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PubMed2003

Long term follow-up of patients with inborn errors of metabolism detected by the newborn screening program in Japan.

A newborn mass-screening program for the early detection of phenylketonuria, maple syrup urine disease, homocystinuria, galactosemia, congenital hypothyroidism, congenital adrenal hyperplasia, using filter paper blood specimens, was started throughout Japan in 1977. The total number of newborns screened by March 2000 reached 29,657,738; this represents 95% of the newborns during this period. A collaborative study group has performed a follow-up study of the cases detected by this program since the start of this screening program. The results we have obtained through this study to date include: hyperphenylalaninemia, 1:70,000; congenital hypothyroidism, 1:5,000; and, congenital adrenal hyperplasia, 1:20,000. The cases of maple syrup urine disease, homocystinuria, and galactosemia type 1 were too few for a reliable incidence. Accumulated data for PKU show that IQ is inversely related to blood phenylalanine level and stricter dietary control guidelines have resulted. We now have a number of adolescents with PKU and long-term follow-up data are being obtained.

Adolescent↗
PubMed2003

Newborn screening in the Philippines.

The Newborn Screening Study Group first introduced newborn screening in the Philippines in 1996. This group of pediatricians and obstetricians from 24 hospitals in the metropolitan Manila area developed a newborn screening program: (1) to establish the incidence of six metabolic conditions--congenital hypothyroidism, congenital adrenal hyperplasia, galactosemia, phenylketonuria, homocystinuria and glucose-6-phosphate dehydrogenase deficiency, and (2) to make recommendations for the adoption of newborn screening nationwide. Newborn screening developed in three phases: (1) routine screening for 5 disorders excluding G6PD deficiency in the 24 member hospitals in Metro Manila, (2) addition of screening for G6PD deficiency to the 5-disorder screening panel, and (3) program evaluation with subsequent reduction in the time of sample collection to 24 hrs of age or older (from the initial requirement of 48 hrs. or older) and discontinuation of screening for homocystinuria as a cost cutting measure (due to non-detection of cases). Data from 201 participating hospitals reported in September 2001 confirmed 48 cases of congenital hypothyroidism, 21 cases of congenital adrenal hyperplasia, 2 cases of galactosemia, 4 cases of hyperphenylalanemia and 1,495 cases of glucose-6-phosphate dehydrogenase deficiency. The Department of Health has recognized the significance of the initial data and efforts are now being undertaken to ensure the nationwide implementation of newborn screening.

Health Policy↗
PubMed1987

Neonatal screening for metabolic and endocrine disorders.

The impact of metabolic diseases (inborn errors of metabolism) and endocrine disorders in pediatrics has markedly increased during the last few decades. Critical periods in the development of the central nervous system need special attention in children with these disorders. Early diagnosis and treatment are important in order to prevent mental retardation and serious handicaps in some of these patients. Certain patients with metabolic and endocrine disorders lack early clinical symptoms or have so non-specific signs that permanent neurological handicaps are present when the patients are finally diagnosed. One way to identify these patients is by means of mass screening. A blood sample is then collected from every newborn infant and analyzed for abnormal levels of metabolites or hormones. It is possible to detect at least thirty different disorders in this way. In most European countries screening programmes involve phenylketonuria (PKU) and congenital hypothyroidism. The prognosis for these patients has improved dramatically after the introduction of screening. The Swedish neonatal metabolic screening programme was started in 1965 by screening for PKU. Subsequently, screening for galactosemia and congenital hypothyroidism was added. The result of the screening programme 1965-1985 is as follows: (table; see text) The main benefit of early detection and treatment of children with PKU, congenital hypothyroidism and galactosemia is the prevention of mental retardation and other handicaps. Recently nationwide pilot screening for congenital adrenal hyperplasia (adrenogenital syndrome) was started.

Endocrine System Diseases↗
PubMed1987

Experience of the Manitoba Perinatal Screening Program, 1965-85.

The Manitoba Perinatal Screening Program is guided by a committee of medical specialists with skills in the diagnosis and management of disorders of metabolism in the newborn. The program is voluntary and is centralized at Cadham Provincial Laboratory, in Winnipeg. A filter card blood specimen is collected from newborns on discharge from hospital, and a filter card urine sample is collected and mailed to the laboratory by the mother when the infant is about 2 weeks of age. The overall compliance rates for the blood and urine specimens are approximately 100% and 84% respectively. The blood specimen is screened for phenylalanine and other amino acids, thyroxine, galactose, galactose-1-phosphate and biotinidase. The urine specimen is screened for amino acids, including cystine, as well as methylmalonic acid and homocystine. Between 1965 and 1985, 83 cases of metabolic disorders were detected, including 23 cases of primary hypothyroidism, 14 of classic phenylketonuria, 5 of galactosemia variants, 3 of galactosemia, 2 of maple syrup urine disease and 1 of hereditary tyrosinemia. The direct cost per infant screened is $5.50, and the cost:benefit ratio is approximately 7.5:1. Maternal serum alpha-fetoprotein screening is being made available as the necessary supporting clinical facilities become available. On the basis of this experience, the author outlines the components that are important for an effective screening program.

Costs and Cost Analysis↗
PubMed1996

Diabetic-like retinopathy ameliorated with the aldose reductase inhibitor WAY-121,509.

PURPOSE: To evaluate the efficacy of WAY-121,509, a potent new aldose reductase inhibitor (ARI), in preventing the retinopathy that develops in the galactose-fed rat model of diabetic ocular complications. METHODS: Sprague-Dawley rats were randomized into treatment and duration groups and fed diets with either 50% starch of 50% galactose with or without WAY-121,509 (25 mg/kg body weight per day). Progression of cataracts was monitored by slit-lamp biomicroscopy. After duration of 4, 8, 16, and 24 months, levels of plasma glucose and glycated hemoglobin, as well as erythrocyte and retinal galactose and galactitol, were measured in rats in each group. Retinal vasculatures of the 24-month rats were isolated by elastase digestion and analyzed by computer-assisted morphometry. RESULTS: Mature, diabetic-like cataracts developed within 5 weeks in all the galactose-fed, untreated rats, but only nonprogressive anterior cortical opacities were present in lenses of 85% of the ARI-treated galactosemic animals after 3 months. Plasma glucose remained the same in all groups. Erythrocyte and retinal galactose and glycated (galactosylated) hemoglobin were elevated with galactosemia and were unaffected by ARI treatment. Erythrocyte and retinal galactitol levels were decreased by 91% and 95%, respectively, with inhibitor treatment. At 24 months, capillary length, width, density, the number of microaneurysms, and the percent of capillary length involved in intraretinal microvascular abnormalities, expressed as hypercellular channels with diameters > 20 microns, were significantly increased by galactosemia and were attenuated in the galactose-fed, ARI-treated group. CONCLUSIONS: A dose of WAY-121,509 sufficient to reduce retinal polyol levels by 95% ameliorated the development of galactose-induced cataracts and diabetic-like retinopathy but was insufficient to prevent early lens opacifications or all the diabetic-like retinal microangiopathies.

Aldehyde Reductase↗
PubMed1996

Lactose metabolism and time to pregnancy.

OBJECTIVE: To investigate whether, in the absence of galactosemia, relatively high intestinal lactase activity or low activity of an enzyme involved in galactose catabolism reduces fertility, as it does in the presence of galactosemia. DESIGN: Retrospective cohort study. SETTING: Healthy women selected from the community. PATIENTS: Fifty-three married women. INTERVENTION: Urinary galactose after an oral lactose challenge (a measure of intestinal lactase activity), erythrocyte galactose-1-phosphate uridyltransferase (transferase) activity, and transferase polymorphisms by isoelectric focusing. MAIN OUTCOME MEASURE: Pregnancy rate (number of pregnancies divided by number of months at risk) in the 12 months after stopping use of birth control to become pregnant. RESULTS: Relatively high urinary galactose was not related to a decreased rate of pregnancy during the first 12 months (> or = 24.6 compared with < or = 14.3 mg: relative risk [RR] = 1.9; 95% confidence interval [CI] = 0.86 to 4.0). Relatively high transferase activity was not related to an increased rate of pregnancy (> or = 19.5 compared with < or = 17.2 mumol/h per g hemoglobin: RR = 1.1; 95% CI = 0.56 to 2.4). Low-activity transferase polymorphisms were not related to a decreased rate (RR = 1.2; 95% CI = 0.58 to 2.5). CONCLUSION: Our study does not support the hypothesis that the biologic variation in galactose metabolism that exists in the general population influences infertility.

Adolescent↗
PubMed1963

THE ASSAY OF GALACTOKINASE AND GALACTOSE-1-PHOSPHATE URIDYL TRANSFERASE ACTIVITY IN HUMAN ERYTHROCYTES. A PRESUMED TEST FOR HETEROZYGOUS CARRIERS OF THE GALACTOSEMIC DEFECT.

A simple, rapid, and direct method for measuring the activities of the galactokinase and Gal-1-P uridyl transferase enzymes in human erythrocytes is presented. The method has been applied to measurement of enzyme activities in a group of 37 presumably normal persons, 3 patients with galactosemia, 6 known heterozygous carriers of the defect, and 9 relatives of carriers. In every case the test unambiguously identified the individual's status as normal, heterozygotic carrier, or homozygously defective. Use of the test in genetic counseling and genetic epidemological studies is discussed.

Benzamides↗
PubMed1997

Capillary electrophoresis for diagnosis of metabolic disease.

Capillary electrophoresis (CE) equipped with a diode-array detector have been used to determine diagnostic metabolites occurring in urine of patients with various diseases. The urine samples were injected directly onto the CE instrument without any pretreatment. Identification of abnormal metabolites was based on relative migration times and characteristic diode-array spectra. The CE-method readily diagnosed alkaptonuria, neuroblastoma and liver failure due to galactosemia. The simple and automated CE method appears to be suitable for implementation as a screening test in analytical systems aimed at diagnosis of metabolic disorders.

Alkaptonuria↗
PubMed1996

An amino acid derived from aldol crosslink of elastin and collagen: structure, distribution, aging, and two models of hyperglycemia.

A novel amino acid named aldosine was isolated from acid hydrolysates of bovine aorta elastin. The mass spectral analysis of aldosine indicated a parent compound with a mass of 256 (C12H20N2O4). From the structure identified by spectroscopy of aldosine and its derivatives, it was deduced that aldosine was derived from aldol crosslink and dehydromerodesmosine of elastin and collagen. The aldosine content in aorta of newborn rats was very low, but increased markedly with growth. After maturity was reached, the aldosine content decreased. The aldosine content in bovine aorta decreased gradually from 7 months to 16 years of age. Aldosine was also quantified in the aorta and tail tendon of rats in two models of hyperglycemia: diabetes and galactosemia. Hyperglycemias were significantly affected on aldosine content of organs. In both diabetic and galactosemic animals, aldosine was remarkably lower relative to controls (about one-half and one-sixth, respectively).

Aging↗
PubMed1999

Homogeneous bioluminescence assay for galactosuria: interference and kinetic analysis.

Elevated galactose concentration in urine is an important clinical symptom of galactosemia and other metabolic disorders. A quantitative assay for galactose using firefly luciferase bioluminescence is presented. The assay couples the galactokinase and firefly luciferase reactions. A higher concentration of galactose present in the sample produces a faster decrease in ATP concentration, which is monitored by firefly luciferase bioluminescence. The kinetic assay is modeled and analyzed. The interference between the two reactions, the interference of certain sugars and other components in the urine, the specificity, and the optimal pH for galactokinase were studied. Calibration curves were constructed and compared with a conventional spectrophotometric assay for galactose. The bioluminescence assay is relatively fast and specific for galactose with a linear range from 1 to 20 mM galactose. The effect of other galactose metabolites (galactonate and galactitol) has also been studied.

Adenosine Triphosphate↗
PubMed1995

Molecular cloning, characterization, and mapping of a full-length cDNA encoding human UDP-galactose 4'-epimerase.

Galactose metabolism in all organisms is catalyzed by three enzymatic steps: the galactokinase, galactose-1-phosphate uridyltransferase, and UDP galactose 4'-epimerase reactions. We report here the molecular cloning, characterization, and mapping of a full-length cDNA encoding human UDP-galactose 4'-epimerase (GALE). Our cDNA is 1488 bp long and matches the mRNA size of 1.5 kg detected in fibroblasts and lymphoblasts. The human GALE cDNA encodes a predicted protein of 348 amino acids with a molecular mass of 38,266. The human GALE enzyme is 87% identical to the rat protein, 53% identical to the homologous GAL10 protein from the yeast Kluyveromyces lactis, and 51% identical to the galE protein from the prokaryote Escherichia coli. This extraordinary degree of sequence identity has allowed us to build a homology model of the human protein based on the bacterial crystal structure. This predicted human structure is very similar to the E. coli galE enzyme, suggesting that both enzymes use similar mechanisms. The human gene encoding GALE maps, as expected, to a single locus on chromosome 1 and appears to be compact. The human GALE gene is structurally intact in 19 patients with epimerase-deficiency galactosemia, an inborn error of metabolism secondary to GALE deficiency. Therefore, we propose that this disorder is due to small mutations within the gene.

Amino Acid Sequence↗
PubMed2001

Evidence for alternate galactose oxidation in a patient with deletion of the galactose-1-phosphate uridyltransferase gene.

The persistent, dietary-independent elevation of galactose metabolites in patients with galactose-1-phosphate uridyltransferase (GALT) deficiency is probably secondary to de novo synthesis of galactose. Relatively constant steady-state levels of galactose metabolites in patients also suggest that non-GALT metabolic pathways must function to dispose of the galactose synthesized each day. The discovery of a patient with a rare deletion of the GALT gene provided a unique opportunity to examine the availability of any alternate galactose oxidative capacity both in vivo and in vitro. Utilizing genomic DNA from the patient, Southern blot data demonstrated that 10 of the 11 GALT exons were homozygously deleted. By measurement of 13CO2 in expired air for up to 24 h after an oral bolus of [1-13C]galactose, it was demonstrated that 17% of the galactose was metabolized, a value comparable to the 3-h elimination rate in a control subject. Furthermore, lymphoblasts prepared from the patient could also convert [1-14C]galactose to 14CO2. This unique study provides the first unambiguous evidence that another pathway exists in man that can be responsible for galactose disposal. Further knowledge of this alternate galactose oxidative route and its regulation may aid in formulating new strategies for the treatment of galactosemia.

Blotting, Southern↗
PubMed2001

Galactose metabolism in mice with galactose-1-phosphate uridyltransferase deficiency: sucklings and 7-week-old animals fed a high-galactose diet.

Mice deficient in galactose-1-phosphate uridyltransferase (GALT) demonstrate abnormal galactose metabolism but no obvious clinical phenotype. To further dissect the pathways of galactose metabolism in these animals, galactose oxidation and metabolite levels were studied in 16-day-old sucklings and the effect of a 4 week prior exposure to a 40% glucose or 40% galactose diet was determined in 7-week-old mice. Suckling GALT-deficient (G/G) mice slowly oxidized [1-14C]galactose to 14CO2, 4.0% of the dose when fed and 7.9% when fasted compared to normal animals 38.3 and 36.4% in 4 h, respectively. Plasma of G/G sucklings contained 11.1 mM galactose and erythrocyte galactose 1-phosphate levels were 28.2 and 31.9 mg/dl packed cells. Galactose, galactitol, galactonate, and galactose 1-phosphate were found in G/G suckling mouse tissues. The tissue galactose concentrations were 10% or less of that in plasma, suggesting that there was limited cellular entry of galactose. In 7-week-old fasted mice with 4 weeks prior exposure to glucose or galactose-containing diet, 4-h oxidation was 12.9 and 15.0% of the administered radiolabeled galactose, respectively. Normal animals oxidized 33.9 and 37.9% of the dose when fed the same diets, respectively. The ability of G/G mice to oxidize galactose in the absence of GALT activity suggests the presence of alternate metabolic pathways for galactose disposition. G/G mice fed the galactose-free 40% glucose diet had erythrocyte galactose 1-phosphate levels ranging from 6.4 to 17.7 mg/dl packed cells and detectable galactose and galactose metabolites in tissues, suggesting that these animals endogenously produced galactose. The plasma of 40% galactose-fed G/G mice contained 9.1 mM galactose with red blood cell galactose 1-phosphate averaging 43.6 mg/dl. Tissues of these animals also contained high levels of galactose and galactose 1-phosphate. Liver contained over 4 micromol/g galactonate but little galactitol. Despite the elevated galactose and galactose 1-phosphate, the animals tolerated the high-galactose diet and were indistinguishable from normal animals, exhibiting no manifestations of galactose toxicity seen in human GALT-deficient galactosemia. The data suggest that high galactose 1-phosphate levels do not cause galactose toxicity and that high galactitol in combination with galactose 1-phosphate may be a prerequisite. Absence of GALT appears necessary but insufficient to produce human galactosemic phenotype.

Animals↗
PubMed1989

Galactose-1-phosphate uridyl transferase in density-fractionated erythrocytes. Studies of normal and mutant enzymes.

Galactose-1-phosphate uridyl transferase (GALT), the deficient enzyme in classical galactosemia, was studied by Percoll-gradient age-fractionation of erythrocytes. For normal GALT, a rapid and substantial decrease in GALT activity and loss of most of two isozymes was found to occur in the reticulocyte fractions. The loss of activity was then followed by relative stabilization of both GALT-specific activity and microheterogeneity in mature and aging erythrocytes. When applied to the study of mutant GALT from galactosemic patients, the Percoll-gradient fractionation method permitted detection in the reticulocyte-enriched fractions of up to 5% of normal GALT-specific activity and an isoelectric focusing pattern essentially the same as that of normal GALT. Percoll-gradient fractionation of erythrocytes offers a simple and direct method to study characteristics of GALT activity and microheterogeneity in normal and galactosemic human erythrocytes.

Cell Separation↗
PubMed1995

Partial deficiency of galactose-1-phosphate uridyltransferase.

In screening programmes testing newborns for galactose-1-phosphate uridyltransferase and/or galactose, partial enzyme deficiency is frequently discovered. This is shown for one laboratory in Switzerland where 104 newborns were singled out from a total of 476,000. Of these, 72 had partial transferase deficiency below 9 mumol/h per g Hb and were assumed to be compound heterozygotes for "classical" galactosemia and the Duarte variant. Present day management of compound heterozygotes consisting of lactose-free diet for 4 months is described and discussed in the light of published opinion. The appropiateness of this pragmatic approach can at present not be judged according to objective criteria.

Galactosemias↗
PubMed2002

Dietary management of inborn errors of metabolism.

Inborn errors of metabolism are individually rare but are an important cause of mortality and morbidity in infants and children. Dietary therapy is the mainstay of treatment in phenylketonuria, maple syrup urine disease, homocystinuria, galactosemia and glycogen storage disease (Type I/III). Some disorders like urea cycle disorders and organic acidurias require dietary modification in addition to other modalities. Certain basic principles of dietary management should be clearly understood for proper management of these disorders. Commercially available diets are very expensive and modification in routine Indian diet may be tried based on content of different nutrients but the desirable fine control is not achieved.

Child↗
PubMed1997

Quantitative assessment of whole body galactose metabolism in galactosemic patients.

We employed [1-13C] galactose in isotope kinetic studies to delineate whole body galactose metabolism in vivo in patients with galactose-1-phosphate uridyltransferase (GALT) deficiency. The data in three control and three adult galactosemic subjects, homozygous for the most common GALT gene defect, the Q188R mutation, and with absent RBC GALT activity, revealed an apparent endogenous galactose synthesis rate of 0.53-1.05 mg/kg per hour. Unlike normal children and adults who eliminated 3%-6% and 21%-47% of an intravenous bolus of [1-13C] galactose as 13CO, in expired air in 1 and 5 h respectively, classic galactosemic patients, either Q188R/Q188R or Q188R/unknown, released almost none in 1 h and 3%-6% in 5 h. In contrast, an African-American galactosemic variant patient with a S135L/S135L mutation and no residual RBC GALT activity oxidized [1-13C]galactose to 13CO2 at a rate comparable to control subjects. Individuals homozygous for the Duarte mutation, N314D/N314D and Q188R/ N314D. Q188R/+ and S135L/+ subjects also had normal breath test results. Not surprisingly, the Q188R/Q188R classic galactosemic patient cannot handle an acute galactose load, failing to match a control subject in the rapid conversion of [1-13C]galactose to [13C]glucose and 13CO2. However, classic patients synthesize substantial quantities of galactose de novo and on a lactose-free diet must oxidize comparable amounts of galactose to maintain steady-state levels of galactose and galactose metabolites such as galactose-1-phosphate, galactitol and galactonate. In vivo isotope kinetic analyses may allow us to understand better these aspects of galactose metabolism and, through the use of studies in variant galactosemics, perhaps allow us to begin to unravel the pathophysiology of galactosemia.

Adolescent↗
PubMed2005

[Inborn errors of metabolism (IEM) in adults. A new challenge to internal medicine].

Improvements in screening programs, diagnostic tests and therapeutic interventions in inborn errors of metabolism (IEM) have led to increasing and prolonged patient survival and improved prognosis of affected subjects. Today, in Germany about 200 patients with IEM survive per year into adulthood. They need specialized adult care. However, adult-oriented care is poor or absent in IEM, because traditionally, no specific adult service exists for this subspecialty and adult patients with IEM are a relatively new phenomenon. Part 1 of this overview deals with the diagnostic procedures of IEM in infancy, the principles of therapy in childhood, and the problems of transition/transfer of patients from pediatric to adult-oriented care. In part 2 the necessities of treatment in adults with the currently most important IEM are reported, which are mainly phenylketonuria and lysosomal storage diseases and less frequently glycogen storage disease type I, galactosemia, urea cycle disorders, and homocystinuria.

Adult↗