Serum Magnesium Level and It's Relation in Predicting Adverse In-Hospital Outcome in Patients with First Attack of Myocardial Infarction.

Acute myocardial infarction (AMI) patients characterize a large proportion of admissions in coronary care unit and their management and risk stratification is of immense importance. Hypomagnesemia is a long-term risk factor for incident of both myocardial infarction and arrhythmia. We assessed whether serum magnesium levels at admission is associated with arrhythmias and in-hospital mortality in patients with acute myocardial infarction (AMI). The aim of the study was to evaluate the prognostic implications of serum magnesium level in patients with acute myocardial infarction. This cross-sectional observational study was conducted in the department of cardiology in Mymensingh Medical College Hospital from October 2017 to March 2019. Total 259 acute myocardial infarction patients were included considering inclusion and exclusion criteria. The sample population was divided into two groups: Group-I: Patients with acute myocardial infarction with serum magnesium ≥1.82mg/dl. Group-II: Patients with acute myocardial infarction with serum magnesium <1.82mg/dl. Serum magnesium level was measured on admission, and the incidence of in-hospital major cardiac events was assessed. In this study mean serum magnesium level of Group-I, Group-II were 2.21±0.14mg/dl, 1.60±0.15mg/dl respectively. It was statistically significant (p<0.05). In-hospital outcomes of the study group revealed that low risk group patients were uneventful outcome during hospitalization period, they had no any complication. In Group-I patient, 9(4.8%) were developed arrhythmias, 26(13.9%) were developed heart failure, 9(4.8%) were developed cardiogenic shock and 3(1.6%) were died and in Group-II patient, 44(61.10%) developed arrhythmias, 9(12.50%) were developed heart failure, 7(9.7%) were developed cardiogenic shock and 12(16.7%) were died out of them which was statistically significant (p<0.05). Mean duration of hospital stay of the study population according serum magnesium level was in Group-I, 4.27±0.68 days, in Group-II, 5.84±1.05 days which was statistically significant (p<0.05). In conclusion patient with serum magnesium level less than 1.82mg/dl increased the risk of in-hospital arrhythmia and death.

Relationship of Conduction Defects and In-Hospital Outcome after Acute ST Segment Elevation Myocardial Infarction.

The presence of conduction defects complicating acute myocardial infarction (MI) is relatively frequent and is associated with increased short and long term mortality. Thrombolytic therapy has been established to reduce the mortality in acute MI, however its role in reducing the incidence of conduction defects is less clearly defined. Morbidity and mortality associated with conduction defects also remain unchanged. This study was aimed to assess the correlation between conduction defects and adverse in-hospital outcome of patients with acute ST segment elevation MI. This cross sectional descriptive type of observational study was conducted among 100 purposively selected patients with acute ST segment elevation MI in the coronary care unit (CCU) of Mymensingh Medical College Hospital, Bangladesh from June 2012 to March 2013. The patients were divided into two groups depending on the presence or absence of conduction defects namely Group A- 40 patients with conduction defects and Group B- 60 patients without conduction defects. Highest number of the patients (36.0%) was in the age group of 45-55 years. In case of inferior MI, age groups 45-55 years and 55-65 years had equal number of patients (30.4%). Only 2.0% patients were in age group of 75-85 years and this group had only inferior MI. Total number of female patients were 16(16.0%). Female patients had more inferior MI (17.4%) than anterior MI (15.9%). Number of MI patients was slightly more in inferior MI (46.0%) than anterior MI (44.0%). Group B had equal number of patients in both anterior and inferior MI. Conduction defects were more common in inferior MI (43.5%) than anterior MI (40.9%). Atrio-ventricular conduction defects were more common in inferior MI whereas intra-ventricular conduction defects were more common in anterior MI. Complete heart block (CHB) was more prevalent in inferior MI. Complications were more common in Group A (65.0%) than Group B (18.3%). In terms of complications the difference between two groups were significant (p<0.001). Group A showed higher rate of mortality (20.0%) than Group B (3.3%). In cases of anterior MI difference in mortality between Group A and Group B was highly significant (p<0.001). Conduction defects in the setting of acute MI are a common finding. Atrio-ventricular conduction defects occur more frequently in inferior MI whereas intra-ventricular conduction defects were more frequently encountered in anterior MI. Patients with conduction defects had more complications than those without conduction defects. Presence of conduction defects significantly increases the mortality of patients with anterior MI.

Estimation of Serum Lipid Profile among Patients Admitted with Myocardial Infarction in a Tertiary Level Hospital of Bangladesh.

Different studies worldwide showed that dyslipidaemia is involved in the pathogenesis of ischemic heart diseases (IHD). This cross sectional descriptive type of observational study was carried out at Mymensingh Medical College Hospital during the period of six months from January 2021 to September 2021 to estimate the lipid profile among patients admitted in the coronary care unit (CCU) with myocardial infarction (MI). Data were collected from purposively selected 343 patients with MI by face to face interview and laboratory investigations using a case record form. Informed written consent of participants was taken prior to interview. Data were analyzed by using SPSS version 21.0. The study results revealed that mean age of the patients with myocardial infarction was 53.16 years with a standard deviation of 11.68 years. Majority of them (284, 82.8%) were male and the remaining (59, 17.2%) were female. Proportion of risk factors for ischaemic heart disease (IHD) were estimated and found that 244(71.1%) patients were smoker; 150(43.7%) had hypertension and 110(32.2%) had family history of IHD. Ninety nine (28.9%) patents were obese with BMI ≥25kg/m². Eighty three (24.2%) patients had diabetes mellitus; 66(19.2%) lead sedentary life and 61(17.8%) patients with myocardial infarction had dyslipidaemia. Mean LDL of patients with myocardial infarction was 103.65±39.73mg/dl; mean total cholesterol (TC) was 189.44±45.41mg/dl; mean TG was 243.11±205.19mg/dl and mean HDL was 39.29±8.98mg/dl. LDL was increased in 10(2.9%) patients; total cholesterol was raised in 121 (35.3%) patients and TG was raised in 195(56.9%) patients. HDL was raised in 26(7.6%) patients and it was lowered in 57(16.6%) patients. Mean LDL, TC, TG and HDL of younger (≤45 years) and older (>45 years) patients were compared and t-test showed no significant difference (p>0.05). Similarly mean LDL, TC, TG and HDL of male and female were compared and again t-test showed no significant difference (p>0.05). Though the pattern of lipid profile was found similar in younger and older patients and in males and females, a significant number of patients (61, 17.8%) with MI had dyslipidaemia which should be address by dietary and lifestyle modification.

Overweight and Obesity among Children of Primary Schools of Mymensingh Municipal Area.

Obesity is now recognized as a major cause of morbidity and mortality throughout the world. The relative percentage of change is higher in developing countries. Childhood obesity has become a serious public health emerging problem because of its strong association with adulthood obesity and related adverse health consequences. The main objective of the study was to find out the status of overweight and obesity among primary school children of Mymensingh municipal area. This cross sectional descriptive study was carried out among primary school children of Mymensingh municipal area from September 2016 to February 2018. Total 1450 students were enrolled from 6 schools. Schools were selected by random lottery method. Data was collected in predesigned case record forms by investigator with the help of students, teachers and parents. Anthropometry was measured by principal investigator. Body mass index (BMI) was calculated and plotted by using Center for disease control (CDC) BMI growth charts for age and sex. Children were categorized as obese, overweight, normal and underweight. Data analysis was done by computer software SPSS version 20.0. Mean age of children was 9.0±1.124 years. There was 47.4% male and 52.6% female. Among the 1450 children 18.6% obese, 17.5% overweight, 53.5% normal and 10.4% underweight. So, total 36.1% children had BMI above normal limit. Obesity was found more common among male children (p<0.001). Obesity and overweight was significantly associated with fast food consumption (p<0.001), playing computer and mobile games (p<0.001), watching TV (p<0.001), higher parent's education (p<0.001), higher parent's income (p<0.001), service holder father (p<0.001), family history of overweight or obesity (p<0.001), single child in family (p<0.001) and increased birth weight (p<0.001). A large number of primary school children in Mymensingh municipal area were overweight and obese. Childhood obesity and overweight varies from school to school. Childhood obesity and overweight is an emerging and growing health issue in municipal area.

Serum Iron Profile and Red Cell Indices in Children with Severe Acute Malnutrition in A Tertiary Level Hospital.

This cross-sectional analytical study was conducted in the department of Paediatrics, Mymensingh Medical College Hospital (MMCH), Mymensingh, Bangladesh from March 2017 to August 2018 to assess the pattern of serum iron profile and red cell indices in children with severe acute malnutrition. Seventy children having severe acute malnutrition were compared with 70 age matched children those had normal growth. Age range of the studied children was 6 months to 59 completed months. Male was found predominant (54.3%) in both study group and comparison group. Mean serum iron, serum ferritin, serum total iron binding capacity and transferrin saturation in severely malnourished children were 45.3±19.3µg/dl, 26.5±20.0ng/ml, 246.3±47.5µg/dl and 16.4±2.0% respectively which were significantly lower than that of healthy children (p<0.05). Mean Hb level in children with severe acute malnutrition was found 8.3±1.6gm/dl which was also found significantly lower than that of normal children (p<0.05). Anaemia was found in all (100%) severely malnourished children compared to 25.7% of children in comparison group. Mean MCV, MCH and MCHC in children with severe acute malnutrition was found 71.7±13.5fl, 24.0±5.8pg and 31.4±4.0gm/dl respectively which were significantly lower than that of comparison group (p<0.05). Serum iron profile and red cell indices should be routinely done in severely malnourished children for early intervention and management of iron deficiency anaemia.

Emotion-Inducing Imagery Versus Motor Imagery for a Brain-Computer Interface.

Neural correlates of intentionally induced human emotions may offer alternative imagery strategies to control brain-computer interface (BCI) applications. In this paper, a novel BCI control strategy i.e., imagining fictional or recalling mnemonic sad and happy events, emotion-inducing imagery (EII), is compared to motor imagery (MI) in a study involving multiple sessions using a two-class electroencephalogram (EEG)-based BCI paradigm with 12 participants. The BCI setup enabled online continuous visual feedback presentation in a game involving one-dimensional control of a game character. MI and EII are compared across different signal-processing frameworks which are based on neural-time-series-prediction-preprocessing (NTSPP), filter bank common spatial patterns (FBCSP) and hemispheric asymmetry (ASYM). Online single-trial classification accuracies (CA) results indicate that MI performance across all participants is 77.54% compared to EII performance of 68.78% ( ). The results show that an ensemble of the NTSPP, FBCSP and ASYM frameworks maximizes performance for EII with average CA of 71.64% across all participants. Furthermore, the participants' subjective responses indicate that they preferred MI over emotion-inducing imagery (EII) in controlling the game character, and MI was perceived to offer most control over the game character. The results suggest that EII is not a viable alternative to MI for the majority of participants in this study but may be an alternative imagery for a subset of BCI users based on acceptable EII performance (CA >70%) observed for some participants.

Acute diabetic neuropathy following improved glycaemic control: a case series and review.

SUMMARY: We present three cases of acute diabetic neuropathy and highlight a potentially underappreciated link between tightening of glycaemic control and acute neuropathies in patients with diabetes. Case 1: A 56-year-old male with poorly controlled type 2 diabetes (T2DM) was commenced on basal-bolus insulin. He presented 6 weeks later with a diffuse painful sensory neuropathy and postural hypotension. He was diagnosed with treatment-induced neuropathy (TIN, insulin neuritis) and obtained symptomatic relief from pregabalin. Case 2: A 67-year-old male with T2DM and chronic hyperglycaemia presented with left lower limb pain, weakness and weight loss shortly after achieving target glycaemia with oral anti-hyperglycaemics. Neurological examination and neuro-electrophysiological studies suggested diabetic lumbosacral radiculo-plexus neuropathy (DLPRN, diabetic amyotrophy). Pain and weakness resolved over time. Case 3: A 58-year-old male was admitted with blurred vision diplopia and complete ptosis of the right eye, with intact pupillary reflexes, shortly after intensification of glucose-lowering treatment with an SGLT2 inhibitor as adjunct to metformin. He was diagnosed with a pupil-sparing third nerve palsy secondary to diabetic mononeuritis which improved over time. While all three acute neuropathies have been previously well described, all are rare and require a high index of clinical suspicion as they are essentially a diagnosis of exclusion. Interestingly, all three of our cases are linked by the development of acute neuropathy following a significant improvement in glycaemic control. This phenomenon is well described in TIN, but not previously highlighted in other acute neuropathies. LEARNING POINTS: A link between acute tightening of glycaemic control and acute neuropathies has not been well described in literature. Clinicians caring for patients with diabetes who develop otherwise unexplained neurologic symptoms following a tightening of glycaemic control should consider the possibility of an acute diabetic neuropathy. Early recognition of these neuropathies can obviate the need for detailed and expensive investigations and allow for early institution of appropriate pain-relieving medications.

Fiber gene based molecular and biological characterization of hydropericardium-hepatitis syndrome associated avian adenoviruses.

This study was designed to perform biological and molecular characterization of avian adenoviruses (AAVs) recovered from suspected cases of hydropericardium-hepatitis syndrome (HHS) in commercial poultry. Initially the samples were screened by Agar Gel Precipitation Test (AGPT) for the presence of AAVs followed by its confirmation and typing through polymerase chain reaction (PCR) focusing on already reported serotypes AAV-4, AAV-8 and AAV-10 elsewhere. These PCR-positive samples were further subjected to amplification of fiber gene, followed by conducting restriction fragment length polymorphism (RFLP) using restriction enzyme Alu. The selected isolates were further propagated through cell culture and pathogenic potential of selected isolates was determined by infecting chickens. In this study, out of a total 190 samples, 57.8% of suspected cases were found positive for AAV presence through AGPT while sub-type identification using PCR revealed 46.3% for these viruses belonging to AAV-4, 41.8% to AAV-8 and 11.8% showed co-infection of AAV-4 and AAV-8. AAV-10 was not detected in any of the tested samples. On the basis of RFLP pattern, AAV-4 isolates were further divided into four sub-groups (A-D) while AAV-8 isolates had identical RFLP pattern. To further evaluate the pathogenic potential of these sub-groups of AAV-4 isolates, specific pathogen free (SPF) chicks were challenged with selected isolates belonging to each of the sub-groups, resulting in variable pattern of pathogenicity. It is concluded that any variation in the fiber gene of AAV-4 isolates may affect its pathogenicity and eventually specificity of the vaccines used against such infections. Therefore, regular monitoring of the circulating AAV serotypes may be helpful in understanding the pathogenic potential of emerging AAVs, which may lead to development of more effective response strategies accordingly.

3D hand motion trajectory prediction from EEG mu and beta bandpower.

A motion trajectory prediction (MTP) - based brain-computer interface (BCI) aims to reconstruct the three-dimensional (3D) trajectory of upper limb movement using electroencephalography (EEG). The most common MTP BCI employs a time series of bandpass-filtered EEG potentials (referred to here as the potential time-series, PTS, model) for reconstructing the trajectory of a 3D limb movement using multiple linear regression. These studies report the best accuracy when a 0.5-2Hz bandpass filter is applied to the EEG. In the present study, we show that spatiotemporal power distribution of theta (4-8Hz), mu (8-12Hz), and beta (12-28Hz) bands are more robust for movement trajectory decoding when the standard PTS approach is replaced with time-varying bandpower values of a specified EEG band, ie, with a bandpower time-series (BTS) model. A comprehensive analysis comprising of three subjects performing pointing movements with the dominant right arm toward six targets is presented. Our results show that the BTS model produces significantly higher MTP accuracy (R~0.45) compared to the standard PTS model (R~0.2). In the case of the BTS model, the highest accuracy was achieved across the three subjects typically in the mu (8-12Hz) and low-beta (12-18Hz) bands. Additionally, we highlight a limitation of the commonly used PTS model and illustrate how this model may be suboptimal for decoding motion trajectory relevant information. Although our results, showing that the mu and beta bands are prominent for MTP, are not in line with other MTP studies, they are consistent with the extensive literature on classical multiclass sensorimotor rhythm-based BCI studies (classification of limbs as opposed to motion trajectory prediction), which report the best accuracy of imagined limb movement classification using power values of mu and beta frequency bands. The methods proposed here provide a positive step toward noninvasive decoding of imagined 3D hand movements for movement-free BCIs.

Length-Scale-Dependent Phase Transformation of LiFePO4 : An In situ and Operando Study Using Micro-Raman Spectroscopy and XRD.

The charge and discharge of lithium ion batteries are often accompanied by electrochemically driven phase-transformation processes. In this work, two in situ and operando methods, that is, micro-Raman spectroscopy and X-ray diffraction (XRD), have been combined to study the phase-transformation process in LiFePO4 at two distinct length scales, namely, particle-level scale (∼1 µm) and macroscopic scale (∼several cm). In situ Raman studies revealed a discrete mode of phase transformation at the particle level. Besides, the preferred electrochemical transport network, particularly the carbon content, was found to govern the sequence of phase transformation among particles. In contrast, at the macroscopic level, studies conducted at four different discharge rates showed a continuous but delayed phase transformation. These findings uncovered the intricate phase transformation in LiFePO4 and potentially offer valuable insights into optimizing the length-scale-dependent properties of battery materials.

E3D hand movement velocity reconstruction using power spectral density of EEG signals and neural network.

Three dimensional (3D) limb motion trajectory is predictable with a non-invasive brain-computer interface (BCI). To date, most non-invasive motion trajectory prediction BCIs use potential values of electroencephalographic (EEG) signals as the input to a multiple linear regression (mLR) based kinetic data estimator. We investigated the possible improvement in accuracy of 3D hand movement prediction (i.e., the correlation of registered and reconstructed hand velocities) by replacing raw EEG potentials with spectrum power values of specific EEG bands. We also investigated if a non-linear neural network based estimator outperformed the mLR approach. The spectrum power model provided significantly higher accuracy (R~0.60) compared to the similar EEG potentials based approach (R~0.45). Additionally, when replacing the mLR based kinetic data estimation module with a feed-forward neural network (NN) we found the NN based spectrum power model provided higher accuracy (R~0.70) compared to the similar mLR based approach (R~0.60).

Do gastroenterologists monitor their patients taking 5-amino-salicylates following initiation of treatment.

BACKGROUND: 5-Amino salicylate (5-ASA) medications may rarely be associated with a significant decline in renal function and interstitial nephritis. British Society of Gastroenterology guidelines advise regular renal function monitoring for patients taking these drugs. AIM: To assess whether gastroenterologists in Kent were following best practice guidelines regarding the monitoring of their patients on 5-ASA therapy. METHODS: Using longitudinal community and regional pathology databases for the Kent population, our renal unit regularly screens a total population of 300 000 for evidence of renal disease. The data extracted are analysed using an automated computerised system to identify patients requiring intervention for kidney disease. All patients taking 5-ASA medication were identified from a population of 300 000. The pathology database was studied to identify the patients on 5-ASA treatment and whether they had had renal function tests. RESULTS: 800 adult patients were identified taking 5-ASA therapy. 612 patients received 5-ASAs for 3 months or more, and these were included in the final analysis. 293 patients had no renal function checks while on treatment. 79 patients had renal function tests less than once every 4 years and 36 patients once every 2-4 years. 204 patients had renal function measurements in 50% or more of years of treatment, of whom 116 were checked every year. Some patients were started on treatment with abnormal results at baseline and some with identified kidney disease continued on their 5-ASAs. CONCLUSIONS: The majority of patients receiving 5-ASA compounds do not have regular renal function monitoring. Clinicians are failing to follow best practice guidelines.

Calcium supplements as source of trace elements: adequacy and safety of supplements with vitamin C, vitamin D and phosphate formulations.

Instrumental neutron activation analysis and atomic absorption spectrometry were used to quantify trace elements in different national and multinational Ca supplements categorized on the basis of Ca with vitamin D, vitamin C and phosphate formulations. The supplements were found to contain low levels of Co, Cr and Cu with elevated amounts of Fe, K and Na. Toxic elements (As, Cd and Sb) were detected in very few samples at very low concentrations. The essential elements contribute to >3% of their respective Dietary Reference Intakes.

Neutron activation analysis of essential elements in Multani mitti clay using miniature neutron source reactor.

Multani mitti clay was studied for 19 essential and other elements. Four different radio-assay schemes were adopted for instrumental neutron activation analysis (INAA) using miniature neutron source reactor. The estimated weekly intakes of Cr and Fe are high for men, women, pregnant and lactating women and children while intake of Co is higher in adult categories and Mn by pregnant women. Comparison of MM clay with other type of clays shows that it is a good source of essential elements.

Isolation, identification, and phylogenetic analysis of reassortant low-pathogenic avian influenza virus H3N1 from Pakistan.

During routine avian influenza surveillance in Pakistan, a low-pathogenic avian influenza virus (LPAI) subtype H3N1 was isolated for the first time from domestic chickens. The higher seroprevalence of H3N1 was recorded in both commercial and domestic poultry in ecological zones of Pakistan where the geographical proximity with neighboring countries and attractive birding sites provide better opportunities for frequent movements of wild and migratory birds, and their intermingling with the local domestic and commercial poultry. Subsequent whole genome sequencing of this virus revealed a new introduction of a reassortant Eurasian avian strain, which was distinguishable from corresponding human and swine strains isolated elsewhere. Phylogenetically, the HA gene was mostly clustered with Nordic (Scandinavian) strains of influenza viruses, whereas the NA and PB1 genes showed a maximum nucleotide sequence homology with the Indian H11N1, and the PB2 gene was found to be closely related to the Altai H5N2. The Matrix and NP genes of H3N1 mostly clustered with the European avian influenza viruses (AIV), whereas its NS and PA genes showed maximum nucleotide homologies with the African (Egypt) AIV strains. A sequence and amino acid analysis revealed an LP motif, avian-like receptor specificity, potential glycosylation sites, and sensitivities to oseltamivir, zanamivir, and amantadine. Some point mutations possessed by this Pakistani AIV H3N1 were also found in human, equine, and swine H3 influenza viruses. This H3N1 isolate showed less nucleotide sequence homology with the previously known Pakistani AIV as compared with other Eurasian AIV strains.

High-performance thin layer chromatographic quantification of bioactive psoralen and daidzein in leaves of Ficus carica L.

This study was undertaken to quantify psoralen and daidzein by high-performance thin layer chromatography (HPTLC). The methanolic extract of 10 mg mL(-1) concentration solution was prepared for HPTLC quantification of psoralen and daidzein. HPTLC aluminium-backed plates coated with 0.2 mm layers of silica gel 60 F(254) were used as the stationary phase. The working standard solution of psoralen and daidzein was applied along with the test sample solution by means of Camag Linomat IV sample applicator. R (f) values of psoralen and daidzein were found to be 0.60 and 0.88, whilst as their percentage values in methanolic extract were found to be 3.02% and 5.64% (w/w), respectively. A simple quantitative estimation method of psoralen and daidzein by HPTLC is reported that can be used for the quality control of marketed preparations containing Ficus carica. However, further study is warranted to isolate and quantify active constituents present in the leaves of F. carica by sophisticated techniques.

Case study on a self-organizing spiking neural network for robot navigation.

This paper presents a Spiking Neural Network (SNN) architecture for mobile robot navigation. The SNN contains 4 layers where dynamic synapses route information to the appropriate neurons in each layer and the neurons are modeled using the Leaky Integrate and Fire (LIF) model. The SNN learns by self-organizing its connectivity as new environmental conditions are experienced and consequently knowledge about its environment is stored in the connectivity. Also a novel feature of the proposed SNN architecture is that it uses working memory, where present and previous sensor states are stored. Results are presented for a wall following application.

Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia.

OBJECTIVE: Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder caused by degeneration of motor neurons. Mutations in the FUS gene were identified in patients with familial ALS (FALS) and patients with sporadic ALS (SALS) from a variety of genetic backgrounds. This work further explores the spectrum of FUS mutations in patients with FALS and patients with FALS with features of frontotemporal dementia (FALS/FTD) or parkinsonism and dementia (FALS/PD/DE). METHODS: All exons of the FUS gene were sequenced in 476 FALS index cases negative for mutations in SOD1 and TARDBP. A total of 561-726 controls were analyzed for genetic variants observed. Clinical data from patients with FUS mutations were compared to those of patients with known SOD1 and TARDBP mutations. RESULTS: We identified 17 FUS mutations in 22 FALS families, 2 FALS/FTD families, and 1 FALS/PD/DE family from diverse genetic backgrounds; 11 mutations were novel. There were 4 frameshift, 1 nonsense, and 1 possible alternate splicing mutation. Patients with FUS mutations appeared to have earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms than those with SOD1 mutations. CONCLUSIONS: FUS gene mutations are not an uncommon cause in patients with FALS from diverse genetic backgrounds, and have a prevalence of 5.6% in non-SOD1 and non-TARDBP FALS, and approximately 4.79% in all FALS. The pathogenicity of some of these novel mutations awaits further studies. Patients with FUS mutations manifest earlier symptom onset, a higher rate of bulbar onset, and shorter duration of symptoms.

Age and founder effect of SOD1 A4V mutation causing ALS.

BACKGROUND: The alanine to valine mutation at codon 4 (A4V) of SOD1 causes a rapidly progressive dominant form of amyotrophic lateral sclerosis (ALS) with exclusively lower motor neuron disease and is responsible for 50% of SOD1 mutations associated with familial ALS in North America. This mutation is rare in Europe. The authors investigated the origin (geographic and time) of the A4V mutation. METHODS: Several cohorts were genotyped: North American patients with confirmed A4V mutation (n = 54), Swedish (n = 3) and Italian (n = 6) A4V patients, patients with ALS with SOD1 non-A4V mutations (n = 66) and patients with sporadic ALS (n = 96), healthy white (n = 96), African American (n = 17), Chinese (n = 53), Amerindian (n = 11), and Hispanic (n = 12) subjects. High-throughput SNP genotyping was performed using Taqman assay in 384-well format. A novel biallelic CA repeat in exon 5 of SOD1, tightly linked to A4V, was genotyped on sequencing gels. Association statistics were estimated using Haploview. p Values less than 0.05 were considered significant. Age of A4V was estimated using a novel method based on r(2) degeneration with genetic distance and a Bayesian method incorporated in DMLE+. RESULTS: A single haplotype of 10 polymorphisms across a 5.86-cM region was associated with A4V (p = 3.0e-11) when white controls were used, suggesting a founder effect. The strength of association of this haplotype progressively decreased when African American, Chinese, Hispanic, and Amerindian subjects were used as controls. The associated European haplotype was different from the North American haplotype, indicating two founder effects for A4V (Amerindian and European). The estimated age of A4V with the r(2) degeneration method was 458 +/- 59 years (range 398-569) and in agreement with the Bayesian method (554-734 years with 80-90% posterior probability). CONCLUSIONS: North American SOD1 alanine to valine mutation at codon 4 descended from two founders (Amerindian and European) 400-500 years ago.