Neonatal Screening For Inborn Errors Research Articles

Implementation of TREC/KREC detection protocol for newborn SCID screening in Bulgaria: a pilot study

Neonatal screening for inborn errors of immunity (IEI), based on quantification of T-cell-receptor- excision circles (TRECs) and kappa-deleting recombination-excision circles (KRECs) from dried blood spots (DBS), allows early diagnosis and improved outcomes for the affected children. Determination of TREC/KREC levels from prospectively collected newborns' Guthrie cards and from DBS samples of patients with confirmed IEI was done using a commercial kit. Retrospective assessment of flow cytometry evaluation of TREC/KREC correspondence with lymphocyte subpopulations and evaluation of the correlations between TREC and KREC with immune cells, based on the data from patients with suspected or confirmed immune disorders, were conducted. 2,228 Guthrie cards were tested, 1276 for TREC only and 952 for both TREC and KREC. Eight newborns (0.36%) were TREC positive and 10 (1.05%) had KREC below the cut-off. The re-testing rate was 1.88%. Retrospective analysis demonstrated that the TREC/KREC assay identifies 100% of severe combined immune deficiencies (SCID) cases when DBS were collected at birth. Correlation analysis showed moderate significant correlations between TREC and the absolute numbers of CD4 cells (r = 0.634, p < 0.01) and total T cells (r = 0.536, p < 0.01). The ability of KREC levels to predict abnormal absolute (AUC of 0.772) and relative (AUC 0.731) levels of B cells was demonstrated.

ИНФОРМИРОВАННОСТЬ ВРАЧЕЙ И ПАЦИЕНТОВ О ВРОЖДЕННЫХ ОШИБКАХ ИММУНИТЕТА

The immune system protects the body. When defenses are compromised, people with hereditary immunological disorders become vulnerable to many life-threatening infections. Inborn errors of immunity (primary immunodeficiencies), manifested in patients in increased susceptibility to infectious diseases, autoimmune diseases, allergies, and malignant neoplasms. Today, this group of diseases is still considered quite rare. However, the development of diagnostic technologies expands the list of nosologies associated with inborn errors of immunity. Neonatal screening for inborn errors of immunity could solve many of the problems of these patients, but the procedure is not carried out in the Russian Federation. Therefore, diagnostics based on an analysis of the clinical manifestations of diseases. In most cases, the disease is diagnosed in early childhood. Here, the role of both the parents of the child-patient and the medical staff is important. The health and life of the child depends on their awareness of the disease, methods of diagnosis, treatment. This group of diseases is chronic, under an hour, severe. In the absence of timely diagnosis and proper therapy, it can be fatal. The article describes the experience of applied quantitative research conducted by the method of questioning patients with primary immunodeficiencies (parents of underage patients), about their disease, methods of treatment, problems arising in the long-term struggle with this complex disease. The author notes that patients and primary care doctors or general practitioners are poorly informed about diseases associated with primary immunodeficiencies. It is concluded that it is necessary to increase the informational medical culture of the population, especially the young, as participants in the interaction "doctor-patient" and representatives of the interests of minor children-patients with inborn errors of immunity.

Favorable course of previously undiagnosed Methylmalonic Aciduria with Homocystinuria (cblC type) presenting with pulmonary hypertension and aHUS in a young child: a case report

BackgroundCobalamin C (cblC) defect is the most common inborn error of Vitamin B12 metabolism often causing severe neurological, renal, gastrointestinal and hematological symptoms. Onset with pulmonary hypertension (PAH) and atypical hemolytic-uremic syndrome (aHUS) is rare.Case presentationWe describe the case of a 2-years old child, previously in good health, admitted to the hospital with severe respiratory symptoms, rapid worsening of clinical conditions, O2 desaturation and palmo-plantar edema. The patient showed PAH and laboratory findings compatible with aHUS. cblC defect, an inborn error of metabolism, was identified as the cause of all the symptoms described (cardiac, respiratory and renal involvement). Results of neonatal screening for inborn errors of metabolism had been negative.Administration of IM OHCbl (intramuscular hydroxocobalamin), oral betaine and symptomatic treatment with diuretics and anti-hypertensive systemic and pulmonary drugs induced dramatic improvement of both cardiac and systemic symptoms.ConclusionsIn this case of cblC defect the metabolic treatment completely reverted symptoms of aHUS and PAH. The course was favorable, and the prognosis is what we foresee for the future.

Neonatal Screening for Inborn Errors of Metabolism Using Tandem Mass Spectrometry: Experience of the Pilot Study in Andhra Pradesh, India

To estimate the prevalence of the Inborn Errors of Metabolism (IEM), evaluate biomarker distributions and determine benefits of screening for the inborn errors of metabolism in Andhra Pradesh, India, using Tandem Mass Spectrometry (MS/MS). The 4,946 newborns born during the period 2006-2008 in four major Government Maternity Hospitals in a rural district in Andhra Pradesh, India, were screened at an established newborn screening laboratory in the US using their previously established norms. Forty-seven neonates had out-of-range results (5 high probability; 28 low probability; 14 indeterminate). Two infants with disorders (carnitine uptake disorder and isovaleric aciduria) identified by screening are currently doing well. One infant with presumed glutaric aciduria type II, was deceased at the time of reporting. Another infant, with glutaric aciduria type I, became symptomatic and died at the age of 1 year despite early detection and treatment. A comparison of the concentrations of biomarkers among babies born in India and those born in Massachusetts, US, was also undertaken and significant differences were noted. A high prevalence of disorders was observed, but to estimate the true extent of the IEM in India larger studies are required. This study also illustrates challenges encountered in disease management highlighting the importance of considering the access to confirmatory testing and continuing clinical care before implementing any large-scale NBS for conditions with resource-intensive health needs such as the IEM detected by MS/MS.

Communicative and psycholinguistic abilities in children with phenylketonuria and congenital hypothyroidism

ABSTRACTThe Neonatal Screening for Inborn Errors of Metabolism of the Association of Parents and Friends of Special Needs Individuals (APAE) - Bauru, Brazil, was implanted and accredited by the Brazilian Ministry of Health in 1998. It covers about 286 cities of the Bauru region and 420 collection spots. Their activities include screening, diagnosis, treatment and assistance to congenital hypothyroidism (CH) and phenylketonuria (PKU), among others. In 2005, a partnership was established with the Department of Speech-Language Pathology and Audiology, Bauru School of Dentistry, University of São Paulo, Bauru, seeking to characterize and to follow, by means of research studies, the development of the communicative abilities of children with CH and PKU. Objective: The aim of this study was to describe communicative and psycholinguistic abilities in children with CH and PKU. Materials and Methods: Sixty-eight children (25 children aged 1 to 120 months with PKU and 43 children aged 1 to 60 months with CH) participated in the study. The handbooks were analyzed and different instruments were applied (Observation of Communication Behavior, Early Language Milestone Scale, Peabody Picture Vocabulary Test, Gesell & Amatruda's Behavioral Development Scale, Portage Operation Inventory, Language Development Evaluation Scale, Denver Developmental Screening Test, ABFW Child Language Test-phonology and Illinois Test of Psycholinguistic Abilities), according to the children's age group and developmental level. Results: It was observed that the children with PKU and CH at risk for alterations in their developmental abilities (motor, cognitive, linguistic, adaptive and personal-social), mainly in the first years of life. Alterations in the psycholinguistic abilities were also found, mainly after the preschool age. Attention deficits, language and cognitive alterations were more often observed in children with CH, while attention deficits with hyperactivity and alterations in the personal-social, language and motor adaptive abilities were more frequent in children with PKU. Conclusion: CH and PKU can cause communicative and psycholinguistic alterations that compromise the communication and affect the social integration and learning of these individuals, proving the need of having these abilities assisted by a speech and language pathologist.

EDTA in Dried Blood Spots Leads to False Results in Neonatal Endocrinologic Screening

Blood samples for neonatal screening for inborn errors of metabolism are collected and shipped on standardized filter paper cards. Occasionally these samples are contaminated with EDTA, which is often used for anticoagulation. EDTA may interfere with newborn screening tests based on lanthanide fluorescence and thus lead to false-negative or false-positive results. We used tandem mass spectrometry (MS/MS) to detect EDTA in dried blood spots by use of an extra experiment that was integrated into the standard MS/MS neonatal screening and did not require an additional sample spot, nor extra time or work. We analyzed the influence of different blood sampling procedures on lanthanide fluorescence tests for thyroid-stimulating hormone (TSH) and 17-hydroxyprogesterone (17-OHP). EDTA was increased in 138 of 190 000 newborn screening samples, 27 of which caused false- positive results in the immunoassay for 17-OHP. No false-negative TSH results were found. False-positive results in the 17-OHP test occurred when EDTA concentrations were >2.0 g/L; the TSH test, however, produced false negatives only when EDTA concentrations were >3.0 g/L. Using EDTA-containing devices the procedure of blood collection significantly influenced the concentration of the anticoagulant. Addition of EDTA quantification into standard MS/MS tests is a simple and useful method to avoid false-positive or false-negative neonatal screening results in lanthanide fluorescence-based tests.

Analyse der Zeitabläufe des Neugeborenenscreenings

Guidelines for neonatal screening for inborn errors of metabolism published by the Federal Joint Committee of physicians and health insurances in Germany include preanalytical specifications, e. g. blood collection at 36 to 72 hours of life and rapid sample transportation which is necessary with respect to those target diseases of the German program that might lead to very early metabolic decompensation. Analysis of 149 854 data sets containing all necessary informations out of a total of 173 221 screening samples sent to our laboratory from April 2006 to the end of March 2007 showed significant discrepancies between the requested and the actual times recorded for blood collection. 11.5 % of samples were drawn later than required. Looking at outpatients only, 43 % of the samples were taken after 72 hours. Sample shipping was delayed in several hospitals and private practises, especially on weekends. This was the reason why 31.2 % of all samples could not be reported on within 72 hours after blood collection as required. In addition the quality of 914 samples (0.52 %) was insufficient so that a repeat sample had to be analysed. In the future, as a rule, every baby should have his/her blood taken around the 48th hour, in any case between the 36th and 72nd hour of life. Moreover, sample shipping needs to be optimised in order to guarantee early diagnosis of inborn errors of metabolism. Also, more attention has to be paid to the quality of blood samples.

Metabolic effects of intravenous LCT or MCT/LCT lipid emulsions in preterm infants

Most lipid emulsions for parenteral feeding of premature infants are based on long-chain triacylglycerols (LCTs), but inclusion of medium-chain triacylglycerols (MCTs) might provide a more readily oxidizable energy source. The influence of these emulsions on fatty acid composition and metabolism was studied in 12 premature neonates, who were randomly assigned to an LCT emulsion (control) or an emulsion with a mixture of MCT and LCT (1:1). On study day 7, all infants received [13C]linoleic (LA) and [13C]alpha-linolenic acid (ALA) tracers orally. Plasma phospholipid (PL) and triacylglycerol (TG) fatty acid composition and 13C enrichments of plasma PL fatty acids were determined on day 8. After 8 days of lipid infusion, plasma TGs in the MCT/LCT group had higher contents of C8:0 (0.50 +/- 0.60% vs. 0.10 +/- 0.12%; means +/- SD) and C10:0 (0.66 +/- 0.51% vs. 0.15 +/- 0.17%) than controls. LA content of plasma PLs was slightly lower in the MCT/LCT group (16.47 +/- 1.16% vs. 18.57 +/- 2.09%), whereas long-chain polyunsaturated derivatives (LC-PUFAs) of LA and ALA tended to be higher. The tracer distributions between precursors and products (LC-PUFAs) were not significantly different between groups. Both lipid emulsions achieve similar plasma essential fatty acid (EFA) contents and similar proportional conversion of EFAs to LC-PUFAs. The MCT/LCT emulsion seems to protect EFAs and LC-PUFAs from beta-oxidation.

Strategies for the prevention of hereditary diseases in a highly consanguineous population

Autosomal recessive hereditary diseases are relatively common in the Saudi population. The consanguinity rate is in excess of 50% and is a practice that remains strongly embedded within Saudi culture. The impact of this practice is recognized and is being addressed. Early detection and treatment of diseases can reduce mortality and minimize morbidity. This is the basis of successful neonatal screening for inborn errors of metabolism where treatment or modification of lifestyle can modulate disease. Ultimately, understanding the genetics of these diseases will provide opportunities for prevention. Options such as prenatal screening can be used to reduce the incidence of live births with inherited diseases. However, prenatal diagnosis and associated intervention is unacceptable to wide sections of all societies. Carrier detection and genetic counselling programmes have been very successful in reducing the incidence of inherited disorders in many populations. These programmes are most successful when they are sensitive to the cultural backgrounds of populations in which they are applied. In Saudi society, premarital screening to identify carrier status and the provision of appropriate counselling has tremendous potential to prevent inherited disease.

Clinical-effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: A systematic review

Objectives: The clinical- and cost-effectiveness of tandem mass spectrometry (MS)-based neonatal screening for inborn errors of metabolism (IEM) were evaluated.

Evidence-based neonatal screening for inborn errors of metabolism

Newborn screening is on the verge of a major revolution. Screening for inborn errors of metabolism (IEM) throughout the United Kingdom (UK) commenced in the 1960s, with the introduction of testing for phenylketonuria. Subsequently, programmes for diagnosis of a number of other conditions in newborn infants, with neonatal bloodspots, have been developed. Tandem mass spectrometry is a technological advance giving rise to the potential for a major expansion in newborn screening for IEMs. This has led to the development of a study to establish whether neonatal screening should be extended to include medium chain acyl CoA dehydrogenase deficiency. A pilot newborn screening service for MCADD has commenced covering approximately half the births in the UK. Samples for tandem mass spectrometry should be collected as part of the diagnostic work-up for neonates and children presenting with a possible inborn error of metabolism, particularly fat oxidation defects.

Clinical effectiveness and cost-effectiveness of neonatal screening for inborn errors of metabolism using tandem mass spectrometry: a systematic review.

To evaluate the clinical and cost-effectiveness of tandem mass spectrometry (MS)-based neonatal screening for inborn errors of metabolism (IEM). Fourteen electronic bibliographic databases covering biomedical, science, economic and grey literature, the reference lists of relevant articles and abstracts of conference proceedings and 18 health services research-related resources. This review is an update of two previous HTA reports of neonatal screening for IEM. These reports have been updated by a systematic review of published research (between 1995 and January 2002) on neonatal screening of inherited metabolic disorders using tandem MS. This was supplemented by a search for economic literature and the application of a modelling exercise to investigate the economics of using tandem MS within a neonatal screening programme in the UK. Evidence from the reviews of IEM found that the UK screening programme for phenylketonuria (PKU) was well established and there was universal agreement that neonatal screening for PKU was justified. Of the many other disorders that can be detected by tandem MS, the best candidate condition for a new screening programme was medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency. For many other IEM that can be detected by tandem MS, robust clinical evidence was limited. Cost-effectiveness analysis using economic modelling indicated that substituting the use of tandem MS for existing technologies for the screening of PKU alone could not be justified. However, results from the economic modelling indicate that the addition of screening for MCAD deficiency as part of a neonatal screening programme for PKU using tandem MS would be economically attractive. Using an operational range of 50,000-60,000 specimens per system per year, the mean incremental cost for PKU and MCAD deficiency screening combined using tandem MS from the model was -23,312 British pounds for each cohort of 100,000 neonates screened. This cost saving is associated with a mean incremental gain of 59 life-years. Additional economic modelling using the available evidence does not support including other inherited metabolic diseases within a neonatal screening programme at present. The evidence appears to support the introduction of tandem MS into a UK neonatal screening programme for PKU and MCAD deficiency combined. Tandem MS has the potential for simultaneous multi-disease screening using a single analytical technique. Although the marginal cost of extending the programme to include other conditions may be relatively small, the application of this new technology to PKU and MCAD deficiency screening does not imply the wholesale inclusion of all disorders detectable by tandem MS. It is suggested that the primary focus of further research should be on the long-term effectiveness of treatment strategies on adverse outcomes (disabilities and impairments) under conventional management and the potential impact of early diagnosis using tandem MS.

Neonatal screening for inborn errors of metabolism: cost, yield and outcome.

OBJECTIVES. To systematically review the literature on inborn errors of metabolism, neonatal screening technology and screening programmes in order to analyse the costs and benefits of introducing screening based on tandem mass-spectrometry (tandem MS) for a wide range of disorders of amino acid and organic acid metabolism in the UK. To evaluate screening for cystic fibrosis, Duchenne muscular dystrophy and other disorders which are tested on an individual basis. HOW THE RESEARCH WAS CONDUCTED. Systematic searches were carried out of the literature on inborn errors of metabolism, neonatal screening programmes, tandem MS-based neonatal screening technology, economic evaluations of neonatal screening programmes and psychological aspects of neonatal screening. Background material on the biology of inherited metabolic disease, the basic philosophy, and the history and current status of the UK screening programme was also collected. Relevant papers in the grey literature and recent publications were identified by hand-searching. Each paper was graded. For each disease an aggregate grade for the state of knowledge in six key areas was awarded. Additional data were prospectively collected on activity and costs in UK neonatal screening laboratories, and expert clinical opinion on current treatment modalities and outcomes. These data were used to construct a decision-analysis model of neonatal screening technologies, comparing tandem MS with the existing phenylketonuria screening methods. This model determined the cost per additional case identified and, for each disease, the additional treatment costs per case, and the cost per life-year saved. All costs and benefits were discounted at 6% per annum. One-way sensitivity analysis was performed showing the effect of varying the discount rate, the incidence rate of each disorder, the number of neonates screened and the cost of tandem MS, on the cost per life-year gained. RESEARCH FINDINGS. The UK screening programmes for phenylketonuria and congenital hypothyroidism have largely achieved the expected objectives and are cost-effective. Current concerns are the difficulty of maintaining adequate coverage, perceived organisational weaknesses, and a lack of overview. For many of the organic acid disorders it was necessary to rely on data obtained from clinically-diagnosed cases. Many of these diseases can be treated very effectively and a sensitive screening test was available for most of the diseases. Except for cystic fibrosis, there have been no randomised controlled trials of the overall effectiveness of neonatal screening. Despite the anxiety generated by the screening process, there is strong parental support for screening. The effects of diagnosis through screening on subsequent reproductive behaviour is less clear. Conflicts exist between current concepts and the traditional principles of screening. The availability of effective treatment is not an absolute prerequisite: early diagnosis is of value to the family concerned and, to the extent that is leads to increased use of prenatal diagnosis, may help to reduce the overall burden of disease. Neonatal screening is also of value in diseases which present early but with non-specific symptoms. Indeed, almost all of the diseases considered could merit neonatal screening. The majority of economic evaluations failed to incorporate the health benefits from screening, and therefore failed to address the value of the information which the screening programmes provided to parents. The marginal cost of changing from present technology to tandem MS would be approximately 0.60 pounds per baby at a workload of 100,000 samples a year, and 0.87 pounds at 50,000 samples per year. The ability to screen for a wider range of diseases would lead to the identification of some 20 additional cases per 100,000 infants screened, giving a laboratory cost per additional diagnosis of 3000 pounds at an annual workload of 100,000 babies per year.(ABSTRACT TRUNCATED)

Newborn screening for inborn errors of metabolism: a systematic review.

OBJECTIVES. To establish a database of literature and other evidence on neonatal screening programmes and technologies for inborn errors of metabolism. To undertake a systematic review of the data as a basis for evaluation of newborn screening for inborn errors of metabolism. To prepare an objective summary of the evidence on the appropriateness and need for various existing and possible neonatal screening programmes for inborn errors of metabolism in relation to the natural history of these diseases. To identify gaps in existing knowledge and make recommendations for required primary research. To make recommendations for the future development and organisation of neonatal screening for inborn errors of metabolism in the UK. HOW THE RESEARCH WAS CONDUCTED. There were three parts to the research. A systematic review of the literature on inborn errors of metabolism, neonatal screening programmes, new technologies for screening and economic factors. Inclusion and exclusion criteria were applied, and a working database of relevant papers was established. All selected papers were read by two or three experts and were critically appraised using a standard format. Seven criteria for a screening programme, based on the principles formulated by Wilson and Jungner (WHO, 1968), were used to summarise the evidence. These were as follows. Clinically and biochemically well-defined disorder. Known incidence in populations relevant to the UK. Disorder associated with significant morbidity or mortality. Effective treatment available. Period before onset during which intervention improves outcome. Ethical, safe, simple and robust screening test. Cost-effectiveness of screening. A questionnaire which was sent to all newborn screening laboratories in the UK. Site visits to assess new methodologies for newborn screening. The classical definition of an inborn error of metabolism was used (i.e., a monogenic disease resulting in deficient activity in a single enzyme in a pathway of intermediary metabolism). RESEARCH FINDINGS. INBORN ERRORS OF METABOLISM. Phenylketonuria (PKU) (incidence 1:12,000) fulfilled all the screening criteria and could be used as the 'gold standard' against which to review other disorders despite significant variation in methodologies, sample collection and timing of screening and inadequacies in the infrastructure for notification and continued care of identified patients. Of the many disorders of organic acid and fatty acid metabolism, a case can only be made for the introduction of newborn screening for glutaric aciduria type 1 (GA1; estimated incidence 1:40,000) and medium-chain acyl CoA dehydrogenase (MCAD) deficiency (estimated incidence 1:8000-1:15,000). Therapeutic advances for GA1 offer prevention of neurological damage but further investigation is required into the costs and benefits of screening for this disorder. MCAD deficiency is simply and cheaply treatable, preventing possible early death and neurological handicap. Neonatal screening for these diseases is dependent upon the introduction of tandem mass spectrometry (tandem MS). This screening could however also simultaneously detect some other commonly-encountered disorders of organic acid metabolism with a collective incidence of 1:15,000.(ABSTRACT TRUNCATED)

Neonatal screening for inborn errors of metabolism in Switzerland

Neonatal screening for inborn errors of metabolism in Switzerland began in 1965 at the Children’s Hospital in Zurich with screening for phenylketonuria (PKU) by assaying for phenylalanine on dried spots of blood. In 1967, this screening was also initiated at the Central Laboratory of the Swiss Red Cross in Berne. The program then rapidly expanded. Screening for maple syrup disease (MSUD) by the Guthrie leucine assay, for homocystinuria by the Guthrie methionine assay, and for galactosemia with first the galactose assay (modified Guthrie test according to Paigen) and then for galactose-l-phosphate uridyltransferase activity (Beutler and Baluda) were added. Over the years some modifications of the program occurred: in 1973, the enzyme fluorimetric test according to Wiedemann that measures galactose was introduced in Berne for galactosemia screening and in 1974 TSH screening by RIA for congenital hypothyroidism (CH) was begun. In 1986, the enzyme immunoassay (Delfia) became the method for CH screening. Histidinemia screening with the Guthrie histidine assay was conducted as a pilot study for one year but a low prevalence, inadequate treatment and the large number of untreated cases described with normal development prompted abandonment of this screening. In 198 1 methionine screening was also abandoned, since no case of homocystinuria was identified during the 16 year screening period. However, four cases of hypermethioninemia, among them patients with fructose intolerance, were discovered with this screening. Biotinidase screening was added 1986. In 1987 leucine screening was also stopped, due to the low prevalance of MSUD and the fact that screening specimens collected on day 4 might be too late for the very early newborn diagnosis required in this

Tandem mass spectrometry: A new method for acylcarnitine profiling with potential for neonatal screening for inborn errors of metabolism

ConclusionA method for analysis of acylcarnitines in blood at physiological concentrations has been developed. Preliminary results from umbilical cord blood and neonatal blood spotted onto Guthrie cards are encouraging. This method will detect up to at least eight inherited metabolic disorders which exhibit diagnostic acylcarnitine profiles, including medium‐chain acyl‐CoA dehydrogenase deficiency. The speed and simplicity of the method permit automation with existing technology, and could enable routine neonatal screening to be carried out in an efficient and cost‐effective manner.

Follow-up study of 16 years neonatal screening for inborn errors of metabolism in West Germany.

Capillary blood samples from almost one million neonates from Baden-Württemberg were investigated for inborn errors of metabolism between 1969 and 1984 in our screening centre. Besides 7 patients with maple syrup urine disease (MSUD), 3 with homocystinuria and 18 with galactosaemia, a follow-up of the positive screening results confirmed 94 patients with phenylketonuria (PKU) and 76 with non-PKU hyperphenylalaninaemia (non-PKU HPA). The incidence of PKU is 1:10000, and that of HPA in the wider sense (PKU and non-PKU HPA) as obtained by newborn screening before further classification at 6 months 1:5532. For West Germany as a whole, the number of newly discovered cases with persistent hyperphenylalaninaemia was 1480 in the same period. The subdivision into PKU and non-PKU HPA is not yet possible from this figure. It is strongly suggested that the abnormal results of newborn screening for phenylalanine be designated as hyperphenylalaninaemia (in the wider sense) and that the terms "PKU" or "non-PKU HPA" be used only after further differentiation as carried out by us at the age of 6 months.

Inter-laboratory quality control in neonatal screening for inborn errors of metabolism.

Screening of neonates for inborn errors of metabolism has been carried out on a national level since 1969 in the Federal Republic of Germany. To raise the reliability of these routine investigations, we introduced an external quality control in March 1982. Every 2 months ten filter paper samples were sent to the screening centres in West Germany. Some of these samples have a normal and others a slightly raised content of phenylalanine, leucine, methionine and galactose. The success of this external quality control is appraised on the basis of the number of false negative results. In the course of time, screening centres in France, Israel, Italy, Japan, Switzerland, Taiwan, Turkey and Yugoslavia have also participated in these inter-laboratory quality controls.

Intellectual development in patients with untreated histidinemia: A collaborative study group of neonatal screening for inborn errors of metabolism in Japan

in the spread of malignant disease, Int J Cancer 11:704, 1973. 4. Weiss L: A pathobiologic overview of metastasis, Semin Oncol 4:5, 1977. 5. Fidler I J, Gerston DM, and Hart IR: The biology of cancer invasion and metastasis, Adv Cancer Res 28:149, 1978. 6. Gastpar H, and Weissgerber PW: The inhibition of cancer ceiI stickiness. A model for investigation of platelet aggregation inhibitors in vivo. V. The effect of penbutolol, J Med 12:1, 1981. 7. Agostino D, and Cliffton EE: Anticoagulants and the development of pulmonary metastases, Arch Surg 84:449, 1962. 8. Fisher B, and Fisher ER: Anticoagulants and tumor cell lodgment, Cancer Res 27:421, 1967. 9. Honn KV, Cicone B, and Skoff A: Prostacyclin: A potent antimetastatic agent, Science 212:1270, 1981. 10. Zeidman 1, and Buss JM: Transpulmonary passage of tumor cell emboli, Cancer Res 12:733, 1952. 11. Liotta LA, Kleinerman J, and Saidel GM: The significance of hematogenous tumor cell clumps in the metastatic process, Cancer Res 36:889, 1976. 12. Akyon MG, and Arslan G: Pulmonary embolism during surgery for a Witms tumour (nephroblastoma), Br J Anaesth 53:903, 1981. 13. Leape LL, Breslow NE, and Bishop HC: The surgical treatment of Wilms tumor: Results of the National Wilms Tumor Study, Ann Surg 187:351, 1978. 14. Gross RE: Embryoma of the kidney (Wilms tumor), in The surgery of infancy and childhood. Its principles and techniques, Philadelphia, 1953, WB Saunders Company, p 590.

BOOK REVIEWS

Book reviewed in this article:C. W. Bierman &amp; D. S. Pearlman: Allergic diseases of infancy, childhood and adolescence.C. A. Rigg &amp; R. B. Shearin: Adolescent medicine: Present and future concepts.Mary Allen Engle: Pediatric cardiovascular disease.G. S. Berenson: Cardiovascular risk factors in children.N. ‐R. Lundström: Pediatric echocardiography‐cross sectional. M‐mode and doppler.J. Öhme &amp; P. Gutjahr: Krebs bei Kindern und Jugendlichen. Ein Leitfaden zur Studium, Praxis und Klinik.H. Bickel, R. Guthrie &amp; G. Hammersen (eds): Neonatal screening for inborn errors of metabolism.D. B. Jelliffe &amp; E. F. P. Jelliffe: Advances in international maternal and child health.R. Shepherd: Physiotherapy in paediatrics. 2nd ed.