Effects of changes in Mg++ ion concentration upon bacterial inhibition by beta-2-thienylalanine in defined media.

Variation in the inhibition of growth of Escherichia coli and Shigella sp. in various media containing beta-2-thienylalanine was attributed to differences in concentrations of Mg++ ions. Random blood samples 112 infants were tested for elevated phenylalanine in the phenylketonuria (PKU) screening assay. Magnesium ion levels also affected the results of this assay. At 0.05 g/1 MgSO4, the concentration present in commerical PKU test agar, four false positives were detected, while no readings could be made due to overgrowth of the Bacillus subtilis test strain when the concentration was increased to 0.1 g/1.     

Referral of mothers and infants for intensive care.

During 1975-7, 96 mothers were referred to University College Hospital for delivery from 39 other hospitals because their pregnancies were considered to be at very high risk. One hundred of the 111 infants born to the 96 mothers weighed 2500 g or less and 60 weighed 1500 g or less. A high proportion of the infants developed serious illnesses necessitating intensive care. The birth-weight-specific neonatal mortality rates of the infants were much lower than those of infants born in England and Wales as a whole and were also lower than those of the 370 infants transported to this hospital for intensive care after delivery elsewhere. Whenever possible mothers with very high-risk pregnancies should be referred for delivery to centres with full facilities for the intensive care of the mother, fetus, and newborn infant.     

Phenylketonuria variants in Ontario.

Since mass screening of the newborn population for phenylketonuria (PKU) by the Guthrie test was begun in Ontario in July 1965 many variants of PKU have been recognized in the 96 to 97% screened. Seventy-one cases of classic PKU were detected (four were missed). Of 48 cases of persistent hyperphenylalaninemia discovered, 18 were classified as atypical PKU and 30 as persistent benign hyperphenylalaninemia. Numerous infants with transient hyperphenylalaninemia (initial values over 10 mg/dl in 12), in many instances the result of transient neonatal tyrosinemia, were discovered. There was a slight predominance of males. Serum phenylalanine values of up to 15 mg/dl seemed to be harmless to the developing brain. A survey of 67 247 adults in the general population revealed 1 person with PKU and 1 with persistent benign hyperphenylalaninemia; both had normal intelligence quotients. Of 1548 mothers of retarded children tested, none had hyperphenylalaninemia.     

Neonatal screening for cystic fibrosis using immunoreactive trypsinogen and direct gene analysis: four years' experience.

OBJECTIVE--To assess the performance and impact of a two tier neonatal screening programme for cystic fibrosis based on an initial estimation of immunoreactive trypsinogen followed by direct gene analysis. DESIGN--Four year prospective study of two tier screening strategy. First tier: immunoreactive trypsinogen measured in dried blood spot samples from neonates aged 3-5 days. Second tier: direct gene analysis of cystic fibrosis mutations (delta F508, delta I506, G551D, G542X, and R553X) in samples with immunoreactive trypsinogen concentrations in highest 1% and in all neonates with meconium ileus or family history of cystic fibrosis. SETTING--South Australian Neonatal Screening Programme, Adelaide. SUBJECTS--All 88,752 neonates born in South Australia between December 1989 and December 1993. INTERVENTIONS--Neonates with two identifiable mutations were referred directly for clinical assessment and confirmatory sweat test; infants with only one identifiable mutation were recalled for sweat test at age 3-4 weeks. Parents of neonates identified as carriers of cystic fibrosis mutation were counselled and offered genetic testing. MAIN OUTCOME MEASURES--Identification of all children with cystic fibrosis in the screened population. RESULTS--Of 1004 (1.13%) neonates with immunoreactive trypsinogen > or = 99th centile, 912 (90.8%) had no identifiable mutation. 23 neonates were homozygotes or compound heterozygotes; 69 carried one identifiable mutation, of whom six had positive sweat tests. Median age at clinical assessment for the 29 neonates with cystic fibrosis was 3 weeks; six had meconium ileus and two had affected siblings. 63 neonates were identified as carriers of a cystic fibrosis mutation. Extra laboratory costs for measuring immunoreactive trypsinogen and direct gene analysis were $A1.50 per neonate screened. CONCLUSION--This strategy results in early and accurate diagnosis of cystic fibrosis and performs better than screening strategies based on immunoreactive trypsinogen measurement alone.     

Influence of perinatal factors and sampling methods on TSH and thyroid hormone levels in cord blood.

To evaluate the effect of perinatal factors and sampling methods on thyroid stimulating hormone (TSH) and thyroid hormone levels in cord blood, serum TSH, free thyroxine (FT4) and free triiodothyronine (FT3) concentrations were measured in 124 healthy term neonates. Eighty-eight infants were born in normal vaginal deliveries, 25 were delivered by vacuum extractor and 11 by Cesarean section. There was no significant difference among the three infant groups in the mean TSH levels. Birth weight, the infant's sex, duration of labor and uterotonic agents had no effect on cord serum TSH and free thyroid hormone levels in the neonates born by normal vaginal delivery. To assess the adequacy of specimen collection, mixed cord blood samples, obtained by a direct application of cord on a filter paper, and venous blood withdrawn with a plastic syringe were collected in another 200 infants. There was a significant linear correlation in the TSH concentration in mixed cord blood and cord venous serum from the same individuals, while a poor correlation was found in T4 values from two specimens. Our results suggest that the TSH value in cord blood is less influenced by perinatal factors, including the sampling method, and the mixed cord blood collected by this technique might be a feasible alternative specimen for a TSH screening program with cord blood which is useful in countries where neonatal blood is not available.     

Survey of neonatal screening for primary hypothyroidism in England,Wales, and Northern Ireland 1982-4

National screening for congenital hypothyroidism was established in the United Kingdom in 1982. During 1982-4, 488 infants with primary congenital hypothyroidism were detected by the 25 regional screening laboratories in England, Wales, and Northern Ireland. In addition, one infant had signs of cretinism at birth and was investigated before the screening test was done and four infants were known to have been missed by the screening programme; among these four infants the initial thyroid stimulating hormone concentrations were normal in two with inherited defects of synthesis of thyroxine, not measured in one, and false negative in one. The overall incidence of primary hypothyroidism was 1:3937 births (boys 1:6640, girls 1:2756). The incidence seemed to be reduced in infants born to black mothers (two cases only) and increased in those born to Asian mothers (61 cases). Congenital anomalies other than those of the thyroid gland were reported in 36 children (7%), and 15 (3%) died from various causes before the age of 4. Infants who were considered to show unequivocal evidence of hypothyroidism started treatment at a median age of 17 days (5th and 95th centiles 10 and 42 days) compared with a median age of 14 days (5th and 95th centiles 9 and 21 days) for infants with classic phenylketonuria also detected by national screening.     

Screening tests for diabetes detection; combined with a chest x-ray survey

A program was carried out to test the value and feasibility of performing blood sugar screening tests in conjunction with a community-wide chest x-ray survey. A simple, rapid and inexpensive blood sugar screening test requiring only about two drops of blood from the finger tip was used. Among 14,681 persons who stated that they did not have diabetes, 191 or 1.3 per cent had "positive" results in screening tests. The number of persons referred to their physicians for diagnostic study because of the possibility of diabetes was reduced from 191 to 127 by means of a more specific secondary screening test. Diagnostic information with regard to 102 of the 127 persons referred to their physicians was supplied by the physicians. In 58 (0.40 per cent of the 14,681 participants) the diagnosis was diabetes-newly discovered as a result of referral by the survey.Some of the persons referred to their physicians because of suspicion of diabetes, while not then diabetic, might be considered prediabetic. The appearance of diabetes in this group during the year following the survey was therefore investigated. Glucose tolerance tests were performed for 32 of the diabetes suspects whose diagnosis immediately following the survey was either "not diabetic" or unknown. In 15 cases the glucose tolerance curves were indicative of diabetes, in seven cases questionable and in ten cases normal. The 58 persons diagnosed immediately after the survey plus the 15 found to have "diabetic" glucose tolerance curves a year later made a total of 73 newly discovered diabetics. This is a discovery rate of 0.50 per cent among the 14,681 participants in the survey. The success of this combined diabetes detection and chest x-ray survey suggests that other screening procedures should be studied to determine the desirability of adding them to similar community-wide case-finding programs.     

Intellectual level (IQ) in heterozygotes for phenylketonuria (PKU)

Summary There is a statistically significant difference in the IQ's of PKU and histidinemia parents. The difference is due entirely to the verbal part of the Hamburg-Wechsler test. There is no significant difference in performance. The heterozygous state of histidinemia does not seem to bear an intellectual (evolutionary) advantage, since the IQ's of histidinemia parents show the same distribution as a normal population. In early and mostly well-treated PKU patients, the same slight deficit in verbal IQ appears with increasing age (changing test methods). These patients, simultaneously tested at 4 years of age with the Bühler-Hetzer and Kramer tests, exhibit a statistically significant difference between the results in favor of the less verbal Bühler-Hetzer. Since heterozygots, for PKU never have elevated phenylalanine blood levels, and because tryosine deficiency as argued by others seems highly improbable, we believe that the PKU gene has a more direct action on (or in) at least certain ganglion cells, lowering the verbal IQ slightly, but significantly. This action is not reflected by phenylalanine increase in the extracellular space in heterozygots and is not abolished by dietary treatment in homozygous PKU patients. The major damage in PKU patients must be due to chronic phenylalanine poisoning, which deteriorates cells and/or functions on a much larger scale, because it can be easily prevented by decreasing the phenylalanine blood level with correct dietary treatment.     

Phenylalanine metabolites as indicators of dietary compliance in children with phenylketonuria

The data from this study showed that the excretion of three major metabolites of phenylalanine in patients with PKU approach normal values at blood phenylalanine levels less than 5.0 mg/dl. The MANOVA showed statistically significant differences in phenyllactate excretion when blood phenylalanine was greater than 10.0 mg/dl. The PL and total metabolite excretion were significantly correlated to blood phenylalanine in multiple samples taken from two individual subjects. Using data obtained from single patient observations may serve as a means for individualizing the PKU diet to insure low levels of phenylalanine metabolites and thus insure optimal development for patients with PKU.     

PKU screening — Is it worth it?

Ontario''s program for PKU screening of newborn infants reached 94.5% of the newborn population from 1966 to 1971. There were 70 infants identified by the program, 47 of whom were classical cases and 23 atypical cases of phenylketonuria. The incidence was 1:16,700 live births for classical cases and 1:34,000 live births for atypical cases. Since the beginning of the program 44 children have been identified in infancy as having PKU and have been treated successfully. Retardation has become evident in only three infants, two of whom were missed by the screening program.The cost of identification and care of one child for five years is about $7000, much less than the $250,000 needed to provide lifetime institutional care for one severely retarded individual.     

Circular RNA expression alteration in whole blood of premature infants with periventricular white matter damage

Circular RNAs (circRNAs) are evolutionarily conserved and tissue-specific types of non-coding RNA and can serve as potential diagnostic biomarkers for disease. However, the clinical significance and levels of expression of circRNAs for whole blood samples of prematurely born infants afflicted by diseases such as periventricular white matter damage (PWMD) are largely unknown. Therefore, we sought to identify measures of expression of circRNAs in whole blood samples obtained from prematurely born infants afflicted by PWMD and comparatively in samples from prematurely born infants without PWMD. We found the expression levels of circRNAs which from premature with PWMD has changed. Further analysis suggests that these circRNAs have important roles in PWMD. This study can improve the understanding for the potential of the circRNAs to serve as biomarkers in PWMD. Moreover, these circRNAs may provide evidence for improving diagnosis and treatment for infants afflicted by PWMD, and merits continued research.     

The Manchester regional screening programme: a 10-year exercise in patient and family care.

Up to the end of 1978 the Willink Biochemical Genetics Unit had screened 506821 babies for metabolic abnormalities over 10 years--98-99% of the children born in the region. Sixty-nine cases of phenylketonuria (PKU), 42 cases of histidinaemia, and six cases of homocystinuria were detected. As well as treating affected children, the staff of the unit have concentrated on providing full support for their families and maintaining good communications with parents, general practitioners, health visitors, and midwives. A clinic liaison sister has provided valuable support for health visitors and an important link between the unit and community services. A study of the costs of screening and treating cases of PKU for the year 1978 showed that this was cheaper, by pound 569000, than the costs of looking after patients with untreated PKU.     

Routine neonatal screening for phenylketonuria in the United Kingdom 1964-78. Medical Research Council Steering Committee for the MRC/DHSS Phenylketonuria Register.

From 1964 to 1968, despite a general policy of routine neonatal screening for phenylketonuria that was usually carried out using the Phenistix nappy test, half to one-quarter of all cases reported to the register had been missed in the screening programme and had not been detected before the age of 4 months. In about two-thirds of the "missed" cases no screening test had been carried out, and in one-third a urine test had been performed but had given a false-negative result. In 1968-9 the screening programme was reorganised according to recommendations made in a Government circular (HM (69) 72), which proposed that a specimen of blood should be obtained by heel prick from all newborn infants between the 6th and 14th day of life and be tested in a central laboratory for the presence of raised blood phenylalanine concentrations. The senior medical officers of the various regions were made responsible for ensuring that all infants were tested. By 1974 only 1 to 2% of surviving infants were not being tested for phenylketonuria in the neonatal period, and only five of the 357 cases born between 1974 and 1978 and notified to the register had been diagnosed after the age of 3 months.     

Cystic fibrosis newborn screening: a pilot study to maximize carrier screening

Newborn screening for cystic fibrosis (CF) is expanding because early diagnosis has been shown to result in improved nutrition and growth. Most newborns identified by a mutation panel have a single detected mutation and require sweat testing to exclude an additional undetected mutation. The resulting identification of CF carrier newborns, although not the primary purpose of screening, has three potential benefits, (1) the detection of trait-trait couples, (2) presymptomatic testing of these couples' previously born children who may have undetected CF, and (3) a carrier parent alerting his/her extended family members to the chance of also being a CF carrier. Reaping each benefit requires genetic counseling of parents and their accepting carrier testing. The purpose of this study was to utilize the sweat testing visit to educate parents about the value of carrier testing for themselves and their blood relatives. We compared special care (genetic counseling after explaining the sweat test result and offering of parental DNA testing, all on the sweat test visit) versus standard care (sweat test result reported by phone to the parents the next day by the newborn's physician, ideally with the recommendation to arrange genetic counseling and parental carrier testing). In the first year of New York State CF screening, 64 newborns with one detected mutation were reported in the nine-county region that includes Rochester. Of these, parents of 39 agreed to participate in the study and to be randomized to special or standard care. Sixty-one parents completed both the initial and 1-year follow-up questionnaires (30 couples and one mother). Of the 61 parents, 23 had carrier testing after the birth of the baby. The frequency of such parental testing was significantly higher in the special care group (17/34 or 50%) than in the standard care group (6/27 or 22%) (p < 0.05). This is the first evidence from a randomized trial that genetic counseling and offering carrier testing to parents on the sweat test visit increases identification of carrier parents. Such identification detects trait-trait parents and facilitates carrier testing among relatives.     

Requirements for a minimum standard of care for phenylketonuria: the patients’ perspective

Phenylketonuria (PKU, ORPHA716) is an inherited disorder that affects about one in every 10,000 children born in Europe. Early and continuous application of a modified diet is largely successful in preventing the devastating brain damage associated with untreated PKU. The management of PKU is inconsistent: there are few national guidelines, and these tend to be incomplete and implemented sporadically. In this article, the first-ever pan- European patient/carer perspective on optimal PKU care, the European Society for Phenylketonuria and Allied Disorders (E.S.PKU) proposes recommendations for a minimum standard of care for PKU, to underpin the development of new pan-European guideline for the management of PKU. New standards of best practice should guarantee equal access to screening, treatment and monitoring throughout Europe. Screening protocols and interpretation of screening results should be standardised. Experienced Centres of Expertise are required, in line with current European Union policy, to guarantee a defined standard of multidisciplinary treatment and care for all medical and social aspects of PKU. Women of childbearing age require especially intensive management, due to the risk of severe risks to the foetus conferred by uncontrolled PKU. All aspects of treatment should be reimbursed to ensure uniform access across Europe to guideline-driven, evidence-based care. The E.S.PKU urges PKU healthcare professionals caring for people with PKU to take the lead in developing evidence based guidelines on PKU, while continuing to play an active role in serving as the voice of patients and their families, whose lives are affected by the condition.     

Genetic screening and genetic counseling: knowledge, attitudes, and practices in two groups of family planning professionals.

67 obstetrical and gynecological physicians and 102 professional staff members of family planning clinics (FPCs) in the Pittsburgh, Pennsylvania, area returned questionnaires relating to knowledge of basic genetic principles and attitudes towards genetic screening and genetic counseling. The best understood genetic risk was Down's syndrome in children born to mothers over 40 years of age. Nearly 90% of physicians and 85% of FPC staff knew this but only 12% of physicians and 30% of FPC staff knew it is caused by chromosomal aberration. Next best understood defect is sickle cell anemia. In overall knowledge the physicians had a mean score of 4.45 of 7 genetic questions, FPC staff, 3.32. However, FPC workers who had received in-service genetic training scored 4.42 (p less than .001). Knowledge of the 2 genetic clinics in the area and acceptance of the principles of genetic screening were associated with the individual's acceptance of sterilization as a method of birth control and acceptance of abortion if the fetus had significant risk of being born deformed. Both of these associations were at the significant level for both physicians and FPC workers. Both physicians and FPC workers who have themselves had genetic counseling or who have family members who have had such counseling show higher acceptance levels. An association was also found between acceptance and genetic educational background. About 92% of respondents who had read articles or textbooks pertaining to genetics during the preceding year approved of including genetic information as part of maternal and child health projects compared with 82% of those who had not (p less than .02). Among the physicians 36% felt it should be required, 34% voluntary, and 30% did not know; for FPC workers, 59, 27, and 14%, respectively. Protestants and Jews tended to favor required premarital screening while Catholics tended to oppose it (p less than .007). It is disconcerting that over 50% of the physicians did not know the recurrence risk of PKU and over 20% did not know the gene is the basic unit of inheritance. While it is true that over 1/2 completed basic professional education more than 20 years ago when genetics was not part of the medical school curriculums this basic knowledge needs to have been acquired during continuing medical education. In this study more than 1/3 of the FPC staff indicated they had been asked to provide genetic counseling or had referred clients. This points up the importance of such workers in a comprehensive genetic counseling service.     

Associated malformations in cases with neural tube defects

Infants with neural tube defects (NTDs) may have other associated congenital defects. The reported incidence and the types of associated malformations vary between different studies. The purpose of this investigation was to assess the prevalence of associated malformations in a geographically defined population. The prevalences at birth of associated malformations in infants with NTDs were collected between 1979 and 2003 on all infants born in the area covered by the registry of congenital anomalies of Northeastern France in 334,262 consecutive births. Of the 360 infants with NTDs born during this period, 20.5 % had associated malformations. Associated malformations were more frequent in infants who had encephalocele (37.5 %) than in infants with anencephaly (11.8 %) or infants with spina bifida (23.7 %). Malformations in the face (oral clefts), in the musculoskeletal system, in the renal system, and in the cardiovascular system were the most common other anomalies. In conclusion the overall prevalence of malformations, which was one in five infants, emphasizes the need for a thorough investigation of infants with NTDs. A routine screening for other malformations especially facial clefts, musculoskeletal, renal and cardiac anomalies may need to be considered in infants with NTDs, and genetic counseling seems warranted in most of these complicated cases.     

Ascertainment of a mid-western US female adolescent twin cohort for alcohol studies: assessment of sample representativeness using birth record data.

Female twin pairs were identified from birth records, and their families invited to participate in a prospective study of the determinants of alcohol problems in women. We investigated sampling biases arising because of failure to locate families, or non-cooperation of families. Out of 2644 families with a live-born pair (born between July 1975 and December 1986) who survived beyond infancy, contact was established and a brief screening interview completed with 90% (N = 2380). Fewer than 6% of located families declined to participate in the initial screening interview. Predictors of failure to locate a family or to obtain a screening interview were identified from information recorded in birth records, and from neighborhood characteristics identified from 1990 US Census block group data for the family residence when the twins were born. African-American families were under-represented in the final sample, but this effect was barely significant when other variables were controlled for. Under-represented were families where the mother was 19 or younger at the birth of the twins, where the mother herself was born out-of-state, or where information about biological father was not reported in the birth record. Non-participating families on average came from neighborhoods with a higher proportion of residents living in poverty, and with a higher proportion of African-American residents. Sampling biases were however small. The unusual cooperativeness in research of families with twins persists.     

Placental transfer of maternally-derived IgA precludes the use of guthrie card eluates as a screening tool for primary immunodeficiency diseases

There is a need for neonatal screening tools to improve the long-term clinical outcome of patients with primary immunodeficiency diseases (PID). Recently, a PCR-based screening method for both TRECs and KRECs using Guthrie card samples has been developed. However, the applicability of these excision circle assays is limited to patients with severe T or B cell lymphopenia (SCID, XLA and A-T), whereas the most common forms of PID are not detected. Absence of serum IgA is seen in a major fraction of patients with immunological defects. As serum IgA in newborns is considered to be of fetal origin, eluates from routinely collected dried blood spot samples might thus be suitable for identification of children with PID. To assess the applicability of such screening assays, stored Guthrie card samples were obtained from 47 patients with various forms of primary immunodeficiency diseases (SCID, XLA, A-T, HIGM and IgAD), 20 individuals with normal serum IgA levels born to IgA-deficient mothers and 51 matched healthy newborns. Surprisingly, normal serum IgA levels were found in all SCID, XLA, A-T and HIGM patients and, additionally, in all those IgAD patients born to IgA-sufficient mothers. Conversely, no serum IgA was found in any of the 16 IgAD patients born by IgA-deficient mothers. Moreover, half of the IgA-sufficient individuals born by IgA-deficient mothers also lacked IgA at birth whereas no IgA-deficient individuals were found among the controls. IgA in neonatal dried blood samples thus appears to be of both maternal and fetal origin and precludes its use as a reliable marker for neonatal screening of primary immunodeficiency diseases.