Search

Introduction: Newborn screening is a public health programme for early diagnosis of treatable diseases., Methods: The subjects included were newborns born 2002-2019. Expanded newborn screening (eNBS) for metabolic diseases was introduced as a pilot project from 2002 to 2009, followed by routine screening with informed dissent. A total of 967,780 newborns were screened; 82,930 were unscreened. Furthermore, a historic cohort of clinically diagnosed children born in the 1992-2001 period was included. Children in the unscreened and historic cohorts were evaluated for the same diseases as were the screened children. Dried blood spot samples were collected locally and sent for screening analyses. We recorded newborns with true and false positive results as well as false negative results and their clinical signs at screening and at the last follow-up., Results: A total of 603 samples were screen positive: 354 false positives and 249 true positives (222 newborns and 27 mothers). The positive predictive value (PPV) was 41% for the entire screening period; 62% for 2018. The false positive rate (FPR) was 0.036% overall; 0.024% for 2018. The overall prevalence of diseases was 1:3,900; in the historic cohort, the prevalence of the same diseases was 1:8,300; 7.3% had symptoms at the time of screening. At follow-up, 93% of the children had no clinically significant sequelae. Among 82,930 unscreened newborns, 27 (1:3,000) had eNBS panel diseases, some with severe manifestations., Conclusions: This update of eNBS in Denmark confirms that eNBS is a successful preventive public health programme. Early treatment in a latent phase of disease is effective and screening should be extended to other diseases not currently in the programme., Funding: The work was supported by grants from The Ronald McDonald Børnefond, Danmarks Sundhedsfond, Direktør Ib Henriksens Fond, Ragnhild Ibsens Legat til Medicinsk Forskning, Gerda og Aage Haenschs Fond, Dronning Louises Børnehospitals Forskningsfond, Læge Sofus Carl Emil Friis og Hustru Olga Doris Friis's Legat, Aase and Ejnar Danielsens Fond, Oda og Hans Svenningsens Fond, Fonden af 1870, Vanførefonden, Fonden til Lægevidenskabens Fremme and Danish Medical Research Council., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Introduction: We investigated the frequency of con-sanguinity among the parents to newborns with inborn errors of metabolism (IEM) diagnosed by neonatal screening., Methods: Data were obtained from 15 years of national newborn screening for selected IEM with autosomal recessive mode of inheritance. Among the 838,675 newborns from Denmark, The Faroe Islands and Greenland, a total of 196 newborns had an IEM of whom 155 from Denmark were included in this study. These results were crosschecked against medical records. Information on consanguinity was extracted from medical records and obtained through telephone contact with the families., Results: Among ethnic Danes, two cases of consanguinity were identified among 93 families (2.15%). Among ethnic minorities, there were 20 cases of consanguinity among a total of 33 families (60.6%). Consequently, consanguinity was 28.2 times more frequent among descendants of other geographic places of origin than Denmark. The frequency of consanguinity was high among children of Pakistani, Afghan, Turkish and Arab origin (71.4%). The overall frequency of IEM was 25.5 times higher among children of these ethnic groups than among ethnic Danish children (5.35:10,000 versus 0.21:10,000). The frequency of IEM was 30-fold and 50-fold higher among Pakistanis (6.5:10,000) and Afghans (10.6:10,000), respectively, compared with ethnic Danish children., Conclusions: The data indicate a strong association between consanguinity and IEM. These figures may be useful to health professionals providing antenatal, paediatric and clinical genetic services., Funding: none., Trial Registration: not relevant., (Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.)

Expanded newborn screening for selected inborn errors of metabolism (IEM) in Denmark, the Faroe Islands and Greenland was introduced in 2002. We now present clinical, biochemical, and statistical results of expanded screening (excluding PKU) of 504,049 newborns during nine years as well as diagnoses and clinical findings in 82,930 unscreened newborns born in the same period. The frequencies of diagnoses made within the panel of disorders screened for are compared with the frequencies of the disorders in the decade preceding expanded newborn screening. The expanded screening was performed as a pilot study during the first seven years, and the experience obtained during these years was used in the development of the routine neonatal screening program introduced in 2009. Methods for screening included tandem mass spectrometry and an assay for determination of biotinidase activity. A total of 310 samples from 504,049 newborns gave positive screening results. Of the 310 results, 114 were true positive, including results from 12 newborns in which the disease in question was subsequently diagnosed in their mothers. Thus, the overall frequency of an IEM in the screening panel was 1:4942 (mothers excluded) or 1:4421 (mothers included). The false positive rate was 0.038% and positive predictive value 37%. Overall specificity was 99.99%. All patients with true positive results were followed in The Center for Inherited Metabolic Disorders in Copenhagen, and the mean follow-up period was 45 months (range 2109 months). There were no deaths among the 102 children, and 94% had no clinically significant sequelae at last follow-up. Our study confirms the higher frequency of selected IEM after implementation of expanded newborn screening and suggests an improved outcome for several disorders. We argue that newborn screening for these disorders should be standard of care, though unresolved issues remain, e.g. about newborns with a potential for remaining asymptomatic throughout life. Well organized logistics of the screening program from screening laboratory to centralized, clinical management is important., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common defect of fatty acid oxidation. Many countries have introduced newborn screening for MCADD, because characteristic acylcarnitines can easily be identified in filter paper blood spot samples by tandem mass spectrometry (MS/MS), because MCADD is a frequent disease, and because of the success of early treatment initiated before clinical symptoms have emerged. In Denmark we have screened 519,350 newborns for MCADD by MS/MS and identified 58 affected babies. The diagnosis of MCADD was confirmed in all 58 newborns by mutation analysis. This gives an incidence of MCADD detected by newborn screening in Denmark of 1/8954. In sharp contrast to this we found that the incidence of clinically presenting MCADD in Denmark in the 10 year period preceding introduction of MS/MS-based screening was only 1 in 39,691. This means that four times more newborns with MCADD are detected by screening than what is expected based on the number of children presenting clinically in an unscreened population. The mutation spectrum in the newborns detected by screening is different from that observed in clinically presenting patients with a much lower proportion of newborns being homozygous for the prevalent disease-causing c.985A>G mutation. A significant number of the newborns have genotypes with mutations that have not been observed in patients detected clinically. Some of these mutations, like c.199T>C and c.127G>A, are always associated with a milder biochemical phenotype and may cause a milder form of MCADD with a relatively low risk of disease manifestation, thereby explaining part of the discrepancy between the frequency of clinically manifested MCADD and the frequency of MCADD determined by screening. In addition, our data suggest that some of this discrepancy can be explained by a reduced penetrance of the c.985A>G mutation, with perhaps only 50% of c.985A>G homozygotes presenting with disease manifestations. Interestingly, we also report that the observed number of newborns identified by screening who are homozygous for the c.985A>G mutation is twice that predicted from the estimated carrier frequency. We therefore redetermined the carrier frequency in a new sample of 1946 blood spots using a new assay, but this only confirmed that the c.985A>G carrier frequency in Denmark is approximately 1/105. We conclude that MCADD is much more frequent than expected, has a reduced penetrance and that rapid genotyping using the initial blood spot sample is important for correct diagnosis and counseling., (Copyright © 2012 Elsevier Inc. All rights reserved.)

We review the evidence that in Denmark and probably certain other European countries the number of individuals identified with homocystinuria due to homozygosity for the widespread c.833T>C (p.I278T) mutation in the gene that encodes cystathionine beta-synthase (CBS) falls far short of the number of such individuals expected on the basis of the heterozygote frequency for this mutation found by molecular screening. We conclude that the predominant portion of such homozygotes may be clinically unaffected, or may be ascertained for thromboembolic events occurring no sooner than the third decade of life. If so, there was significant ascertainment bias in the time-to-event curves previously published describing the natural history of untreated CBS deficiency Mudd et al. and these curves should be used with care.

Diagnosis of and care for people with rare diseases are a challenge. Most rare diseases are inherited with clinical presentation in early childhood, complex with involvement of several organ systems and progressive with ever changing phenotype. Physical and neurological disability makes many families dependent on social security. In Denmark and in a few other EU countries, centres of reference for the care of people with rare diseases have been established. The impression is that the effect of establishing such centres for these rare diseases in Denmark has been good and that it remains the most rational way of treatment.

Carbohydrate-deficient glycoprotein syndrome type 1 (CDG1; McKusick No. 212065) is an autosomal recessively inherited disease characterised clinically by central nervous system dysfunction and biochemically by hypoglycosylation of many serum proteins. Most patients with CDG1 have deficient activity of phosphomannomutase. The locus for this enzyme has been mapped to 16p13, and a gene, PMM2, encoding phosphomannomutase has been isolated. We identified 34 mutations on 36 disease chromosomes in 18 unrelated Danish patients with CDG1. All patients have less than 15% residual activity of phosphomannomutase. Two mutations account for 88% of all mutations: F119L and R141H were each found in 16 out of 36 CDG1 alleles. These two mutations were found to be in linkage disequilibrium with two different alleles of the marker D16S3020, suggesting that there is one ancestral origin for each mutation. Two new mutations, G117R and D223E, were identified also. Surprisingly, no patient was homozygous for either of the two common mutations, suggesting that homozygosity for these mutations is either lethal or so benign that such patients are not detected.

A working group was established to evaluate the need for an increased folate intake in Danish women to decrease the risk of neural tube defects (NTDs). NTD are birth defects which include anencephaly, encephalocele and spina bifida. In Denmark the incidence is about 1.4 per 1,000 pregnancies. Folate is a B-vitamin found in most food groups. In case-control studies and randomised studies, a protective effect of folic acid supplements on NTDs has been found. The studies show that a periconceptional folic acid supplement of 360 micrograms to 4 mg daily decreases the recurrence rate of NTDs. Likewise, in the few studies which calculate folate intake from the diet, a lower risk of NTD with higher intake of folate from the diet has been found. The folate intake can be increased by the diet, by folic acid supplements or by fortification of food with folic acid. It is concluded that the incidence of NTDs in Denmark will decrease if the folate intake in fertile women increases. All women planning pregnancy should receive dietary counselling. Women who do not eat according to the Nordic Nutrition Recommendations, and women with an increased risk due to diseases are recommended a supplement of 400 micrograms folic acid daily from a multivitamin/folic acid tablet. Women who have had a child with NTD and women who themselves have NTDs are recommended a supplement of 5 mg folic acid daily. Dietary changes and supplements should be initiated when pregnancy is planned.

Carbohydrate-deficient glycoprotein syndrome type I (CDG I) is characterized clinically by severe nervous system involvement and biochemically by defects in the carbohydrate residues in a number of serum glycoproteins. The CDG1 gene was recently localized by us to a 13-cM interval in chromosome region 16p13. In this study 44 CDG I families from nine countries were analyzed with available markers in a region ranging from marker D16S495 to D16S497, and haplotype and linkage disequilibrium analyses were performed. One specific haplotype was found to be markedly overrepresented in CDG I patients from a geographically distinct region in Scandinavia, strongly indicating that CDG I families in this region share the same ancestral CDG1 mutation. furthermore, analysis of the extent of the common haplotype in these families indicates that the CDG1 gene is located in the region defined by markers D16S513-AFMa284wd5-D16S768-D16S406-D16S502 . The critical CDG1 region, in strong linkage disequilibrium with markers AFMa284wd5, D16S768, and D16S406, thus constitutes less than 1 Mb of DNA and less than 1 cM in the very distal part of the CDG1 region defined by us previously.

Total prevention of cystic fibrosis (CF) is possible if all carrier women are found before pregnancy or early enough during pregnancy so that prenatal diagnosis can be offered. The delta 508 allele constitutes almost 90% of the mutations causing CF in the Danish population. We have examined 6599 pregnant women and found 172 carriers of delta F508. Partners of carrier women were examined for delta F508 and five other mutations. Three couples at risk and one foetus with CF were identified. Giving information to couples before and after testing is time consuming. A comprehensive questionnaire was sent to 200 non-carriers and all 172 carriers (response rate 72%). It can be concluded that the project has been very well accepted. However, the majority of carriers were shocked or very worried when they had the test result. Based on this pilot study we recommend nationwide screening for delta F508 early in pregnancy.

A total of 3025 families with school children aged six to eight years were offered pilot screening for familial hypercholesterolaemia by measurement of the concentration of apolipoproteins A-1 and B in the children's capillary blood and by analysis of their family histories of early ischaemic heart disease. The concentrations of the apolipoproteins were determined by double rocket immunoelectrophoresis of an eluate of blood spotted on filter paper. Results were available from 2085 children. Because their B:A-1 ratio was above the 97.5 centile and their concentration of B was above the 99th centile, 54 children (2.6%) were selected to have their apolipoprotein concentrations reassessed. The 17 children (0.8%) whose values were persistently above the chosen cut-off points, and all of their available first and second degree relatives, had fasting determinations of serum lipid concentrations carried out. Raised serum concentrations of low density lipoprotein cholesterol and an autosomal dominant pattern of hypercholesterolaemia were found in respectively 12 children and 10 families, suggesting a higher incidence of familial hypercholesterolaemia than the reported 1:500. Further investigations among family members disclosed hypercholesterolaemia in 29 relatives. A family history of early ischaemic heart disease was elicited by questionnaire, and was positive in only five of the 12 school children with hypercholesterolaemia. We conclude that analysis of apolipoproteins from capillary blood spotted on filter paper is suitable for screening for familial hypercholesterolaemia, and that this method is more efficient than screening based on family history.

Food costs for 30 children under dietary treatment for familial hypercholesterolaemia were compared with those of 105 other Danish children. The daily intake of macronutrients and the daily cost of the diet for each child were calculated from dietary intakes and average prices of 365 different food items. The mean +/- SE percentages of energy (E%) from fat in the diet of children with and without known familial hypercholesterolaemia were 23.6 +/- 0.8 E+ and 34.5 +/- 0.5 E%, respectively (P < 0.001). The dietary costs per MJ in these two groups were 3.79 +/- 0.12 Danish crowns (DKr) and 3.34 +/- 0.05 DKr (P < 0.001), taking into account food wastage due to preparation and cooking. The cost per unit of energy increased with decreasing fat energy percentage of the diet for all children as one group (r = -0.37, P < 0.001), as well as for the group of children without familial hypercholesterolaemia (r = -0.35, P < 0.001). Stepwise multiple regression analysis showed that the differences in cost per MJ between the groups could be explained primarily by differences in percentage of energy from fat. We conclude that a reduction of dietary fat from 35 E% to 25 E% may increase food costs by 10-20% for Danish children.

During the first 12 months of the Danish Liver Transplantation program, which began in October 1990, 21 transplantations were performed in 11 women, six men and three children. One patient required a retransplant. Fourteen operations were performed electively and six patients were transplanted for acute and subacute fulminant liver failure and coma, two patients had reduced size livers because of large donor liver. There were no peroperative deaths. One of the elective patients died after three weeks from multiorgan failure and sepsis. Two of the emergency patients died after 20 and 22 days. One from graft dysfunction due to stenosis of the celiac trunk and the other of exudative pericarditis. One patient died from chronic rejection and CMV-infection after seven months. Complications were relatively few and acute rejection occurred in 40% of the patients. Fifteen patients are discharged with normal liver function and 11 of these were back at work, school or previous functions in the home. It is concluded that these results are comparable to the best results from other centres but that 21 transplants in 12 months must be a minimum activity.

The section for preventive cardiology within the Danish Society for Cardiology has established a lipid group with representatives from The Danish Society for Clinical Chemistry, The Danish Society for Internal Medicine, The Danish Society for Cardiology, The Danish Society of Hypertension, The Danish College of General Practitioners, and The Danish Paediatric Society. The lipid group has elaborated recommendations for clinical chemical departments regarding lipid and lipoprotein analyses. The group suggests that doctors ordering lipid and lipoprotein analyses are offered the following: S-Cholesterol (total), substance conc., (fPt)S-Triglycerides, substance conc., S-HDL-cholesterol, substance conc., and (fPt)S-LDL-cholesterol, substance conc. (calculated). It is recommended that the biological variation be minimized by sampling in a sitting position after a 15 minutes' rest and by basing the clinical decision on a minimum of 2-3 determinations with an interval of about one month. The analytical variations should be reduced to below 3% (calculated as the variation coefficient), and it is recommended that laboratories participate in external quality control systems at least four times annually by reporting at least two human reference materials with different concentrations. As the use of reference intervals dependent on age and sex, based on random samplings of the background population, are less informative, it is recommended to refer to cutoff values for the clinical decision. The following cutoff values are recommended: S-Cholesterol (total), substance conc.: 6 mmol/l, (fPt)S-Triglycerides, substance conc.; 2.5 mmol/l, S-HDL-cholesterol, substance conc.: 0.9 mmol/l (fPt)-LDL-cholesterol, substance conc. (calculated): 4.5 mmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

The indication for liver transplantation is the end stage of liver disease. Liver transplantations are not carried out in Denmark at present, one of the reasons being that it requires introduction of the brain death criterion, because the donor liver must be removed during maintained circulation. To date (November 1988), liver transplantations have been carried out abroad on seven Danes. One of these died after operation, one has chronic rejection and is to have retransplantation while the remaining five patients are well. In Europe (including Sweden, Norway and Finland) and USA, more than 5,000 patients have been liver transplanted. The one-year survival is approximately 75%. After this, only few liver-related deaths occur and the majority of patients can resume their previous activities. A total of 18 Danes have been assessed in transplantation centres abroad: Two are waiting for transplantation in the near future and seven have been accepted for transplantation at a later date, depending on the course of the disease. In a number of Danes, liver transplantation has been considered indicated but has not been effectuated because the disease was so advanced at the time of referral, that the patient died before transfer or the patient did not desire operation abroad.