Neonatal Screening For Phenylketonuria Research Articles

Random forest classifier improving phenylketonuria screening performance in two Chinese populations.

Phenylketonuria (PKU) is a genetic disorder with amino acid metabolic defect, which does great harms to the development of newborns and children. Early diagnosis and treatment can effectively prevent the disease progression. Here we developed a PKU screening model using random forest classifier (RFC) to improve PKU screening performance with excellent sensitivity, false positive rate (FPR) and positive predictive value (PPV) in all the validation dataset and two testing Chinese populations. RFC represented outstanding advantages comparing several different classification models based on machine learning and the traditional logistic regression model. RFC is promising to be applied to neonatal PKU screening.

Диференціальна діагностика фенілкетонурії і порушень обміну птеринів у хворих із гіперфенілаланінемією

Актуальність. Гіперфенілаланінемія (HPA), або підвищення концентрації фенілаланіну (Phe) в крові, є наслідком порушення перетворення фенілаланіну в тирозин. Яскравим прикладом цього клінічного стану є класична фенілкетонурія (PKU). У 1970-х роках стало зрозуміло, що в частини хворих із PKU, незважаючи на ефективну дієтотерапію, розвивалися тяжкі неврологічні порушення. Ці випадки верифікували як атипові, або злоякісні, варіанти PKU, що, як було досліджено, спричинялось мутаціями в генах, які регулюють синтез та регенерацію тетрагідробіоптерину (ВН4). Порушення метаболізму тетрагідробіоптерину, або ВН4-дефіцитні синдроми, — гетерогенна група спадкових захворювань ЦНС, спричинених дефіцитом моноамінів-нейротрансмітерів, які в низці випадків супроводжуються гіперфенілаланінемією. ВН4-дефіцитні синдроми, які є рідкісними вродженими порушеннями метаболізму, спричиненими недостатністю нейротрансмітерів, за відсутності своєчасного лікування призводять до прогресуючої, нерідко летальної, енцефалопатії. Упровадження в медичну практику ранньої диференціальної клінічної та лабораторної діагностики гіперфенілаланінемій дозволить запобігти розвитку летальних енцефалопатій та суттєво підвищити ефективність їх лікування. Матеріали та методи. Були обстежені 59 пацієнтів із діагнозом PKU віком від 2 до 16 років. Гіперфенілаланінемія була загальним симптомом і встановлена в усіх обстежених пацієнтів. Усім хворим було проведено молекулярно-генетичне обстеження на панель мутацій у гені РАН (R408W, Y414C (12-й екзон), R158Q (5-й екзон), Ivs10nt546 (5-й інтрон), Ivs12nt1 (12-й інтрон), R252W, R261W, R261Q, R261X, G272X, P281L, S273F (7-й екзон). Усі хворі були обстежені на спектр птеринів (біоптерин та неоптерин) в крові та сечі. У 4 пацієнтів із вираженими неврологічними симптомами додатково визначали активність дигідроптеринредуктази в сухих краплях крові. Двом пацієнтам проводилося вимірювання концентрації гомованілової кислоти та 5-гідроксііндолоцтової кислоти в спинномозковій рідині методом високоефективної рідинної хроматографії. Усі пацієнти лікувались за допомогою дієтотерапії з використанням продуктів спеціалізованого лікувального харчування. Результати. 59 пацієнтів із гіперфенілаланінемією були обстежені на птериновий профіль. У 55 пацієнтів був установлений діагноз PKU, у 4 пацієнтів із прогресуючим ураженням нервової системи та порушенням птеринового профілю було встановлено діагноз ВН4-дефіцитних синдромів: 3 пацієнти — із діагнозом «PTPS-синдром», 1 пацієнт — «DHPR-синдром». Основні клінічні прояви ВН4-дефіцитних синдромів у виявлених пацієнтів були такими: затримка розумового розвитку, судоми, прогресування екстрапірамідних симптомів, порушення тонусу м’язів і пози, ковтання, гіперсалівація. Перші симптоми виникали частіше протягом перших місяців життя дитини. Головним біохімічним маркером на початку захворювання була гіперфенілаланінемія. При застосуванні дієтотерапії рівень Phe швидко досягав рекомендованих безпечних для нервової системи значень, але хвороба прогресувала. Висновки. Гіперфенілаланінемія — основний прояв гетерогенної групи рідкісних нейрометаболічних захворювань, які вимагають подальшої діагностичної верифікації. У новонароджених, у яких під час проведення масового неонатального скринінгу на фенілкетонурію виявлений підвищений рівень фенілаланіну, необхідно застосовувати додатковий діагностичний протокол (визначення птеринового профілю в крові та сечі, обов’язкове дослідження активності дигідроптеринредуктази у сухій краплі крові). Дослідження птеринів необхідне в пацієнтів із раніше встановленим діагнозом «фенілкетонурія» за неефективності дієтотерапії, прогресування когнітивних і неврологічних порушень, зниження тонусу м’язів, виникнення судомного синдрому, наявності екстрапірамідних симптомів. Рання діагностика ВН4-дефіцитних синдромів та своєчасно розпочате лікування дозволяють суттєво покращити стан хворих. Для деяких ВН4-дефіцитних синдромів гіперфенілаланінемія не характерна, що унеможливлює раннє виявлення таких пацієнтів під час неонатального скринінгу. Тому виявлення прогресуючих неврологічних симптомів у пацієнтів віком до 1 року й у ранньому дитинстві, які супроводжуються втратою когнітивних функцій на тлі м’язової гіпотонії, дистонічних порушень і судом, зумовлює необхідність дослідження птеринового профілю в крові й сечі.

Molecular diagnosis of phenylketonuria in 157 Chinese families and the results of prenatal diagnosis in these families.

Molecular diagnosis of phenylketonuria in 157 Chinese families and the results of prenatal diagnosis in these families.

Molecular Analysis of PKU-Associated PAH Mutations: A Fast and Simple Genotyping Test.

Neonatal screening for phenylketonuria (PKU, OMIM: 261600) was introduced at the end of the 1960s. We developed a rapid and simple molecular test for the most frequent phenylalanine hydroxylase (PAH, Gene ID: 5053) mutations. Using this method to detect the 18 most frequent mutations, it is possible to achieve a 75% detection rate in Italian population. The variants selected also reach a high detection rate in other populations, for example, 70% in southern Germany, 68% in western Germany, 76% in Denmark, 68% in Sweden, 63% in Poland, and 60% in Bulgaria. We successfully applied this confirmation test in neonatal screening for hyperphenylalaninemias using dried blood spots and obtained the genotype in approximately 48 h. The method was found to be suitable as second tier test in neonatal screening for hyperphenylalaninemias in neonates with a positive screening test. This test can also be useful for carrier screening because it can bypass the entire coding sequence and intron–exon boundaries sequencing, thereby overcoming the questions that this approach implies, such as new variant interpretations.

Prevention of phenylketonuria as an example of the system of preventive measures in orphan diseases

In the article on the example of phenylketonuria, modern aspects of the prevention of rare diseases are considered. Phenylketonuria is a hereditary disease, in the absence of treatment characterized by progressive mental retardation, epilepsy, severe dermatitis, but with early diagnosis and diet therapy, clinical manifestations of the disease can be avoided. Primary prophylaxis of phenylketonuria is aimed at preventing the appearance of a sick child in the family and is most effectively carried out with the help of medical genetic counseling. Secondary prophylaxis consists in prenatal diagnosis of pathology, as well as neonatal screening for phenylketonuria. Tertiary prevention includes treatment, abilitation and rehabilitation of patients. In practice, these approaches are closely interrelated, which is reflected in the article. The role of pregravid preparation of women with phenylketonuria to prevent the syndrome of «maternal phenylketonuria» in a future child is underlined.

Overview of neonatal screening for phenylketonuria in Brazil

Objectives: To present an overview of neonatal screening for phenylketonuria in Brazil. Methodology: An electronic search was made in LILACS, employing the terms “neonatal screening” and “Brazil” and “Phenylketonuria”. Ten papers were selected for reading because they met the established criteria. Results: The studies were conducted in the states of Sergipe, Tocantins, Bahia, Rio de Janeiro, Santa Catarina, Mato Grosso and São Paulo, and the coverage ranged from 32.3% to 95%. Publications on the situation of neonatal screening for phenylketonuria are scarce in several states of our country, making it difficult to generalize and compare the data. Conclusions: Screening for phenylketonuria needs to be improved, especially with regard to the age of starting treatment. It is a complex public health program that requires greater attention to fully achieve its goals and increase its effectiveness

ADHD, autism and neuroradiological complications among phenylketonuric children in Upper Egypt.

The aim of this study is to evaluate the neuropsychological status in a cohort of children with early and continuously treated phenylketonuria in Assiut, Upper Egypt. The study was implemented in seventy-eight phenylketonuria (PKU) children. Only 34 patients met the inclusion criteria. Investigated patients were evaluated according to detailed history, neurological examination, Childhood Autism Rating Scale, full scale Intelligence Quotient, attention deficit hyperactivity disorder, electroencephalography and magnetic resonance imaging (MRI). This study concluded that the prognosis for early diagnosed children with PKU treated from the first weeks of life is generally good. However, they are at increased risk for neurological complications and behavioral problems. So, neonatal screening for PKU is highly recommended in Egypt, for early detection and management. In addition, neuropsychological and MRI assessments in PKU children should be done.

Child Neurology: Paroxysmal stiffening, upward gaze, and hypotonia

Sepiapterin reductase deficiency (SRD) is a dopa-sensitive neurotransmitter disorder, caused by mutation of the SPR gene located on chromosome 2p14-p12.1 To date, 31 patients with 14 mutations have been diagnosed (BIODEF database, update November 2010, www.biopku.org). While classic tetrahydrobiopterin deficiencies present with hyperphenylalaninemia and deficiency of monoamine neurotransmitters, SRD is typically associated with normal phenylalanine levels in blood and pterins in urine2 and not detectable by neonatal screening for phenylketonuria. This implies how important it is to diagnose this condition clinically, in order to provide timely and proper treatment. A summary of the pathophysiology and biochemical pathway is provided by Bonafe et al.2 With the following case report and review of 21 published cases,2,–,10 we elucidate the clinical features of SRD as well as the diagnostic strategy and therapeutic approach. We present a 5-month-old girl, the first and only child born to consanguineous Turkish parents. The parents described the girl's abnormal movements at 3 months of age as sudden stiffening of the whole body, extension of the extremities, upward gaze, and chewing movements lasting for several minutes often after meals, which we also could observe during her hospital stay. Pregnancy and delivery were uneventful. Birthweight, length, and head circumference were within normal ranges. During EEG, a few episodes with chewing movements could be recorded, but no epileptic discharges were evident. The brain MRI was unremarkable. We suspected gastroesophageal reflux and started therapy with omeprazole. The parents reported that the episodes diminished. At 8 months of age, the patient was readmitted because the crises recurred with an increased frequency and duration of up to 25 minutes. During the episodes, the patient revealed circling movements of the hands and rhythmic tremor of the tongue in addition to the previously mentioned symptoms. Remarkably, the …

Evaluation of the diagnostic efficacy of enzyme colorimetric assay compared to tandem mass spectrometer in neonatal screening for phenylketonuria

The present study aims at evaluating the diagnostic efficacy of an enzyme-based colorimetric method (Enzolve’s kit) for quantitative determination of phenylalanine in comparison to the gold standard tandem mass spectrometer (MS/MS). This study was conducted on 155 neonates aged 3–7 days attending the neurometabolic clinic of Cairo University Children Hospital as a part of the neonatal screening program. Samples of patients were selected according to their phenylalanine levels obtained by MS/MS. Group 1 included 49 normal neonates with phenylalanine level 150 μmol/L selected to cover the analytical range of the commercial kit. Blood samples on filter paper cards were reassayed by an enzyme-based colorimetric test kit. On correlating the phenylalanine level assayed using enzyme-based colorimetric technique using Enzolve kit and MS/MS technique, r = 0.83 and P < 0.01 were found. Also it yielded a regression equation; phenylalanine level assayed using Enzolve kit = (30.6 + 0.98 × phenylalanine level assayed using MS/MS). Upon detecting positive PKU cases using Enzolve’s kit at a phenylalanine cutoff level of 127 μmol/L and by MS/MS technique at a cutoff level of 150 μmol/L, a statistically significantly association (P = 0.000) and an agreement with kappa of 0.64 (P = 0.000) were produced. On constructing ROC curve for assay of phenylalanine using Enzolve’s kit, an area under the curve of 0.963 was found. The Enzolve kit is a simple ,cost-effective, rapid with an accepted overall accuracy test that can be used preliminary to the use of the more sophisticated and expensive MS/MS in screening as well as monitoring patients with PKU.

Cost Effectiveness of Establishing a Neonatal Screening Programme for Phenylketonuria in Libya

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. To estimate the cost effectiveness of neonatal screening for PKU compared with no neonatal screening in Libya. 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. 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. 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.

The role of intelligence in phenylketonuria: A review of research and management

Phenylketonuria (PKU) results in profound intellectual disability in untreated individuals and more subtle cognitive deficits in individuals treated early and continuously. The assessment of intellectual functioning has been an important outcome variable and the focus of extensive research. Since the implementation of neonatal PKU screening programs in the 1960s, research on intellectual functioning in individuals with PKU has played a significant and positive role in guiding therapy and improving results. This is a literature review examining the relationship between intellectual outcome and treatment parameters including initiation of treatment, duration of treatment, and blood phenylalanine (Phe) levels from infancy through adulthood. While current PKU treatment practices have eliminated severe neurological and cognitive impairment, evidence suggests that intellectual functioning, although typically within the average range when PKU is treated early and continuously, may not be maximized under the current definition of well-controlled PKU, which is based on blood Phe levels. Future research assessing intellectual and neurocognitive outcome in PKU will enhance the development of new treatment strategies.

Measurement of functional independence level and falls-risk in individuals with undiagnosed phenylketonuria.

The aim of the study was to determine the level of functional independence in adult patients with previously undiagnosed or untreated phenylketonuria (PKU). The study was conducted among 400 intellectually impaired adult residents of Social Welfare Homes in South-Eastern Poland born prior to the introduction of neonatal PKU screening programs. PKU was screened by filter paper test using tandem mass spectrometry methods, and confirmed by gas chromatography-mass spectrometric analysis of PKU organic acids in urine. Degree of functional independence included the assessment of activities of daily living (Barthel Index) and measures of balance and gait (Tinetti scale). Eleven individuals with previously untreated PKU were identified whereby eight presented with moderate disability and three with mild disability. Six had a high risk of falls and five had a moderate risk of falls. This study indicates that there is considerable number of undiagnosed PKU patients within the Polish population who require assessment and management in order to reduce the impact of the neurological and neuropsychiatric problems associated with the condition. Appropriate therapy for those with undiagnosed PKU should, in particular, address the risk of falls.

Article Commentary: The contributions of Louis I Woolf to the treatment, early diagnosis and understanding of phenylketonuria

Early diagnosis of phenylketonuria (PKU) became a goal worth pursuing following demonstration of the efficacy of the dietary treatment conceived by Louis I Woolf. This paper narrates the history of this treatment, describes Woolf's role in the establishment of neonatal PKU screening and surveys his other contributions to our understanding of this condition. If Woolf, Centerwall, Baird and Berry had waited until all the scientific evidence about PKU that is now at our disposal had been brought to light, there would still be no neonatal screening programmes.

TETRAHYDROBIOPTERIN PATHWAY DEFICITS IN SCHIZOPHRENIA

DOPA responsive dystonia (DRD) and sepiapterin reductase (SR) deficiency are inherited disorders of tetrahydrobiopterin (BH4) metabolism characterized by the signs and symptoms related to monoamine neurotransmitter deficiency. In contrast to classical forms of BH4 deficiency DRD and SR deficiency present without hyperphenylalaninemia and thus cannot be detected by the neonatal screening for phenylketonuria (PKU). While DRD is mostly caused by autosomal dominant mutations in the GTP cyclohydrolase I gene (GCH1), SR deficiency is an autosomal recessive disease. The most important biochemical investigations for the diagnosis of these neurological diseases includes CSF investigations for neurotransmitter metabolites and pterins as well as neopterin and biopterin production in cytokine-stimulated fibroblasts. Discovery of SR deficiency opened new insights into alternative pathways of the cofactor BH4 via carbonyl, aldose, and dihydrofolate reductases. As a consequence of the low dihydrofolate reductase activity in the brain, dihydrobiopterin intermediate accumulates and inhibits tyrosine and tryptophan hydroxylases and uncouples nitric oxide synthase (nNOS), leading to neurotransmitter deficiency and possibly also to neuronal cell death.

Le dépistage néonatal généralisé par des tests d'analyse biologique

Implementation of a generalized screening program for neonatal diseases obeys precise guidelines. The disease must be severe, recognizable at an early stage, accessible to an effective treatment, detected with a non expansive and widely applicable test and it must represent an important health problem. In case of positive results, treatment or prevention shall be offered immediately and any screening program has to be regularly evaluated. There is in France since 1978 a national screening program that depends on a private association (“Association française pour le dépistage et la prévention des handicaps de l'enfant”) and is supervised by the “Caisse nationale d'assurance maladie” and the “Direction Générale de la Sante”. Presently, five diseases are included in the screening program: phenylketonuria, hypothyroidism, congenital adrenal hyperplasia, cystic fibrosis and sickle cell disease, the latter only in at risk newborns. Toxoplasmosis represents a particular problem because screening takes place only in children of mothers that have not been controlled during their pregnancy or in case of seroconversion. Neonatal screening of phenylketonuria and hypothyrodism is unanimously recommended. That of congenital adrenal hyperplasia is approved in most countries. The cases of sickle cell disease and cystic fibrosis are more complex because: 1) all the children that carry the mutations are not affected with a severe disease; 2) there is no curative treatment; 3) parents given information are made anxious, sometimes wrongly if the disease is mild or asymptomatic. The supporters of the screening insist on the interest of an early diagnosis which makes longer the life time of these children, the possibility for the parents to utilize prenatal screening in case of a future pregnancy, and the information given to the heterozygous carriers following a familial screening. The question is raised of the extension of neonatal screening to other diseases. This is now possible due to technical progresses such as the tandem mass spectrometry that can detect about 50 diseases in an only testing. In addition of its cost and of the difficulty to ensure an efficient organization, increasing the number of the screened diseases will raise ethical problems including how the parents will be informed of an incurable disease or a late-onset disease or an entirely asymptomatic disease. It is unanimously admitted that only mendelian diseases should be detected excluding genetic polymorphisms. Analysis of the present situation suggests the following developments: 1) to actualize the guidelines for deciding of a new neonatal screening; 2) to experiment on a local scale any new screening before its extension to the whole country; 3) to create an evaluation committee including paediatricians and epidemiologists and to evaluate on the long term the future of the children; 4) to precisely define the conditions in which the heterozygous carriers will be informed following a familial investigation; 5) to store in a resource biological centre the blood samples in order to utilize this bank for epidemiology studies.

Le dépistage néonatal généralisé par des tests d’analyse biologique

Implementation of a generalized screening program for neonatal diseases must obey precise rules. The disease must be severe, recognizable at an early stage, amenable to an effective treatment, detectable with a non expensive and widely applicable test; it must also be a significant public health problem. Subjects with positive results must be offered immediate treatment or prevention. All screening programs must be regularly evaluated. In France, since 1978, a national screening program has been organized by a private association ("Association française pour le dépistage et la prévention des handicaps de l'enfant") and supervised by the "Caisse nationale d'assurance maladie" and "Direction Générale de la Sante". Five diseases are now included in the screening program: phenylketonuria, hypothyroidism, congenital adrenal hyperplasia, cystic fibrosis and sickle cell disease (the latter only in at-risk newborns). Toxoplasmosis is a particular problem because only the children of mothers who were not tested during the pregnancy or who seroconverted are screened. Neonatal screening for phenylketonuria and hypothyrodism is unanimously recommended. Screening for congenital adrenal hyperplasia is approved in most countries. Cases of sickle cell disease and cystic fibrosis are more complex because--not all children who carry the mutations develop severe forms;--there is no curative treatment;--parents may become anxious, even though the phenotype is sometimes mild or even asymptomatic. Supporters of screening stress the benefits of early diagnosis (which extends the life expectancy of these children, particularly in the case of sickle cell disease), the fact that it opens up the possibility of prenatal screening of future pregnancies, and the utility of informing heterozygous carriers identified by familial screening. Neonatal screening for other diseases is under discussion. Indeed, technical advances such as tandem mass spectrometry make it possible to detect about 50 diseases in a single run. In addition to issues of cost and organization, any increase in the number of screened diseases will raise ethical problems, such as how to inform parents of an incurable disease, a late-onset disease, or an entirely asymptomatic disorder. It is unanimously agreed that only Mendelian diseases should be screened for (excluding genetic polymorphisms). Analysis of the present situation suggests the following changes:--guidelines for choosing new diseases for neonatal screening should be updated;--all new screening programs should be tested locally before nationwide implementation;--an evaluation committee of paediatricians and epidemiologists should be created, and the children's long-term outcome should be studied;--the conditions in which heterozygous carriers are informed after familial investigations need to be precisely defined;--blood samples should be banked for epidemiological studies.

Economic evaluation of neonatal screening for phenylketonuria and congenital hypothyroidism

To evaluate the costs and benefits of neonatal screening for phenylketonuria (PKU) and congenital hypothyroidism (CH). Neonatal screening for PKU and CH is common throughout the developed world. It represents a model of preventive care in that the screening procedure is simple and intellectual disability is otherwise irreversible. Changes in treatment and care, and in particular the advent of maternal PKU, require regular evaluation of a programme that also impacts on a large healthy population. Costs of screening were based on the programme provided within Western Australia. Costs averted were derived using patterns of care currently adopted in Western Australia and applied according to historical patterns of intellectual disability for each condition. A net saving of dollar A2.9 million is attributable to the programme annually. The economic benefits derive from the prevention of intellectual disability which otherwise incurs costs throughout the life of the affected individual. Maternal PKU represented a minor proportion of overall costs. Sensitivity analysis showed that the cost savings were robust, given changes in the levels of intellectual disability, but varied according to the discount rate. The result of a net saving was evident under all assumptions. Neonatal screening for PKU and CH is a cost saving use of resources and the emergence of maternal PKU has not had a significant effect on the economic outcomes.

Multiple positive results during a neonatal screening program: a retrospective analysis of incidence, clinical implications and outcomes

Neonatal screening programs perform different screening tests on the same blood-spot sample collected on a Guthrie card. We retrospectively investigated the incidence of multiple positive results as well as the outcomes and the physical characteristics of newborns with more than one positive result for phenylketonuria (PKU), congenital hypothyroidism (CH) and congenital adrenal hyperplasia (CAH). Neonatal screening was performed on blood-spot for PKU (phenylalanine concentration by fluorescent ninhydrine method), for CH (simultaneous total thyroxin (tT4) and thyroid-stimulating hormone (TSH) levels by fluoroimmunometric assay); and for CAH (17-hydroxyprogesteron level by fluoroimmunometric assay). During three years of screening, 39 newborns (37 preterms) showed multiple positive results at screening tests (incidence 1:6387). The most frequent positive results were the combinations of CH and CAH (25/39) and PKU and CH (12/39). At recall, only two newborns were confirmed positive and each for only one disease: one, premature baby, for PKU from the PKU and CH combination; the other, born at term, for CAH from the CH and CAH combination. Multiple positive results are a rare observation at neonatal screening for PKU, CH and CAH, more frequently observed in preterm babies. However, multiple positive results must not be overlooked because of true positive results at recall.

Screening for phenylketonuria and congenital hypothyroidism in 5.8 million neonates in China

To summarize neonatal screening for phenylketonuria (PKU) and congenital hypothyroidism (CH) in China, to further clarify incidence of the two kinds of diseases in newly-born babies, and to explore issues in neonatal screening and their solutions. Neonatal screening for PKU and CH was conducted by 39 neonatal screening centers all over the country, sponsored by the Group of Neonatal Screening, Chinese Society of Child Health Care, Chinese Preventive Medical Association and the Center for Neonatal Screening Quality Control Laboratory, National Center for Clinical Laboratories (NCCL). In each infant a heel prick blood sample was collected at 72 hours postnatal onto standard filter paper. PKU was screened by bacterial inhibition assay and fluorometric method, and CH was screened by TSH measurement by time-resolved fluorescence immunoassay (TRFIA), fluorescence enzyme immunoassay (FEIA) and enzyme immunoassay (EIA). From 1985 to 2001 in China, totally of 5 817 280 newborns were screened for PKU, 522 cases of PKU detected with an incidence of 1:11 144, and 5 524 019 newborns were screened for CH, 1 836 cases of CH detected with an incidence of 1:3 009. Annual average number of newborns screened for congenital genetic diseases was increased by 45.5% in recent six years. Neonatal screening was developed quickly in China in recent years, especially in some developed cities, such as Shanghai with a coverage of 98.3% in 2001. But, its coverage was about only 10% in China as a whole. In development of neonatal screening, it is necessary to attach more importance to quality of screening and increasing coverage of screening, as well as gradual development of new screening techniques for other neonatal preventable diseases, in addition to PKU and CH, and their application, and improvement of level of child health care in China.

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.