Growth Patterns in the Irish Pyridoxine Nonresponsive Homocystinuria Population and the Influence of Metabolic Control and Protein Intake

A low methionine diet is the mainstay of treatment for pyridoxine nonresponsive homocystinuria (HCU). There are various guidelines for recommended protein intakes for HCU and clinical practice varies. Poor growth has been associated with low cystine levels. This retrospective review of 48 Irish pyridoxine nonresponsive HCU patients assessed weight, height, body mass index (BMI), protein intake, and metabolic control up to 18 years at nine set time points. Patients diagnosed through newborn screening (NBS) were compared to late diagnosed (LD) patients. At 18 years the LD group (n=12, mean age at diagnosis 5.09 years) were heavier (estimated effect +4.97 Kg, P=0.0058) and taller (estimated effect +7.97 cm P=0.0204) than the NBS group (n=36). There was no difference in growth rate between the groups after 10 years of age. The HCU population were heavier and taller than the general population by one standard deviation with no difference in BMI. There was no association between intermittently low cystine levels and height. Three protein intake guidelines were compared; there was no difference in adult height between those who met the lowest of the guidelines (Genetic Metabolic Dietitians International) and those with a higher protein intake

A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype

Background Isolated Complex I deficiency is the most common paediatric mitochondrial disease presentation, associated with poor prognosis and high mortality. Complex I comprises 44 structural subunits with at least 10 ancillary proteins; mutations in 29 of these have so far been associated with mitochondrial disease but there are limited genotype-phenotype correlations to guide clinicians to the correct genetic diagnosis. Methods Patients were analysed by whole-exome sequencing, targeted capture or candidate gene sequencing. Clinical phenotyping of affected individuals was performed. Results We identified a cohort of 10 patients from 8 families (7 families are of unrelated Irish ancestry) all of whom have short stature (C, p.Trp22Arg NDUFB3 variant. Two sibs presented with primary short stature without obvious metabolic dysfunction. Analysis of skeletal muscle from three patients confirmed a defect in Complex I assembly. Conclusions Our report highlights that the long-term prognosis related to the p.Trp22Arg NDUFB3 mutation can be good, even for some patients presenting in acute metabolic crisis with evidence of an isolated Complex I deficiency in muscle. Recognition of the distinctive facial features—particularly when associated with markers of mitochondrial dysfunction and/or Irish ancestry—should suggest screening for the p.Trp22Arg NDUFB3 mutation to establish a genetic diagnosis, circumventing the requirement of muscle biopsy to direct genetic investigations

Genotypic diversity and phenotypic spectrum of infantile liver failure syndrome type 1 due to variants inLARS1

Purpose: Biallelic variants in LARS1, coding for the cytosolic leucyl-tRNA synthetase, cause infantile liver failure syndrome 1 (ILFS1). Since its description in 2012, there has been no systematic analysis of the clinical spectrum and genetic findings. Methods: Individuals with biallelic variants in LARS1 were included through an international, multicenter collaboration including novel and previously published patients. Clinical variables were analyzed and functional studies were performed in patient-derived fibroblasts. Results: Twenty-five individuals from 15 families were ascertained including 12 novel patients with eight previously unreported variants. The most prominent clinical findings are recurrent elevation of liver transaminases up to liver failure and encephalopathic episodes, both triggered by febrile illness. Magnetic resonance image (MRI) changes during an encephalopathic episode can be consistent with metabolic stroke. Furthermore, growth retardation, microcytic anemia, neurodevelopmental delay, muscular hypotonia, and infection-related seizures are prevalent. Aminoacylation activity is significantly decreased in all patient cells studied upon temperature elevation in vitro. Conclusion: ILFS1 is characterized by recurrent elevation of liver transaminases up to liver failure in conjunction with abnormalities of growth, blood, nervous system, and musculature. Encephalopathic episodes with seizures can occur independently from liver crises and may present with metabolic stroke

National Clinical Review on the Impact of COVID-19 Restrictions on Children and Guidance on Reopening of Schools and the Normalisation of Paediatric Healthcare Services in Ireland

This National Clinical Review Document was developed in May/June 2020 following extensive consultation with Child Health Professionals with a deep and wide understanding of the needs of the child. The document has been updated in August 2020 to reflect more recent developments. It has been written to describe the impact of the COVID-19 lockdown measures on children and what needs to be done now. In essence the document explores where we have come from, where we are now, and where we should be in the coming months. It is our collective opinion that the two key adverse consequences for all children across the State are the prolonged closure of the schools and the curtailment of services to children - specifically paediatric medical services, GP services, and multidisciplinary community support services. We feel that there needs to be a recalibration of how children are catered for in this pandemic. The document provides a template for how best to address children’s needs during this difficult time. At present, children have become invisible despite the fact that they account for 25% of the country’s population. There needs to be more leadership and better co- ordination in both planning and implementation on their behalf. They need strong advocates. Children are not the face of this pandemic, but they risk being among its biggest victims. The short turnaround time between the inception and completion of the document is a reflection of our perceived urgency to set out what next must be done to halt and reverse the adverse effects of the current restrictions

Emergency department utilisation by homeless children in Dublin, Ireland: a retrospective review.

Introduction: Despite increasing prevalence, European family homelessness remains under-researched. Methods: A retrospective review was performed of homeless children attending a paediatric emergency department in Dublin, Ireland, from 1 January 2017 to 31 December 2020. Comparison was made with a random cohort of 1500 non-homeless paediatric attendances in 2019. Homelessness was defined using the European Typology of Homelessness and Housing Exclusion, including those with addresses of no fixed abode, government homeless accommodation and certain residential settings. The objectives were to compare presentations between homeless and non-homeless children. We were interested in determining differences regarding demographics, healthcare utilisation, clinical presentation and outcomes. Results: Of 197 437 attendances 3138 (1.59%) were homeless. Compared with the non homeless, homeless children were less likely to be ethnically Irish (37.4% vs 74.6%, p<0.001) or have been born in Ireland (82.3% vs 96.2%, p<0.001). Irish Travellers (3% vs 0.8%), Roma (22.5% vs 2.4%) and black (21.1% vs 4.2%) ethnicities were over-represented (p<0.001) in the homeless cohort. Homeless children were younger (age <12 months: 26% vs 16%; p<0.001), less likely to be fully vaccinated (73.6% vs 81.9%, p<0.001) and have registered general practitioners (89.7% vs 95.8%, p<0.001). They were more likely to represent within 2 weeks (15.9% vs 10.5%, p<0.001), and use ambulance transportation (13.2% vs 6.7%, p<0.001). Homeless children had lower acuity presentations (triage category 4–5: 47.2% vs 40.7%, p<0.001) and fewer admissions (5.9% vs 8.4%, p<0.001) than non-homeless children. Discussion: Infants, Irish Travellers, Roma and black ethnicities were over-represented in homeless presentations. Homeless children had increased reliance on emergency services for primary healthcare needs

Amino Acids and Inherited Amino Acid-Related Disorders

Amino acids perform multiple essential physiological roles in humans, and accordingly, their importance to health has been the subject of extensive attention. In this special issue of the Journal of Nutrition and Metabolism, we focus on the various inborn errors of amino acid metabolism, their diagnostic challenges, new treatment approaches, and recent advances in patient monitoring as well as clinical outcomes

Clinical and genetic characterisation of infantile liver failure syndrome type 1, due to recessive mutations in LARS

Background: Recessive LARS mutations were recently reported to cause a novel syndrome, infantile liver failure syndrome type 1 (ILFS1), in six Irish Travellers. We have since identified four additional patients, including one of Ashkenazi origin, representing the largest ILFS1 cohort to date. Our study aims to define the ILFS1 clinical phenotype to help guide diagnosis and patient management. Methods: We clinically evaluated and reviewed the medical records of ten ILFS1 patients. Clinical features, histopathology and natural histories were compared and patient management strategies reviewed. Results: Early failure to thrive, recurrent liver dysfunction, anemia, hypoalbuminemia and seizures were present in all patients. Most patients (90 %) had developmental delay. Encephalopathic episodes triggered by febrile illness have occurred in 80 % and were fatal in two children. Two patients are currently >28 years old and clinically well. Leucine supplementation had no appreciable impact on patient well-being. However, we suggest that the traditional management of reducing/stopping protein intake in patients with metabolic hepatopathies may not be appropriate for ILFS1. We currently recommend ensuring sufficient natural protein intake when unwell. Conclusions: We report the first non-Irish ILFS1 patient, suggesting ILFS1 may be more extensive than anticipated. Low birth weight, early failure to thrive, anemia and hypoalbuminemia are amongst the first presenting features, with liver dysfunction before age 1. Episodic hepatic dysfunction is typically triggered by febrile illness, and becomes less severe with increasing age. While difficult to anticipate, two patients are currently >28 years old, suggesting that survival beyond childhood may be associated with a favourable long-term prognosis.Health Research BoardThe Children's Fund for Health, Temple Street Children's University Hospita

Maple syrup urine disease: Clinical outcomes, metabolic control, and genotypes in a screened population after four decades of newborn bloodspot screening in the Republic of Ireland

Since 1972, 18 patients (10 females/8 males) have been detected by newborn bloodspot screening (NBS) with neonatal-onset maple syrup urine disease (MSUD) in Ireland. Patients were stratified into three clusters according to clinical outcome at the time of data collection, including developmental, clinical, and IQ data. A fourth cluster comprised of two early childhood deaths; a third patient died as an adult. We present neuroimaging and electroencephalography together with clinical and biochemical data. Incidence of MSUD (1972-2018) was 1 in 147 975. Overall good clinical outcomes were achieved with 15/18 patients alive and with essentially normal functioning (with only the lowest performing cluster lying beyond a single SD on their full scale intelligence quotient). Molecular genetic analysis revealed genotypes hitherto not reported, including a possible digenic inheritance state for the BCKDHA and DBT genes in one family. Treatment has been based on early implementation of emergency treatment, diet, close monitoring, and even dialysis in the setting of acute metabolic decompensation. A plasma leucine ≥400 μmol/L (outside therapeutic range) was more frequently observed in infancy or during adolescence, possibly due to infections, hormonal changes, or noncompliance. Children require careful management during metabolic decompensations in early childhood, and this represented a key risk period in our cohort. A high level of metabolic control can be achieved through diet with early implementation of a "sick day" regime and, in some cases, dialysis as a rescue therapy. The Irish cohort, despite largely classical phenotypes, achieved good outcomes in the NBS era, underlining the importance of early diagnosis and skilled multidisciplinary team management