers that correlate with Type II diabetes. We identified and characterized coding exons of the syntaxin 1A gene and scanned the newly identified 10 exons using direct sequencing. In the single nucleotide polymorphism (SNP) of exon 3 (D68D, T to C) among three newly identified SNPs, genotype frequency of the homozygote of C allele (CC) occurred more frequently in a Type II diabetic group than in a non-diabetic group (16.48 %, n = 182, vs 11.05 %, n = 181, p = 0.0499). Among the diabetic patients, age of onset in patients with CC genotype was lower than that in patients with the TT and TC genotypes [40.10 +/- 1.50 years old (means +/- SEM) vs 44.20 +/- 0.58, p = 0.005]. Patients with the CC genotype had a higher frequency of insulin treatment (78.30 % vs 46.80 %, p = 0.006) with a duration equal to, or longer than, 10 years. Multiple regression analysis confirmed that the genotype was significantly and independently associated with age at onset and mode of treatment, respectively. These data indicate that the SNP in the syntaxin 1A gene (D68D, T to C) correlates to the age of onset and insulin requirements of Type II diabetic Japanese patients.

An association between cartilaginous tumours and breast cancer in the national pathology registration in The Netherlands points towards a possible genetic trait.

Breast cancer and cartilaginous tumours (enchondroma and chondrosaroma) were found to occur rather frequently in the same patient. In order to identify a possible association between occurrence of these tumour types, a population-based study was performed. This was a nation-wide case-control study, using the Dutch national pathology database. Between 1973 and 1998, the study identified 2295 cases of cartilaginous tumours in female patients and 132 636 females with breast cancer. Of these patients, 61 were diagnosed with both tumour types. To exclude a possible bias due to screening for occult bone metastases in breast cancer patients, a similar analysis was performed for lung cancer, since screening is performed similarly in lung cancer patients. Of 16 559 females diagnosed with lung cancer, only one case with a cartilaginous tumour was found. The odds ratio for a potential association of breast and cartilaginous tumours is 7.62, implicating a 7.62 increased risk for the same female patient having both breast cancer and a cartilaginous tumour. Furthermore, the mean age of onset in patients with breast cancer as the first tumour is nearly 10 years earlier than breast cancer in general, i.e. 51 years versus 60.9 years. The association of breast cancer and cartilaginous tumours and the early age of onset of breast cancer in these patients may suggest a genetic trait.

Progressive supranuclear palsy: earlier age of onset in patients with the tau protein A0/A0 genotype.

Genetic studies have detected an association between the presence of the tau gene A0 allele and patients with progressive supranuclear palsy (PSP). This study examined whether patients with this polymorphism exhibit distinct demographic or clinical characteristics. We studied 26 patients who fulfilled clinical criteria for the diagnosis of PSP, 20 who had the A0/A0 genotype and 6 who had other genotypes. A questionnaire on demographic data, past medical history, familial history, and initial symptoms was completed as part of the consultation. A complete neurological examination was performed and PSP symptoms were quantified following Golbe's PSP disability scale. We found a significant difference in the age at onset of PSP symptoms, which was 65.9 +/- 5.3 years in the A0/A0 group and 71.2 +/- 5.6 in the non-A0/A0 group (P = 0.016). There were no significant differences in the years from disease onset between the two groups. Symptom severity did not differ significantly in patients with the different A0/A0 genotypes. The detection of significantly lower age at onset with the A0/A0 alleles is consistent with the known association of this genotype as a risk factor for PSP. No significant differences were detected in symptom severity between the two groups of patients.

Mannose binding lectin polymorphisms are associated with early age of disease onset and autoimmunity in common variable immunodeficiency.

Mannose binding lectin (MBL) is an important component of the innate immune response. Low producing MBL alleles are associated with an increased risk of infection, especially when adaptive immunity is already compromized. We investigated the role of MBL polymorphism in common variable immunodeficiency (CVID), a disease of unknown aetiology characterized by defective humoral immunity, recurrent infections and highly variable clinical phenotype. Six biallelic single nucleotide polymorphisms in the MBL promoter and coding region (- 550, - 221, + 4, codons 52, 54 and 57) were haplotyped using a novel PCR-SSP method in 163 CVID patients and 100 controls. Low producing coding alleles and promoter haplotypes were associated with early age of disease onset. The mean age of disease onset was 14.5 years in patients with low producing MBL coding alleles, compared with 25 years in patients with wild type coding regions (t-test P = 0.002). Mean age of onset in patients with the low producing LXPA haplotype was 6.8 years, compared with 29.3 years for the HYPA haplotype (P = 0.003). The MBL + 4 Q allele was associated with autoimmune disease (P = 0.003, OR 4.4). These results suggest that MBL deficiency compounds the antibody deficiency in CVID, and reinforces the ostensible role of MBL in innate immunity. MBL deficiency may also facilitate the development of autoimmune disease in CVID.

Change in the age of onset in patients with familial amyloidotic polyneuropathy (FAP) type i in Japan

Change in the age of onset in patients with familial amyloidotic polyneuropathy (FAP) type i in Japan

Change in the age of onset in patients with familial amyloidotic polyneuropathy type I.

To investigate the influence of environmental factor(s) on the pathogenesis of familial amyloidotic polyneuropathy (FAP) type I, the age of onset in 33 FAP patients in the Arao district of Kumamoto Prefecture in Japan and in 20 of their ancestors to the 3rd prior generation was carefully examined. The age of onset in FAP patients progressively became younger. This tendency was more apparent in female FAP patients than in male patients. Since the pathogenesis of amyloid formation in FAP as well as other amyloidosis diseases is not still elucidated, this phenomenon may be of interest.

Chronic inflammatory demyelinating polyradiculoneuropathy. A clinical and electrophysiological study of 92 cases.

Ninety-two patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) have been studied in order to define better the clinical features, course and prognosis of the condition and to identify possible aetiological factors. Sural nerve biopsy was performed on 87 subjects. Electrophysiological studies were undertaken on all patients and demonstrated marked slowing of motor conduction and impairment of sensory conduction. The onset was usually gradual but there was a rapid rate of onset in 15 (16%) patients. Males were more commonly affected than females. Weakness and paraesthesiae were the most common symptoms but pain was frequently a feature. Age of onset ranged from 2 to 72 years. Sixty patients (65%) had a relapsing course and 32 patients (35%) a progressive or monophasic course; there was a significantly earlier age of onset in patients with relapsing disease. Thirty-two patients (35%) gave a history of preceding infection or some other possible antecedent precipitating event and there was a significantly higher titre for cytomegalovirus antibodies in the serum of patients with CIDP than in controls. The patients were followed up for an average time of approximately ten years. Most patients (73%) had made a good recovery and were independent, but 7 patients had either died or were completely immobilized as a result of their disease. The value of treatment with corticosteroid therapy, immunosuppressive agents and plasma exchange is discussed.

Uveitis: aetiology and disease associations in an Australian population.

Over a five-year period 245 patients with uveitis were investigated at the Uveitis Clinic, Sydney Eye Hospital, for possible aetiological and relevant disease associations. Uveitis was anterior in 75% of patients, posterior in 21% and generalized in 4%. Anterior uveitis (AU) was idiopathic in 52% of cases. In patients tested for the HLA-B27 antigen, 47% were HLA-B27 positive, including all cases of ankylosing spondylitis (8% of cases) and Reiter's syndrome (3% of cases). There was a marked male predominance in patients with AU, especially in HLA-B27 positive individuals. Posterior uveitis (PU) was most frequently unilateral, chronic and idiopathic (24% of cases), whilst recognizable aetiologies included toxoplasmosis (20%), Behcet's syndrome (14%), sarcoidosis (12%) and pars planitis (12%). The peak age of onset in patients presenting with AU was 30 to 40 years, whilst patients with PU presented a decade earlier. There were no major differences between males and females in the age of onset of their uveitis.

Occurrence of depression in the postpartum state

Using multiple variables of illness, comparisons were made between 17 post-partum depressives with recurrent affective disorder and 37 women with children and recurrent affective disorder but no postpartum depressions. An earlier age of onset in patients with postpartum depression was the only variable that was significantly different between groups. The occurrence of depression for the 17 subjects was significantly greater in the postpartum period than in the non-post-partum period. The postpartum depression rate for pregnancies subsequent to the initial postpartum episode was 75%.