Classical homocystinuria (HCU) due to cystathionine β-synthase deficiency is an inherited disorder of methionine metabolism. HCU has a reported worldwide prevalence ranging from 1 in 344 000 to 1 in 65 000 in Ireland. Molecular studies indicate a much higher incidence of between 1 in 6500–20 000 and as high as 1 in 1800 in a highly consanguinous Qatari population. Recognized complications from the untreated disease affect four major systems: ocular (ectopia lentis), skeletal (osteoporosis), vascular (thromboembolic events) and central nervous systems (intellectual disabilities). The natural history is such that 82% will have ectopia lentis by the age of 10 years, 27% will have had a clinically detected thromboembolic event by the age of 15 years, 64% will have radiological evidence of spinal osteoporosis by the age of 15 years and 23% will not survive to the age of 30 years. Long-term outcome studies on a group of Irish patients detected by newborn screening and commenced on early treatment document that homocysteine-lowering treatment is effective in preventing complications and normal intelligence is achieved. Vascular events are the major cause of morbidity and mortality. The results from a multicentre study show that homocysteine-lowering therapy is effective in significantly reducing the vascular risk during treatment. In the half-century since its discovery in 1962, homocystinuria with its devastating complications has been discovered to be a treatable condition, with the best possible clinical outcome in cases detected early by newborn screening.

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Aim. To present the lifework of Prof. Dr. med. Dr. h. c. mult. Erich Saling, obstetrician and perinatologist, with regard to his impact on the history and development of perinatal medicine. Methods. Discussion of some of Erich Saling's most important scientific contributions as well as his contributions to the development of perinatal medicine as a new field of medicine by founding societies and journals, organizing congresses, etc. Results. Fetal blood analysis, performed by Erich Saling in 1960 (and published in 1961), was the first direct approach to the human fetus that could already be used in routine clinical practice. Erich Saling also developed amnioscopy and made several other important contributions, most of them aiming to reduce the infant mortality and morbidity rate and the number of preterm births. In addition to his scientific contributions, Erich Saling played an important role in the development of perinatal medicine by founding the very first national and international scientific associations – in 1967 he founded the German Society of Perinatal Medicine and in 1968 he founded the European Association of Perinatal Medicine. He also organized the first scientific congresses – in 1967 the first national congress and in 1968 the first European Congress of Perinatal Medicine that was held in Berlin – and was involved in the organization of many scientific meetings. Erich Saling also published the first book concerning the infant within obstetrics and founded the very first journal in this field, entitled Journal of Perinatal Medicine. Conclusion. Erich Saling can truly be regarded as one of the main pioneers of perinatal medicine.

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Background. The epidemiology of inborn errors of purine and pyrimidine (PnP) metabolism in developing countries is unknown. Facilities for the analysis of PnP metabolites in Malaysia are currently lacking owing to limited resources and expertise in this field. To achieve the correct diagnosis for these disorders is a time-consuming and costly process. The tests are not readily available for our seriously ill patients. Objective. The primary aim of this study was to establish a simple and cost-effective method using rapid-resolution high-performance liquid chromatography (RR-HPLC) for the diagnosis of inborn errors of PnP metabolism among Malaysian children who are suspected to have disorders of PnP metabolism. The secondary aim was to study the epidemiology and biochemical phenotype in our patients. Methods. The analytical method was developed using a reversed-phase high-performance liquid chromatography (RP-HPLC) with C₁₈ column coupled to a diode array detector for simultaneous determination of the PnP metabolites. A total of 1499 patients were studied. 556 healthy children and adults were recruited as normal controls to establish age-related reference ranges and urinary uric acid – creatinine ratios. Results. The method established was able to separate up to 18 PnP metabolites in a single analytical run time of 28 minutes. Good precision (coefficient variation of <2%) and a linearity range up to 2000 μmol/l (r²>0.9993) was also observed. Recoveries were 99.8–108.4% for the tested metabolites. The detection limit of 2.18–12.5 μmol/l was adequate to detect patients with slightly increased concentration of these metabolites. Age-related reference ranges among our population were established and were used for diagnostic interpretation related to this group of disorders. Twelve patients (0.8%) were diagnosed, including four with combined molybdenum cofactor deficiency, three with isolated sulphite oxidase deficiency, two with thymidine phosphorylase deficiency, one with adenylosuccinate lyase deficiency and two with dihydropyrimidine dehydrogenase deficiency. Four cases of urea cycle defects were also detected. Conclusions. The method that we developed was proven to be efficient, reliable and sensitive enough to be applied in our clinical laboratory for the diagnosis of inborn errors of PnP metabolism disorders among Malaysian children. Early recognition and correct diagnosis allowed prompt treatment, better outcome and genetic counselling.

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Oesophageal atresia (OA) is a congenital anomaly with an interruption of the oesophageal continuity with or without tracheo-oesophageal fistula (TOF). Type IIIB is the most common (85%) and shows hypersalivation post partum followed by recurrent attacks of suffocation as a consequence of recurrent aspirations. A nasogastric tube cannot be passed and radiodiagnostic investigations visualize the blind-ending upper oesophageal pouch. Surgical management includes the closure of the TOF and primary anastomoses of the blind ends. In case of a long gap, narrowing and delayed primary repair can be performed. Prognosis and survival are related to birthweight and to associated major cardiac defects. In patients with congenital duodenal atresia (DA), the complete interruption of the bowel continuity can be diagnosed antenatally by sonography and post partum by plain abdominal radiographs, showing the classic ‘double bubble’ sign. The obstruction can be due to an intraluminal web, complete separation of the duodenal ends, or caused by an extraluminal pancreas annulare or Ladd bands seen in the case of malrotation. Infants show bilious vomiting after birth and consecutive metabolic alkalosis. The surgical method to bypass the obstruction is a duodenoduodenostomy. Mortality rate is <5%. Jejunoileal atresia (JIA) is a common cause of neonatal intestinal obstruction. More than 90% of patients have a single atresia. In the case of multiple atresias, most of the children are born prematurely with low birthweight. JIAs can be suspected prenatally via sonography. Main symptoms are bilious vomiting, a distended abdomen and signs of life-threatening sepsis in the case of bowel perforation. Surgical treatment has the aim of reconstructing bowel continuity and saving as much bowel length as possible to avoid the complications of short bowel syndrome and malabsorptive syndromes. Anorectal malformations (ARMs) comprise not only defects of the lowest part of the intestinal tract but also of the urinary and genital tract. In minor low types, the rectum and its fistula open into the perineal region and primary surgical repair by posterior sagittal approach is performed. In higher, more complex types, meconium passes into the male urethra or bladder or into the female vagina. In these cases, a colostomy and staged repair has to be performed. Complex types of ARM have a poorer outcome regarding bowel and urinary control. The original version of this article was published in December 2012 and this updated version was published online in February 2013.

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Aims. Middle Eastern cultures are tribal and heavily consanguineous. Marriage between cousins has been part of the culture for millennia, leading to ‘founder’ effect and a large number of autosomal diseases. In Saudi Arabia, like other Middle Eastern countries, first-cousin marriages account for almost 60–70% of all marriages, leading to uniquely common disorders which are either rare by Western standards or completely unknown. Most of these disorders lead to physical and mental handicap; affected children have poor development and reduced mental capacity. Therefore, accurate diagnosis of the exact molecular defect and prevention is the main aim of our management of these children. Material and Methods. Applying personalized genomics for the diagnosis, prevention and treatment of our patients with genetic metabolic disorders in accordance with our Islamic ethical guidelines is our most important strategy in managing our patients. An example of such an application in Saudi Arabia is the previously described novel autosomal recessive osteolysis/arthritis syndrome, multicentric osteolysis nodulosis with arthritis (MONA) (NOA) (Al-Aqeel Syndrome) (MIM#605156), a distinctive autosomal recessive multicentric osteolysis in Saudi Arabian families with distal arthropathy of the metacarpal, metatarsal and interphalangeal joints, with ultimate progression to the proximal joints with decreased range of movements and deformities with ankylosis and generalized osteopenia. In addition, patients have large, painful to touch palmar and plantar pads; they are also found to have hirsutism and mild dysmorphic facial features including proptosis, a narrow nasal bridge, bulbous nose and micrognathia. Results. The syndrome is caused by inactivating mutations in the MMP2 gene, for which we have established prevention and therapeutic strategy. We have also established with other colleagues the exact genetic defect after establishing the accurate diagnosis and the systematic prevention of genetic disorders by pre-implantation genetic diagnosis with a success in over 160 cases in which the result was the birth of normal children, including patients with Al-Aqeel Sewairi syndrome. We are also establishing stem cell therapy for Genetic Metabolic disorders, with Al-Aqeel Sewairi syndrome as the prototype for such promising modality for treatment of mental and physical handicap in children. These strategies must be done in accordance with our ethical and religious background, with priorities given to the rights of patients and families to know and to make their own decisions as dictated by our Islamic ethics. Conclusion. Personalized medicine includes diagnostic and prognostic approaches, and must include personalized preventive and therapeutic strategies in accordance with our Islamic ethical standards.

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Very low-birthweight (VLBW) infants represent an overall growing number of patients with unique demands for caretakers involved at the neonatal intensive care unit (NICU). The rate of VLBW infants is rising owing to the higher incidence of premature births from multiple gestations, resulting from assisted-reproductive techniques. VLBW infants are at high risk of various health problems, making successful prevention and therapy a daily challenge. This review intends to outline the major diseases of VLBW infants and will present the most recent advances in medical care for this patient population.

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Caffeine and other methylxanthines have been used to treat apnoea of prematurity for over 30 years. However, until recently, experimental evidence of the potential harm and lack of rigorous evaluation of this drug therapy in controlled clinical trials resulted in substantial uncertainty about the safety of the routine use of methylxanthines in preterm infants. The international Caffeine for Apnoea of Prematurity (CAP) trial group was formed in 1998. This collaborative research team enrolled over 2000 very low-birthweight infants in North America, Australia and Europe, and followed the children to the end of their second year of life. The CAP trial investigators showed for the first time that neonatal caffeine therapy reduces the rates of important short- and long-term morbidities such as bronchopulmonary dysplasia, severe retinopathy of prematurity, cerebral palsy and cognitive delay. Of all the neonatal treatments that have been subjected to economic evaluations, caffeine therapy is the most certain to be both cost saving and beneficial. It is therefore imperative that responsible drug manufacturers make safe and affordable formulations of caffeine available worldwide.

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It is becoming increasingly apparent that the in utero environment in which a fetus grows and develops may have long-term effects on subsequent health and survival. The abnormal intrauterine milieu of intrauterine growth retardation (IUGR) permanently alters gene expression and function of pancreatic beta-cells, leading to the development of diabetes in adulthood. Beta-cell function is markedly impaired in IUGR offspring in very early life. This is accompanied by a reduction in beta-cell proliferation and neogenesis. Expression of the pancreatic and duodenal homeobox 1 (Pdx1) transcription factor is permanently reduced in IUGR and epigenetic modifications are responsible for this decrease. Pdx1 encodes a homeobox transcription factor critically important for beta-cell function and development. Expression of Pdx1 is permanently reduced in IUGR beta-cells and epigenetic modifications are responsible for this. The fetal IUGR state is characterized by loss of upstream stimulatory factor 1 (USF1) binding at the proximal promoter of Pdx1, with deacetylation of histones H3 and H4 due to recruitment of histone deacetylase 1 (HDAC1) and the co-repressor mSin3A. After birth, histone 3 lysine 4 (H3K4) is demethylated and histone 3 lysine 9 (H3K9) is methylated. During the neonatal period, the reduction in Pdx1 expression and these epigenetic changes can be reversed by HDAC inhibition. Finally, once diabetes occurs, DNA methylation of the cytosine-phosphate-guanine (CpG) island in the proximal promoter ensues, resulting in permanent silencing of the Pdx1 locus.

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Recently, considerable interest has been shown in the role of maternal vitamin D status on growth, bone development and mineral homeostasis of the developing fetus, infant and child, especially in view of our better understanding of the possible long-term effects of impaired early growth and development on body composition and bone mass in later life. Although the fetus is to a large extent well protected against the possible deleterious effects of maternal vitamin D deficiency, there is evidence that maternal vitamin D deficiency might result in impaired fetal mineralization and growth. Further maternal vitamin D deficiency increases the risk of neonatal hypocalcaemia and its complications during the first month of life. Maternal vitamin D deficiency is a major risk factor for vitamin D deficiency rickets in the breastfed infant, and thus attention should be paid to ensuring maternal vitamin D sufficiency during pregnancy and preventing vitamin D deficiency in the infant through either maternal or infant vitamin D supplementation. The long-term consequences of maternal vitamin D deficiency during pregnancy are not clearly defined, although some studies have suggested impaired growth during infancy and reduced bone mass in pre-pubertal children. Further research is required to unravel the role of maternal vitamin D not only on children's bone mass and growth but also on the possible non-skeletal effects of vitamin D. The importance of ensuring vitamin D sufficiency in the breastfed infant and methods of achieving this are discussed, and the recently released recommendations of the Institute of Medicine with regard to recommended dietary allowances for vitamin D are placed in context.

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Zellweger syndrome (ZS) in its classic form is an autosomal recessive lethal disease characterized by the absence of morphologically recognizable peroxisomes. Detailed studies on ZS in the early 1980s have led to the discovery of a set of peroxisomal biomarkers in blood which has revolutionized our knowledge about peroxisomes and peroxisomal disorders, and formed the basis for the discovery of the group of peroxisomal diseases known at present. Peroxisomal disorders are classified into two distinct groups including the disorders of peroxisome biogenesis (group 1) and peroxisome function (group 2). The enzymatic and molecular basis of most peroxisomal disorders has been identified through the years and pre- and post-natal diagnostic methods have been established. This review describes the current state of knowledge with respect to peroxisomes and peroxisomal disorders with particular emphasis on the clinical biochemical and genetic aspects of these disorders.

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Survival rates for extremely preterm or tiny babies have increased dramatically with advances in perinatal and neonatal intensive care. However, the rates of neurological impairments and disabilities are too high in survivors relative to term controls; major neurological disability rates in those <1000 g or <28 weeks are four to five times higher than in term controls. There are some recent advances, however, that improve the outcome, both short and long term, for extremely preterm or tiny babies. Magnesium sulphate given to the mother just prior to very preterm birth reduces the rate of cerebral palsy in survivors. Caffeine given to very tiny babies not only reduces several short-term morbidities, such as patent ductus arteriosus and bronchopulmonary dysplasia, but also reduces the rates of death or disability, cerebral palsy and cognitive delay. Docosahexanoic acid, an omega-3 fatty acid important in brain function, given as a supplement to feeds in very preterm babies, improves cognitive function, but mostly in females and in those <1250 g birthweight. Developmental interventions after discharge home designed to improve baby cognitive and motor development have been shown to increase cognitive development over the preschool years; however, the effect is no longer evident after the patients start school. In summary, several recent interventions look promising in improving long-term outcomes for very preterm infants; however, their effects when implemented into usual clinical practice must be determined.

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Globally, neonatal and perinatal mortality has been declining over the years, yet many countries are failing to make progress to attain the Millennium Development Goals. Each year, 2.9 million newborns die in the first week of life and the highest neonatal mortality rates and rates of stillbirth are seen in sub-Saharan Africa, followed by Asia and Latin America, where most of the deliveries take place at home. Despite limited resources and multiple challenges including lack of human resources, competing priorities and lack of consensus on what needs to be done, there is much effort taking place to achieve these goals. This paper underscores the evidence-based research published during the last decade on neonatal interventions and strategies for scaling up these interventions in developing countries.

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Major scientific advances in prenatal and neonatal physiology have provided the basis for improved outcomes for preterm and other infants with disorders causing respiratory failure. Critical for the improved diagnosis and treatment of preterm infants was the recognition of the importance of the pulmonary surfactant system in the pathogenesis of respiratory distress syndrome in preterm infants. Dr Whitsett and colleagues in the Division of Neonatology, Perinatal and Pulmonary Biology, with many collaborators worldwide, have focused their attention on the molecular basis of lung formation, maturation and function for more than three decades. Initial questions regarding the regulation of surfactant synthesis and secretion in newborn infants led to the identification and study of the structure and function of the surfactant proteins (SP-A, SP-B, SP-C and SP-D) and the genes encoding them. The critical and distinct roles of each of the surfactant proteins in surfactant homeostasis and innate immunity were systematically explored and, in particular, their important role in surfactant replacement preparations used to treat newborn infants was elucidated. Reagents, including peptides, antibodies and transgenic mouse models, were developed for general use by the field of pulmonary biology for the study of common and idiopathic lung diseases. Molecular tools to add, mutate or delete genes selectively, in the respiratory epithelium of transgenic mice, enabled the development of models of human disease. Basic advances made in understanding the molecular basis of surfactant homeostasis, lung formation and function have provided the tools and strategies for the diagnosis and treatment of pulmonary diseases that were previously termed ‘idiopathic’.

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I will discuss the background of how ideas for research projects evolve. This is a topic that researchers rarely explain. It is obviously very important. Unfortunately, editors rarely, if ever, request that such material be included in publications. My friend, Dr Mary Ellen Avery, Professor at Harvard University, suggested the subject to me and intended to write such an article herself. Unfortunately, she never did. I will discuss the birth of three good ideas I have had over a long career in neonatology, from 1952 to 2011! These were phototherapy, the Vermont Oxford Network and helping to organize large, international randomized control trials of xenon. I am now 85 years old, long past the age you are supposed to have ‘hot’ ideas, but I think I have important ideas about the future. It is my belief that brain care, brain cooling plus some other agents are the future. Proving this, however, will take reorganization of our current ways of carrying out clinical research. It is my personal belief, based on the basic research to date, that xenon gas is likely to be successful. To prove this ‘idea’, our field needs to reorganize into large consortia. It will probably take a decade or longer to prove this hypothesis by carrying out the necessary, very large, randomized trials. We need to encourage neonatologists to unite and work together on new advances.

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Introduction. Split-hand or split-foot malformation associated with a fibula aplasia is a rare limb malformation; it results from failure of formation of parts of hands, feet or both due to a variable deficiency of central rays of the autopad. This anomaly can be isolated or associated with genetic or non-genetic syndromes. Routine examination of fetal hands and feet during second-trimester ultrasonography should make the detection of hand and foot malformations more frequent. Method. We report a case of familial non-syndromic form of ectrodactyly with aplasia of fibula because of its rarity, detected by ultrasonography. The anomaly was confirmed after birth and conservative orthopaedic management with further surgical reparation later was decided. Conclusion. Although it is rarely seen, limbs defects may be detected by detailed prenatal ultrasonography; however, the impact of these anomalies is assessed after birth, to choose the best option for the correction of the defect.

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For centuries the causation of neural tube defects remained unknown. Neural tube defects are serious birth defects that occur worldwide, in some places as frequently as 1 in every 200 births. About half of cases are spina bifida, and most of the remainder are anencephaly, with or without spina bifida. Anencephaly is fatal within a few days of birth and spina bifida usually results in severe physical disability. In 1991, in the MRC vitamin study, it was shown that lack of a B vitamin, folic acid, was an important cause of these defects. The study showed that folic acid supplementation could prevent about three-quarters of neural tube defects. This result led to governments recommending that women who may become pregnant take a folic acid supplement before pregnancy. It also led to over 70 countries mandating the fortification of flour with folic acid to help overcome the fact that many women overlook taking supplements before pregnancy. The preferred fortification level should be to provide an additional 0.4 mg a day of folic acid to the population and the preferred supplement dose for women who may become pregnant is 4 mg or 5 mg a day, as there is evidence that the higher dose confers additional protection. Many countries, including the UK, have failed to introduce mandatory fortification and as a result children have been born with serious birth defects that could have been prevented. This represents a governmental failure. It is like having a polio vaccine and not using it in countries in which paralytic polio occurs.

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In utero haematopoietic stem cell transplantation (IUHCT) is a potential therapeutic alternative to postnatal allogeneic bone marrow transplantation (BMT) for congenital haematologic disorders that can be diagnosed early in gestation and can be cured by BMT. The rationale is to take advantage of normal events during haematopoietic and immunologic ontogeny to facilitate allogeneic haematopoietic engraftment. The most important of these is the normal process of thymic processing of self-antigen to create a state of self-tolerance. Introduction of allogeneic antigen in the form of haematopoietic stem cells results in a state of permanent donor specific tolerance, eliminating the need for immunosuppression. Although the rationale remains compelling, IUHCT has only been clinically successful in X-linked severe combined immunodeficiency syndrome, a disease in which a competitive advantage exists for donor lymphoid cells. In other disorders, such as the haemoglobinopathies, where host-cell competition is a major barrier, IUHCT has not yet succeeded. However, great experimental progress has recently been made in pre-clinical animal models. Strategies based on prenatal tolerance induction to facilitate post-natal non-toxic cellular transplantation appear promising and clinical application is likely imminent. Because donor specific tolerance induction requires relatively minimal engraftment, this strategy may hold the key to broad clinical application of IUHCT in the near future.

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As placental insufficiency-related complications are one of the leading causes of maternal, as well as perinatal, morbidity and mortality, it is imperative to develop effective methods for their prediction prior to the development of clinical signs (ideally during the first trimester of gestation). There has been a trend in prenatal medicine over the last 10 years to develop non-invasive methods to monitor excessive placental trophoblast apoptosis associated with placental insufficiency utilizing extracellular nucleic acids quantification in maternal plasma. The recent advances demonstrated by our group are reviewed with a focus on the diagnostic potential of particular extracellular DNA and micro-RNA markers and their application in routine praxis.

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Sudden unexpected death syndrome (SUDS) is the abrupt, unexpected natural death of an apparently healthy individual. In many cases, the cause of SUDS in young people is a genetic heart disorder. These disorders may be structural abnormalities, which are responsible for a large majority of cases, or arrhythmogenic abnormalities, which account for only a small minority of cases (e.g. long QT syndrome, Burgada syndrome and catecholaminergic polymorphic ventricular tachycardia). Mutations in the genes responsible for these arrhythmogenic abnormalities as well as modes of inheritance and clinical presentations will be shortly discussed.

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This review is devoted to the treatment of five disorders: three disorders of serine biosynthesis, one in the first step of the sphingolipid biosynthesis (using serine) and one in the mannose pathway. The serine biosynthesis pathway and the mannose pathway are both side-branches of the glycolytic pathway. The feature that they have in common is that they are efficiently treatable by simple and natural molecules, serine and mannose respectively. This treatment bypasses the defect, thus restoring the pathway. This review summarizes their clinical features and provides an update on their treatment.

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Ultrasound screening is the most important contribution for prenatal detection of fetal developmental disorders. The time period between 11 and 14 weeks has proved to be the most suitable for detecting the majority of aneuploidies, a great number of malformations, the differentiation between mono- and dichorionic twin pregnancies and the early assessment of maternal pregnancy risks such as pre-eclampsia in order to start prophylactic treatment. The period between 18 and 22 weeks is used for the detection of structural fetal abnormalities. For this purpose a great number of clearly defined sonographic planes have to be visualized and electronically stored. The main task for the sonographer in the third trimester is to determine fetal and placental position and to detect fetal growth disorders. Using fetal Doppler studies allows determination of the optimal time and mode of delivery. In the case that a particular fetal malformation requires post-natal treatment, the mother can be transferred before birth to the most appropriate hospital. With the aforementioned sonographic techniques most of the major fetal and maternal problems can be detected on time and effective steps for a solution be taken.

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