Ongoing studies
Diagnosis, treatment and development in patients with Tyrosinemia Type 1 before and after newborn screening in Norway.
Project leader: Trine Tangeraas. Description: Tyrosinemia type 1 is a rare disease in the metabolism of the amino acid tyrosine that, if untreated, leads to liver failure/liver cancer and death. In 1992, a medicine, NTBC, became available that stops toxic metabolites for the liver, but a handful of patients still developed liver cancer and in 2012, newborn screening (NFS) was introduced to avoid liver damage before NTBC treatment. All receive a strict protein-reduced diet with lifelong biochemical, radiological monitoring for liver cancer and diet. A proportion has neurocognitive effects despite treatment. Purpose: Diagnosis, monitoring, treatment and development of patients before (n=20) and after NFS (n=10-14). Only already collected medical records. Knowledge of markers that led to liver cancer is important learning for monitoring Tyr-1. The mandate of newborn screening is also to monitor results of newborn screening and optimize treatment. Knowledge of neurocognitive development for the group as a whole is essential for planning patient care and facilitating and further research into causes. The study is carried out partly as a student thesis (newborn screening part), Approval: REK792216, 08.10.2024.
Recon4IMD: Reconstruction and Computational Modeling for Inherited Metabolic Diseases
Project leader: Trine Tangeraas for the Norwegian part of the project. Participates via MetabERN in Recon4IMD
which is a European multicenter project led by Ronan Fleming, University of Galway Ireland.
Description: Inherited metabolic diseases (IMDs) are rare genetic conditions that affect
the body's ability to process nutrients. With over 1450 different types, diagnosis is often long
and complicated. Recon4IMD is an EU-funded study (Recon4IMD project, Univ Galway Ireland) that will improve diagnostics and treatment of IMD using advanced computer modeling and biological analysis. The aim is to: 1) classify patients by genetic profile, 2) shorten time to diagnosis with personalized models, 3) tailor treatment to the individual's biology, and 4) develop software for individual diagnosis and treatment. The study analyzes biological samples with so-called "omics" technologies to provide detailed insight into the patients' condition. Participants are recruited from medical centers in Europe and the UK, including people with confirmed (the majority) or suspected IMD and healthy control subjects. Norway will participate with 50 patients' clinical data, urine and plasma (and probable newborn screening filter card punch).
Retrospective validation study of metachromatic leukodystrophy in newborn screening
Project leader: Andreas Øberg. Description: Testing of newborn screening filter cards 10 MLD patients and
3000 healthy controls. Analysis biochemical and enzymatic and genetic testing of the ARSA gene.
Main collaborators are Kristoffer Gudesen Solbakke and Jin Hui Zhang at the Newborn Screening.
Article in preparation.
Evaluation of the Norwegian newborn screening for congenital hypothyroidism - a national study.
Project leader: Trine Tangeraas. Description: To evaluate the quality of Norwegian newborn screening in relation
to identifying newborns with congenital hypothyroidism; To map the etiology behind congenital hypothyroidism
in Norwegian newborns diagnosed with this condition by newborn screening on the 3rd day of life; To determine
the distribution of TSH levels in newborns with elevated TSH at newborn screening, registered on the 3rd day of life in the period from 2012 to 2022; Determine the best possible alert level (cut-off) for TSH in relation to both sensitivity and specificity; Identify regional differences in the assessment, treatment and follow-up of newborns with ambiguous TSH levels reported from the Newborn Screening. REK 187511.
Study of the utility of genetic analysis for congenital hypothyroidism in TSH-based newborn screening
Project leaders: A. Stray-Pedersen/Janne Strand. This is a collaborative project internally in the Newborn Screening. A method development project that is also considered quality work. Evaluates the utility of genetic testing as a 2nd tier performed in DNA extracted from the screening card on all discharged patients with an elevated TSH. Focus on the years 2018-2022 to support the evaluation of an increased cut-off limit for TSH
from 10 to 15. The TSH cut-off limit for alert was increased at the turn of the year 2022/2023. But the project
also evaluates the utility of continuous 2nd tier genetic testing of all discharged patients with high TSH values in 2023 and beyond. Work carried out by Silje Hogner and others at the newborn screening. Data presented at the
ISNS conference.
Machine learning and automation as decision support in newborn screening for hypothyroidism.
Project leader: Alexander D. Rowe. Description: Explores the possibilities for integration of
automated tools for interpretation of biomarkers and biochemical profiles in newborn screening, as well as
development of machine learning methods to improve current bioinformatic interpretation tools. Is part of
a broad international collaboration with Mayo Clinic, several states in the USA and Sweden. The focus is
comparison and improvement of the different algorithms used in hypothyroidism screening. Screening for
congenital hypothyroidism is currently associated with a high proportion of false positive screening responses. The results will form the basis for a new bioinformatic tool in CLIR that will be available to newborn screening laboratories worldwide.
Quality of life in children and adolescents with fatty acid oxidation deficiency and their parents.
Principal supervisor Trine Tangeraas. REK 2016/1113, Background: Fatty acid oxidation defects are rare, congenital metabolic disorders that result in a lack or reduced ability to metabolize fat from food and a lack/reduced ability to metabolize one's own body fat into energy during fasting. Ongoing project. Description: The fatty acid oxidation defect very long chain acyl-CoA dehydrogenase defect (VLCAD-
Evaluation of gene findings for reported and unreported cases of fatty acid oxidation defect VLCAD.
defect) is one of the 26 screening diseases. The first biochemical analysis when screening for VLCAD defect often gives uncertain findings that must be supplemented with gene sequencing to confirm a certain serious diagnosis. Mild gene variants are not reported as they are associated with residual enzyme activity. There is a need for and initiated evaluation and publication of our gene findings in ACADVL for reported and unreported, the information is useful for other newborn screening labs. Ongoing project.
Collaborative project between doctors and molecular biologists and biochemical engineers at the Newborn Screening.
Evaluation and improvement of screening for congenital adrenal hyperplasia (CAH)
Project leader: Ingjerd Sæves. The purpose of the ongoing project and publication is to evaluate the screening for CAH after the expansion in 2012 and improve result interpretation by revising the current algorithm and use of the Collaborative Laboratory Integrated Reports (CLIR) tool and introduction of 2nd tier in the routine can improve both sensitivity and specificity. Ongoing. Article under preparation .
Evaluation and improvement of screening for MMA/PA
Project leader: Ingjerd Sæves. Document whether the introduction of 2nd-tier analyses into the routine can improve
both sensitivity and specificity in screening for methylmalonic acidemia and propionic acidemia. Ongoing.
Genotype-phenotype in phenylketonuria in Norway.
Collaborative project between physicians and clinical nutritionists and molecular biologists at the Newborn Screening Program. Description: evaluate and publish gene findings in Norwegian patients in light of phenylalanine values, dietary needs and clinical presentation. Nature & nurture, PAH findings in PKU and HPA. Ongoing.
Evaluation and further development of NGS methods in Newborn Screening.
The DNA group is led by Janne Strand. Description: Next-generation sequencing (NGS) provides opportunities
for rapid and cost-effective validation of first-tier biochemical analyses and determination of
genetic diagnoses in newborn screening programs. Methods include: Whole genome sequencing, RNA sequencing, gene panels and qPCR, Digital droplet PCR, digital MLPA. Comparing Sanger with new methods. Ongoing. NGS article in preparation. Sanger article published.
Evaluation of CF screening with whole genome sequencing of the CFTR gene
Project owner: Emma Lundman. Description New methods and test algorithm for CF screening were introduced in 2015 and have since been improved. The study summarizes findings and experiences with the use of new NGS methods for CFTR gene analysis. Ongoing. Data presented at ESHG 2024 and ISNS conference. Lundman, E. et al., Increasing specificity, sensitivity and PPV using next generation CFTR sequencing in newborn screening for cystic fibrosis.
Rapid identification of serious disease using new technology in newborn screening.
Project leader: Asbjørg Stray-Pedersen. REK 2016/2270. The purpose of this project is to
investigate whether, using new methods in genetic testing and analyses of biochemical markers,
effective testing methods for congenital treatable diseases can be developed and thus contribute to ensuring that more child patients with serious disease can quickly receive a confirmed genetic diagnosis and contribute to providing effective targeted treatment. The results will form the basis for assessing expanded
screening services for newborns for serious congenital diseases. Ongoing. Publications in preparation.
Development of a bioinformatic pipeline for evaluating WGS data for PKU and other
newborn screening-related conditions. Project by Cassandra Trier. Article in preparation.
Improving newborn screening with long-read sequencing.
Project leader Cassandra Trier. William Tourniaire is the main collaborator in the project.
Biomarker profiles and biochemical phenotyping of gene variants detected by newborn screening
Project leader: Alexander D. Rowe – Health South-East Project 2018080, uses NGS data and biochemical results from newborn screening, and links the different gene variants to biochemical phenotypes. Mapping the effect of the specific gene variant in relation to the relevant biomarker with high precision, with both a numerical estimate of the change and an uncertainty margin. Expected to lead to significantly improved understanding of the link between gene variant and measurable biochemical outcome, and better precision in interpreting newborn screening results. Ongoing.
Aagenæs syndrome extended project.
Collaborative project with Runar Almaas' research group at the Pediatric Research Institute.
Contributors from Newborn Screening are Mari Ytre-Arne and Janne Strand.
Newborn screening for severe immunodeficiency
Project leader: Asbjørg Stray-Pedersen REK 2014/128. The project and approval include development and testing of TREC and KREC for SCID and agammaglobulinemia as well as NGS analyses for verification of molecular genetic diagnosis. Evaluate results of SCID screening.
Mapping of genetic causes of primary immunodeficiency and immune dysregulation
Project leader: Asbjørg Stray-Pedersen REK 2014/1270. Description: WES and WGS and RNA
sequencing to determine the cause of disease in patients with primary immunodeficiency and/or
immune dysregulation. Ongoing.
EryDex treatment for Ataxia Telangiectasia, blinded study, open study, and open extension study
as an observational study. Project leader: Asbjørg Stray-Pedersen REK 2016/1113 and REK 93784 and
608995. Description: A special method of administration for long-term steroid treatment has been studied:
50ml of blood is withdrawn from the patient, and using a machine (Red Cell Loader) the red blood cells are prepared and dexamethasone is added intracellularly, then the patients are reinfused with their own dexamethasone-loaded erythrocytes. The drug is slowly released from the red blood cells over a period of about 3 weeks, and the procedure must therefore be repeated every 3-4 weeks. The treatment causes fewer side effects than if the drug is given as a tablet or injection. The patients have Ataxia Telangiectasia, a rare, hereditary neurodegenerative disease that leads to motor difficulties and early death. Immunodeficiency and increased cancer risk are also included. Steroid treatment delays disease progression. The goal is to improve symptoms while avoiding the typical long-term side effects of steroid treatment. The multinational study in which Norway has been the Nordic node has now been completed, and the article was published in Lancet Neurology May 2024. Five pediatric patients in Norway have participated in a blinded study, followed by an open study and a long-term study. The patients who have participated are now aged 11-15 years. The 5 have been given the opportunity to continue the EryDex treatment approved by the Norwegian Medicines Agency on an individual basis and the treatment is given as part of a REK-approved clinical study with long-term observation. The long-term study with EryDex treatment for Ataxia Telangiectasia is conducted at the Children's Clinical Research Unit at OUS Rikshospitalet, and falls under the BTX/BAMS1 area of responsibility.
The efficacy measure is neuromotor function, and the standardized neuromotor tests with video filming are performed at the Children's Rehabilitation Service at Innlandet Hospital.
A similar new confirmatory clinical treatment study has been initiated, the NEAT study (IEDAT-04-
2022) with other younger (age 6-9 years) Norwegian patients with Ataxia Telangiectasia, sponsored by EryDel
SpA/Quince Therapeutics. Start 2024, the study is ongoing, 5/6 patients met the inclusion criteria, of which 2 from Sweden. The study is conducted in collaboration with the Children's Clinical Research Unit at OUS Rikshospitalet.
Mechanisms of cancer risk, neurodegeneration and premature aging in patients with the disease
Ataxia-Telangiectasia (A-T) and their relatives. Biobank manager: Asbjørg Stray-Pedersen REK
2014/1270 REK 2017/443 Previous Prosj: 9794, REK: S96223. Collection of skin samples for banking of
fibroblast culture from affected individuals: doctor Tønnes S-P Aspholm (MIK, OUS).
Development of adeno-associated virus vector based gene therapy for Ataxia Telangiectasia.
Project leaders: Asbjørg Stray-Pedersen NFS and Prof. Hilde Loge Nilsen, Microbiological Research Unit OUS. Received study funds from A-T Childrens Project USA. Project staff are
Tønnes S-P Aspholm and Solveig Osnes Lund (MIK, OUS).
A-T & AI, Decentralized monitoring of neuromotor function and quality of life.
Project leader: Asbjørg Stray-Pedersen. The goal of this innovation project is to develop and
integrate AR glasses and accelerometry bracelets in the follow-up of children and adolescents with the disease Ataxia-Telangiectasia (A-T). This is to document disease progression at home and provide the opportunity to
obtain more data points to be able to see the effect of future interventions. The project has
received support from DAM and will be carried out in collaboration with the Child Neurology (BNE) Department OUS
and the Child Rehabilitation Service Innlandet Hospital.
NAD supplementation to prevent progressive neurological disease in Ataxia Telangiectasia (A-T),
Collaborative project with Prof. Hilde Nilsen. Collaborative partner at NFS with responsibility for the clinical part of the project and supervisor is Asbjørg Stray-Pedersen, REK 2017/419. Research student is Rebecca
Presterud. Published parts of the project (PMID: 37899683). The quality of life part and the RNA study in the project in progress. Collection of skin samples for banking of fibroblast culture control material:
Helle Graneng Holmen Research student with a degree in medicine (UiO)
Carbaglu in organic aciduria, Trine Tangeraas REK 2018/2525. Completed. Article submitted.
Treatment of MoCD Type A: A Phase 2/3, Multicenter, Multinational, Open-Label Study to Evaluate the
Efficacy and Safety of ORGN001 (formerly ALXN1101) in Neonates, Infants, Children, and Adolescents
with Molybdenum Cofactor Deficiency (MoCD) Type A, Trine Tangeraas REK 194445. Completed.
Article submitted J Pediatrics. PMID: 38808412.
Vitamin B12 deficiency in infants Collaborative project with Sørlandet Hospital and Vestfold Hospital: REK 2018/179. PhD fellow Ulf Wike Ljungblad. Supervisor: Trine Tangeraas. Description: Vitamin B12 deficiency in infants is underdiagnosed in Norway. The symptoms are often nonspecific and difficult to detect, but can also be dramatic with respiratory arrest and seizures. The aim of this retrospective control study of 85 infants aged 0-1 year who have been diagnosed with B12 deficiency is to describe clinical and biochemical presentation, investigate risk factors and whether analyses at the Newborn Screening could predict the disease. Ref. following article: “Breastfed infants with spells, tremor, or irritability –
first rule out vitamin B12 deficiency. Completed. More articles published, see publication list below.
Ulf Wike Ljungblad defended his thesis on 22 April 2024
Palliative care in metabolic disorders under the auspices of MetabERN, Trine Tangeraas represents NFS,
collaboration with Anja Lee who heads the palliative care service PALBU.
Cobalamin G defects in Norway. Project leader: Trine Tangeraas Cobalamin G defect (= methionine synthase defect) is a very rare congenital remethylation defect with which there are < 50 people described
in the world. In Norway, 9 people have been diagnosed, which is a proportionally large proportion of
published cases. The purpose of the project is to describe presentation, diagnostics
(biochemistry/genetics), treatment and outcomes in this cohort in Norway and to evaluate factors
that contribute to kidney disease in this patient group. The project will be an important basis for
future NFS of this group conditions. REK approved project May 2024.
Bile duct atresia, Anders Ziegler at NFS in collaboration with Runar Almaas PFI, see publication list
Nutrition Therapy in the Immature Infant, ImNuT study, Ingjerd Sæves and Alex Rowe at NFS in
collaboration with Sissel Moltu Newborn intensive care
Biomarker analysis for lipid diseases in filter cards from the Newborn Screening
Project leaders Siv M. Løvoll and Asbjørg Stray-Pedersen. Master's student NTNU Tolera Bayisa Disasa