Publications by authors named "Rolf Zetterstrom"

91 Publications

'Curiosity and restlessness drove him not only in his work, but also privately'.

Acta Paediatr 2021 Jul;110 Suppl 472:16-17

Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden.

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http://dx.doi.org/10.1111/apa.15923DOI Listing
July 2021

[Neonatal screening in Europe revisited: An ISNS-perspective on the current state and developments since 2010].

Med Sci (Paris) 2021 May 18;37(5):441-456. Epub 2021 May 18.

International Society for Neonatal Screening (ISNS) Office, Bilthoven, Pays-Bas.

Neonatal screening (NBS) was initiated in Europe during the 1960s with the screening for phenylketonuria. The panel of screened disorders ("conditions") then gradually expanded, with a boost in the late 1990's with the introduction of tandem mass spectrometry (MS/MS), making it possible to screen for 40-50 conditions in one blood spot. The most recent additions to screening programmes (screening for cystic fibrosis, severe combined immunodeficiency and spinal muscular atrophy) were assisted by or realised through the introduction of molecular genetics techniques. For this survey we collected data from 51 European countries. We report on the developments between 2010 and 2020, and highlight the achievements made during this period. We also identify areas where further progress can be made, mainly by exchanging knowledge and learning from experiences in neighbouring countries. Between 2010 and 2020, most NBS programmes in geographical Europe have matured considerably, both in terms of methodology (modernised) and with regards to the panel of conditions screened (expanded). These developments indicate that more collaboration in Europe through European organisations is gaining momentum. Only by working together can we accomplish the timely detection of newborn infants potentially suffering from one of the many rare diseases and take appropriate actions.
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http://dx.doi.org/10.1051/medsci/2021059DOI Listing
May 2021

A Novel Approach to Improve Newborn Screening for Congenital Hypothyroidism by Integrating Covariate-Adjusted Results of Different Tests into CLIR Customized Interpretive Tools.

Int J Neonatal Screen 2021 Apr 23;7(2). Epub 2021 Apr 23.

Norwegian National Unit for Newborn Screening, Division of Paediatric and Adolescent Medicine, Oslo University Hospital, 0424 Oslo, Norway.

Newborn screening for congenital hypothyroidism remains challenging decades after broad implementation worldwide. Testing protocols are not uniform in terms of targets (TSH and/or T4) and protocols (parallel vs. sequential testing; one or two specimen collection times), and specificity (with or without collection of a second specimen) is overall poor. The purpose of this retrospective study is to investigate the potential impact of multivariate pattern recognition software (CLIR) to improve the post-analytical interpretation of screening results. Seven programs contributed reference data (N = 1,970,536) and two sets of true (TP, N = 1369 combined) and false (FP, N = 15,201) positive cases for validation and verification purposes, respectively. Data were adjusted for age at collection, birth weight, and location using polynomial regression models of the fifth degree to create three-dimensional regression surfaces. Customized Single Condition Tools and Dual Scatter Plots were created using CLIR to optimize the differential diagnosis between TP and FP cases in the validation set. Verification testing correctly identified 446/454 (98%) of the TP cases, and could have prevented 1931/5447 (35%) of the FP cases, with variable impact among locations (range 4% to 50%). CLIR tools either as made here or preferably standardized to the recommended uniform screening panel could improve performance of newborn screening for congenital hypothyroidism.
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http://dx.doi.org/10.3390/ijns7020023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167643PMC
April 2021

Neonatal Screening in Europe Revisited: An ISNS Perspective on the Current State and Developments Since 2010.

Int J Neonatal Screen 2021 Mar 5;7(1). Epub 2021 Mar 5.

Norwegian National Unit for Newborn Screening, 0424 Oslo, Norway.

Neonatal screening (NBS) was initiated in Europe during the 1960s with the screening for phenylketonuria. The panel of screened disorders ("conditions") then gradually expanded, with a boost in the late 1990s with the introduction of tandem mass spectrometry (MS/MS), making it possible to screen for 40-50 conditions using a single blood spot. The most recent additions to screening programmes (screening for cystic fibrosis, severe combined immunodeficiency and spinal muscular atrophy) were assisted by or realised through the introduction of molecular technologies. For this survey, we collected data from 51 European countries. We report the developments between 2010 and 2020 and highlight the achievements reached with the progress made in this period. We also identify areas where further progress can be made, mainly by exchanging knowledge and learning from experiences in neighbouring countries. Between 2010 and 2020, most NBS programmes in geographical Europe matured considerably, both in terms of methodology (modernised) and with regard to the panel of conditions screened (expanded). These developments indicate that more collaboration in Europe through European organisations is gaining momentum. We can only accomplish the timely detection of newborn infants potentially suffering from one of the many rare diseases and take appropriate action by working together.
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http://dx.doi.org/10.3390/ijns7010015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006225PMC
March 2021

Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients.

Genome Med 2021 Mar 17;13(1):40. Epub 2021 Mar 17.

Science for Life Laboratory, School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institutet of Technology, Stockholm, Sweden.

Background: We report the findings from 4437 individuals (3219 patients and 1218 relatives) who have been analyzed by whole genome sequencing (WGS) at the Genomic Medicine Center Karolinska-Rare Diseases (GMCK-RD) since mid-2015. GMCK-RD represents a long-term collaborative initiative between Karolinska University Hospital and Science for Life Laboratory to establish advanced, genomics-based diagnostics in the Stockholm healthcare setting.

Methods: Our analysis covers detection and interpretation of SNVs, INDELs, uniparental disomy, CNVs, balanced structural variants, and short tandem repeat expansions. Visualization of results for clinical interpretation is carried out in Scout-a custom-developed decision support system. Results from both singleton (84%) and trio/family (16%) analyses are reported. Variant interpretation is done by 15 expert teams at the hospital involving staff from three clinics. For patients with complex phenotypes, data is shared between the teams.

Results: Overall, 40% of the patients received a molecular diagnosis ranging from 19 to 54% for specific disease groups. There was heterogeneity regarding causative genes (n = 754) with some of the most common ones being COL2A1 (n = 12; skeletal dysplasia), SCN1A (n = 8; epilepsy), and TNFRSF13B (n = 4; inborn errors of immunity). Some causative variants were recurrent, including previously known founder mutations, some novel mutations, and recurrent de novo mutations. Overall, GMCK-RD has resulted in a large number of patients receiving specific molecular diagnoses. Furthermore, negative cases have been included in research studies that have resulted in the discovery of 17 published, novel disease-causing genes. To facilitate the discovery of new disease genes, GMCK-RD has joined international data sharing initiatives, including ClinVar, UDNI, Beacon, and MatchMaker Exchange.

Conclusions: Clinical WGS at GMCK-RD has provided molecular diagnoses to over 1200 individuals with a broad range of rare diseases. Consolidation and spread of this clinical-academic partnership will enable large-scale national collaboration.
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http://dx.doi.org/10.1186/s13073-021-00855-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7968334PMC
March 2021

Update on the Swedish Newborn Screening for Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency.

Int J Neonatal Screen 2020 Aug 28;6(3). Epub 2020 Aug 28.

Centre for Inherited Metabolic Diseases, Karolinska University Hospital, SE-171 76 Stockholm, Sweden.

Congenital adrenal hyperplasia (CAH) was the fourth disorder added to the national Swedish neonatal screening program in 1986, and approximately 115,000 newborns are screened annually. Dried blood spot (DBS) screening with measurement of 17-hydroxyprogesterone (17OHP) is also offered to older children moving to Sweden from countries lacking a national DBS screening program. Here, we report an update on the CAH screening from January 2011 until December 2019. : During the study period, 1,030,409 newborns and 34,713 older children were screened. In total, 87 newborns were verified to have CAH, which gives an overall positive predictive value (PPV) of 11% and 21% for term infants. Including the five missed CAH cases identified during this period, this gives an incidence of 1:11,200 of CAH in Sweden. Among the older children, 12 of 14 recalled cases were found to be true positive for CAH. All patients were genotyped as part of the clinical follow-up and 70% of the newborns had salt wasting (SW) CAH and 92% had classic CAH (i.e., SW and simple virilizing (SV) CAH). In the group of 12 older children, none had SW CAH and two had SV CAH. : The incidence of classic CAH is relatively high in Sweden. Early genetic confirmation with genotyping has been a valuable complement to the analysis of 17OHP to predict disease severity, make treatment decisions and for the follow-up and evaluation of the screening program.
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http://dx.doi.org/10.3390/ijns6030071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570065PMC
August 2020

Performance of Expanded Newborn Screening in Norway Supported by Post-Analytical Bioinformatics Tools and Rapid Second-Tier DNA Analyses.

Int J Neonatal Screen 2020 Sep 27;6(3):51. Epub 2020 Jun 27.

Department of Paediatrics, Division of Paediatric and Adolescent Medicine, Oslo University Hospital, 0424 Oslo, Norway; (G.G.); (R.L.); (T.R.).

In 2012, the Norwegian newborn screening program (NBS) was expanded (eNBS) from screening for two diseases to that for 23 diseases (20 inborn errors of metabolism, IEMs) and again in 2018, to include a total of 25 conditions (21 IEMs). Between 1 March 2012 and 29 February 2020, 461,369 newborns were screened for 20 IEMs in addition to phenylketonuria (PKU). Excluding PKU, there were 75 true-positive (TP) (1:6151) and 107 (1:4311) false-positive IEM cases. Twenty-one percent of the TP cases were symptomatic at the time of the NBS results, but in two-thirds, the screening result directed the exact diagnosis. Eighty-two percent of the TP cases had good health outcomes, evaluated in 2020. The yearly positive predictive value was increased from 26% to 54% by the use of the Region 4 Stork post-analytical interpretive tool (R4S)/Collaborative Laboratory Integrated Reports 2.0 (CLIR), second-tier biochemical testing and genetic confirmation using DNA extracted from the original dried blood spots. The incidence of IEMs increased by 46% after eNBS was introduced, predominantly due to the finding of attenuated phenotypes. The next step is defining which newborns would truly benefit from screening at the milder end of the disease spectrum. This will require coordinated international collaboration, including proper case definitions and outcome studies.
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http://dx.doi.org/10.3390/ijns6030051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7570219PMC
September 2020

The Success of a Screening Program Is Largely Dependent on Close Collaboration between the Laboratory and the Clinical Follow-Up of the Patients.

Int J Neonatal Screen 2020 Sep 26;6(3):68. Epub 2020 Aug 26.

Department of Women's and Children's Health, Karolinska Institutet, SE-17176 Stockholm, Sweden; (S.L.); (L.K.).

Neonatal screening for congenital adrenal hyperplasia due to 21-hydroxylase deficiency is now performed in an increasing number of countries all over the world. The main goal of the screening is to achieve early diagnosis and treatment in order to prevent neonatal salt-crisis and death. The screening laboratory can also play an important role in increasing the general awareness of the disease and act as the source of information and education for clinicians to facilitate improved initial care, ensure prompt and correct glucocorticoid dosing to optimize the long-term outcome for the patients. A National CAH Registry and genotyping provide valuable information both for evaluating the screening program and the clinical outcome. The Swedish experience is described.
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http://dx.doi.org/10.3390/ijns6030068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569867PMC
September 2020

Expanded Screening of One Million Swedish Babies with R4S and CLIR for Post-Analytical Evaluation of Data.

Int J Neonatal Screen 2020 06 27;6(2):42. Epub 2020 May 27.

Centre for Inherited Metabolic Diseases, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden; (U.v.D.); (H.Å.); (A.O.); (M.E.); (K.N.); (C.B.-J.); (Y.N.); (A.W.); (R.H.Z.).

Sweden has one neonatal screening laboratory, receiving 115 to 120 thousand samples per year. Among the one million babies screened by tandem mass spectrometry from November 2010 until July 2019, a total of 665 babies were recalled and 311 verified as having one of the diseases screened for with this methodology, giving a positive predictive value (PPV) of 47% and an incidence of 1:3200. The PPV was high (41%) already in the first year after start of screening, thanks to the availability of the collaborative project Region 4 Stork database. The PPV is presently 58%. This improvement was achieved by the implementation of second-tier analyses in the screening for methylmalonic aciduria, propionic aciduria, isovaleric aciduria, and homocystinuria, and the employment of various post analytical tools of the Region 4 Stork, and its successor the collaborative laboratory integrated reports.
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http://dx.doi.org/10.3390/ijns6020042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423009PMC
June 2020

Regulatory landscape of providing information on newborn screening to parents across Europe.

Eur J Hum Genet 2021 Jan 10;29(1):67-78. Epub 2020 Oct 10.

Centre for inherited metabolic diseases, Karolinska University Hospital, Solna, Sweden.

Newborn screening (NBS) is an important part of public healthcare systems in many countries. The provision of information to parents about NBS is now recognised as an integral part of the screening process. Informing parents on all aspects of screening helps to achieve the benefits, promote trust and foster support for NBS. Therefore, policies and guidelines should exist to govern how the information about NBS is provided to parents, taking into account evidence-based best practices. The purpose of our survey was to explore whether any legally binding provisions, guidelines or recommendations existed pertaining to the provision of information about NBS to parents across Europe. Questions were designed to determine the regulatory process of when, by whom and how parents should be informed about screening. Twenty-seven countries participated in the survey. The results indicated that most countries had some sort of legal framework or guidelines for the provision of information to parents. However, only 37% indicated that the provision of information was required prenatally. The majority of countries were verbally informing parents with the aid of written materials postnatally, just prior to sample collection. Information was provided by a neonatologist, midwife or nurse. A website dedicated to NBS was available for 67% of countries and 89% had written materials about NBS for parents. The survey showed that there is a lack of harmonisation among European countries in the provision of information about NBS and emphasised the need for more comprehensive guidelines at the European level.
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http://dx.doi.org/10.1038/s41431-020-00716-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7853088PMC
January 2021

Mutations in an Adult Patient with Parkinson's Disease, Dementia, Stroke and Elevated Levels of Methylmalonic Acid.

Int J Mol Sci 2019 May 29;20(11). Epub 2019 May 29.

Department of Neurology, Karolinska University Hospital, 141 86 Stockholm, Sweden.

Methylmalonic aciduria (MMA-uria) is seen in several inborn errors of metabolism (IEM) affecting intracellular cobalamin pathways. Methylmalonyl-CoA epimerase (MCE) is an enzyme involved in the mitochondrial cobalamin-dependent pathway generating succinyl-CoA. Homozygous mutations in the corresponding gene have been shown in children to cause MCE deficiency with isolated MMA-uria and a variable clinical phenotype. We describe a 78-year-old man with Parkinson's disease, dementia and stroke in whom elevated serum levels of methylmalonic acid had been evident for many years. Metabolic work-up revealed intermittent MMA-uria and increased plasma levels of propionyl-carnitine not responsive to treatment with high-dose hydroxycobalamin. Whole genome sequencing was performed, with data analysis targeted towards genes known to cause IEM. Compound heterozygous mutations were identified in the gene, c.139C>T (p.Arg47X) and c.419delA (p.Lys140fs), of which the latter is novel. To our knowledge, this is the first report of an adult patient with mutations and MMA-uria, thus adding novel data to the possible phenotypical spectrum of MCE deficiency. Although clinical implications are uncertain, it can be speculated whether intermittent hyperammonemia during episodes of metabolic stress could have precipitated the patient's ongoing neurodegeneration attributed to Parkinson's disease.
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http://dx.doi.org/10.3390/ijms20112631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600349PMC
May 2019

Newborn screening for homocystinurias: Recent recommendations versus current practice.

J Inherit Metab Dis 2019 01;42(1):128-139

Unidad de Metabolismo, Hospital Infantil Miguel Servet, Zaragoza, Spain.

Purpose: To assess how the current practice of newborn screening (NBS) for homocystinurias compares with published recommendations.

Methods: Twenty-two of 32 NBS programmes from 18 countries screened for at least one form of homocystinuria. Centres provided pseudonymised NBS data from patients with cystathionine beta-synthase deficiency (CBSD, n = 19), methionine adenosyltransferase I/III deficiency (MATI/IIID, n = 28), combined remethylation disorder (cRMD, n = 56) and isolated remethylation disorder (iRMD), including methylenetetrahydrofolate reductase deficiency (MTHFRD) (n = 8). Markers and decision limits were converted to multiples of the median (MoM) to allow comparison between centres.

Results: NBS programmes, algorithms and decision limits varied considerably. Only nine centres used the recommended second-tier marker total homocysteine (tHcy). The median decision limits of all centres were ≥ 2.35 for high and ≤ 0.44 MoM for low methionine, ≥ 1.95 for high and ≤ 0.47 MoM for low methionine/phenylalanine, ≥ 2.54 for high propionylcarnitine and ≥ 2.78 MoM for propionylcarnitine/acetylcarnitine. These decision limits alone had a 100%, 100%, 86% and 84% sensitivity for the detection of CBSD, MATI/IIID, iRMD and cRMD, respectively, but failed to detect six individuals with cRMD. To enhance sensitivity and decrease second-tier testing costs, we further adapted these decision limits using the data of 15 000 healthy newborns.

Conclusions: Due to the favorable outcome of early treated patients, NBS for homocystinurias is recommended. To improve NBS, decision limits should be revised considering the population median. Relevant markers should be combined; use of the postanalytical tools offered by the CLIR project (Collaborative Laboratory Integrated Reports, which considers, for example, birth weight and gestational age) is recommended. tHcy and methylmalonic acid should be implemented as second-tier markers.
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http://dx.doi.org/10.1002/jimd.12034DOI Listing
January 2019

Raising Awareness of False Positive Newborn Screening Results Arising from Pivalate-Containing Creams and Antibiotics in Europe When Screening for Isovaleric Acidaemia.

Int J Neonatal Screen 2018 Mar 10;4(1). Epub 2018 Feb 10.

Reference Laboratory for Neonatal Screening, Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), 3720 BA Bilthoven, The Netherlands.

While the early and asymptomatic recognition of treatable conditions offered by newborn screening confers clear health benefits for the affected child, the clinical referral of patients with screen positive results can cause significant harm for some families. The use of pivalate-containing antibiotics and more recently the inclusion of neopentanoate as a component within moisturising creams used as nipple balms by nursing mothers can result in a significant number of false positive results when screening for isovaleric acidaemia (IVA) by measuring C5 acylcarnitine. A recent survey conducted within centres from nine countries indicated that this form of contamination had been or was a significant confounding factor in the detection of IVA in seven of the nine who responded. In three of these seven the prominent cause was believed to derive from the use of moisturising creams and in another three from antibiotics containing pivalate; one country reported that the cause was mixed. As a result, four of these seven centres routinely perform second tier testing to resolve C5 isobars when an initial C5 result is elevated, and a fifth is considering making this change within their national programme. The use of creams containing neopentanoate by nursing mothers and evolving patterns in the prescription of pivalate-containing antibiotics during pregnancy require those involved in the design and operation of newborn screening programmes used to detect IVA and the doctors who receive clinical referrals from these programmes to maintain an awareness of the potential impact of this form of interference on patient results.
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http://dx.doi.org/10.3390/ijns4010008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510208PMC
March 2018

Surge of immune cell formation at birth differs by mode of delivery and infant characteristics-A population-based cohort study.

PLoS One 2017 14;12(9):e0184748. Epub 2017 Sep 14.

Division of Pediatrics, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.

Background: Birth by cesarean section is associated with increased risks of immune disorders. We tested whether establishment of immune function at birth relates to mode of delivery, taking other maternal and infant characteristics into account.

Methods And Findings: Using a prospectively collected database, we retrieved information on maternal and infant characteristics of 6,014 singleton infants delivered from February to April 2014 in Stockholm, Sweden, with gestational age ≥35 weeks, Apgar scores ≥7, and without congenital malformations or any neonatal morbidity. We linked our data to blood levels of T-cell receptor excision circles (TREC) and κ-deleting recombination excision circles (KREC), determined as part of a neonatal screening program for immune-deficiencies, and representing quantities of newly formed T- and B-lymphocytes. Multivariate logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for participants having TREC and KREC levels in the lowest quintile. Multivariate models were adjusted for postnatal age at blood sampling, and included perinatal (mode of delivery, infant sex, gestational age, and birth weight for gestational age), and maternal characteristics (age, parity, BMI, smoking, diabetes, and hypertensive disease). Low TREC was associated with cesarean section before labor (adjusted OR:1.32 [95% CI 1.08-1.62]), male infant sex (aOR:1.60 [1.41-1.83]), preterm birth at 35-36 weeks of gestation (aOR:1.89 [1.21-2.96]) and small for gestational age (aOR:1.67 [1.00-2.79]). Low KREC was associated with male sex (aOR:1.32 [1.15-1.50]), postterm birth at ≥42 weeks (aOR:1.43 [1.13-1.82]) and small for gestational age (aOR:2.89 [1.78-4.69]). Maternal characteristics showed no consistent associations with neonatal levels of either TREC or KREC.

Conclusion: Cesarean section before labor was associated with lower T-lymphocyte formation, irrespective of maternal characteristics, pregnancy, and neonatal risk factors. The significance of a reduced birth-related surge in lymphocyte formation for future immune function and health remains to be investigated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0184748PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5599043PMC
October 2017

Newborn Screening for Severe Primary Immunodeficiency Diseases in Sweden-a 2-Year Pilot TREC and KREC Screening Study.

J Clin Immunol 2017 01 21;37(1):51-60. Epub 2016 Nov 21.

Department of Clinical Immunology, Karolinska University Hospital Huddinge, SE-14186, Stockholm, Sweden.

Newborn screening for severe primary immunodeficiencies (PID), characterized by T and/or B cell lymphopenia, was carried out in a pilot program in the Stockholm County, Sweden, over a 2-year period, encompassing 58,834 children. T cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) were measured simultaneously using a quantitative PCR-based method on DNA extracted from dried blood spots (DBS), with beta-actin serving as a quality control for DNA quantity. Diagnostic cutoff levels enabling identification of newborns with milder and reversible T and/or B cell lymphopenia were also evaluated. Sixty-four children were recalled for follow-up due to low TREC and/or KREC levels, and three patients with immunodeficiency (Artemis-SCID, ATM, and an as yet unclassified T cell lymphopenia/hypogammaglobulinemia) were identified. Of the positive samples, 24 were associated with prematurity. Thirteen children born to mothers treated with immunosuppressive agents during pregnancy (azathioprine (n = 9), mercaptopurine (n = 1), azathioprine and tacrolimus (n = 3)) showed low KREC levels at birth, which spontaneously normalized. Twenty-nine newborns had no apparent cause identified for their abnormal results, but normalized with time. Children with trisomy 21 (n = 43) showed a lower median number of both TREC (104 vs. 174 copies/μL blood) and KREC (45 vs. 100 copies/3.2 mm blood spot), but only one, born prematurely, fell below the cutoff level. Two children diagnosed with DiGeorge syndrome were found to have low TREC levels, but these were still above the cutoff level. This is the first large-scale screening study with a simultaneous detection of both TREC and KREC, allowing identification of newborns with both T and B cell defects.
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http://dx.doi.org/10.1007/s10875-016-0347-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226987PMC
January 2017

The Spectrum of PAH Mutations and Increase of Milder Forms of Phenylketonuria in Sweden During 1965-2014.

JIMD Rep 2017 28;34:19-26. Epub 2016 Jul 28.

Centre for Inherited Metabolic Diseases (CMMS), L7:05, Karolinska University Hospital, Stockholm, SE-171 76, Sweden.

Newborn screening (NBS) for phenylketonuria (PKU) which has a continuum of disease severities has been performed for more than 50 years. The screening method has undergone a continuous development with not only improvements of the positive predictive value but also identification of milder forms of the disease. With the introduction of genetic testing the confirmation of the diagnosis has improved. The Swedish NBS is centralized to one laboratory, which also performs confirmatory testing.Here we present the results of NBS for PKU in Sweden during 1965-2014 describing an increase in diagnosed patients and a shift in the spectrum of phenylalanine hydroxylase (PAH) mutations towards an increasing heterogeneity. Milder mutations common in southern Europe and the Middle East together with lowering of the recall level for phenylalanine (Phe) have led to a shift towards milder phenotypes among the patients identified by the screening program. The inclusion of a Phe and tyrosine (Tyr) ratio as an additional marker has improved the positive predictive value to the present 0.92. Also discussed is what impact earlier sampling has had on the prediction of disease severity, concluding that the shift of age at sampling from 72 to 48 h does not increase the risk of missing patients in need of treatment.
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http://dx.doi.org/10.1007/8904_2016_4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5509542PMC
July 2016

Rescue of primary ubiquinone deficiency due to a novel COQ7 defect using 2,4-dihydroxybensoic acid.

J Med Genet 2015 Nov 17;52(11):779-83. Epub 2015 Jun 17.

Centre for Inherited Metabolic Diseases, Karolinska University Hospital, Stockholm, Sweden Max Planck Institute Biology of Ageing - Karolinska Institutet Laboratory, Division of Metabolic Diseases, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden Department of Molecular Medicine and Surgery, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.

Background: Coenzyme Q is an essential mitochondrial electron carrier, redox cofactor and a potent antioxidant in the majority of cellular membranes. Coenzyme Q deficiency has been associated with a range of metabolic diseases, as well as with some drug treatments and ageing.

Methods: We used whole exome sequencing (WES) to investigate patients with inherited metabolic diseases and applied a novel ultra-pressure liquid chromatography-mass spectrometry approach to measure coenzyme Q in patient samples.

Results: We identified a homozygous missense mutation in the COQ7 gene in a patient with complex mitochondrial deficiency, resulting in severely reduced coenzyme Q levels We demonstrate that the coenzyme Q analogue 2,4-dihydroxybensoic acid (2,4DHB) was able to specifically bypass the COQ7 deficiency, increase cellular coenzyme Q levels and rescue the biochemical defect in patient fibroblasts.

Conclusion: We report the first patient with primary coenzyme Q deficiency due to a homozygous COQ7 mutation and a potentially beneficial treatment using 2,4DHB.
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http://dx.doi.org/10.1136/jmedgenet-2015-102986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4680133PMC
November 2015

Rapid pulsed whole genome sequencing for comprehensive acute diagnostics of inborn errors of metabolism.

BMC Genomics 2014 Dec 11;15:1090. Epub 2014 Dec 11.

Department of Molecular Medicine and Surgery, Science for Life Laboratory, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

Background: Massively parallel DNA sequencing (MPS) has the potential to revolutionize diagnostics, in particular for monogenic disorders. Inborn errors of metabolism (IEM) constitute a large group of monogenic disorders with highly variable clinical presentation, often with acute, nonspecific initial symptoms. In many cases irreversible damage can be reduced by initiation of specific treatment, provided that a correct molecular diagnosis can be rapidly obtained. MPS thus has the potential to significantly improve both diagnostics and outcome for affected patients in this highly specialized area of medicine.

Results: We have developed a conceptually novel approach for acute MPS, by analysing pulsed whole genome sequence data in real time, using automated analysis combined with data reduction and parallelization. We applied this novel methodology to an in-house developed customized work flow enabling clinical-grade analysis of all IEM with a known genetic basis, represented by a database containing 474 disease genes which is continuously updated. As proof-of-concept, two patients were retrospectively analysed in whom diagnostics had previously been performed by conventional methods. The correct disease-causing mutations were identified and presented to the clinical team after 15 and 18 hours from start of sequencing, respectively. With this information available, correct treatment would have been possible significantly sooner, likely improving outcome.

Conclusions: We have adapted MPS to fit into the dynamic, multidisciplinary work-flow of acute metabolic medicine. As the extent of irreversible damage in patients with IEM often correlates with timing and accuracy of management in early, critical disease stages, our novel methodology is predicted to improve patient outcome. All procedures have been designed such that they can be implemented in any technical setting and to any genetic disease area. The strategy conforms to international guidelines for clinical MPS, as only validated disease genes are investigated and as clinical specialists take responsibility for translation of results. As follow-up in patients without any known IEM, filters can be lifted and the full genome investigated, after genetic counselling and informed consent.
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http://dx.doi.org/10.1186/1471-2164-15-1090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4299811PMC
December 2014

[The effect of light on the mind, and neuroendocrinological function. Let there be light!].

Lakartidningen 2011 Feb 9-15;108(6):257

Acta Paediatrica, Karolinska universitetssjukhuset, Solna.

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May 2011

European Society of Pediatric Research at its 50th anniversary: past, present, and future.

Pediatr Res 2010 Nov;68(5):456-8

Acta Paediatrica, Karolinska University Hospital, Stockholm 171 76, Sweden.

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http://dx.doi.org/10.1203/PDR.0b013e3181fc9eebDOI Listing
November 2010

Investigations on a child with familial hypercholesterolaemia.

Acta Paediatr 2011 Feb 8;100(2):311-3. Epub 2010 Oct 8.

Acta Paediatrica, Stockholm, Sweden.

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http://dx.doi.org/10.1111/j.1651-2227.2010.02020.xDOI Listing
February 2011

Water transfer through biological membranes.

Acta Paediatr 2011 Jan 29;100(1):143-6. Epub 2010 Sep 29.

Acta Paediatrica, Stockholm, Sweden.

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http://dx.doi.org/10.1111/j.1651-2227.2010.02007.xDOI Listing
January 2011

The discovery of misfolded prions as an infectious agent.

Acta Paediatr 2010 Dec;99(12):1910-3

Acta Paediatrica, Stockholm, Sweden.

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http://dx.doi.org/10.1111/j.1651-2227.2010.01930.xDOI Listing
December 2010

[Risks with violent police actions].

Lakartidningen 2010 Jan 20-26;107(3):121

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March 2010

The risk of overuse injuries.

Acta Paediatr 2009 Dec;98(12):1864

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http://dx.doi.org/10.1111/j.1651-2227.2009.01578.xDOI Listing
December 2009

[Surely it's possible to increase the productivity of Swedish medical research].

Lakartidningen 2009 Jul 8-21;106(28-29):1838-9

Acta Paediatrica Karolinska universitetssjukhuset Solna.

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August 2009

[Honour to whom honour is due].

Lakartidningen 2009 Jun 10-23;106(24-25):1629

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July 2009

Nobel Prize to Willem Einthoven in 1924 for the discovery of the mechanisms underlying the electrocardiogram (ECG).

Acta Paediatr 2009 Aug 8;98(8):1380-2. Epub 2009 Jun 8.

Acta Paediatrica, Karolinska University Hospital, S-171 76 Stockholm, Sweden.

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http://dx.doi.org/10.1111/j.1651-2227.2009.01311.xDOI Listing
August 2009

The 1964 Nobel Prize for the discovery of the biosynthesis of cholesterol.

Acta Paediatr 2009 Jul 16;98(7):1223-7. Epub 2009 Apr 16.

Acta Paediatrica, Karolinska University Hospital, Stockholm, Sweden.

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http://dx.doi.org/10.1111/j.1651-2227.2009.01282.xDOI Listing
July 2009

[Registry check ups of all applicants to health professions education].

Lakartidningen 2009 Feb 11-17;106(7):450

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April 2009