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PubMed2000

Quantitative Beutler test for newborn mass screening of galactosemia using a fluorometric microplate reader.

BACKGROUND: The Beutler enzyme spot test is an effective assay for newborn mass screening of galactosemia, but it is qualitative and relies on visual interpretation. We describe a quantitative, instrumental modification of the assay. METHODS: We modified the macroscopic visual Beutler enzyme spot test by adding extraction of blood components from filter paper, deproteinization with acetone-methanol, and quantification and recording by a fluorescent microplate reader and personal computer. All handling was performed in microplates. The measurement time was 90 min. RESULTS: Fluorescence intensity (FI) of healthy controls correlated with hematocrit and galactose-1-phosphate uridyltransferase (GALT) activity. Patients with GALT deficiency were distinguished clearly from healthy subjects and heterozygous carriers by FI. FI decreased to 75% of the initial activity after storage at 25 degrees C for 3 days and to 40% after storage at 37 degrees C for 7 days. Screening of 46 742 newborns yielded 1 false-positive result (in a heterozygous carrier), 1 patient with glucose-6-phosphate dehydrogenase deficiency, and no apparent false negatives as judged by concurrent measurements of galactose and galactose-1-phosphate. CONCLUSIONS: The quantitative Beutler test can provide precise GALT activity in newborn mass screening, and can take into consideration the influence of high temperature and humidity, duration between sampling and testing, and anemia. This method is clinically useful, simple, automated, and highly reliable for newborn mass screening of galactosemia.

Blood Specimen Collection↗
PubMed1975

Reversibility of extensive liver damage in galactosemia.

An infant with galactosemia is reported in whom extensive liver damage developed by 1 month of age. Liver biopsy obtained prior to treatment indicated extensive periportal and intralobular fibrosis, ductular cysplasia. "pseudoglandular" transformation, and distortion of periportal vasculature. Three months after institution of a galactose-free diet, clinical and biological evidence of liver disease disappeared, and follow-up biopsy at 5 months of age showed normal hepatic histology. These findings demonstrate that functional and histological abnormalities consistent with cirrhosis can be completely reversed by dietary management in galactosemia.

Biopsy, Needle↗
PubMed2002

Termination of experimental galactosemia in rats, and progression of retinal metabolic abnormalities.

PURPOSE: To investigate the effect of termination of galactose feeding after a very short duration of experimental galactosemia on the biochemical abnormalities that are postulated to contribute to the development of retinopathy. METHODS: Experimentally galactosemic rats (normal rats fed a 30% galactose-rich diet for 2 months) were fed a galactose-free diet for an additional 1 month. At the end of 3 months, retinas were removed to measure oxidative stress, nitric oxides (NOs), activity of PKC, and levels of nitrotyrosine. Data were compared between rats in the control group (fed a normal diet) and those in the experimentally galactosemic group (30% galactose diet for the entire 3 months). RESULTS: Interruption of 2 months of galactose feeding by withdrawal of galactose from the diet for 1 additional month had partially beneficial effects on retinal lipid peroxides, but the levels of an endogenous antioxidant, reduced glutathione (GSH), remained subnormal in the retina of galactose-withdrawal rats (P < 0.05 vs. normal and P > 0.05 vs. galactose group). Cessation of the galactose-rich diet had partially beneficial effects on NO levels in the retina, but the levels of nitrotyrosine, an indicator of the formation of peroxynitrite, and activation of PKC were not affected. CONCLUSIONS: The results show that retinal dysmetabolism continues to progress after experimental galactosemia is terminated in rats: Particularly, antioxidant levels remain subnormal, and nitrotyrosine levels are elevated for at least 1 month. Identification of metabolic abnormalities associated with the progression of incipient retinopathy after hyperglycemia is normalized may help in the search for the cause of retinopathy.

Animals↗
PubMed1975

[Development of a rat subline with symptoms of hereditary galactosemia and study of its biochemical characteristics].

It was established earlier that the maintenance of rats on a galactose-rich diet induced in rat liver a sequental induction of enzymes, converting galactose to glucose (galactokinase, galactoso-1-phosphaturidytransferase and uridyndiphosphogalactose-4-epimerase); this was followed by the repression of these enzymes. Against the background of the enzyme repression, the continuation of galactose treatment leads to the development of galactosemia symptoms; cataracts, liver lesions growth retardation. Animals with the increased susceptibility to galactose were found in population of Wistar rats; in these animals rapidly developing enzyme induction is followed by sharp repression of enzymes of the galactose metabolism and in them cataracts appear 17-19 days after the start of feeding a galactose-rich diet. A part of the population is resistant to the galactosemic effect of galactose and in these animals cataracts develope only 40-44 days after the beginning of the galactose feeding. By inbreeding of individuals extremely susceptible to galactose and those resistant to it, new substrains of rats were obtained. It is found that in the rats of the galactose-susceptible substrain a number of galactosemic features develope spontaneously and that these features are inheritable. Thus, 85% of the animals of the age of 2.5-6 months have cataract, lens opacities and other lens impairments. In the galactose-resistant substrain no cataracts or lens opacities develope and only slight changes of the lens are observed in 15% of the animals. In the susceptible substrain other features characteristic of galactosemia occur: an increase in the size of thymus, spleen and liver. It is established that in 3.5-5 month old rats of the galactose-susceptible substrain the galactoso-1 phosphaturidyltransferase activity in blood hemolysates is 15 times lower than in rats of galactose-resistant substrain, and in liver the activity of this enzyme is 1.4 times lower. The activity of liver galactokinase and uridyldiphosphogalactose-4-epimerase is slightly higher in rats of galactose-susceptible substrain than in galactose-resistant 1.

Animals↗
PubMed1976

[Investigation of the frequency of heterozygotes for galactose-1-phosphate-uridyl-transferase-deficiency(galactosemia) in the Vienna area. Comparison with the frequency of homozygotes found by newborn screening (author's transl)].

By routine newborn screening for galactose blood level elevations a great difference in the frequency of Galactosemia by transferase deficiency was observed between Eastern- and Western-Austria. This made enzymatic heterozygousity determinations desirable. At the same time it should be examined whether the frequency of homozygotes found by screening correlates with the frequency derived from the heterozygousity frequency. In a first step the region of Vienna was studied. 377 unselected blood samples were examined following BEUTLER-BALUDA's method. As technical control samples of 9 homozygotes and 12 heterozygotes as found by screening were examined but not included in the frequency study. Arranged following age groups a slight but significant decrease of enzym activity with increasing age could be confirmed (23,89 versus 21,99 U/g Hb). This, increasing the overlapping between normals and heterozygotes of different ages possibly should be kept in mind in individual heterzygousity determinations. The enzymatically determined frequency of heterozygotes was found to be twice as high as the frequency calculated from the frequency of biochemically detected but enzymatically proven homozygotes (1:53 versus 1:99). A comparison of the heterozygousity frequencies found in literature with the results of the most efficient (technically most reliable) screening programs shows that this discrepancy is great and general. Bases on heterozygousity frequencies the frequency of homozygotes found by screening programs seems to be at least 50% too low. Analysis of theoretical possibilities for loss of homozygotes by screening programs makes this explanation highly improbable. It seems more probable that the enzymatically determined heterozygotes frequency is too high by including still undefined allels or allel combinations which result in about half normal activity but not in disturbances resembling classical Galactosemia.

Age Factors↗
PubMedDate not supplied

[Galactosemia: the genotype and phenotype of seven patients].

INTRODUCTION: Despite early dietary therapy, many patients with galactosemia show a neurodegenerative disease specially evident in speech impairment and movement disorders. Magnetic resonance imaging of the brain, show cerebral white matter changes with hypomielinization bilateral and symetrical periventricular hypersignal in T2. PATIENTS AND METHODS: We presented clinical and neuroradiological data of seven children (3 to 12 years of age) with classical galactosemia. All had a typical presentation in neonatal period. Two children had normal development (10 and 12 years-old), four presented developmental delay (10, 7, 4 and 3 years-old), and one showed a dystonic cerebral palsy (kernicterus). RESULTS: The brain MRI showed the typical involvement of white matter, in five children, and basal ganglia abnormalities in the kernicterus patient. Three patients are homozygous for Q188R mutation and two are compound heterozygous. CONCLUSION: We found a positive correlation among developmental delay, white matter involvement and Q188R mutation.

Brain↗
PubMedDate not supplied

[Hypotonia and lethargy: initial manifestations of a new case of galactosemia].

INTRODUCTION: Galactosemia is a metabolic disease that is transmitted by autosomal recessive inheritance in which there is an enzymatic deficit that prevents the metabolism of galactose. Three enzymes could be involved, but the lack of galactose-1-phosphate uridyltransferase (GALT) is the most frequent. Incidence is two cases per 100,000 newborn infants. As a consequence of this enzymatic deficit, on ingesting milk the newborn infant will present a progressive neurological deterioration, cataracts and digestive tract and kidney disorders. An early diagnosis is essential so that galactose can be withdrawn from the diet as soon as possible, which in the newborn infant means discontinuing mother's milk and feeding with galactose-free milk. CASE REPORT: We report the case of a newborn female, the daughter of consanguineous parents (second cousins) from the gypsy ethnic group, who was diagnosed as suffering from galactosemia with a total GALT deficit. The patient was given normal milk for the first 10 days of her life and presented hypotonia, lethargy, jaundice, hepatomegaly, refusal to eat, low weight gain and a urinary infection caused by gram negative bacteria. Following diagnosis, galactose was withdrawn from the diet (she was given soy milk) and the physical exploration became progressively more normal. CONCLUSIONS: This is an extremely unusual pathology, but the patient's outcome is largely dependent on an early diagnosis and treatment.

Female↗
PubMed2003

Dietary management of galactosemia.

Galactosemia is detected by newborn screening in New South Wales and managed by the metabolic team at the Children's Hospital at Westmead. Infants with the Duarte variant are not treated. Management is based on the Handbook for Galactosemia prepared in 1998. This handbook provides information for the family on the dietary management, inheritance and ovarian function. The major dietary sources of galactose are milk and milk products. Breastfeeding must be ceased and replaced with a soy formula. Once solid foods are commenced certain foods should be avoided. Other foods, which may contain some free galactose are recommended in limited quantities only. There is no restriction on other fruits and vegetables. An ongoing issue with dietary management is adequate nutrient intake, particularly of calcium. Intake of milk substitutes and calcium supplements is often inadequate.

Australia↗
PubMed1991

Florida newborn screening for galactosemia.

Galactosemia, an inborn error of metabolism characterized by the inability to transform galactose-1-phosphate into glucose-1-phosphate, occurs in 1:50,000 live births. If not diagnosed and treated within the newborn period, it can lead to severe morbidity and mortality within a few weeks of life. All children in Florida are screened for this disorder by a fluorescence assay system to measure galactose-1-phosphate uridyltransferase (GALT) activity in a dried blood spot. Genetic factors and external forces can affect the activity of the GALT enzyme and lead to confusing results. Parents of infants heterozygous for galactosemia should be offered the opportunity for carrier detection. If both are carriers, genetic counseling should be provided.

Florida↗
PubMed1991

Verbal dyspraxia in treated galactosemia.

Galactosemia is an inborn error of metabolism that causes life-threatening illness a few days after galactose-containing milk is fed to a newborn. Early treatment with a strict lactose-free diet results in rapid improvement, and, until recently, it was thought that the long-term prognosis in such infants was usually good. The speech characteristics of 24 patients treated for galactosemia were examined. Fifty-four percent had the specific speech disorder, verbal dyspraxia. This finding was not related to age at diagnosis, severity of symptoms in the newborn period, or to biochemical control. There may be, however, a relation between dyspraxia and diminished IQ scores observed in the group of patients with dyspraxia judged as "severe." The findings indicate the association of a specific and unusual speech defect with a specific and rare metabolic disorder.

Adolescent↗
PubMedDate not supplied

[Elevated galactose transport into cells as the cause of development of hereditary galactosemia in rats].

A strain of rats with symptoms of inherited galactosemia (cataracts, hepatosplenomegaly, aminoaciduria etc) was produced by selection and inbreeding of Wistar rats highly susceptible to the galactosemic effect of galactose. The salient biochemical feature of these rats, like human galactosemics, is manifested as a decrease in the activity of galactose-I-phosphate uridyltransferase (Gal-I-PUT) in liver tissue and erythrocytes. However, the cross experiments have shown that the decrease in Gal-I-PUT activity was not required for expression of main galactosemia symptoms. Genetic analysis of cataract formation demonstrated that this trait was controlled by a single dominant gene. High transport rate of 14C-galactose into erythrocytes was a characteristic of galactosemic rats. Genetic analysis demonstrated that this trait was under the control of a single dominant gene, similar to the cataract formation. The intracellular accumulation of galactose ensured by its high transport, simultaneously with a decrease in Gal-I-PUT activity, were assumed to be the main reasons of galactosemic symptoms. The glucose transporter isolated from erythrocytes of the galactosemic rats, when integrated into the liposome membrane transferred more actively galactose into the liposomes than that of the control galactose resistant rats.

Animals↗
PubMed1982

Clinical significance of plasma galactose and erythrocyte galactose-1-phosphate measurements in transferase-deficient galactosemia and in individuals with below-normal transferase activity.

We correlated the clinical symptoms of transferase-deficient galactosemia with the plasma galactose and erythrocyte galactose-1-phosphate concentrations in six galactosemic patients during dietary treatment, in a child before treatment, and in 12 individuals with below-normal erythrocyte hexose-1-phosphate uridylyltransferase activity. All the treated patients were asymptomatic. Normal galactose and either normal or above-normal galactose-1-phosphate concentrations were found. Three of these patients were clinically normal as newborns while ingesting galactose-containing foods and may resemble the asymptomatic Negro galactosemic. The clinical symptoms of galactosemia were observed in the untreated patient, who showed markedly above-normal concentrations of galactose and galactose-1-phosphate, protein and reducing substances in the urine, above-normal bilirubin and alkaline phosphatase in the plasma, with normal values for glucose, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltransferase. Clinical improvement in this patient paralleled the decline in erythrocyte galactose-1-phosphate. The individuals with below-normal hexose-1-phosphate uridylyltransferase activity (range 7--17 U/g of hemoglobin) had normal galactose and galactose-1-phosphate concentrations and were asymptomatic.

Adolescent↗
PubMed1978

[Galactosemia and cow's milk intolerance (author's transl)].

The clinical, biochemical and anatomical studies of one case of galactosemia with cow's milk intolerance in a one month old infant are reported. Diagnosis was ascertained measuring the enzyme (Gal-1-P-Uridyl-transferase) deficiency with the methods of Anderson, Kalckar and Isselbacher. Overload and enzymatic studies were also carried out in relatives. The interest of this association of galactosemia with cow's milk intolerance, and its clinical and therapeutic implications are pointed out in the discussion.

Animals↗
PubMed1978

Prenatal diagnosis of galactosemia.

We have monitored 3 pregnancies at risk for galactosemia by deficiency in Galactose-1-Phospho uridyl transferase. Galactosemia was diagnosed in the 1st case; heterozygoty in the 2nd, and a "double heterozygoty" in the 3rd. The latter is the first example of such a diagnosis. Post natal confirmation was obtained in the three cases. Arguments are given for the usefulness of this prenatal diagnosis.

Amniocentesis↗
PubMedDate not supplied

[Efficacy of dietetic treatment in a case of galactosemia diagnosed late].

The authors describe a six months old girl affected by galactosemia, due to Galacto-1-phosphate Uridyl Transferase deficiency. The patient presented with hepatosplenomegaly and failure to thrive, without neurological impairment or cataracts. In this case removal of galactose from diet, although lately performed, resulted in normal growth and development. The authors emphasize the importance of ruling out galactosemia, even if clinical picture is unusual.

Female↗
PubMed1982

[Correction of the symptoms of hereditary galactosemia in W/SSM strain rats by enzymatic imprinting].

It was recently shown in this laboratory that treatment of newborn animals with certain enzymic inducers causes stable changes in the activities of the inducible enzymes at a later adult stage. Cataracts, hepato-splenomegaly and other galactosemia symptoms in galactosemic W/SSM rats develop spontaneously. The increased uptake of galactose by erythrocytes, but not the decreased level of galactose-1-phosphate uridyl transferase (Gal-1-PUT) activity was assumed to be the major cause of the disease. The administration of galactose to the newborn W/SSM rats (2 mg/g of body weight for 14 days) resulted in a sustained decline in the uptake of 14C-galactose by erythrocytes at least for five months, in an increase of glucoso-6-phosphate dehydrogenase activity and in a continuous fall of Gal-1-PUT activity. The neonatal treatment of the galactosemic rats with galactose abolished the main symptoms of galactosemia (cararacts, hepato-splenomegally) in adult animals, perhaps ar a consequence of the stable changes in the galactose metabolism.

Animals↗
PubMed1993

[Late diagnosis of classical galactosemia. An adult with special biochemistry].

The atypical case history of a galactosemic patient who was not recognized as such until his 22nd year is described. As in classical galactosemia there was not found any galactose-1-phosphate uridyl transferase activity in the erythrocytes. However, after the patient was on a galactose-free diet, there was no demonstrable elevation of galactose-1-phosphate in the erythrocytes. We would advocate a limited screening on galactosemia.

Adult↗
PubMed1997

Molecular basis for Duarte and Los Angeles variant galactosemia.

Human orythrocytes that are homozygous for the Duarte enzyme variant of galactosemia (D/D) have a characteristic isoform on isoelectric focusing and 50% reduction in galactose-1-phosphate uridyltransferase (GALT) enzyme activity. The Duarte biochemical phenotype has a molecular genotype of N314D/N314D. The characteristic Duarte isoform is also associated with a variant called the "Los Angeles (LA) phenotype," which has increased GALT enzyme activity. We evaluated GALT enzyme activity and screened the GALT genes of 145 patients with one or more N314D-containing alleles. We found seven with the LA biochemical phenotype, and all had a 1721C-->T transition in exon 7 in cis with the N314D missense mutation. The 1721C-->T transition is a neutral polymorphism for leucine at amino acid 218 (L218L). In pedigree analyses, this 1721C-->T transition segregated with the LA phenotype of increased GALT activity in three different biochemical phenotypes (LA/N, LA/G, and LA/D). To determine the mechanism for increased activity of the LA variant, we compared GALT mRNA, protein abundance, and enzyme thermal stability in lymphoblast cell lines of D and LA phenotypes with comparable genotypes. GALT protein abundance was increased in LA compared to D alleles, but mRNA was similar among all genotypes. When LA/D and D/D GALT biochemical phenotypes were compared to N/N GALT phenotypes, both had 50%, as compared to 21%, reduction in GALT activity in the wild type (N/N) after exposure at identical initial enzyme activity to 50 degrees C for 15 min. We conclude that the codon change N314D in cis with the base-pair transition 1721C-->T produces the LA variant of galactosemia and that this nucleotide change increases GALT activity by increasing GALT protein abundance without increasing transcription or decreasing thermal lability. A favorable codon bias for the mutated codon with consequently increased translation rates is postulated as the mechanism.

Alleles↗