Newborn screening for inborn errors of metabolism

The aim of screening is to identify newborns who appear healthy but could be at risk of developing rare conditions that can lead to serious complications and if left untreated even death (table 1). The need for prompt and effective intervention in screen positive patients is particularly important in cases of inherited metabolic diseases (IMD). These conditions often have complex or urgent needs and evidence suggests that outcome may be strongly influenced by referral and treatment pathways. Referrals of all IMD screen positive patients are undertaken in co-ordination with a paediatric IMD centres across the UK. From early 2015 the NHS Newborn Blood Spot Screening Programme in England is offering screening for a total of nine disorders, six of which are inborn errors of metabolism. The UK screening programme is regulated by the Department of Health through the National Screening Committee (UK NSC) and clear recommendations exist regarding management and follow-up of positive screen results.The newborn screening process has evolved as understanding of the conditions, availability of diagnostic tests and treatment option has also changed. Decisions as to which conditions should be included in newborn screening programmes have become controversial with varying practices across the globe.     

Group tests for selective screening of inborn errors of metabolism

Selective screening for inherited metabolic disorders can be performed efficiently by chromatographic techniques. Each technique is suited for a well-defined group of substances present in urine, plasma and CSF. A comprehensive screening programme may involve the analysis of amino acids, organic acids, imidazoles, purines and pyrimidines, oligosaccharides and mucopolysaccharides in urine as well as very longchain fatty acids in plasma. The experienced laboratory, in close co-operation with a specialized paediatrician, will make a positive diagnosis in 6% of the refered samples, providded a careful selection of the patients is made. Our experience of 10 years of screening revealed 100 different defects; 30% of these were so-called amino acid disorders, 50% organic acidurias and the remaining 20% miscellaneous defects. Chromatographic methods are well suited for the discovery of novel defects. In this respect group screening tests will remain of major importance for the study of inborn errors of metabolism.     

Emergency treatment of inborn amino errors of amino acid metabolism detected in the neonatal period]

The indications and effects of exchange transfusion, peritoneal dialysis, osmotic diuresis and early feeding have been studied in 28 children with inborn errors of aminoacid metabolism presenting in the neonatal period. Exchange-transfusion has only a transitory and incomplete effect but it is simple and quick. Peritoneal dialysis has a remarkable and often life-saving effect because the blood levels of toxic metabolites are reduced very effectively in organic acidaemias. However the rate of removal may decline if plasma concentrations fall below a critical level (1.2 mmol/L foor leucine). If the dialysis is prolonged for more than 36 hours it may cause hypoprotidaemia. Osmotic diuresis increases the 45 ml/min. However it is of little elimination of methylmalonic acid because the renal clearance is between 15 and 45 ml/min. However it is of little value in maple syrup urine disease, propionic acidaemia or isovaleric acidaemia because the renal clearance of the toxic metabolites is so low. The early re-introduction of low protein high calorie of a low protein and high calorie diet by continuous intragastric feeding is very important. The authors propose a protocol for the treatment of babies presenting inborn errors of aminoacid metabolism in the neonatal period. Peritoneal dialysis should be started as soon as the diagnosis is considered and continued for 24 to 36 hours. An exchange of transfusion shold be undertaken before and after the dialysis, together with an osmotic diuresis if appropriate. Continuous enteral feeding should be given, the quantity being adjusted to the baby's requirements.     

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 practicipated in these inter-laboratory quality controls.Abbreviations QC quality control - BIA bacterial inhibition assay - HPLC high pressure liquid chromatography     

Selenium requirements in patients with inborn errors of amino acid metabolism and selenium deficiency

The diets of 5 patients with phenylketonuria or maple-syrup-urine disease were supplemented with yeast which was rich in selenium. For 120 days the patients received 45 g Se/day to increase the Se content of their diets to 10–12ng Se/Kjoule. Before supplementation the selenium content of serum (5–15 ng/ml) and whole blood (10–27 ng/ml), and the activity of the erythrocyte glutathione peroxidase (0.19–2.69 U₃₇/g Hb), amounted to only 10–20% of normal. The serum selenium content reached normal values within 4 weeks of supplementation, followed by normalisation of the selenium content of whole blood within 4–8 weeks. Restoration of the activity of erythrocyte glutathione peroxidase took 9 to 15 weeks —the red cell life span. There was a significant positive correlation between the selenium content of the erythrocytes and the activity of erythrocyte glutathione peroxidase.With support of Deutsche Forschungsgemeinschaft     

深入开展遗传性代谢缺陷病的筛查诊断工作

随着人类生活环境的改善、医疗保健水平的逐步提高 ,由感染、营养等因素导致的疾病显著减少 ,遗传性疾病相对日趋重要。遗传性代谢缺陷所致疾病种类繁多 ,虽单一病种发病率较低 ,但其总体发病率甚高。对遗传性代谢缺陷病 (ｉｎｂｏｒｎｅｒｒｏｒｓｏｆｍｅ ｔａｂｏｌｉｓｍ ,ＩＥＭ )进行及时筛查诊断 ,并正确治疗 ,是衡量国家医学发展水平的重要指标。对于我国实行优生优育国策和提高人口素质意义重大。遗传性代谢缺陷病是由于人体内某些酶、膜或受体等生物合成的遗传缺陷 ,引起细胞和体液内毒性中间代谢产物积聚或必需代谢产物的缺乏 ,…     

新生儿遗传性代谢病筛查的回顾和展望

遗传性代谢病(inbornerrorofmetabolism,IEM)是一类涉及氨基酸、有机酸、脂肪酸、尿素循环、碳水化合物、类固醇、金属等多种物质代谢的疾病[1,2]。其种类繁多,是儿科临床的疑难杂症。虽然其单一病种患病率较低,但总体发病率较高,对人口素质、家庭乃至社会的发展构成了极大的威胁。其诊断主要依赖实验室的特异性检查。我国每年出生约2000万新生儿,仅高苯丙氨酸血症(包括苯丙酮尿症)这类疾病,每年就新增患儿1600～1800例。面对这类危害严重的疾病,是等待其发病,产生严重后果之后再进行治疗,还是在发病前即给予干预?显然,是后者对患者、家庭…     

Assessment of the perimortem protocol in neonates for the diagnosis of inborn errors of metabolism

AimTo assess the efficacy of the perimortem protocol in neonates with suspected inborn errors of metabolism (IEM).MethodsRetrospective analysis of medical records from January 2000 through December 2007 was performed. Only neonates (≤1 month of life) in whom the perimorterm protocol was applied were included in the study. The samples were collected following the instructions of our exitus kit, which contains the perimortem protocol and the material for the extraction of biological specimens.ResultsAmong the 42 neonates studied, in 28 an IEM was suspected during hospitalization and 15 (36%) were diagnosed with IEM. Mitochondrial disorders were the most frequent diagnosis (8 patients), followed by urea cycle disorders (3 patients), organic acidemias (2 patients), one patient with congenital disorder of glycosylation (CDG type Ia), and one patient with molybdenum cofactor deficiency. Sepsis and other life-threatening conditions appeared to have a biochemical profile very similar to IEM.ConclusionThis protocol was especially useful for collecting all biological samples in patients with rapidly fatal evolution with a non-specific diagnostic suspicion, and to collect special tissues in previously diagnosed patients. However, only the combination of clinical and biochemical data could lead to a diagnosis which would be confirmed by enzymatic/genetic studies.