Screening For Galactosemia Research Articles

Clinical features and outcome of eight infants with intrahepatic porto-venous shunts detected in neonatal screening for galactosaemia.

Of 18 newborn infants found to have persistent galactosaemia and without enzyme deficiencies, intrahepatic porto-venous (P-V) shunts were the cause in 8 cases. We retrospectively analysed the clinical and biochemical features of the eight infants. Four patients received prednisolone, one of whom with heart failure owing to arteriovenous shunts also underwent hepatic arterial embolization. The other four patients were merely observed without receiving drug therapy. Regardless of treatment, the P-V shunts disappeared in five infants before the age of 1 y and persisted in three others. All infants showed mild or moderate abnormalities in liver function tests. None exhibited hyperammonemia or neuropsychiatric symptoms related to the shunts. The data indicated that the prognosis of infants with intrahepatic P-V shunts is generally good. In the absence of complications related to the P-V shunts, no treatment other than galactose elimination diet is indicated.

Incidence and features of galactosaemia in Saudi Arabs.

Over a 12-year period (1983 to 1994), 11 cases of classical galactosaemia were identified in the Saudi Aramco Medical Services Organization (SAMSO). This yields an incidence of 12 cases per 100,000 live births in the Easter Province of Saudi Arabia. A higher proportion of infants presented with infections compared to reports in the literature. Screening for galactosaemia is highly recommended in this high-risk population.

Use of a transfer plate with supporting frame for increased accuracy and efficiency in fluorometric microplate methods for mass screening

Introduction: Although the fluorometric method for galactosemia screening established by Yamaguchi et al. (Clin Chem 1989; 35: 1962) is an excellent method, it requires many pipette manipulations which increase the possibility of human errors. Method: We developed a novel technique using a transfer plate combined with a supporting frame (Fujimoto et al., in: Neonatal Screening in the Nineties, Australia: Kelvin Press, 1991; p. 359). Results: This method simplified the manipulative procedures, thereby causing less human error and increasing accuracy. Discussion: This technique can be applied to improve other microplate systems which have been introduced for mass screening as well as to improve the microplate fluorometric method for galactosemia screening.

Newborn mass screening for galactosemia.

Methods for mass screening of newborns for galactosemia have been available since 1964. Although galactosemia is rare, many countries have included screening for galactosemia in their national screening programs, yet other countries deny the necessity for screening. Despite the early appearance of clinical symptoms, newborns may be reliably diagnosed in time only through mass screening.

Erythrocyte uridine diphosphate galactose-4-epimerase deficiency identified by newborn screening for galactosemia in the United States

Eight infants (two whites and six blacks) with erythrocyte uridine diphosphate galactose-4-epimerase (epimerase) deficiency were identified in four newborn screening programs for galactosemia in the United States. The initial biochemical findings in all cases were elevated blood galactose-l-phosphate with normal or only slightly increased blood galactose and normal galactose-l-phosphate uridyltransferase (GALT) activity. Epimerase deficiency was confirmed in erythrocytes by a two-step enzymatic assay involving fluorometric measurements of NADH generated by coupling the uridine diphosphate glucose dehydrogenase reaction to epimerase. Seven of the eight infants appeared to be clinically normal at birth and one newborn had neonatal jaundice. The infrequent recognition of epimerase deficiency is likely due to the methods of newborn screening for galactosemia which are often only for GALT deficiency and perhaps also due to incomplete follow-up of increased metabolite levels in newborn blood specimens with normal GALT activity. Our results confirm a preliminary report of a high frequency of erythrocyte epimerase deficiency in the American black population.

Comparison of the effects of season and prematurity on the enzymatic newborn screening tests for galactosemia and biotinidase deficiency

In the Commonwealth of Virginia, 299,420 newborns were screened for biotinidase deficiency and galactosemia during the years 1989–1991 using enzymatic assays for galactose-l-phosphate uridyl transferase activity and biotinidase activity on dried blood filter paper cards. Retrospectively, false-positive initial samples for galactosemia or biotinidase deficiency were identified, and monthly frequencies of false-positive results were determined. The false-positive rates for galactosemia and biotinidase deficiency screening decreased over the 3-year period and were significantly higher in galactosemia screening for each year examined P < 0.001). For galactosemia screening, monthly false-positive rates were highest during May through September, seasonal differences in false-positive rates were significant for each year evaluated ( P < 0.001). and seasonal false-positive rates for the 3 years combined were highest during the summer and lowest during the winter. For biotinidase deficiency, differences in seasonal false-positive rates were significant in 1989 ( P<0.001) and 1991 ( P<0.01), and the highest seasonal false-positive rate for the 3 years combined occurred in the spring. Average monthly temperature and year of measurement were significant factors in galactosemia screening only ( P< 0.0001) and accounted for much of the variance in false-positive rates ( r 2 = 0.43). Approximately half of the infants with false-positive results for biotinidase deficiency were premature, significantly more than the incidence of prematurity in Virginia (7–8%) during the 3 years ( P<0.001). Prematurity in false-positive galactosemia screens was not significantly different from expected rates.

Minimizing false positive diagnoses in newborn screening for galactosemia.

Heat and humidity, rather than summertime heat alone, cause extensive loss of galactose-1-phosphate uridyltransferase activity in mailed blood spots and seem to account for false positive diagnoses of galactosemia. The spots are partially protected from the effects of atmospheric humidity if they are allowed to dry and then are sealed in a plastic freezer bag before being exposed to higher humidity. Conversely, extensive loss of transferase activity occurs if the samples are sealed in the bags before the spots are dry. The fluorescence from transferase activity can be monitored with greater sensitivity fluorometrically than visually. A simultaneous fluorometric determination of phosphoglucomutase activity reveals whether decreased transferase activity represents sample deterioration or galactosemia. Mg2+ and a sulfhydryl agent, such as dithiothreitol, are needed for activity of phosphoglucomutase, an enzyme in the sequence leading to the fluorescent substance (NADPH). They must be added in certain modifications of the assay.

Neonatal screening for inborn errors of metabolism in Switzerland

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

Laboratory quality control issues related to screening newborns for cystic fibrosis using immunoreactive trypsin

We have incorporated the IRT assay for CF to our newborn screening program, relying heavily on electronic data processing to optimize the test results in order to provide the most reliable data possible from the specimen at hand. We have established an internal cut-off of 100 ng/mL and an external referral of 180 ng/mL; this virtually eliminates the possibility that analytical imprecision will result in misidentifying a positive patient specimen. The relationship between IRT levels and various mutant forms of CF are not well established, and it is possible that various forms of CF may exhibit different levels of IRT in the first few days of life. We believe that IRT screening for CF could be a useful procedure for early identification of potential CF. However, by comparison with other newborn screening tests, its sensitivity, 90%, presents a concern. The expectation for PKU, hypothyroidism, MSUD, and galactosemia screening is 100% sensitivity. A false-negative usually results in litigation. The use of IRT in routine newborn screening will require considerable education of the general public and physicians receiving test results. Our program, along with many others, is anxiously watching the developments in the area of gene testing. We feel the relatively inexpensive IRT, used for mass screening can be successfully coupled with the more definitive (and expensive) gene test on a selected population to identify CF at the earliest possible age in a more effective manner. It is possible that in the near future gene probe tests will be applied in a cost effective manner to the initial filter paper specimen.

A clinician's view of the mass screening of the newborn for inherited diseases: Current practice and future considerations

The case for or against mass screening for inherited diseases is discussed. There is universal acceptance for mass screening for phenylketonuria and congenital hypothyroidism. The case for mass screening for galactosaemia and for maple syrup urine disease is not very strong; they could be considered under the heading of 'urgent screening of the sick newborn'. It is difficult to find good arguments for mass screening for congenital adrenal hyperplasia. For screening for glucose-6-phosphate dehydrogenase deficiency and sickle cell disease, the established criteria for mass screening do not apply. A simple tool for early detection is now available and the population afflicted with a mutant gene which causes major health problems should receive special attention from its government. It is too early to offer any comment about cystic fibrosis screening; further developments must be awaited.

Pitfalls in Diagnosing Galactosemia

Newborn galactosemia screening programs using the fluorescence spot test to detect red cell galactose‐1‐phosphate uridyltransferase activity are prone to inaccuracy if the screened infants have received blood transfusions. We describe an infant with galactosemia who received packed red cell transfusions in the first few days of life and was misdiagnosed after an initial positive screening test result. Although the patient was thought to have cytomegaloviral hepatitis, a percutaneous liver biopsy helped direct the evaluation toward identifying the galactosemia carrier state in both parents. This case report illustrates the need for careful consideration of the patient's history of transfusion of blood products when evaluating newborn screening results.

Pitfalls in Diagnosing Galactosemia

Newborn galactosemia screening programs using the fluorescence spot test to detect red cell galactose-1-phosphate uridyltransferase activity are prone to inaccuracy if the screened infants have received blood transfusions. We describe an infant with galactosemia who received packed red cell transfusions in the first few days of life and was misdiagnosed after an initial positive screening test result. Although the patient was thought to have cytomegaloviral hepatitis, a percutaneous liver biopsy helped direct the evaluation toward identifying the galactosemia carrier state in both parents. This case report illustrates the need for careful consideration of the patient's history of transfusion of blood products when evaluating newborn screening results.

Galactosemia—To Screen or Not to Screen?

In Reply.— Norway has discontinued galactosemia screening because only 1 case has been identified per 96,000 infants screened. Members of a recent workshop on galactose screening1 in the United States reported that 37 states had an average incidence of 1:62,000 or 312 cases identified per 19 million infants screened. However, there was an incidence range from 1:30,000 to 1:191,000 from state to state. Those states using both an enzyme assay and a measure of galactose content in the blood identified more enzyme defects, and, in general, laboratories with the longest experience appeared to be better able to recognize abnormalities in the screens.

An evaluation of a new test kit to screen for galactosemia

A new galactosemia screening kit has been evaluated. The kit employs the Yoshida modification of the Paigen et al. Escherichia coli bacteriophage assay and is produced by Eiken Co. Ltd. of Japan. The assay estimates galactose and galactose-1-phosphate in dried blood specimens. The kit is sufficiently sensitive to detect possible heterozygotes as well as possible homozygotes.

Interference by antibiotics with neonatal screening for galactosemia

Some centers screen for galactosemia using the metabolite inhibition assay described by Guthrie. L2 In this test, inhibition of bacterial growth caused by galactose (or galactose-1-phosphate) may also be caused by antimicrobial agents contained in the blood sample. In our newborn screening center, all infants born in the 36 hospitals of the northern German cities of Hamburg and Bremen are tested. Every year, of a total of 27,000 infants approximately 20 show positive results in galactosemia screening, but afterward it is found they do not have galactosemia. The purpose of this study was to determine which antimicrobial agents interfere with the galactosemia screening test and at what concentration.

Neonatal screening for congenital adrenal hyperplasia: a programme based on a novel direct radioimmunoassay for 17-hydroxyprogesterone in blood spots.

We have assessed the feasibility of screening newborn babies for congenital adrenal hyperplasia (CAH) by the direct measurement of 17-hydroxyprogesterone (17-OHP) in blood spots collected on filter paper (Guthrie cards) for the phenylketonuria, hypothyroidism and galactosaemia screening programmes run in Scotland. The procedure described for CAH uses an iodinated 17-OHP tracer and a specific 17-OHP antiserum sheathed within semipermeable nylon microcapsules. The method does not require a solvent extraction step, is inexpensive, precise, efficient and, therefore, practical for large-scale use. With this system the value of a neonatal screening programme was assessed in a retrospective analysis and a prospective trial. The retrospective study of 15 paediatric cases of CAH illustrated that at least half were not diagnosed within 3 weeks of birth. Analysis of the original Guthrie card samples revealed increased levels of 17-OHP in all cases. The prevalence of CAH as calculated in the retrospective study was 1 in 20 907 with a range (within 95% confidence limits) of from 1 in 12 675 to 1 in 32 604 (n = 301 450). In the prospective trial a total of 92 051 consecutive samples was screened. Five cases of CAH were correctly identified with a current false positive rate of 0.042%. Analysis of urinary steroids confirmed defective adrenal 21-hydroxylase activity in all positive cases. In the prospective trial the prevalence was 1 in 18 401 with a range of from 1 in 7422 to 1 in 50 006. We conclude that mass screening for CAH is both feasible and desirable.

A proposed scheme for galactosemia screening

A proposed scheme for galactosemia screening

Speech and language deficits in early-treated children with galactosemia

ROUTINE NEWBORN SCREENING for galactosemia was initiated on the premise that early detection and treatment ensure normal development as well as prevention of liver disease and cataracts? However, early in our follow-up of children with galactosemia detected and treated from birth, we were impressed with the severity and frequency of speech difficulties, Thus we studied the intelligence and speech and language development in eight children with classic galactosemia (galactose-l-phosphate uridyl transferase deficiency) detected by routine newborn screening in the Massachusetts Metabolic Disorders Screening Program at the State Laboratory Institute, Massachusetts Department of Public Health. The ages of the children ranged from 3.6 to 11.6 years (Table I). There were six boys and two girls. Four of the eight children were sick during the neonatal period with jaundice, hepatomegaly, failure to thrive, and vomiting. One child had, in addition, a urinary tract infection caused by Escherichia coli and a bleeding diathesis. Treatment with a lactose-free diet was initiated before 16 days of age in all the children. Two children (Patients 4 and 7), each with an older affected sibling, were diagnosed at birth on the basis of cord blood studies. One of these children (Patient 4) never received milk, and the other received only two milk feedings. All of the children have continued dietary treatment and have been in good biochemical control since four to five days after treatment began, with no detectable galactose in blood or urine and whole blood galactose-l-phosphate concentrations less than 2 mg/dl. All have normal growth and normal physical develop

Health economic analysis of the Swedish neonatal metabolic screening programme. A method of optimizing routines.

A benefit-cost analysis was carried out to optimize the routines for neonatal metabolic screening. The basis of the study was provided by results of the Swedish neonatal screening programme from 1965 to 1979. During this period over one million infants were screened by the Guthrie test for phenylketonuria and galactosaemia, and for limited periods also for tyrosinaemia, homocystinuria and histidinaemia. The benefit-cost ratio was calculated for combinations of different screening tests, recall routines, and varying degrees of coverage. The largest benefit-cost ratio was obtained with combined screening for phenylketonuria and galactosaemia, using a borderline blood phenylalanine level of 0.50 mmol/L in the Guthrie test for phenylketonuria. However, the inaccuracy of this test necessitated the use of a lower blood phenylalanine level of 0.25 mmol/L and the acceptance of a lower benefit-cost ratio. An increase in the present 98% coverage of newborns by the screening programme was found to be an effective means of improving the benefit-cost ratio in the present programme.

Microdetermination of galactose and galactose 1-phosphate in dried blood spots

Newborn screening for galactosemia (galactose-1-phosphate uridyltransferase deficiency), as well as for other defects in galactose metabolism (galactokinase deficiency and uridine diphosphogalactose 4-epimerase deficiency), requires a method of determining both galactose and galactose 1-phosphate in dried blood. We have developed a sequential quantitative method for the microdetermination of galactose and galactose 1-phosphate that can be applied to 3-mm-diameter disks of dried blood and that can be used with a Technion Autoanalyser II equipped with a fluorometer. Galactose is determined by the fluorescence of NADH following treatment with β-galactose dehydrogenase and with the consequent reduction of NAD. The complete system includes alkaline phosphatase for the hydrolysis of galactose 1-phosphate, so that the total amounts of a galactose and galactose 1-phosphate are determined. For the measurement of galactose alone, alkaline phosphate is omitted from the system. The difference in fluorescence between that from the complete system and that from the alkaline phosphatase-omitted system yields the concentration of galactose 1-phosphate.