Age Of Onset In Patients Research Articles

Features of Patients Aged 80 Years or Older with Embolic Stroke of Undetermined Source

Background: Embolic stroke of undetermined source has not been thoroughly investigated in older patients. In this study, we investigated the features of this condition in patients greater than or equal to 80 years of age. Methods: All patients with acute ischemic stroke in our hospital underwent diffusion-weighted imaging, magnetic resonance angiography, T2-weighted imaging, and fluid-attenuated inversion recovery sequence imaging. Embolic stroke of undetermined source was defined as a radiologically confirmed nonlacunar brain infarct on diffusion-weighted imaging without (1) extracranial or intracranial atherosclerosis causing greater than or equal to 50% luminal stenosis in arteries supplying the ischemic area, (2) major-risk cardioembolic source, and (3) any other specific cause of stroke. We retrospectively identified consecutive patients hospitalized for acute ischemic stroke who met the embolic stroke of undetermined source diagnostic criteria and investigated patients’ baseline and diagnostic findings. Results: We divided 122 consecutive embolic stroke of undetermined source patients (median age: 73 years; 49 men, 73 women) into 2 groups by age at admission. Patients aged greater than or equal to 80 years had higher D-dimer and brain natriuretic peptide levels, more frequent premature atrial complexes/day in 24-hour Holter electrocardiography, and thicker maximum intima media thickness on ultrasound compared with patients aged less than 80 years (P < .05, U test). Conclusions: Our results suggest that high admission D-dimer and brain natriuretic peptide levels are associated with age of onset in patients with embolic stroke of undetermined source. Patients aged greater than or equal to 80 years tended to have more frequent premature atrial complexes and thicker maximum intima media thickness compared with patients aged less than 80 years.

Epidemiology of ATTRV30M neuropathy in Cyprus and the modifier effect of complement C1q on the age of disease onset

Background: ATTRV30M amyloidosis is a lethal autosomal dominant sensorimotor and autonomic neuropathy caused by amyloid deposition composed of aggregated misfolded TTR monomers with the V30M mutation. The age of onset in patients with ATTRV30M varies in different foci and the mechanism behind it is still unknown.Methods: The tertiary neurology center following all ATTRV30M patients in Cyprus was used to collect demographic data to estimate; prevalence, incidence, penetrance, anticipation, time from disease onset to diagnosis and transplantation. Ocular, cardiac and leptomeningeal involvement in transplanted patients was explored. Correlation of C1q tagging SNPs with age of disease onset was carried out.Results: Prevalence and incidence for ATTRV30M neuropathy in Cyprus are 5.4/100,000 and 0.3/100,000 respectively. Mean age of onset is 40.6 years and anticipation is 8.3 years. Penetrance reaches 51% and 75% by the ages of 50 and 80 years respectively. In liver transplanted patients rates of ocular, cardiac and leptomeningeal involvement were estimated to be 60%, 20% and 16%, respectively. C1q polymorphisms correlated with age of disease onset.Conclusions: ATTRV30M neuropathy has a rising prevalence in Cyprus due to improved survival of patients. Late onset complications are becoming a major problem. Complement C1q appears to be a modifier in this disease.

Genetic risk analysis for an individual according to the theory of programmed onset, illustrated by lung and liver cancers

ObjectiveTo investigate cancer association in the genome and the genetic risk of death from major cancers according to the theory of programmed onset for an individual. MethodsAlleles of 15 randomly selected short tandem repeat (STR) loci, including D6S1043, D12S391, CSF1PO, D7S820, D2S1338, D3S1358, vWA, FGA, D8S1179, D21S11, D18S51, D5S818, D13S317, D16S539 and D19S433, were determined in 50 patients with lung cancer and 50 patients with liver cancer. The onset age of patients with and without the alleles was compared with Cox regression. Frequencies of significant alleles from Cox regression between the cancer group and control population were analysed through logistic regression for cross-validation. The death probability in an individual carrying two or one of two cancer-related alleles or not carrying two cancer-related alleles was calculated with outcomes of case-control studies translated into the results of the cohort studies. ResultsIt was confirmed that D18S51-20 was a lung cancer-related allele and that D21S11-30.2 and D6S1043-18 were liver cancer-related alleles. Probabilities of death from lung or liver cancers ranged from 0.115 to 0.395, respectively, for those who carry and/or do not carry D18S51-20, D21S11-30.2, D6S1043-18. ConclusionsA more efficient method could be devised for genetic risk analysis according to the theory of programmed onset. The analysis of the CODIS-STR loci (STR loci listed in the US combined DNA indexing system) as genetic markers may provide an efficient and reliable approach to estimate an individual's genetic predisposition.

Morphometric and Microstructural Alterations Differ with Age of Onset in Patients with Essential Tremor

Essential tremor (ET) is typically characterized with postural and kinetic tremor generally in upper distal limbs and head. Due to the heterogeneity of the disease, possibly different set of risk factors, pathophysiological mechanisms and clinical course affect structural architecture based on the onset of the disease. In this sense, we restricted genetic effect by recruiting early- and late-onset ET patients who were homozygous and heterozygous for the HTRA2 p.G399S gene mutation, respectively. A detailed analysis of how ET onset could affect the structural brain architecture is lacking in the literature. In this sense, brain morphometry and white matter microstructural integrity were assessed to investigate the effect of the onset of the disease on brain architecture in early- and late-onset ET patients using magnetic resonance imaging. Our results showed disruptions in late-onset ET was closely specific to motor areas including both cortical and subcortical structures, whereas affected areas in early-onset ET were more extensive in frontal, parietal and occipital areas. Results of our study indicate different brain structures and possibly different functions could be affected based on the onset of ET. Our findings highlight the potential role of age onset on structural cortical and subcortical architecture.

Oxytocin receptor gene polymorphisms exert a modulating effect on the onset age in patients with obsessive-compulsive disorder

The oxytocin receptor (OXTR) is a potential candidate in the pathophysiology of obsessive-compulsive disorder (OCD). The present study investigated the association between common single-nucleotide polymorphism (SNPs) of the OXTR gene and the affected status of OCD or distinct clinical subtypes of OCD including the age at onset and symptom dimensions. Ten SNPs of OXTR were examined in 615 patients with OCD and 581 healthy controls. Single-marker and haplotype-based association analyses were conducted. While OXTR variants were not associated with the affected status of OCD or its clinical symptom dimensions, rs2268493 (p=0.00185) and rs13316193 (p=0.00461) of the OXTR gene were associated with the age at onset in patients with OCD. In addition, in haplotype-based association analyses, there was a significant association between the OXTR gene and the onset age in patients with OCD. In particular, the G-C-G haplotype of rs2268493-rs2254298-rs11316193 and the T-G-A haplotype of rs237887-rs2268490-rs4686301 were positively associated with late-onset OCD. Our results suggest that common variants of OXTR may exert a modulating effect on the onset age in OCD pathophysiology. The potential involvement of the oxytocin system in the development and expression of OCD warrants further longitudinal research.

Descriptive study of symptomatic epilepsy by age of onset in patients with a 3-year follow-up at the Neuropaediatric Department of a reference centre

ObjectiveWe conducted a descriptive study of symptomatic epilepsy by age at onset in a cohort of patients who were followed up at a neuropaediatric department of a reference hospital over a 3-year period. Patients and methodsWe included all children with epilepsy who were followed up from January 1, 2008 to December 31, 2010. ResultsOf the 4595 children seen during the study period, 605 (13.17%) were diagnosed with epilepsy; 277 (45.79%) of these had symptomatic epilepsy. Symptomatic epilepsy accounted for 67.72% and 61.39% of all epilepsies starting before one year of age, or between the ages of one and 3, respectively. The aetiologies of symptomatic epilepsy in our sample were: prenatal encephalopathies (24.46% of all epileptic patients), perinatal encephalopathies (9.26%), post-natal encephalopathies (3.14%), metabolic and degenerative encephalopathies (1.98%), mesial temporal sclerosis (1.32%), neurocutaneous syndromes (2.64%), vascular malformations (0.17%), cavernomas (0.17%), and intracranial tumours (2.48%). In some aetiologies, seizures begin before the age of one; these include Down syndrome, genetic lissencephaly, congenital cytomegalovirus infection, hypoxic-ischaemic encephalopathy, metabolic encephalopathies, and tuberous sclerosis. ConclusionsThe lack of a universally accepted classification of epileptic syndromes makes it difficult to compare series from different studies. We suggest that all epilepsies are symptomatic because they have a cause, whether genetic or acquired. The age of onset may point to specific aetiologies. Classifying epilepsy by aetiology might be a useful approach. We could establish 2 groups: a large group including epileptic syndromes with known aetiologies or associated with genetic syndromes which are very likely to cause epilepsy, and another group including epileptic syndromes with no known cause. Thanks to the advances in neuroimaging and genetics, the latter group is expected to become increasingly smaller.

Abstract 973: Methylation accurately predicts age of cancer onset in patients with Li Fraumeni Syndrome

Abstract Introduction: Li Fraumeni Syndrome (LFS) is a rare hereditary genetic cancer predisposition syndrome. Germline mutations of the TP53 tumor suppressor gene are the underlying cause in &amp;gt;80% of patients with LFS, and are associated with an increased risk of second tumors and a spectrum of early onset cancers, even in the absence of a family history of cancer. We have previously developed and implemented a comprehensive life-long clinical surveillance protocol for individuals with a germline TP53 mutation. We set out to make this screening process more targeted by building a predictive model of age of onset. We accomplished this goal by implementing machine learning methods on germline methylation data. Methods: We made use of the Toronto Hospital for Sick Children (SickKids) LFS family cohort in our predictive model of age of onset. In all, we have 74 patients with germline methylation data, consisting of ~450,000 probe sites. We subset this data by identifying probes that fall into differentially methylated regions between LFS and cancer patients with wild-type TP53. The probes identified in these regions were used in our predictive model of age of onset. Because age of sample collection was highly correlated with age of onset (r2 ~ .90), we corrected for confounding using a strategy that is two-fold: (1) we extracted the variation of each probe that is independent of the age of sample collection (the residual after regressing on the age of sample collection) and use these as predictors in our model, and (2) we test our models on the task of predicting the age of sample collection for LFS patients that do not have cancer. The former provided us with more robust predictions while the latter verified that we are in fact predicting age of onset, rather than simply predicting age at which the sample was collected. Results: Our machine learning model was able to achieve 86% correlation between true and predicted values of the age of onset. Additionally, we have tested the ability of our models to predict whether an individual will be diagnosed before or after the age of 4. Our classification machine learning model achieved 91% accuracy on average. We verified that our model does not simply predict age of sample collection by using our cohort of LFS patients that do not have cancer (n = 37). The distribution of the age of sample collection matched those of the patients used in our model. The model has no predictive power on the age of sample collection, thus confirming that our model is highly predictive of the age of cancer onset in LFS TP53 Mutation patients. Conclusions: We identified two predictive models for age of cancer onset in LFS patients that achieve high accuracy, both when predicting the age of onset as a continuous variable (86% correlation) and whether cancer onset will occur before or after the age of 4 (91% accuracy). Our model will assist clinicians in targeting high risk patients for screening, lower the cost of treatment, and raise the likelihood of survival among LFS patients. Citation Format: Benjamin M. Brew, David Malkin, Lauren Erdman, Andrea Doria, Jason Berman, Adam Shlien, Tanya Guha, Ana Novokmet, Anna Goldenberg. Methylation accurately predicts age of cancer onset in patients with Li Fraumeni Syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 973. doi:10.1158/1538-7445.AM2017-973

Clinical features comparison of ST segment elevation and non ST segment elevation in adult patients with acute myocarditis

Objective ST segment elevation in adult patients with acute myocarditis is rare in adult. The purpose of this study was to report the outcome of ST segment elevation in adult patients with acute myocarditis in our hospital, in order to provide reference for clinical diagnosis and treatment. Methods A retrospective analysis of Beijing Anzhen Hospital during January 2002 to December 2015 for the diagnosis of acute myocarditis were 105 cases , divided into two groups, one group of ST elevation (ST elevation group) total 57 cases, another group of non ST elevation (non ST elevation group) total 48 cases. The clinical features, laboratory examination, treatment and prognosis were compared between the two groups. The composite primary endpoint of major cardiovascular events (MACE) during hospitalization included: mortality, cardiac shock and ventricular fibrillation. Results The average onset age of patients with ST segment elevation group and non ST segment elevation group were similar [ (27.7 ±10.1) years vs.(28.7 ±10.0) years , P=0.603]. There was a significant difference between the two group in patients of heart rate [(89±22)beats/min vs.(80±23)beats/min , P=0.028], systolic blood pressure on admission [(105±17)mmHg vs.( 115±17) mmHg, P=0.003], diastolic blood pressure on admission [(66±11)mmHg vs. (74±11) mmHg, P=0.000], and total number of acute fulminant myocarditis[20(35.1%)vs.7(14.6%), P=0.024)]. ST segment elevation acute myocarditis patients were significantly more at risk for MACE than non ST segment elevation acute myocarditis patients during hospitalization (P=0.04). Conclusion ST segment elevation acute myocarditis has acute onset and rapid progression. The incidence of MACE during hospitalization was significantly high. Mechanical support can be very favourable.ST segment elevation acute myocarditis is associated with excellent short-term prognosis. Key words: Adult; Acute myocarditis; ST segment elevation; Clinical features; Major cardiovascular events; Mortality; Cardiac shock; Ventricular fibrillation

Clinical analysis of 82 cases of generalized pustular psoriasis

To analyze clinical features, laboratory tests, treatment and prognosis for patients with generalized pustular psoriasis (GPP). Methods: Clinical data of 82 patients with GPP (16 cases of children, 66 cases of adults) from the Department of Dermatology, Second Xiangya Hospital, Central South University were retrospectively analyzed. Results: Among the GPP patients, the male to female ratio was 1:1.1. Average age of onset in patients without history of psoriasis vulgaris (GPPPSO-) was earlier than that of patients with history of psoriasis vulgaris (GPPPSO+)[(25.5±21.2) years vs (32.7±18.0) years]. The average day of hospitalization in GPPPSO- group was longer than that in GPPPSO+ group [(12.1±6.7) days vs (11.6±10.2) days]. The transformation time from psoriasis vulgaris to GPP was (77.8±71.9) months. Infection (33.3%) and drugs (33.3%) were the main etiological factors in children with GPP. In adults with GPP, 75.0% of GPPPSO+ patients were caused by infection, but 41.7% of GPPPSO- patients were caused by drugs. Acitretin had favorable effect in the treatment of GPP. Conclusion: The clinical features of GPP in children and adults are different. Acitretin could be considered as a first-line therapy for GPP in children and adults, but corticosteroid should be used cautiously.

Genotype and Phenotype Analysis in Pediatric Patients with Cystinuria

Cystinuria is an inherited disorder characterized by defective renal reabsorption of cystine and dibasic amino acids leading to nephrolithiasis. This study was conducted to analyze the genotypes and phenotypes of pediatric patients with cystinuria. Eight children from Seoul National University Hospital and Asan Medical Center presenting with cystinuria from January 2003 to June 2016 were retrospectively analyzed. Mutational studies were performed by direct sequencing. Two of the 8 were male and 6 were female. The median ages at onset and diagnosis were 1.5 (range, 0.3–13.6) and 2.6 (range, 0.7–16.7) years, respectively. The median followed up was 7.7 (range, 3.4–14.0) years. Mutational analyses were performed in 7 patients and revealed biallelic SLC3A1 mutations (AA genotype) in 4 patients, a single heterozygous SLC3A1 mutation (A- genotype) in 1 patient, biallelic SLC7A9 mutations (BB genotype) in 1 patient, and a single heterozygous SLC7A9 mutation (B- genotype) in 1 patient. Two of the mutations were novel. No genotype-phenotype correlations were observed, except for earlier onset age in patients with non-AA genotypes than in patients with the AA genotype. All patients suffered from recurrent attacks of symptomatic nephrolithiasis, which lead to urologic interventions. At the last follow-up, 3 patients had a mild-to-moderate degree of renal dysfunction. This is the first study of genotypic and phenotypic analyses of patients with cystinuria in Korea.

The 5-HTT gene polymorphisms correlated with the clinical manifestations of depression

Objective To determine the potential correlation of 5-HTT gene polymorphisms (5-HTTLPR and STin2) with clinical manifestations in depression. Methods A total of 401 depressed patients, all of Chinese Han region, were collected and genotyped by polymerase chain reactions (PCR). All patients were evaluated using a 17-item Hamilton depression rating scale (HAMD-17) and Hamilton anxiety rating scale (HAMA), and then associated analysis was applied. Results (1) The age of onset in patients with L/S genotype of 5-HTLPR polymorphism were much younger than that of patients with L/L and S/S genotype (F=3.281, P=0.039). Besides, there was also a significant difference of HAMA1 (anxious mood) scores among patients with different genotypes for 5-HTTLPR polymorphism, where the scores of those with L/S genotype were the highest (2.34±0.80, P=0.010). (2) The scores of HAMD10 (mental anxiety), HAMA1 (anxious mood), HAMA3 (fear) and mental anxiety factor were higher in patients with 12/10 genotype than patients with 12/12 and 10/10 genotype for STin2 polymorphism (2.40±0.83, 2.38±0.90, 1.42±1.04, 14.60±4.26 respectively; P value: 0.014, 0.044, 0.03 and 0.006 respectively). The scores of HAMD10(mental anxiety) and mental anxiety factor were (2.11±0.77), ( 12.96±3.78) in the 12/12 genotype patients, and significantly lower than that in the 12/10 genotype patients (adjusted P value: 0.018, 0.006). Conclusions A positive association of the 5-HTT polymorphisms with anxious symptoms in depressed patients is revealed. These findings might provide some evidences for the clinical phenotype and optimization of depression treatment. Key words: 5-HTT; Gen polymorphism; Depression

Increased Rab35 expression is a potential biomarker and implicated in the pathogenesis of Parkinson's disease.

Parkinson's disease (PD) is the second common neurodegenerative disease. Identification of biomarkers for early diagnosis and prediction of disease progression is important. The present comparative proteomic study of serum samples using two-dimensional fluorescence differential gel electrophoresis followed by ELISA confirmation demonstrated that protein expression of Rab35 was increased in PD patients compared with matched control subjects and other parkinsonian disorders, progressive supranuclear palsy (PSP) and multiple system atrophy (MSA). The serum level of Rab35 was significantly correlated with the age at onset of PD. The median age of onset in patients with higher Rab35 serum level was 5 years younger than those with lower Rab35 serum level. There was a positive correlation between the Rab35 level and disease duration of PD. Moreover, the protein expression of Rab35 was increased in the substantia nigra but not in the striatum of mouse models of PD, including MPTP-treated mice, rotenone-treated mice, (R1441C) LRRK2 or (G2019S) LRRK2 transgenic mice. Furthermore, overexpression of Rab35 increased the aggregation and secretion of mutant A53T α-synuclein in dopaminergic SH-SY5Y cells. Co-expression of Rab35 with wild-type or A53T α-synuclein in SH-SY5Y cells deteriorated cell death. Our results suggest that Rab35 is potentially useful in the differential diagnosis of parkinsonian disorders and is implicated in the pathogenesis of PD.

BRCA1/2 gene mutation and clinicopathologic features of triple negative breast cancer

To investigate the incidence of BRCA1/2 gene mutation among triple negative breast cancer (TNBC) patients. Polymerase chain reaction and DNA sequencing were used to detect mutations of BRCA1 (exons 2, 11 and 20) and BRCA2 (exon 11) genes using paraffin-embedded tissue samples of 33 TNBC patients (21 Uyghur patients and 12 Han patients ) in Xinjiang Uygur Autonomous Region. Among 33 cases of TNBC, 5 cases (5/33, 15.2%) were found to have BRCA1 gene mutation. The exon 11 of BRCA1 gene mutation proportion was seen in 4/5 and exon 20 of BRCA1 gene mutation proportion was seen in 1/5. No germline mutation was found in exon 2 of BRCA1 gene and exon 11 of BRCA2 gene. The onset age of patients with BRCA1 mutations were younger than 50 years. Four BRCA1 mutation patients were premenopausal. The proportions of BRCA1 gene mutation of Uygur TNBC patients and Han TNBC patients were 2/12 and 3/21, respectively, without significant difference (P=0.854). BRCA mutations were mainly found in stageⅠtoⅡ (4/5) and only 1 case (1/5) was found with stage Ⅲ disease. No significant difference was found in fertility status, menstrual status and age at menarche between mutated and non-mutated patients (P>0.05) . Germline mutation of BRCA1 may be more often associated with TNBC than BRCA2 for its higher mutation rate. Compared with non-mutated TNBC cases, several clinicopathologic features could be identified among mutated cases.

Antecedent Disease and Amyotrophic Lateral Sclerosis: What Is Protecting Whom?

Multiple studies have shown that antecedent diseases are less prevalent in amyotrophic lateral sclerosis (ALS) patients than the general age-matched population, which suggests possible neuroprotection. Antecedent disease could be protective against ALS or, conversely, the asymptomatic early physiological underpinnings of ALS could be protective against other antecedent disease. Elucidating the impact of antecedent disease on ALS is critical for assessing diagnostic risk factors, prognostic outcomes, and intervention timing. The objective of this study was to examine the relationship between antecedent conditions and ALS onset age and disease duration (i.e. survival). Medical history surveys for 1439 Emory ALS Clinic patients (Atlanta, GA, USA) were assessed for antecedent hypertension, hyperlipidemia, diabetes, obesity, asthma, arthritis, chronic obstructive pulmonary disease (COPD), thyroid, kidney, liver, and other non-ALS neurological diseases. The ALS onset age and disease duration are compared between the antecedent and non-antecedent populations using chi square, Kaplan–Meier, and ordinal logistic regression. When controlled for confounders, antecedent hypertension (high blood pressure), hyperlipidemia (high cholesterol), arthritis, COPD, thyroid disease, and non-ALS neurological disease are found to be statistically associated with a delayed ALS onset age, whereas antecedent obesity [body mass index (BMI) > 30] was correlated to earlier ALS onset age. With the potential exceptions of liver disease and diabetes (the latter without other common comorbid conditions), antecedent disease is associated with overall shorter ALS disease duration. The unique potential relationship between antecedent liver disease and longer ALS disease duration warrants further investigation, especially given liver disease was found to be a factor of 4–7 times less prevalent in ALS. Notably, most conditions associated with delayed ALS onset are also associated with shorter disease duration. Pathological homeostatic instability exacerbated by hypervigilant regulation (over-zealous homeostatic regulation due to too high regulatory feedback gains) is a viable hypothesis for explaining the early-life protection against antecedent disease and the overall lower antecedent disease prevalence in ALS patients; the later ALS onset age in patients with antecedent disease; and the inverse relationship between ALS onset age and disease duration.

Association of Family History of Epilepsy with Earlier Age Onset of Juvenile Myoclonic Epilepsy.

Juvenile myoclonic epilepsy (JME) is supposedly the most frequent subtype of idiopathic generalized epilepsies (IGE). The aim of this study was to determine the prevalence of JME and comparison of patients' demographics as well as timeline of the disease between positive family history epileptic patients (PFHE) and negative family history epileptic patients (NFHE) among sample of Iranian epileptic patients. From Feb. 2006 to Oct. 2009, 1915 definite epileptic patients (873 females) referred to epilepsy clinics in Isfahan, central Iran, were surveyed and among them, 194 JME patients were diagnosed. JME was diagnosed by its specific clinical and EEG criteria. Patients were divided into two groups as PFHE and NFHE and data were compared between them. JME was responsible for 10% (194 patients) of all types of epilepsies. Of JME patients, 53% were female. In terms of family history of epilepsy, 40% were positive. No significant differences was found between PFHE and NFHE groups as for gender (P>0.05). Age of epilepsy onset was significantly earlier in PFHE patients (15 vs. 22 yr, P<0.001). Occurrence of JME before 18 yr old among PFHE patients was significantly higher (OR=2.356, P=0.007). A family history of epilepsy might be associated with an earlier age of onset in patients with JME.

Genetic Polymorphisms in Autophagy-Associated Genes in Korean Children With Early-Onset Crohn Disease.

The aim of the present study was to investigate the genetic polymorphisms of the autophagy-associated genes autophagy-related 16-like 1 (ATG16L1), immunity-related GTPase M (IRGM), Unc-51-like kinase 1 (ULK1), and NOD2 with respect to early-onset Crohn disease (CD) among Korean children. A total of 65 patients with CD from the Seoul National University Children's Hospital, from January 2000 to May 2012, and 72 unaffected controls were selected. Twelve different single nucleotide polymorphisms (SNPs) were analyzed (TaqMan assay: ATG16L1 rs2241880, IRGM SNPs [rs13361189, rs4958847, rs1000113, rs10065172, and rs72553867], ULK1 SNPs [rs12303764, rs10902469, and rs7488085], NOD2 SNPs [Arg702Trp and Gly908Arg]; direct sequencing: NOD2 leu1007fsinsC). The onset age of patients was 8.6 ± 4.7 years. Twelve patients (18.5%) had an onset age of <1 year. Two of the 12 SNPs showed significant results. IRGM rs1000113 exhibited an association with CD with respect to its minor allele frequency (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.05-2.79, P = 0.03) and genotype distribution (dominant model: OR 2.17, 95% CI 1.07-4.39, P = 0.03). IRGM rs72553867 exhibited association with CD with respect to its minor allele frequency (OR 0.50, 95% CI 0.27-0.91, P = 0.02) and genotype distribution (dominant model: OR 0.50, 95% CI 0.23-0.94, P = 0.03). The 3 SNPs of NOD2 existed only as wild types for both groups. In the genotype-phenotype analysis, the onset age, disease location, and disease behavior exhibited no association. IRGM rs1000113 and IRGM rs72553867 exhibited associations with early-onset CD as risk loci and defense loci, respectively. This suggests that the autophagy pathway plays an important role in early-onset CD.

Genotype Versus Phenotype: The Yin and Yang of Germline TP53 Mutations in Li-Fraumeni Syndrome

Genotype Versus Phenotype: The Yin and Yang of Germline <i>TP53</i> Mutations in Li-Fraumeni Syndrome

Abstract 19687: Morphological and Clinical Characteristics of Late and Young Age Onset Apical Hypertrophic Cardiomyopathy: Insight from a 13-Year Registry of Hypertrophic Cardomyopathy

Background: Apical hypertrophic cardiomyopathy (ApHCM) might have different morphological and clinical features according to the age of disease onset, probably result from the distinct mechanism of pathogenesis. The aim of this study was to evaluated the morphological and clinical differences according to the age of disease onset in patients with ApHCM. Methods: This was a retrospective, observational study of 56 ApHCM patients (31 males, mean 65±9 years). Among 426 patients with diagnosed ApHCM from 2000 until 2013, we selected 56 patients who met the inclusion criteria: [[Unable to Display Character: &amp;#9332;]] patiens who diagnosed with ApHCM before 60 years old and current age &gt;60 years old, (group A, early onset, n=16); and [[Unable to Display Character: &amp;#9333;]] who diagnosed with ApHCM after 60 years old who had no evidence of apical hypertrophy confirmed by previous echocardiography (group B, late onset, n=40). Morphological LV feature was assessed by transthoracic echocardiography, which were divided into pure and mixed type. Furthermore, hemodynamic parameters and clinical events were also evaluated. Results: There were no differences in the presence of hypertension, LV systolic function and left atrial volume index between group A and B. However, early onset group A had more increased maximal wall thickness of LV apex (17.08±2.02 vs 15.43±1.68mm, p=0.005), and more incidence of pure type (100% (16/16) vs 56.8% (21/40), p=0.001) compare than late onset group B. Group B had older age (65±5 vs 72±4 years, p=0.001), increased LV end-diastolic dimension (51.25±2.32 vs 48.58±3.37mm, p=0.006), increased E/E’ (11.24±2.94 vs 14.60±6.37, p=0.049) with decreased E’ (5.61±1.34 vs 4.66±1.38cm/s, p=0.024) respectively.There were no significant differences in the risk of cardiovascular complication such as atrial fibrillation and stoke between group A and B. Conclusions: There was obvious different clinical characteristics according to the age of disease onset. Early onset ApHCM has typical morphological feature and relatively preserved LV diastolic function, compared with late onset ApHCM. Our result supports that late onset ApHCM was related to decreased LV diastolic function and increased LV wall thickness, which reflects the potential myocardial remodeling with aging.

MAPT as a predisposing gene for sporadic amyotrophic lateral sclerosis in the Chinese Han population.

A previous study of European Caucasian patients with sporadic amyotrophic lateral sclerosis demonstrated that a polymorphism in the microtubule-associated protein Tau (MAPT) gene was significantly associated with sporadic amyotrophic lateral sclerosis pathogenesis. Here, we tested this association in 107 sporadic amyotrophic lateral sclerosis patients and 100 healthy controls from the Chinese Han population. We screened the mutation-susceptible regions of MAPT – the 3' and 5' untranslated regions as well as introns 9, 10, 11, and 12 – by direct sequencing, and identified 33 genetic variations. Two of these, 105788 A > G in intron 9 and 123972 T > A in intron 11, were not present in the control group. The age of onset in patients with the 105788 A > G and/or the 123972 T > A variant was younger than that in patients without either genetic variation. Moreover, the pa-tients with a genetic variation were more prone to bulbar palsy and breathing difficulties than those with the wild-type genotype. This led to a shorter survival period in patients with a MAPT genetic variant. Our study suggests that the MAPT gene is a potential risk gene for sporadic amyotrophic lateral sclerosis in the Chinese Han population.

Effects of a polymorphism in the GFAP promoter on the age of onset and ambulatory disability in late-onset Alexander disease

Alexander disease (AxD) is a rare neurodegenerative disorder. Most patients with AxD have a de novo dominant missense mutation in the glial fibrillary acidic protein (GFAP) gene. Patients with late-onset AxD exhibit a more variable onset and severity than patients with early-onset AxD, suggesting the existence of factors that modify the clinical phenotype of late-onset AxD. A -250-bp C/A single-nucleotide polymorphism (SNP) of the GFAP promoter (rs2070935) in the activator protein-1 binding site is a candidate factor for modification of the clinical phenotype. We analyzed the SNP in 10 patients with late-onset AxD and evaluated the effects of the SNP on the clinical course of late-onset AxD. Three of four cases with the C/C genotype lost the ability to walk in their 30s or 40s, whereas all six cases with the other genotypes retained the ability to walk throughout their 30s. The age of onset in patients with the C/C genotype was significantly earlier than in patients with the other genotypes (P<0.05). A more severe phenotype was observed in the patient in whom the C allele of rs2070935 was in cis with the GFAP mutation compared with the patient in whom the C allele of rs2070935 was in trans with the GFAP mutation. Our investigation revealed the possibility that the C/C genotype at rs2070935 of the GFAP promoter in late-onset AxD was associated with an earlier onset and a more rapid progression of ambulatory disability compared with the other genotypes.