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

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

Long-Term Follow-Up of Newborns with 22q11 Deletion Syndrome and Low TRECs.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadBackground: Population-based neonatal screening using T-cell receptor excision circles (TRECs) identifies infants with profound T lymphopenia, as seen in cases of severe combined immunodeficiency, and in a subgroup of infants with 22q11 deletion syndrome (22q11DS). Purpose: To investigate the long-term prognostic value of low levels of TRECs in newborns with 22q11DS. Methods: Subjects with 22q11DS and low TRECs at birth (22q11Low, N=10), matched subjects with 22q11DS and normal TRECs (22q11Normal, N=10), and matched healthy controls (HC, N=10) were identified. At follow-up (median age 16 years), clinical and immunological characterizations, covering lymphocyte subsets, immunoglobulins, TRECs, T-cell receptor repertoires, and relative telomere length (RTL) measurements were performed. Results: At follow-up, the 22q11Low group had lower numbers of naïve T-helper cells, naïve T-regulatory cells, naïve cytotoxic T cells, and persistently lower TRECs compared to healthy controls. Receptor repertoires showed skewed V-gene usage for naïve T-helper cells, whereas for naïve cytotoxic T cells, shorter RTL and a trend towards higher clonality were found. Multivariate discriminant analysis revealed a clear distinction between the three groups and a skewing towards Th17 differentiation of T-helper cells, particularly in the 22q11Low individuals. Perturbations of B-cell subsets were found in both the 22q11Low and 22q11Normal group compared to the HC group, with larger proportions of naïve B cells and lower levels of memory B cells, including switched memory B cells. Conclusions: This long-term follow-up study shows that 22q11Low individuals have persistent immunologic aberrations and increased risk for immune dysregulation, indicating the necessity of lifelong monitoring. Clinical implications: This study elucidates the natural history of childhood immune function in newborns with 22q11DS and low TRECs, which may facilitate the development of programs for long-term monitoring and therapeutic choices. Keywords: 22q11.2 deletion syndrome; DiGeorge syndrome; T lymphopenia; TREC; long-term outcome; newborn screening; severe combined immunodeficiency.University of Gothenburg Regional research grant Region Halland Swedish Research Council European Commission Queen Silvia Jubilee Foundation Swedish Primary Immunodeficiency Organization Sparbanken Foundation Varberg Frimurare Barnhusdirektionen Foundation Gothenburg Medical Society Medical Faculty at Umea University Cancer Research Foundation in Northern Sweden Swedish government county councils, the ALF-agreement Umea University Vasterbottens County Counci

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

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

On retinoid receptors, Nurr1 and related transcription factors in the CNS

It has long been known that retinoids (vitamin A derivatives) are required for normal development and growth; in excess however metabolites such as all-trans retinoic acid are potent teratogens. Retinoids exert their effects through transcription factors known as the retinoic acid receptors (RARam -ß and -y) and retinoid X receptors (RXRa, -ß and -y). Intracellularly, two types of binding proteins also appear to be involved in retinoid homeostasis, cellular retinol binding protein I and II (CRBP I and II) and cellular retinoic acid binding protein I and II (CRABP I and II). RARs and RXRs belong to the nuclear receptor superfamily which also includes receptors for the steroid and thyroid hormones, vitamin D3 and several other small lipophilic molecules. Moreover, the superfamily includes a large group of receptors which lack identified ligands (termed "orphan receptors"). Nurr1, NGFI-B and Nor1 are closely related members of this latter group of proteins. This study was undertaken in order to explore the roles of retinoids and the Nurr1/NGFI-B/Norl subfamily of orphan receptors in the developing and adult CNS. The expression patterns of CRBPs and CRABPs and RARs and RXRs in the postnatal and adult CNS were investigated using immunocytochemistry and in situ hybridization histochemistry (ISH). In addition, an in vitro reporter assay was used to detect retinoids in striatal tissue. It was found that many of the retinoid binding proteins and receptors are present in the CNS. Striatum, a part of the basal ganglia, contains all necessary components for retinoid signaling. Both CRBP I and CRABP I as well as RARß RXRß and RXRy are highly expressed within this region. In addition, it has also been possible to detect retinoids in striatal tissue. The role of Nurr1, NGFI-B and Nor1 has been explored. In particular, these studies have emphasized the role of NuTrl. All three members have previously been shown to interact with DNA as monomers, but Nurr1 and NGFI-B have also been shown to heterodimerize with RXR, thereby defining a distinct pathway for retinoid signaling. The most recently cloned member, Nor1, was shown to lack the ability to heterodimerize with RXR. To begin to understand the function of these orphan receptors, ISH was used to localize the mRNA expression patterns in both developing and adult tissues. All three members are highly expressed in the CNS; a striking observation was that Nurr1 mRNA was present in the developing ventral midbrain as well as in the mature dopamine (DA) neurons of the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA). To further investigate the function of Nurr1, a targeted mutation was introduced into the Nurr1 locus. Mice lacking Nurr1 are born alive but die within the first two days after birth. The mice were found to completely lack DA neurons in the ventral midbrain as demonstrated by the absence of several markers, such as the rate limiting enzyme in DA synthesis, tyrosine hydroxylase, a postulated retinoic acid converting enzyme, AHD2, and the DA transporter in SNC, the VTA as well as in the retrorubral field. In addition, high-pressure liquid chromatography was used to demonstrate the absence of DA itself in the major target area for the DAergic midbrain neurons, striatum. The role of Nurrl during early development of the ventral midbrain has been further studied and the relation to other factors postulated to be important for DA cell generation such as sonic hedgehog explored. Since survival could not be prolonged by administration of either the DA precursor L-DOPA, the DA receptor agonist apomorphine or DA itself despite apparently normal DA receptor expression, it is hypothesized that the mice do not die from lack of DA. Interestingly, brains of newborn and two months old heterozygous, apparently healthy, mice contained less DA than wild type littermates, indicating a function for Nurr1 not only in the generation of the DA cells, but also for maturation and maintenance of a normal DAergic phenotype. These studies demonstrate that retinoids most likely are important signaling molecules in the postnatal and adult CNS and establish Nurr1 as a key component for proper development of DA midbrain neurons, known to degenerate in patients with Parkinson's disease

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

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 CYP21A2 genotyping provide valuable information both for evaluating the screening program and the clinical outcome. The Swedish experience is described

<i>MCEE</i> Mutations in an Adult Patient with Parkinson’s Disease, Dementia, Stroke and Elevated Levels of Methylmalonic Acid

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 MCEE 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&#8217;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 MCEE gene, c.139C&gt;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 MCEE 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&#8217;s ongoing neurodegeneration attributed to Parkinson&#8217;s disease

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

Le dépistage néonatal a débuté en Europe dans les années 1960 avec celui de la phénylcétonurie. Le nombre de maladies dépistées a, par la suite, augmenté progressivement, de manière plus marquée à la fin des années 1990 avec l’arrivée de la spectrométrie de masse en tandem (MS/MS) qui a permis le dépistage de 40 à 50 maladies sur une seule goutte de sang séché. Les ajouts les plus récents à cette liste de maladies (mucoviscidose, déficits immunitaires combinés sévères et atrophie musculaire spinale) ont été rendus possibles grâce à la génétique moléculaire. À partir des informations provenant de 51 pays d’Europe, nous décrivons dans cette revue l’évolution du dépistage entre 2010 et 2020, ainsi que les progrès réalisés pendant cette période, tout en soulignant les aspects qui méritent d’être améliorés. Des progrès pourront en effet être accomplis grâce aux échanges d’informations et, pour certains pays, en tirant profit de l’expérience acquise dans des pays voisins. La plupart des programmes de dépistage mis en place dans l’Europe « géographique » au cours de cette période ont gagné en maturité en termes méthodologiques (modernisation des techniques) et en termes quantitatifs (augmentation du nombre des maladies dépistées). Ces développements nous montrent que la collaboration entre les différentes organisations s’accélère en Europe. Ce n’est qu’en travaillant ensemble que nous pourrons identifier en temps opportun les nouveau-nés atteints d’une des nombreuses maladies rares détectables et prendre les mesures qui s’imposent

First Year of TREC-Based National SCID Screening in Sweden

Screening for severe combined immunodeficiency (SCID) was introduced into the Swedish newborn screening program in August 2019 and here we report the results of the first year. T cell receptor excision circles (TRECs), kappa-deleting element excision circles (KRECs), and actin beta (ACTB) levels were quantitated by multiplex qPCR from dried blood spots (DBS) of 115,786 newborns and children up to two years of age, as an approximation of the number of recently formed T and B cells and sample quality, respectively. Based on low TREC levels, 73 children were referred for clinical assessment which led to the diagnosis of T cell lymphopenia in 21 children. Of these, three were diagnosed with SCID. The screening performance for SCID as the outcome was sensitivity 100%, specificity 99.94%, positive predictive value (PPV) 4.11%, and negative predictive value (NPV) 100%. For the outcome T cell lymphopenia, PPV was 28.77%, and specificity was 99.95%. Based on the first year of screening, the incidence of SCID in the Swedish population was estimated to be 1:38,500 newborns