Different Viewpoints: International Perspectives on Newborn Screening.

Newborn blood-spot screening to detect potentially treatable disorders is widely practiced across the globe. However, there are great variations in practice, both in terms of disorders covered, screening technologies, disease definition, information provision, parental informed consent, and storage and disposal of residual specimens, partly reflecting the degree to which screening is the subject of explicit legislation (and thus public and media pressure) or is embedded in a general health care system and managed at an executive level. It is generally accepted that disorders to be screened for should comply with the ten Wilson and Jungner criteria, but the way that compliance is assessed ranges from broadly-based opinion surveys to detailed analysis of quantitative data. Consequently, even countries with comparable levels of economic development and health care show large differences in the number of disorders screened for. There are several areas on which there are no generally accepted guidelines: how should parents be informed about screening and to what extent should they be encouraged to regard screening as an option to choose to refuse? Is DNA mutation analysis acceptable as part of a screening protocol? How soon should the blood samples be destroyed once screening has been completed? As technology advances and the potential scope of screening expands at both the metabolite and genome level, challenging policy issues will have to be faced.

Cost effectiveness of establishing a neonatal screening programme for phenylketonuria in Libya.

BACKGROUND: Inborn errors of metabolism (IEM) are a significant cause of morbidity and mortality in North Africa and the Middle East. With the evident success of neighbouring countries in initiating neonatal screening for IEM, the Libyan Authorities are now considering introducing neonatal screening for phenylketonuria (PKU) in Libya in the first instance, with the prospect of expanding the programme to cover other IEM in the future. OBJECTIVE: To estimate the cost effectiveness of neonatal screening for PKU compared with no neonatal screening in Libya. METHODS: A decision model was constructed to estimate the cost effectiveness of neonatal screening for PKU, from the perspective of Libyan society. Healthcare resource use and other input parameters were based on expert opinion. RESULTS: The expected discounted cost to Libyan society of screening over 15 years and managing ∼374 patients with detected PKU over their lifetime was estimated to be $US213.6 (95% CI 211.9, 214.3) million (year 2007-8 values). The current expected discounted cost of managing these same PKU patients over their lifetime as a result of not screening was estimated to be $US321.2 (95% CI 318.0, 322.7) million. Hence, screening would save Libyan society $US107.6 (95% CI 105.5, 109.1) million over the lifetime of PKU patients and lead to an additional 6947 life-years (95% CI 6837, 7056). The expected cost per undiscounted life-year gained was estimated to be -$US15,500 (95% CI -16,600, 1100). There would be a 90% return on investment in the screening programme since society would gain $US1.9 for every $US1 invested. Probabilistic sensitivity analysis demonstrated that the screening programme has a 0.95 probability of being cost effective even at a willingness-to-pay threshold of $US4000 per life-year gained. CONCLUSIONS: Within the model's limitations, neonatal screening for PKU appears to offer Libyan society a strategy that is cost effective compared with no neonatal screening.

New technologies extend the scope of newborn blood-spot screening, but old problems remain unresolved.

UNLABELLED: The potential of newborn blood-spot screening is expanding rapidly with the development of new analytical techniques and treatment methods. At the same time, some existing programmes, particularly that for congenital hypothyroidism, are coming under scrutiny because of suspicion that they are being shaped by analytical performance rather than evidence of clinical need. Screening policy varies greatly from country to country. CONCLUSION: Ethical and political considerations may sometimes override formal scientific decision models.

Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy).

BACKGROUND & AIMS: Trichohepatoenteric syndrome (THES) is an autosomal-recessive disorder characterized by life-threatening diarrhea in infancy, immunodeficiency, liver disease, trichorrhexis nodosa, facial dysmorphism, hypopigmentation, and cardiac defects. We attempted to characterize the phenotype and elucidate the molecular basis of THES. METHODS: Twelve patients with classic THES from 11 families had detailed phenotyping. Autozygosity mapping was undertaken in 8 patients from consanguineous families using 250,000 single nucleotide polymorphism arrays and linked regions evaluated using microsatellite markers. Linkage was confirmed to one region from which candidate genes were analyzed. The effect of mutations on protein production and/or localization in hepatocytes and intestinal epithelial cells from affected patients was characterized by immunohistochemistry. RESULTS: Previously unrecognized platelet abnormalities (reduced platelet alpha-granules, unusual stimulated alpha granule content release, abnormal lipid inclusions, abnormal platelet canalicular system, and reduced number of microtubules) were identified. The THES locus was mapped to 5q14.3-5q21.2. Sequencing of candidate genes showed mutations in TTC37, which encodes the uncharacterized tetratricopeptide repeat protein, thespin. Bioinformatic analysis suggested thespin to be involved in protein-protein interactions or chaperone. Preliminary studies of enterocyte brush-border ion transporter proteins (sodium hydrogen exchanger 2, sodium hydrogen exchanger 3, aquaporin 7, sodium iodide symporter, and hydrogen potassium adenosine triphosphatase [ATPase]) showed reduced expression or mislocalization in all THES patients with different profiles for each. In contrast the basolateral localization of Na/K ATPase was not altered. CONCLUSIONS: THES is caused by mutations in TTC37. TTC37 mutations have a multisystem effect, which may be owing to abnormal stability and/or intracellular localization of TTC37 target proteins.

European best practice guidelines for cystic fibrosis neonatal screening.

There is wide agreement on the benefits of NBS for CF in terms of lowered disease severity, decreased burden of care, and reduced costs. Risks are mainly associated with disclosure of carrier status and diagnostic uncertainty. When starting a NBS programme for CF it is important to take precautions in order to minimise avoidable risks and maximise benefits. In Europe more than 25 screening programmes have been developed, with quite marked variation in protocol design. However, given the wide geographic, ethnic, and economic variations, complete harmonisation of protocols is not appropriate. There is little evidence to support the use of IRT alone as a second tier, without involving DNA mutation analysis. However, if IRT/DNA testing does not lead to the desired specificity/sensitivity ratio in a population, a screening programme based on IRT/IRT may be used. Sweat chloride concentration remains the gold standard for discriminating between NBS false and true positives, but age-related changes in sweat chloride should be taken into account. CF phenotypes associated with less severe disease often have intermediate or normal sweat chloride concentrations. Programmes should include arrangements for counselling and management of infants where the diagnosis is not clear-cut. All newborns identified by NBS should be managed according to internationally accepted guidelines. CF centre care and the availability of necessary medication are essential prerequisites before the introduction of NBS programmes. Clear explanation to families of the process of screening and of implications of normal and abnormal results is central to the success of CF NBS programmes. Effective communication is especially important when parents are told that their child is affected or is a carrier. When establishing a NBS programme for CF, attention should be given to ensuring timely and appropriate processing of results, to minimise potential stress for families.

Newborn bloodspot screening in the UK--past, present and future.

Screening newborn babies for inherited metabolic disease began in the UK in the late 1950s with the 'nappy test' for phenylketonuria. In 1969 the Department of Health recommended changing to bloodspot screening using the techniques developed in the USA by Robert Guthrie and his associates. Bloodspot screening for various other disorders (galactosaemia, maple syrup urine disease, homocystinuria, cystic fibrosis and others) was introduced on a patchy local basis but, until 2000, the only additional disorder officially recommended was congenital hypothyroidism. Screening for haemoglobinopathies received official support in 2000 and for cystic fibrosis in 2001 though implementation was slow, particularly for the latter. Both these screens have raised difficult issues relating to genetic privacy and the detection of carrier status in children. During the last decade screening has become increasingly subject to central control. Though a more consistent and systematic approach was clearly needed, this has undoubtedly slowed the rate of innovation. In particular the UK has lagged behind many other European countries in the application of tandem mass spectrometry (MS-MS) though, following a major pilot study, screening for medium-chain acyl-CoA dehydrogenase deficiency is now in the process of introduction. Attempts to codify clinical and laboratory procedures have also proved controversial, highlighting marked differences in practice in various parts of the country and the difficulty of rationalizing these within a practicable and scientifically justified framework. Notwithstanding this, there are many positive developments and newborn screening remains a stimulating and rewarding field in which to work.

A survey of newborn screening for cystic fibrosis in Europe.

BACKGROUND: Cystic fibrosis (CF) is a recessively inherited condition caused by mutation of the CFTR gene. Newborn infants with CF have raised levels of immuno-reactive trypsinogen (IRT) in their serum. Measurement of IRT in the first week of life has enabled CF to be incorporated into existing newborn screening (NBS) blood spot protocols. However, IRT is not a specific test for CF and NBS therefore requires a further tier of tests to avoid unnecessary referral for diagnostic testing. Following identification of the CFTR gene, DNA analysis for common CF-associated mutations has been increasingly used as a second tier test. The aim of this study was to survey the current practice of CF NBS programmes in Europe. METHOD: A questionnaire was sent to 26 regional and national CF NBS programmes in Europe. RESULTS: All programmes responded. The programmes varied in number of infants screened and in the protocols employed, ranging from sweat testing all infants with a raised first IRT to protocols with up to four tiers of testing. Three different assays for IRT were used; in the majority (24) this was a commercially available kit (Delfia). A number of programmes employed a second IRT measurement in the 4th week of life (as the IRT is more specific at this point). Nineteen programmes used DNA analysis for common CFTR mutations on samples with a raised first IRT. Three programmes used a second IRT measurement on infants with just one recognised mutation to reduce the number of infants referred for sweat testing. Referral to clinical services was prompt and diagnosis was confirmed by sweat testing, even in infants with two recognised mutations in most programmes. Subsequent clinical pathways were less uniform. Multivariate analysis demonstrated a relationship between the age of diagnosis and the timing of the first IRT. More sweat tests were undertaken if the first IRT was earlier and the diagnosis was later. CONCLUSIONS: Annually these programmes screen approximately 1,600,000 newborns for CF and over 400 affected infants are recognised. The findings of this survey will guide the development of European evidence based guidelines and may help new regions or nations in the development and implementation of NBS for cystic fibrosis.

The epidemiology of medium chain acyl-CoA dehydrogenase deficiency: an update.

The most common fatty acid oxidation disorder, medium chain acyl-CoA dehydrogenase deficiency (MCADD), has become the focal point for the adoption of tandem mass spectrometry to detect it and related inborn errors of metabolism. This article updates a human genome epidemiology review of MCADD published in 1999. The focus of this update is on epidemiologic parameters rather than mutations associated with MCADD. Currently available information from screening studies on the frequency of detection of MCADD in newborns, as well as the frequency of homozygotes for the common mutation in the ACADM gene, is summarized. In the United States, the average incidence of the disorder is from 1 in 15,000 to 1 in 20,000 births, with individual states reporting frequencies from 1 in 10,000 to 1 in 30,000 births. In addition, a systematic review was undertaken of the published literature on the frequency of mortality and developmental disabilities among children with MCADD, both in screened and unscreened cohorts. It seems that in the absence of newborn screening for MCADD, premature death or serious disability occurs in 20% to 25% of children with the disorder. Systematic collection and analysis of follow-up data are still needed to ascertain the frequencies of outcomes in screened cohorts.

Haemochromatosis-associated HFE genotypes in English blood donors: age-related frequency and biochemical expression.

BACKGROUND/AIMS: There are limited data on the frequency and biochemical expression of the haemochromatosis-associated mutations C282Y and H63D in healthy people. METHODS: We genotyped (bi-directional PCR amplification of specific alleles method) and performed serum iron studies in randomly selected English male blood donors (<4 previous units donated) in four age bands <30, 30-40, 40-50 and >50 years. RESULTS: In 6261 subjects, frequency of C282Y homozygosity (+/+) was 0.3%, C282Y/H63D compound heterozygosity (+/-) 2.0%, and H63D and C282Y heterozygosity +/-, 21.7 and 10.4%, respectively. Genotype distribution was within Hardy-Weinberg equilibrium in each age band. C282Y +/- frequency fell from 11.7% in subjects <30 years to 8.2% in subjects >50 (Chi2 7.19; P<0.005). No such trend was seen for C282Y +/+. In C282Y +/+ subjects, median serum ferritin was 247 (range 60-2449) microg/l and exceeded >500 microg/l in only two of 18 subjects. Compared to wild/wild (-/-) subjects, C282Y and H63D +/- subjects had slightly higher serum iron and lower unsaturated iron binding concentrations, similar overall serum ferritin values but higher serum ferritin values in subjects who had previously donated blood. CONCLUSIONS: C282Y +/+ shows limited biochemical expression and no trend towards age-related attrition. C282Y and H63D +/- may protect against iron deficiency.

Novel OCTN2 mutations: no genotype-phenotype correlations: early carnitine therapy prevents cardiomyopathy.

Primary systemic carnitine deficiency or carnitine uptake defect (OMIM 212140) is a potentially lethal, autosomal recessive disorder characterized by progressive infantile-onset cardiomyopathy, weakness, and recurrent hypoglycemic hypoketotic encephalopathy, which is highly responsive to L-carnitine therapy. Molecular analysis of the SLC22A5 (OCTN2) gene, encoding the high-affinity carnitine transporter, was done in 11 affected individuals by direct nucleotide sequencing of polymerase chain reaction products from all 10 exons. Carnitine uptake (at Km of 5 microM) in cultured skin fibroblasts ranged from 1% to 20% of normal controls. Eleven mutations (delF23, N32S, and one 11-bp duplication in exon 1; R169W in exon 3; a donor splice mutation [IVS3+1 G > A] in intron 3; frameshift mutations in exons 5 and 6; Y401X in exon 7; T440M, T468R and S470F in exon 8) are described. There was no correlation between residual uptake and severity of clinical presentation, suggesting that the wide phenotypic variability is likely related to exogenous stressors exacerbating carnitine deficiency. Most importantly, strict compliance with carnitine from birth appears to prevent the phenotype.