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PubMed1977

[Lens changes occuring as a result of lowered pH (acidosis) (author's transl)].

In the lens, disorders of the metabolism occur, and, with them, active permeability (the cation pump with uptake of K and release of Na) changes to passive permeability and consequently Na ions enter with water. As a result, the lens increases in weight and a subcapsular (permeability) cataract develops. It is shown that the cattle lens in vitro increases in weight the lower the pH (6.5 greater than 7.5 greater than 8.5) of the surrounding fluid becomes. In a further experiment, 1 ml of buffered liquids with different pH were injected into the anterior chamber of the eyes of freshly slaughtered cattle. Here, too, the mechanically undamaged, untouched lens increased in weight more greatly as the pH (5.5 greater than 6.5 greater than 7.5 greater than 8.5) of the injected fluid was lowered. The significance of the lowering of the pH, e.g., in local inflammation (iritis, cyclitis, retinitis, etc.) or general acidoses (diabetes mellitus, galactosemia, hunger, extracorporeal circulation for atrophic kidney. Albright-, Love-, Fanconi-syndrome) for the appearance of incipient subcapsular clouding of the lens is pointed out.

Acidosis↗
PubMed1981

Reversion from deficiency of galactose-1-phosphate uridylytransferase (GALT) in an SV40-transformed human fibroblast line.

Control SV40-transformed human fibroblasts can be readily adapted to growth on medium containing galactose as sole hexose source (galactose-MEH). However, most cells from a line of SV40-transformed skin fibroblasts from a patient with galactosemia (galactose-1-phosphate uridylyltransferase (GALT) deficiency) died in galactose-MEM. Surviving cells of this line either grew in completely sugar-free media or had acquired significant amounts of GALT activity. Two presumptive revertant cell lines with GALT activity were characterized in detail. The expression of GALT in these two lines was stable in nonselective conditions. Each had different reaction maximum velocities with respect to uridine diphosphoglucose (UDPg) concentration as compared to residual activity in the parental cell strain or control cells. Both appeared to demonstrate heat-inactivation profiles for GALT than differed from the parental cells or controls. UDPG concentration was found to significantly alter the thermostability of GALT. A competitive radioimmunoassay for GALT showed that these two lines had amounts of the GALT protein comparable to that of the parental cell strain or control cells. The electrophoretic mobility of GALT from the two presumptive revertants was found to differ from control cells. It was concluded that structural gene changes were probably responsible for the apparent reversion in these lines.

Cell Line↗
PubMed1982

Long-term management of inherited renal tubular disorders.

In inherited renal tubular disorders with isolated defects of tubular transport medical treatment is usually either not indicated or is simple and effective. In some inherited metabolic disorders with complex defects of renal tubular transport a specific therapy is known. For example, in galactosemia and hereditary fructose intolerance crude products may be restricted or in cases of Wilson's disease copper stores may be reduced. In idiopathic Fanconi syndrome, cystinosis, oculocerebrorenal syndrome and glycogenosis Fanconi-Bickel, a symptomatic replacement treatment based on supplementation of water, electrolytes and vitamin D has improved the non-uremic survival of these patients considerably within the last 20 years. For long-term management of inherited renal tubular disorders, treatment of tubular dysfunction, chronic renal failure, and involved extrarenal organs must be supported by genetic counseling and assistance for social integration.

Acidosis, Renal Tubular↗
PubMed1991

Chromosomal and biochemical screening on mentally retarded school children in Taiwan.

Governmental officials as well as medical scientists in Taiwan have worked hard in recent years to develop and to implement various measures, such as prenatal diagnosis and neonatal screening, to lower the incidence of hereditary diseases and mental retardation in the population. An inquiry into the possibility of devising a chromosomal and biochemical screening program and to apply it routinely to all the mentally retarded school children island-wide was the major aim of the present study. A collection of 1,614 blood samples was screened for phenylketonuria (PKU), galactosemia, homocystinuria, biotinidase deficiency, and congenital hypothyroidism. The IQ of these children ranged from 50-75 (1,397 children, moderate group) to less than 50 (217 children, severe group). Six cases of PKU (one tetrahydrobiopterin deficient and five classical) and three cases of thyroid dysfunction were found. The overall incidence of these two diseases was 0.56%. Of the 1,614 blood samples, 1,323 were cultured and karyotyped successfully. One hundred and twenty-five of them had chromosome abnormalities. The majority (64 out of 125) were trisomy 21. A remarkable difference in the percentage of mentally retarded children with chromosome abnormalities was observed between the moderate (7.87%) and severe (17.51%) retarded.

Blood Chemical Analysis↗
PubMed2002

Nutrition management in chronic liver disease.

Liver has a central role in nutritional homeostasis and any liver disease leads to abnormalities in nutrient metabolism and subsequent malnutrition. All children with chronic liver disease (CLD) must undergo a periodic nutritional assessment--medical history, anthropometry esp. skinfold thickness and mid-arm circumference, and biochemical estimation of body nutrients. Nutritional rehabilitation is catered to the individual child but generally the caloric intake is increased to 130% of RDA by adding glucose polymers and/or MCT oil (coconut oil) with essential fatty acid supplementation (sunflower oil). The enteral route is preferred and occasionally nasogastric and/or nocturnal feeding are required to ensure an adequate intake. Proteins rich in branched chain amino acids are given in moderation (2-3 gm/kg/day) in compensated cirrhotics unless encephalopathy occurs when protein restriction may be necessary (1 gm/kg/day). Fat-soluble vitamins are supplemented in large quantities esp. in cholestasis along with other vitamins and minerals. Dietary therapy is the mainstay of management of some metabolic liver diseases and may be curative in disorders like galactosemia, fructosemia and glycogen storage disorders. Pre and postoperative nutritional support is an important factor in improving survival after liver transplantation.

Cholestasis↗
PubMed2000

Burden of genetic disorders in India.

India, like other developing countries, is facing an accelerating demographic switch to non-communicable diseases. In the cities congenital malformations and genetic disorders are important causes of morbidity and mortality. Due to the high birth rate in India a very large number of infants with genetic disorders are born every year almost half a million with malformations and 21,000 with Down syndrome. In a multi-centric study on the causes of referral for genetic counselling the top four disorders were repeated abortions (12.4%), identifiable syndromes (12.1%), chromosomal disorders (11.3%) and mental retardation (11%). In a more recent study in a private hospital the top reasons for referral were reproductive genetics (38.9%)--comprising prenatal diagnosis, recurrent abortions, infertility and Torch infections--mental retardation +/- multiple congenital anomalies (16.1%), Down syndrome (9.1%), thalassemia/haemophilia (8.8%), and muscle dystrophy/spinal muscular atrophy (8.4%). The disorders for which prenatal has been done over an 18-month-period are given. A recent study carried out in three centers (Mumbai, Delhi and Baroda) on 94,610 newborns by using a uniform proforma showed a malformation frequency of 2.03%, the commonest malformations are neural tube defects and musculo-skeletal disorders. The frequency of Down syndrome among 94,610 births was 0.87 per 1000, or 1 per 1150. Screening of 112,269 newborns for aminoacid disorders showed four disorders to be the commonest--tyrosinemia, maple syrup urine disease and phenylketonuria. Screening of cases of mental retardation for aminoacid disorders revealed four to be the commonest--hyperglycinemia, homocystinuria, alkaptonuria, and maple syrup urine disease. Metabolic studies of cases of mental retardation in AIIMS, Delhi and KEM Hospital, Mumbai, demonstrated that common disorders were those of mucopolysaccharides, lysosomes, Wilson disease, glycogen storage disease and galactosemia. It is estimated that beta- thalassemia has a frequency at birth of 1:2700, which means that about 9,000 cases of thalassemia major are born every year. Almost 5200 infants with sickle cell disease are born every year. Disorders, which deserve to be screened in the newborn period, are hypothyroidism and G-6-PD deficiency, while screening for aminoacid and other metabolic disorders could presently be restricted to symptomatic infants.

Amino Acid Metabolism, Inborn Errors↗
PubMed2005

[Inborn errors of metabolism (IEM) in adults. A new challenge to internal medicine (Part 2)].

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↗
PubMed2006

Congenital cataract and macular hypoplasia in humans associated with a de novo mutation in CRYAA and compound heterozygous mutations in P.

BACKGROUND: An isolated form of congenital cataract associated with macular hypoplasia and a generally hypopigmented fundus in infancy was observed in a German family. To test the hypothesis that a de-novo mutation had occurred in one of the parental germ lines, a functional candidate gene approach was applied. METHODS: The family was carefully examined by a senior paediatric ophthalmologist according to routine procedures (slit lamp, funduscopy, ERG). Blood was taken from the proband and his parents, genomic DNA was isolated and some candidate genes for cataract (CRYAA, CRYBB2, GJA8) or macular hypoplasia (OA1, P) or both (PAX6) were analyzed. RESULTS: The proband showed bilateral cataracts at the age of 4 months; the fundus appeared pale, the optic disc grayish, and macular reflexes were absent. After cataract surgery, the nystagmus persisted, and a control ERG at age 9 years showed essentially normal scotopic and photopic wave forms. An infectious aetiology as well as galactosemia were excluded. However, a heterozygous mutation was found in the proband in exon 1 of CRYAA (62 C-->T), which leads to an exchange from Arg to Leu at amino acid position 21 (R21L). This sequence alteration was not found in the parents and in 96 randomly selected DNA samples from ophthalmologically normal individuals of the KORA S4 study population. In addition, two heterozygous mutations in P were identified (R419Q and A481T); one of both was present in each of the unaffected parents. CONCLUSION: Based upon the unique finding of the mutation and the expression of CRYAA in the lens, this R21L mutation in the CRYAA is considered to be causative for the dominant cataract phenotype. Moreover, the macular hypoplasia has to be considered a concerted interaction with compound heterozygous mutations in the P gene manifesting a mild form of oculocutaneous albinism. Nevertheless, this combination is rare and future studies will focus on identifying similar phenotypes.

Cataract↗
PubMed1998

Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene.

Newborn screening for biotinidase deficiency has identified children with profound biotinidase deficiency (<10% of mean normal serum activity) and those with partial biotinidase deficiency (10%-30% of mean normal serum activity). Children with partial biotinidase deficiency and who are not treated with biotin do not usually exhibit symptoms unless they are stressed (i.e., prolonged infection). We found that 18 of 19 randomly selected individuals with partial deficiency have the transversion missense mutation G1330>C, which substitutes a histidine for aspartic acid444 (D444H) in one allele of the biotinidase gene. We have previously estimated that the D444H mutation results in 48% of normal enzyme activity for that allele and occurs with an estimated frequency of 0.039 in the general population. The D444H mutation in biotinidase deficiency is similar to the Duarte variant in galactosemia. The D444H mutation in one allele in combination with a mutation for profound deficiency in the other allele is the common cause of partial biotinidase deficiency.

Alleles↗
PubMed1993

Neonatal screening for maple syrup urine disease by an enzyme-mediated colorimetric method.

A microplate-based, enzyme-mediated, colorimetric method using L-leucine dehydrogenase (EC 1.4.1.9) has been developed for the determination of the combined branched-chain amino acids in plasma and blood-spot specimens. The test exhibits acceptable precision and fits into a new concept according to which the different parameters of neonatal screening programs for metabolic disorders, such as phenylalanine (phenylketonuria), galactose/galactose-1-phosphate (galactosemia) and branched-chain amino acids (maple syrup urine disease) can be measured in the same blood-spot eluate by use of different specific NAD(H)-dependent enzymes.

Amino Acid Oxidoreductases↗
PubMed1990

Diabetes-related histopathologies of the rat retina prevented with an aldose reductase inhibitor.

Recent evidence obtained from both galactosemic dogs and rats indicated that aldose reductase inhibitors could prevent several capillary lesions which were similar to those typical of diabetic retinopathy in humans. The present study demonstrates that diabetes-like histopathological changes in the intact retina, which were not visible in the vessel whole mounts used previously, can also be prevented. Sprague-Dawley rats were fed diets containing 50% galactose with or without an aldose reductase inhibitor (tolrestat). After 28 months of galactose feeding, the findings from retinal transections examined by light and electron microscopy were consistent with reports on vessel whole mounts, but showed several additional changes. There was a marked increase in the thickness of the retinal inner limiting membrane, as well as in the capillary basement membranes. There was extensive gliosis and disruption of retinal layers as well as pericyte degeneration, endothelial cell proliferation, accellularity, capillary dilation, and microaneurysm formation. The contents of pericyte compartments in the capillary wall were often replaced with non-pericyte cytoplasm, which appeared glial cell-like. Many of the lumens of acellular capillaries were occluded with debris from degenerating endothelial cells or with cytoplasm possibly originating from glial cell processes. Structures suggestive of degenerated microaneurysms were present mainly in the inner nuclear and outer plexiform layers. The microaneurysms and other major changes were limited to the central and paracentral retina. All these retinal lesions were prevented with orally administered tolrestat. Thus, long-term galactosemia in rats induced histopathologically visible angiopathies, simulating those occurring in background diabetic retinopathy in humans, and these were prevented by treatment with an aldose reductase inhibitor.

Aldehyde Reductase↗
PubMed1994

Regulatory effects of galactose on galactose-1-phosphate uridyltransferase activity on human hepatoblastoma HepG2 cells.

Galactose-1-phosphate uridyltransferase (GALT) deficiency results in galactosemia in man. We have studied the regulation of the GALT gene expression on the HepG2 cell line by growing the cells in glucose or galactose medium. No difference of Km values was observed in glucose or galactose media but the Vmax value with galactose was 50% higher than that with glucose. Also in galactose medium, an increased GALT specific activity was detected suggesting the production of more enzyme proteins. Yet, slot dot quantification of GALT mRNA revealed a decreased amount of these transcripts in cells cultured with galactose or inosine while Northern blot analysis revealed the normal 1.4 kb transcript in all culture media used. Finally, IEF gel analysis displayed different isozymic patterns for the GALT enzyme in cells grown in glucose, galactose or inosine media. With glucose-free media, the major band of GALT corresponds to that found in human liver. Altogether, these results suggest that the control of GALT gene expression in HepG2 cells is located at the post-transcriptional level and correlated to the growth rate of the cell.

Blotting, Northern↗
PubMed1986

The effect of aldose reductase and its inhibition on sugar cataract formation.

Cataracts associated with diabetes and galactosemia are characterized by their rapid onset and bilateral appearance. These cataracts display similar morphology and histology and have common biochemical mechanisms initiating the cataractous processes. An understanding of these biochemical mechanisms have been aided both by the ability to reproduce these cataracts in various animal models and by the development of potent inhibitors of aldose reductase. This is a US government work. There are no restrictions on its use.

Aldehyde Reductase↗
PubMed1994

Metabolic effects of galactose on human HepG2 hepatoblastoma cells.

HepG2 cells were used as a model system to study the effects of galactose overload on the liver, a target organ of galactose toxicity in patients suffering from transferase-deficient galactosemia. In the presence of galactose, HepG2 cell growth was slow and the pattern of gene expression remained characteristic of liver cells (secretion of alpha-fetoprotein [AFP] albumin, and transferrin). Galactose-1-phosphate (Gal-1-P) accumulated, as it does in galactosemic cells, but did not affect the energetic status of the cells (no adenosine triphosphate [ATP] depletion). However, the substitution of galactose for glucose as the sole hexose in the medium affected the specific activities of the galactose-metabolizing enzymes. Galactokinase (GALK) activity was decreased, and those of galactose-1-phosphate uridyltransferase (GALT), phosphoglucomutase, and glucose-6-phosphate dehydrogenase (G6PDH) were increased. The conversion of radiolabeled galactose to glucose (CO2 production and glycogen level) was greater in galactose medium than in glucose medium after a 7-day culture. Therefore, the culture of HepG2 cells in galactose medium indicates that the enhanced utilization of this hexose is due to the increased enzyme activities regulating its own metabolism. Hence, HepG2 cells constitute a good model for the study of modulation of galactose-metabolizing enzymes by galactose.

Analysis of Variance↗
PubMed1990

In vivo metabolism and UTP-depleting action of 2-deoxy-2-fluoro-D-galactose.

The metabolism of 2-deoxy-2-fluoro-D-galactose (dGalF) was studied in rodents using HPLC, enzymatic methods, and 19F-NMR spectroscopy in vivo and in vitro. The liver took up the major part of the administered dose of the 14C-labeled D-galactose analog. This was confirmed in vivo by use of the 18F-labeled sugar (1.5 mCi/kg; 25 mumol/kg) and examination by positron emission tomography. After a dose of 1 mmol/kg, dGalF-1-phosphate accumulated rapidly (5.3 +/- 0.4 mmol/kg after 30 min), followed by formation of UDP-dGalF and UDP-2-deoxy-2-fluoro-D-glucose (0.7 +/- 0.1 and 1.8 +/- 0.1 mmol/kg, respectively, after 5 hr). Good quantitative agreement was obtained between the measurements by HPLC and enzymatic analyses and by 19F-NMR. The noninvasive in vivo 19F-NMR technique is particularly advantageous, since it allows the simultaneous analysis of all dGalF metabolites. The diversion of uridylate, due to the accumulation of UDP-2-deoxy-2-fluoro-D-hexoses, was associated with a rapid depletion of hepatic UTP, UDP-glucose, and UDP-galactose. The UTP content was decreased to 11 +/- 6% of normal within 15 min after administration of dGalF at a dose of 1 mmol/kg. The UTP-depleting action was minimal, however, at a dose of 25 mumol/kg or less, indicating that interference in uridylate metabolism will be negligible at the doses required for positron emission tomography of the liver using the 18F-labeled compound. At higher doses the UTP deficiency induced by dGalF may be useful in the chemotherapy of D-galactose-metabolizing tumors such as hepatocellular carcinoma. At moderate doses of dGalF, 19F-NMR spectroscopy in vivo or in vitro could be used to pinpoint defects of the enzymes that cause galactosemia, i.e. of galactokinase, uridyltransferase, or 4-epimerase.

Animals↗
PubMed1996

In vivo and in vitro expression of rat galactose-1-phosphate uridyltransferase (GALT) in the developing central and peripheral nervous system.

Galactose-1-phosphate uridyltransferase (GALT) is a key enzyme in the metabolism of galactose. GALT activates the galactose-glucose interconversion and enables the synthesis of glucose-1-phosphate and UDP-galactose (UDP-Gal). UDP-Gal is the galactosyl donor for the incorporation of galactose into complex oligosaccharides, glycoproteins and glycolipids. The expression of GALT was characterized both in vivo and in vitro during late embryonic and postnatal development of the brain and peripheral nerve of the rat. Assays of GALT mRNA and protein showed that it is weakly expressed during late embryonic development with a second peak of expression concomitant with myelinogenesis. GALT was prominently expressed in myelinating Schwann cells in a rat dorsal root ganglia culture system. GALT deficiency in humans results in galactosemia, a disease characterized by long-term intellectual impairment, and probably dysmyelination. The developmentally regulated pattern of GALT expression during maturation of the nervous system may provide a molecular basis for these neurological complications which seriously compromise the outcome of many galactosemic patients.

Animals↗
PubMed2005

[Breast feeding: health benefits for child and mother].

Breast milk contains hormones, growth factors, cytokines, cells, etc., and offers many advantages over cow's milk or soy protein infant formulae. The composition of breast milk is influenced by gestational and postnatal age. Prevalence of breastfeeding in France is one of the lowest in Europe: in 2003, only 58% of infants were breastfed when leaving the maternity ward, for a median duration of 10 weeks. Breastfeeding allows normal growth until at least 6 months of age, and can be prolonged until the age of 2 years or more, provided that complementary feeding is started after 6 months. Breastfeeding is associated with slightly enhanced performance on tests of cognitive development. Exclusive breastfeeding for at least 3 months is associated with a lower incidence and severity of diarrhoea, otitis media and respiratory infection. Exclusive breastfeeding for at least 6 months is associated with a lower incidence of allergic disease in at-risk infants (infants with at least one first-degree relative presenting with allergy). Breastfeeding is also associated with a lower incidence of obesity during childhood and adolescence, as well as with a lower incidence of hypertension and hypercholesterolemia in adulthood. Maternal infection with hepatitis B and C virus is not a contraindication to breastfeeding, as opposed to HIV infection and galactosemia. A supplementation with vitamin D and K is necessary in the breastfed infant. Very few medications contraindicate breastfeeding. Premature babies can be breastfed and/or receive mother's milk and/or bank milk, provided they receive energy, protein and mineral supplements. Return to prepregnancy weight is earlier in breastfeeding mothers. Breastfeeding is also associated with a decreased risk of breast and ovarian cancer in the premenopausal period, and of hip fractures and osteoporosis in the postmenopausal period.

Breast Feeding↗
PubMed2005

Metabolic derangements in deficiency of citrin, a liver-type mitochondrial aspartate-glutamate carrier.

Citrin, encoded by SLC25A13, is a liver-type mitochondrial aspartate-glutamate carrier (AGC), of which deficiency, in autosomal recessive trait, causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). NICCD patients have jaundice, hypoproteinemia, hypoglycemia, galactosemia, growth retardation, fatty liver and multiple aminoacidemia including citrulline, methionine, threonine and tyrosine. Some of the neonates who have experienced NICCD suffer from severe CTLN2 more than 10 years or several decades later. In CTLN2, neuropsychotic symptoms such as disorientation, aberrant behavior, coma and death are observed. Laboratory findings reveal hyperammonemia, citrullinemia, fatty liver and liver-specific decrease in a urea cycle enzyme, argininosuccinate synthetase (ASS). In some cases, hyperlipidemia, pancreatitis and hepatoma are accompanied with CTLN2. Citrin as a liver-type AGC plays a role in supplying aspartate to the cytosol for urea, protein and nucleotide synthesis by exchanging mitochondrial aspartate for cytosolic glutamate and proton, and transporting cytosolic NADH reducing equivalent to mitochondria as a member of malate aspartate shuttle essential for aerobic glycolysis. AGC is also important for gluconeogenesis from lactate. Although it is difficult to explain pathogenesis of the symptoms such as cholestasis in NICCD and liver-specific decrease of ASS protein in CTLN2 from the functions of the AGC, some are understandable by the loss of citrin functions. Many CTLN2 patients have been treated with a low protein and high carbohydrate diet and glycerol at the hyperammonemic coma. We argue that those treatments may result in fatty liver, hyperlipidemia, hyperammonemia and even death due to loss of the citrin functions. Loss of citrin first cause deficiency of aspartate in the cytosol, which results in an increase in cytosolic NADH/NAD(+) ratio and then activation of fatty acid synthesis pathway to compensate the aberrant ratio. This follows inhibition of fatty acid oxidation. The peculiar fondness for food of CTLN2 patients who like protein and dislike carbohydrate and sweets may be related to their metabolic requirements.

Journal Article↗