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 global obesity epidemic: Snacking and obesity may start with free meals during infant feeding.

Feeding is vital for survival. The brain has strong hunger and reward mechanisms that ensure optimal food intake for adequate nutrition. The drive for feeding is particularly strong in humans whose large brains require large energy support. This starts immediately after birth; the newborn child being able to taste sucrose and suck the sweet and fat from its mother's milk. At present, mothers are generally advised to breastfeed children as often as they like, which may be up to 15 times a day. At the same time, childhood obesity is rapidly developing. One reason for the rapidly increasing prevalence of childhood obesity may be overfeeding with snack food.Conclusion: We hypothesize that non-rule breastfeeding favours the development of snacking throughout the day during childhood, a habit which in turn favours the development of obesity

Long-chain polyunsaturated fatty acids in Chinese and Swedish mothers: diet, breast milk and infant growth

Long-chain polyunsaturated fatty acids (LC-PUFAs) are essential dietary nutrients required for the optimal growth and development of infants, particularly of the brain and retina. It is important for exclusively breastfed infants to receive milk of a correct balance between &ohgr;-6 and &ohgr;-3 fatty acids. In this study, we compared the composition of LC-PUFAs in the diet and milk of mothers and their infants' growth between Chinese and Swedish. Twenty-three and 19 mother-term infant pairs from a rural area of northern Beijing, China, and Stockholm, Sweden, who were 3 mo old and exclusively breastfed, were studied. The Chinese diet was higher in carbohydrate (17% of energy) but lower in protein (4% of energy) and fat (12% of energy) than the Swedish diet. The intake of Chinese mothers contained more linoleic acid (LA, C18:2 &ohgr;-6) and less arachidonic acid (AA, C20:4 &ohgr;-6), eicosapentaenoic acid (EPA, C20:5 &ohgr;-3) and docosahexaenoic acid (DHA, C22:6 &ohgr;-3) than that of Swedish mothers. The breast milk of the Chinese mothers had significantly higher LA and lower EPA and DHA levels than that of the Swedish mothers. However, in Chinese breast milk the AA level was significantly higher than that in Swedish breast milk. The recommended ranges of the ratios of LA to &agr;-linolenic acid (LNA, C18:3 &ohgr;-3) and of AA to DHA in human milk are 5-10 and 0.5-1 compared with 23.0 and 3.1 in the Chinese breast milk, and 7.5 and 1.6 in the Swedish breast milk, respectively. Conclusion: The diet of the studied Chinese mothers is less balanced with regard to the levels of &ohgr;-6 and &ohgr;-3 polyunsaturated fatty acids (PUFAs) than that of the Swedish mothers, which is also mirrored in the breast milk of these mothers. The clinical relevance of the difference between the levels of LC-PUFAs in the breast milk of Chinese and Swedish mothers may be elucidated by a follow-up study of the cognitive and visual functions of the infants involved

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