Identification of Mutations Causing 6-Pyruvoyl- Tetrahydrobiopterin Synthase Deficiency in Polish Patients With Variant Hyperphenylalaninemia.

Background: 6-Pyruvoyl-tetrahydrobiopterin synthase (PTPS) is required for biosynthesis of tetrahydrobiopterin, the cofactor of various enzymes including the hepatic phenylalanine hydroxylase. Mutations in the PTS gene result in a variant type of hyperphenylalaninemia, requiring cofactor replacement therapy for treatment. Methods and Results: Four Polish patients with PTPS deficiency were screened for mutations in the PTS gene. Three novel mutations E35G, N36K, and F100V were identified. In one patient, a known mutation D136V was identified in both PTS alleles. Conclusions: Mutation D136V present in both alleles was proposed to be connected with a mild form of PTPS deficiency. The other three mutations were found in heterozygous patients with a central type of PTPS deficiency. D136V mutation is a common mutation in the Polish population.

[Maternal PKU syndrome as an obstetric problem: literature review and own clinical experience]. / Zespól fenyloketonurii matczynej jako problem polozniczy--przedstawienie wspólczesnych pogladów i wlasnych doswiadczen klinicznych.

Maternal phenylketonuria (M-PKU) is a syndrome of embryo- and fetopathy observed in the offsprings of mothers with increased blood level of phenylalanine. These women fall into two groups: phenylketonuria (PKU) and mild hyperphenylalaninemia (MHP). The Phe--level safe for the fetus is 4-6 mg%. Typical for M-PKU syndrome is: microcephalia, mental retardation, intrauterine growth retardation, congenital heart diseases and other anomalies like esophageal atresia, meningocoele, Pierre-Robin syndrome, cataract. The only way to prevent this syndrome is Phe--restricted diet that should be initiated before conception. We reviewed updated literature on the pathogenesis of this syndrome, clinic, possibility of prophylaxis and treatment. We present also 5 pregnancies of 3 patients with PKU, treated in National Research Institute of Mother and Child in Warsaw. On that ground we propose the scheme of prevention of maternal PKU syndrome.

[Standards for diagnosis and treatment of phenylketonuria].

The aim of this study is to unify the diagnostic and therapeutic standards in phenylketonuria. The course of the disease, diagnostic methods as well as treatment procedures is presented. Standards of treatment are based on the experiences and research carried out by the Screening Tests Unit of the Department of Public Health and the Clinical Department of Paediatrics of the National Research Institute of Mother and Child in Warsaw.

Longitudinal study on early diagnosis and treatment of phenylketonuria in Poland.

Early diagnosis and treatment of phenylketonuria (PKU) in Poland was started in 1965, initially on a voluntary and then on a obligatory basis. Guthrie tests have been used for newborn screening. For confirmation of diagnosis changing with time methods of blood phenylalanine (Phe) and tyrosine estimation were used. In addition, Phe and its urinary metabolites were estimated. A total of 560 cases of classical PKU, 99 mild hyperphenylalaninaemia and six atypical PKU cases were detected. The age of confirmatory estimations was from the 1st to 3rd month, in some cases above 3 months. Pretreatment Phe levels ranged from 12.5 to 70.7 mg/dl. The diet was started on a hospital basis and continued at home, controlled with Guthrie tests with age dependent frequency. Periodical multidimensional controls allowed evaluation of physical and mental development, together with biochemical scores (Hb, RBC, total plasma protein, Phe and tyrosin). In some patients trace elements (copper, iron, zinc and selenium) were also determined. Physical development of treated patients was normal. Biochemical scores presented transient relatively low Hb and iron concentrations especially in the youngest patients. DQ/IQ scores correlated with dietary control and social environment. In adults (age 19-26 years) off diet, mean IQ was 97.2 +/- 15.5 in those with good dietary control and 81.0 +/- 13.8 in those poorly controlled during treatment. In adults the average level of education attained was various types of professional school. Some patients attended or graduated from university.

[Galactosemia]. / Galaktozemia.

This paper is a review of inborn errors in galactose metabolism with special attention being paid to practical aspects of this problem. The authors presented the history of experimental research on galactose metabolism in human body, patomechanisms of biochemical abnormalities and clinical course of the disease as well as the review of genetic papers regarding polymarphism of galactose-1-phosphate uridyl transferase, galactosemic variants in human population and the possibilities of early diagnosis and treatment of galactosemia.

[Clinical and biochemical diagnosis of galactosemia among our cases]. / Kliniczna i biochemiczna diagnostyka galaktozemii na podstawie wlasnych przypadków.

Clinical and biochemical diagnostic studies concerned 17 cases of galactosemia coming from 15 not consauguineous families. Galactosemia was diagnosed between 1-st day and 11-th month of life. Tentative diagnosis based on clinical picture was made in 12 infants, others were detected through family history of galactosemia and/or biochemical newborn screening carried out at the National Research Institute of Mother and Child since 1969. Clinical symptoms of galactosemia occurred in most patients in the first week of life. They were the following (tab. II): hepatomegaly (in 94%), jaundice (81%), splenomegaly (79%), vomitus (62%) and diarrhoea in 56% of patients. Cataract was found in 6 infants (38%). Biochemical diagnosis was based on the results of enzymatic estimation of galactose-1-phosphate uridyl transferase activity in blood, galactose-1-phosphate in red blood cells and galactose in blood and urine. No activity of galactose-1-phosphate uridyl transferase was found in all patients, and the concentration of galactose-1-phosphate was higher than 25 mg/100 ml of red blood cells. High galactose level was observed in blood and urine in all patients with typical clinical course of galactosemia. In 2 patients however without clinical symptoms of the disease only trace amounts of galactose was detected in blood and urine. All these patients were treated with galactose free diet.

Preliminary results of UDP galactose pyrophosphorylase in the erythrocytes of healthy persons and in patients with galactosaemia.

Direct chromatographic isolation of UDP galactose and galactose-1-phosphate was used for determination of the activity of UDP galactose pyrophosphorylase in erythrocytes. The activity was determined by measuring the amount of UDP galactose produced from galactose-1-phosphate and uridine triphosphate. In homozygotes with galactosaemia the activity of the enzyme was nearly ten times lower than in controls, so this difference was highly significant statistically (p less than or equal to 0.001) and the respective values were 0.0051 +/- 0.0003 and 0.0418 +/- 0.0038 mumol of UDP galactose formed during 1 hour by 1 ml of erythrocytes (300 mg of haemoglobin). In heterozygotes with galactosaemia the activity of the enzyme had intermediate values between those in homozygotes and healthy controls.

[Mutations causing hereditary hyperphenylalaninemia]. / Mutacje powodujace dziedziczna hiperfenyloalaninemie.

Mutations in the genes encoding different parts of phenylalanine hydroxylation system cause persistent hyperphenylalaninaemia. The most frequent form of hyperphenylalaninaemia is caused by mutations in the PAH gene. The most common variant result from defect of tetrahydrobiopterin synthase. Mutations in the PAH and PTS genes in the Polish population are presented. Genotype--phenotype correlations are discussed.

[Progress in the early detection of inborn errors of metabolism]. / Postepy we wczesnym rozpoznawaniu genetycznie uwarunkowanych zaburzen metabolicznych.

The aim of present study was to evaluate the effectiveness of screening program for early detection of some metabolic errors in newborn population. The examinations included: early diagnostic of some amino acids and carbohydrates disturbances, cystic fibrosis and congenital hypothyreosis. Guthrie test and multidirectional urine screening test were used for the diagnostics of inborn errors in amino acids metabolism. Guthrie test for phenylalanine proved its high effectiveness and taking into account the relatively high frequency of phenylketonuria in our population this screening has been introduced as obligatory. The evaluation of pilot screening for tyrosinemia, homocystinuria and histidinemia in spite of no objections as to the tests themselves proved low frequency of these disorders in our country, sofar these tests have been abandoned. Multidirectional urine screening carried out in 6-8 weeks old infants allows for follow up control for some aminoacidopathies, and also for the detection of some transport metabolism and other metabolic errors. There is no doubt that screening tests for galactosemia should be carried out because of severe course of the disease and good results of its treatment. Problem to be discussed is the choice of screening procedure and age at which it should be performed. Cystic fibrosis being one of the most common disease in the group of metabolic disorders needs to be screened, because the detection allows for early introduction of complex palliative treatment. The comparative evaluation of three meconium tests for cystic fibrosis revealed dry paper meconium test to be the most useful and following to organize central screening center. Skin chloride system being fast and easy test is too expensive to be introduced as mass screening. Results of pilot screening study for congenital hypothyreosis point out the necessity for the mass diagnostic of this disorders. Choice of the test however is connected with economical aspects of the screening procedure.

Red blood cells and serum antioxidant defense systems of galactosaemic children.

Many reports have pointed out that oxidative damage and disturbances in antioxidant defense systems of the lenses may play an important role in the development of cataract. In the present study the activities of glutathione peroxidase, glutathione reductase, glutathione-S-transferase, glucose-6-phosphate dehydrogenase, catalase and the level of glutathione and lipid peroxides were measured in red blood cells of galactosaemic children with cataract and without cataract. Furthermore the serum antioxidant activity and the level of uric acid. ceruloplasmin and transferrin in serum were estimated. It was found that in red blood cells of galactosaemic children with cataract the activity of glutathione reductase was slightly lower than in a control age-matched group of children and in galactosaemic children without cataract. The increase of serum antioxidant activity in both groups of galactosaemic children was also observed. Probably it could be due to the increase of the level of ceruloplasmin. Except glutathione reductase activity no other differences were found in the investigated components of the antioxidant defense systems of red blood cells and serum between galactosaemic children with cataract and those without cataract. Therefore it seems that red blood cells and serum metabolism are no good reflections of disturbances in antioxidant defense mechanisms which may be involved in the cataract development in galactosaemic children.