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Plasma methionine concentrations and incidence of hypermethioninemic encephalopathy during infancy in a large cohort of 36 patients with classical homocystinuria in the Republic of Ireland.

ABSTRACT: Background:Classical homocystinuria is an autosomal recessive disorder caused by profound cystathionine ?-synthase deficiency. Its biochemical hallmarks are high concentrations of plasma homocyst(e)ine and methionine. Clinical manifestations include lens dislocation, developmental delay, skeletal anomalies, or thromboembolism. Limited literature exists outlining the risk of encephalopathy associated with hypermethioninemia presenting in children with classical homocystinuria. Aim:To assess the quality of metabolic control and plasma methionine concentrations in infancy in a cohort of 36 patients with classical homocystinuria in the Republic of Ireland. Methods:Review of biochemical and clinical data including neuroradiological results that are available for the first year of life in our patients diagnosed on newborn screening was performed with appropriate consent and ethical approval. Results and Discussion:Median total homocyst(e)ine and methionine plasma concentrations were 78 and 55??mol/L, respectively. Methionine concentrations were significantly higher in neonates as opposed to older children. The highest methionine level identified was 1329??mol/L in a child who presented clinically with encephalopathy. Elevated homocyst(e)ine and methionine levels are associated with significant morbidities. Therefore, prevention of complications requires prompt recognition and treatment. Chronic and acute complications may be encountered in patients with classical homocystinuria and plasma methionine concentrations pose an additional risk factor.

SUBMITTER: Allen J

PROVIDER: S-EPMC6498867 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Plasma methionine concentrations and incidence of hypermethioninemic encephalopathy during infancy in a large cohort of 36 patients with classical homocystinuria in the Republic of Ireland.

Allen John J Power Bronwyn B Abedin Aida A Purcell Orla O Knerr Ina I Monavari Ahmad A

JIMD reports 20190326 1

<h4>Background</h4>Classical homocystinuria is an autosomal recessive disorder caused by profound cystathionine β-synthase deficiency. Its biochemical hallmarks are high concentrations of plasma homocyst(e)ine and methionine. Clinical manifestations include lens dislocation, developmental delay, skeletal anomalies, or thromboembolism. Limited literature exists outlining the risk of encephalopathy associated with hypermethioninemia presenting in children with classical homocystinuria.<h4>Aim</h4> ...[more]

PMID: 31240166

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Project description:BACKGROUND:Classical homocystinuria due to cystathionine β-synthase (CBS) deficiency (OMIM 236200) is a recessively inherited condition caused by mutations in the CBS gene. The founder mutation p.R336C accounts for almost all CBS deficiency in Qatar, affecting approximately 1 in 1,800 births, making it the most prevalent monogenic disease among the Qatari population. Untreated patients can have severe intellectual disability (ID), devastating multisystem complications and premature death. Current treatment is based on pharmacology therapy and life-long methionine-restricted diet, which is difficult to maintain particularly in late diagnosed individuals. Data on the neurodevelopmental and psychological impact of the disease on outcomes among Qatari patients are generally lacking and have not been studied. OBJECTIVES:To examine the cognitive, educational and psychological outcomes of classical homocystinuria on Qatari patients. SUBJECTS AND METHODS:Thirty-two cases with classical homocystinuria and 25 sibling controls were recruited to evaluate the neurodevelopmental and cognitive outcomes. We reviewed the subjects' medical record and collected pertinent clinical and educational data from parents. Stanford-Binet Intelligence Test (Arabic translation - 4th ed.) was used for cognitive (IQ) testing. RESULTS:The mean age for the subjects was 11.2 years (range 0.6-29) with 56% males. The majority of cases (93%) carried the mutation (p.R336C), and parental consanguinity was 84%. There were no differences between the two groups in the fine motor, expressive language, behavioural and visual skills. However, cases have much lower total IQ particularly in the domains of short memory, quantitative reasoning and visual-spatial domains. A significant number of adolescents and adult cases had medical co-morbidities as well as behavioural and emotional problems. CONCLUSION:Individuals with classical homocystinuria have many developmental and cognitive difficulties with significant number of cases having learning disability and lower IQs (cf. sibling controls) with adolescents and adults more affected. Those diagnosed by newborn screening have better developmental and cognitive outcomes compared to late diagnosed cases. Psychological and psychiatric referrals should be part of the standard of care for those cases.

Project description:BackgroundTo constrain propagation and mitigate the burden of COVID-19, most countries initiated and continue to implement several non-pharmaceutical interventions (NPIs), including national and regional lockdowns. In the Republic of Ireland, the first national lockdown was decreed on 23rd of March 2020, followed by a succession of restriction increases and decreases (phases) over the following year. To date, the effects of these interventions remain unclear, and particularly within differing population subsets. The current study sought to assess the impact of individual NPI phases on COVID-19 transmission patterns within delineated population subgroups in the Republic of Ireland.Methods and findingsConfirmed, anonymised COVID-19 cases occurring between the 29th of February 2020 and 30th November 2020 (n = 72,654) were obtained. Segmented modelling via breakpoint regression with multiple turning points was employed to identify structural breaks across sub-populations, including primary/secondary infections, age deciles, urban/commuter/rural areas, patients with underlying health conditions, and socio-demographic profiles. These were subsequently compared with initiation dates of eight overarching NPI phases. Five distinct breakpoints were identified. The first breakpoint, associated with a decrease in the daily COVID-19 incidence, was reported within 14 days of the first set of restrictions in mid-March 2020 for most population sub-groups. Results suggest that moderately strict NPIs were more effective than the strictest Phase 5 (National Lockdown). Divergences were observed across population sub-groups; lagged response times were observed among populations >80 years, residents of rural/ commuter regions, and cases associated with a below-median deprivation score.ConclusionsStudy findings suggest that many NPIs have been successful in decreasing COVID-19 incidence rates, however the strictest Phase 5 NPI was not. Moreover, NPIs were not equally successful across all sub-populations, with differing response times noted. Future strategies and interventions may need to be increasingly bespoke, based on sub-population profiles and required responses.

Project description:IntroductionThe identification of genomic "targets" through next-generation sequencing (NGS) of patient's NSCLC tumors has resulted in a rapid expansion of targeted treatment options for selected patients. This retrospective study aims to identify the proportion of patients with advanced NSCLC in the Republic of Ireland whose tumors harbor actionable genomic alterations through broad NGS panel testing.MethodsInstitutional review board approval was obtained before study initiation. Patients with NSCLC whose tumors underwent genomic testing through the largest available NGS panel at a nationally funded Cancer Molecular Diagnostics laboratory (St. James's Hospital) between June 2017 and June 2022 were identified. Patient demographics and tumor-related data were collected by retrospective review from all cancer centers in Ireland, referring to the Cancer Molecular Diagnostics laboratory. A total of 203 (9%) tumor samples were excluded due to insufficient neoplastic cell content. Genomic data were collected through retrospective search of Ion Reporter software. The spectrum and proportion of patients with oncogenic driver mutations were evaluated using descriptive statistics (SPSS version 29.0).ResultsIn total, 2052 patients were identified. Patients were referred from 23 different hospital sites and all four geographic regions (Leinster = 1091, 53%; Munster = 763, 37.2%; Connacht = 191, 9.3%; Ulster = 7, 0.3%). Median age was 69 (range: 26-94) years; 53% were male. The most common tumor histologic subtype was adenocarcinoma (77%, n = 1577). An actionable genomic alteration was identified in 1099 cases (53%), the most common of which was KRAS (n = 657, 32%). Less frequently, NSCLC tumors harbored the following: MET exon 14 skipping (n = 53, 2.6%), MET amplification (n = 26, 1.3%), EGFR (n = 181, 8.8%), HER2 (n = 35, 1.7%), and BRAF (n = 72, 3.5%) mutations. Fusions were detected in 76 patients (3.7%) including ALK (n = 44, 58%), RET (n = 11, 14.5%), ROS1 (n = 16, 21%), and FGFR3 (n = 5, 6.6%), whereas no NTRK fusion was identified. Co-alterations were detected in 114 patients (5.6%), the most common of which was KRAS/PIK3CA (n = 19, 17%), EGFR/PIK3CA (n = 10, 8.5%), and KRAS/IDH1 (n = 9, 8%). Other co-alterations of interest identified included KRAS G12A/ROS1 fusion (n = 1) and KRAS G12C/BRAF G469A (n = 2).ConclusionsThis is the first retrospective study to comprehensively characterize the genomic landscape of NSCLC in Ireland, using the broadest available NGS panel. Actionable alterations were identified in 53.4% of the patients, and KRAS was the most common oncogenic driver alteration. Our study revealed a lower prevalence of patients whose tumor harbors ALK, ROS1, and RET fusions, compared with similar data sets.

Project description:Introduction and aimsSince 2013 MenC and MenW disease incidence and associated mortality rates have increased in the Republic of Ireland. From 2002/2003 to 2012/2013, the average annual MenC incidence was 0.08/100,000, which increased to 0.34/100,000 during 2013/2014 to 2017/18, peaking in 2016/17 (0.72/100,000) with an associated case fatality rate (CFR) of 14.7%. MenW disease incidence has increased each year from 0.02/100,000 in 2013/2014, to 0.29/100,000 in 2017/18, with an associated CFR of 28.6%. We aimed to characterise and relate recent MenC isolates to the previously prevalent MenC:cc11 ET-15 clones, and also characterise and relate recent MenW isolates to the novel 'Hajj' clones.MethodsUsing WGS we characterised invasive (n = 74, 1997/98 to 2016/17) and carried (n = 16, 2016/17) MenC isolates, and invasive (n = 18, 2010/11 to 2016/17) and carried (n = 15, 2016/17) MenW isolates. Genomes were assembled using VelvethOptimiser and stored on the PubMLST Neisseria Bacterial Isolate Genome Sequence Database. Isolates were compared using the cgMLST approach.ResultsMost MenC and MenW isolates identified were cc11. A single MenC:cc11 sub-lineage contained the majority (68%, n = 19/28) of recent MenC:cc11 disease isolates and all carried MenC:cc11 isolates, which were interspersed and distinct from the historically significant ET-15 clones. MenW:cc11 study isolates clustered among international examples of both the original UK 2009 MenW:cc11, and novel 2013 MenW:cc11clones.ConclusionsWe have shown that the majority of recent MenC disease incidence was caused by strain types distinct from the MenC:cc11 ET-15 clone of the late 1990s, which still circulate but have caused only sporadic disease in recent years. We have identified that the same aggressive MenW clone now established in several other European countries, is endemic in the RoI and responsible for the recent MenW incidence increases. This data informed the National immunisation Advisory Committee, who are currently deliberating a vaccine policy change to protect teenagers.

Project description:BackgroundThis study aimed to capture public beliefs about living with obesity, examine how these beliefs have changed over time and to explore whether certain characteristics were associated with them in a nationally representative sample of adults from the Republic of Ireland (RoI) and Northern Ireland (NI).MethodsA cross-sectional survey employed a random quota sampling approach to recruit a nationally representative sample of 1046 adults across NI and RoI. Telephone interviews captured information on demographics; health behaviours & attitudes; and beliefs about the consequences of obesity (measured using the Obesity Beliefs Scale). Univariable analyses compared beliefs about the consequences of living with obesity between participants with a self-reported healthy weight and those living with overweight or obesity, and non-responders (those for whom weight status could not be ascertained due to missing data). Multiple linear regression examined associations between obesity-related beliefs and socio-demographics, self-rated health and perceived ability to change health behaviours. Multiple linear regression also compared changes in obesity-related beliefs between 2013 and 2020 in the RoI.ResultsHigher endorsement of the negative outcomes of obesity was significantly associated with living with a healthy weight, higher self-rated health, dietary quality and perceived ability to improve diet and physical activity. Those who lived with overweight, with obesity and non-responders were less likely to endorse the negative consequences of obesity. Those living with obesity and non-responders were also more likely to support there is an increased cost and effort in maintaining a healthy weight. Comparison with survey data from 2013 showed that currently, there is a greater endorsement of the health benefits of maintaining a healthy weight (p < 0001), but also of the increased costs associated with it (p < 0001).ConclusionBeliefs about the consequences of maintaining a healthy body weight are associated with individuals' weight, self-rated health, diet and perceived ease of adoption of dietary and exercise-related improvements. Beliefs about the health risks of obesity and perceived greater costs associated with maintaining a healthy weight appear to have strengthened over time. Present findings are pertinent to researchers and policy makers involved in the design and framing of interventions to address obesity.

Dataset Information

Plasma methionine concentrations and incidence of hypermethioninemic encephalopathy during infancy in a large cohort of 36 patients with classical homocystinuria in the Republic of Ireland.

Publications

Plasma methionine concentrations and incidence of hypermethioninemic encephalopathy during infancy in a large cohort of 36 patients with classical homocystinuria in the Republic of Ireland.

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