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Newborn bloodspot screening for inborn metabolic disorders

By Prof Ina Knerr, Dr Joanne Hughes, Dr Ellen Crushell, and Prof Ahmad A Monavari, Consultant Metabolic Paediatricians, Children's Health Ireland (CHI) at Temple Street, National Centre for Inherited Metabolic Disorders (NCIMD) - 01st Oct 2019

Macro shot of Newborn baby feet after a prick from a blood test with a bandaid on his heal.

Current Irish perspectives on expanded newborn bloodspot screening for inborn metabolic disorders in Ireland

All newborns in Ireland are currently screened via the ‘heel-prick test’ at 72-120 hours after birth for six inborn metabolic disorders (IMDs), as well as congenital hypothyroidism and cystic fibrosis. Other countries screen for many more IMDs, using a similar amount of dried blood spots. Ireland was the first country to introduce a National Newborn Bloodspot Screening Programme (NNBSP) for phenylketonuria (PKU) over 50 years ago, a condition that if untreated results in severe and irreversible brain damage. The main IMDs now screened for in Ireland include PKU (since 1966), classical Homocystinuria (1971), Maple Syrup Urine Disease (MSUD, 1972), and classical Galactosaemia (1972). In 2018, two further serious conditions were incorporated into the NNBSP, Glutaric Aciduria Type 1 (GA-1) and Medium chain acyl-CoA dehydrogenase deficiency (MCAD-D). Ireland has a higher incidence rate for a number of IMDs than most continental European countries. The goal of the NNBSP for IMDs is to achieve early diagnosis and treatment, and thus to lower morbidity, disease burden, and mortality rates in children. 

There are more than 700 different IMDs

To-date, there are more than 700 known IMDs (MetabERN, 2016). These conditions are generally rare; some are more common in certain populations due to their genetic basis. Neonatal-onset IMDs, such as classical Galactosaemia and MSUD, require early, life-saving treatment and warrant screening newborns for. For many IMDs, early diagnosis is crucial as it prevents the onset of symptoms, such as developmental delay and brain damage, thus reducing morbidity and mortality.

Expanded newborn screening programmes

In recent years, advancements in diagnostic technologies, including tandem mass spectrometry (MS/MS) and molecular genetic testing, have deeply expanded our knowledge of IMDs (Ghosh et al, 2017), along with improved diagnostic and monitoring approaches. In countries with expanded and improved newborn screening programmes, which may include more than 20 different conditions, as in many other European countries, Australia and the US, 75-80 per cent of the disorders tested for are IMDs (Recommended Uniform Screening Panel, 2018). The disorders are chosen based on medical evidence, which supports the net benefit of the screening programme, the ability to screen for these disorders, and the availability of effective treatments and access to high-quality care, along with the recommendation that every newborn be screened for these disorders as part of the programme (Recommended Uniform Screening Panel, 2018).

Since the late 1990s/early 2000s, MS/MS-based expanded newborn screening programmes have been introduced in Europe, the US and Australia (Wiley et al, 1999, Liebl et al, 2000, Medical Advisory Secretariat, 2003), allowing the identification of numerous IMDs, including a number of amino acid, organic acid and fatty acid disorders, on a single dried blood spot sample. MS/MS along with automation of sample handling has become a key technology in the field of newborn screening (Garg and Dasouki, 2006). It has changed the former newborn screening approach of ‘one-analysis, one-metabolite, one-disease’ to ‘one analysis, many-metabolites, many-diseases’.   In general, investment in early childhood has been shown to be highly cost-effective. Cost-effectiveness of expanded newborn screening from the health service perspective has been demonstrated in many countries for IMDs such as MCAD-D and GA-1, for example (Pfeil et al, 2013, Hamers et al., 2012, Norman et al, 2009). Expanded newborn screening has been demonstrated to significantly lower morbidity and mortality, as we and others have shown in collaborative studies (Nennstiel-Ratzel et al, 2005, Tran et al, 2007). Expansion and evaluation of NNBSP protocols and clinical guidelines together with gathering of outcome data is warranted to improve healthcare, to minimise disease burden and to ensure the best possible outcome and health services use. Overall, expanded newborn screening of IMDs is considered to be one of the most successful preventative healthcare initiatives (Shanmuganathan et al, 2019). In Ireland, MS/MS became available for diagnosing IMDs in 2004-2005. However, it was not until 2018 that just two more IMDs were added to the NNBSP. We need to consider screening for more treatable IMDs to catch up with international best practice.

National Centre for Inherited Metabolic Disorders (NCIMD) at Children’s Health Ireland

The National Centre for Inherited Metabolic Disorders (NCIMD) has been a national centre for the diagnosis, treatment and management of paediatric patients with IMDs in the Republic of Ireland since 1986. In recent years, clinical service activities and overall workload at NCIMD Children’s Health Ireland at Temple Street, Dublin, have shown a remarkable increase, making it one of the largest paediatric metabolic centres in Europe.

The metabolic specialists at NCIMD have extensive collaborations with other metabolic experts internationally, which places Ireland every bit as much to the forefront of, eg, guideline development and treatment of IMDs, as other countries. At NCIMD we have contributed to the development of European/international guidelines and treatment recommendations for a number of IMDs, including, for example, Homocystinuria and Galactosaemia (Morris et al, 2017, Welling et al, 2017) and fatty acid oxidation defects (Spiekerkoetter et al, 2009). 

Based on a multidisciplinary approach to research, we also published outcome data for our screened Irish cohorts of patients with, eg, Homocystinuria (Allen et al, 2019, Purcell et al, 2017), PKU (Clark et al, 2019) and Galactosaemia (Coss et al, 2013, Hughes et al, 2009). We have shown in collaboration with our European colleagues that, for example, early diagnosis of Propionic Acidaemia (a rare metabolic disorder characterised by deficiency of propionyl CoA carboxylase, an enzyme involved in the catabolism of certain essential amino acids) through newborn screening is associated with a lower mortality rate (Grünert et al 2012); (there is no newborn screening available in Ireland for Propionic Acidaemia). Furthermore, we recently demonstrated that outcomes of ‘high-risk’ screened patients with GA-1 in Ireland are better compared with patients who presented acutely unwell with encephalopathy (Healy et al, 2019). This gives hope to future cases diagnosed through the NNBSP in the Irish context.


Screening of newborns for treatable childhood disorders can improve survival rates and outcomes due to early diagnosis and timely treatment, but the highest attainable standards must be in place, including immediate disease confirmation and specialised high-quality acute and long-term care that is available and accessible to these affected children and their families. Expanding the NNBSP should be co-ordinated with clinical services and appropriate treatment facilities, which are able to deal with the expansion in workload. An expanded NNBSP requires an enhanced infrastructure for result interpretation within a clinical context, specialised medical care and follow-up (Medical Advisory Secretariat, 2003), so newborn ‘screening’ consumes more resources than ‘no screening’, but it achieves better health outcomes in a vulnerable cohort. Many new treatments are expensive and the screening and post-screening processes need consideration and serious levels of investment, as do basic essential multidisciplinary care services, which should be available to all children with complex needs but, invariably, are not. The outcomes of newborn screening are overall reassuring, even though these illnesses cannot be cured. As new therapies are now available for previously untreatable IMDs, we need to consider further expanding the NNBSP in Ireland to improve outcomes and quality-of-life for all children affected and their families. As much can be done to enable early diagnosis and possible treatment, NCIMD strongly supports expanding the NNBSP for IMDs in the Irish context, but this will only be possible if the necessary resources can be made available. However, careful consideration is required as to which diseases should be added for newborn screening, in line with the ‘Wilson and Jungner criteria’ for screening (Wilson and Jungner, 1968). This includes, but is not limited to: “The object of screening for disease is to discover those among the apparently well who are in fact suffering from disease. They can then be placed under treatment (…).” Oversight of the NNBSP is currently through the National Newborn Screening Governance Group, the HSE and the Department of Health combined with the work of healthcare professions and in effective communication with its stakeholders.

On a global scale, newborn screening will continue to expand due to advancements in diagnostic technologies along with the development of effective new therapies for an increasing number of children with IMDs. 


The authors wish to acknowledge the staff at the NCIMD and Department of Paediatric Laboratory Medicine CHI at Temple Street, Metabolic Laboratory and National Newborn Bloodspot Screening Laboratory (NNBSL). We would like to thank the Temple Street Foundation for the very important support of our research. We would like to express our gratitude to all our patients and their families who trust us with their care and to those who participate in our clinical studies.

References on request

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