bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of high phenylalanine concentration on chick embryonic development
Authors: Kirby M. L. , Miyagawa S. T. 
Published: June 2005

SummaryCells from a particular portion of the cranial neural crest (cardiac neural crest) migrate from the neural fold into pharyngeal arches 3, 4 and 6, where they provide the support for the endothelium of the aortic arch arteries, and by migration into the outflow tract become involved in septation of the truncus arteriosus. Ablation of the premigratory cardiac neural crest results in persistent truncus arteriosus and other defects reminiscent of the DiGeorge syndrome in man. Removal of a small area of the cardiac neural crest causes a spectrum of heart defects classified together as dextraposed aorta including changes like that of Fallot's tetralogy in man. Some inflow tract anomalies have also been found. Pilot studies injecting phenylalanine into developing chick embryos at a very early stage had little effect on embryo viability or on the incidence of congenital heart defects. However, sham‐treated animals produced predominantly small simple ventricular septal defects but phenylalanine‐treated embryos had more serious and complex heart anomalies. It is not possible to say yet that congenital heart disease in the offspring of mothers with untreated phenylketonuria is due to phenylalanine‐induced damage to the neural crest, but the pilot studies in chick suggest that this idea is worth pursuing.
Clinical aspects of mitochondrial disorders
Authors: Munnich A. , Rustin P. , Rötig A. , Chretien D. , Bonnefont J.‐P. , Nuttin C. , Cormier V. , Vassault A. , Parvy P. , Bardet J. , Charpentier C. , Rabier D. , Saudubray J.‐M. 
Published: June 2005

SummaryMitochondrial disorders have long been regarded as neuromuscular diseases only. In fact, owing to the ubiquitous nature of the oxidative phosphorylation, a broad spectrum of clinical features should be expected in mitochondrial disorders. Here, we present eight puzzling observations which give support to the view that a disorder of oxidative phosphorylation can give rise to any symptom in any organ or tissue with any apparent mode of inheritance. Consequently, we suggest giving consideration to the diagnosis of a mitochondrial disorder when dealing with an unexplained association of symptoms, with an early onset and a rapidly progressive course involving seemingly unrelated organs. Determination of lactate/pyruvate and ketone body molar ratios in plasma can help to select patients at risk for this condition.
Nucleus‐driven mutations of human mitochondrial DNA
Authors: Zeviani M. 
Published: June 2005

SummaryNeuromuscular disorders due to abnormalities of mitochondrial energy supply have become an important area of human pathology. In particular, lesions of the mitochondrial genome (mtDNA), a small extra‐nuclear chromosome which encodes 13 subunits of the respiratory chain complexes, are responsible for a steadily increasing number of neuromuscular syndromes. In addition to sporadic or maternally‐inherited mutations, either qualitative or quantitative abnormalities of mtDNA can be transmitted as Mendelian traits, leading to well‐defined mitochondrial encephalomyopathies. The latter are presumably caused by mutations in still unknown nucleus‐encoded genes which deleteriously interact with the mitochondrial genome. These observations are of importance from both clinical and theoretical points of view, because they are the first examples of diseases produced by abnormalities of the nuclear control over mitochondrial biogenesis.
Molecular detection of altered X‐inactivation patterns in the diagnosis of genetic disease
Authors: Malcolm S. 
Published: June 2005

SummaryIt is widely assumed that when a female carrier of a genetic disorder exhibits clinical signs of the disorder it is due to chance non‐random X‐inactivation in particular tissues. Recently molecular methods have become available for the analysis of X‐chromosome inactivation status. These are based either on the methylation patterns of DNA from the active and inactive chromosomes or on the rescue of active X chromosomes in somatic cell hybrids. As a consequence of the molecular studies, it has become obvious that there are some special cases of non‐random X‐inactivation patterns. These include females carrying X‐linked immunodeficiencies and, sometimes, one of a pair of identical female twins.
Molecular analysis of the fragile X syndrome
Authors: Hirst M. C. , Knight S. M. , Nakahori Y. , Roche A. , Davies K. E. 
Published: June 2005

SummaryThe molecular analysis of human X‐linked disease has progressed rapidly over the last few years owing to advances in power of mapping techniques. Physical DNA maps covering more than 5 million base pairs have been constructed for several chromosomal regions. Many of these regions have now also been cloned into overlapping cosmid and YAC contigs facilitating the search for disease genes. The recent identification of the mutation in the fragile X syndrome is such an example of the power of YAC technology in the characterization of human genetic disease mutations.
Molecular genetics of mineral metabolic disorders
Authors: Thakker R. V. 
Published: June 2005

SummaryThe recent advances in molecular biology and cytogenetics have made it possible to localize, clone and characterize some of the genetic abnormalities which result in disorders of phosphate and calcium homeostasis. Thus, the genes causing X‐linked hypophosphataemic rickets, Lowe syndrome, X‐linked recessive hypoparathyroidism, Di George syndrome, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2 and vitamin D‐dependent rickets type I have been mapped. In addition the genes involved in the pathogenesis of the humoral hypercalcaemia of malignancy, vitamin D‐dependent rickets type II, pseudohypoparathyroidism, and some of the autosomal forms of hypoparathyroidism have been cloned and the mutations characterized. The molecular and genetic studies which have mapped and identified these disease genes are described and the implications of these developments in clinical practice and in further elucidation of the mineral metabolic defects are discussed.
X‐linked hypophosphataemia: A homologous phenotype in humans and mice with unusual organ‐specific gene dosage
Authors: Scriver C. R. , Tenenhouse H. S. 
Published: June 2005

SummaryXLH (X‐linked hypophosphataemia, gene symbolHYP, McKusick 307800, 307810) and its murine counterparts (Hyp andGy) map to a conserved segment on the X‐chromosome (Xp 22.31‐p.21.3, human; distal X, mouse). Gene dosage has received relatively little attention in the long history of research on this disease, which began over 50 years ago. Bone and teeth are sites of the principal disease manifestations in XLH (rickets, osteomalacia, interglobular dentin). Newer measures of quantitative XLH phenotypes reveal gene dose effects in bone and teeth with heterozygous values distributed between those in mutant hemizygotes and normal homozygotes. On the other hand, serum phosphate concentrations (which are low in the mutant phenotype and thereby contribute to bone and tooth phenotypes) do not show gene dosage. InHyp mice serum values in mutant hemizygotes, mutant homozygotes and heterozygotes are similar. Phosphate homeostasis reflects its renal conservation. Renal absorption of phosphate on a high‐affinity, Na+ ion‐gradient coupled system in renal brush border membrane is impaired and gene dosage is absent at this level; the mutant phenotype is fully dominant. Synthesis and degradation of 1,25(OH)2D are also abnormal in XLH (andHyp), but gene dosage in these parameters has not yet been measured. An (unidentified) inhibitory trans‐acting product of the X‐linked locus, affecting phosphate transport and vitamin D metabolism, acting perhaps through cytosolic protein kinase C, could explain the renal phenotype. But why would it have a normal gene dose effect in bone and teeth? Since the locus may have duplicated (to formHyp andGy), and shows evidence of variable expression in different organs (inner ear, bone/teeth, kidney), it may have been recruited during evolution to multiple functions.
Mouse models of hypoxanthine phosphoribosyltransferase deficiency
Authors: Williamson D. J. , Hooper M. L. , Melton D. W. 
Published: June 2005

SummaryLesch‐Nyhan syndrome is an X‐linked disease caused by the deficiency of hypoxanthine phosphoribosyltransferase, an enzyme involved in the purine salvage pathways. It is characterized by severe gout, choreoathetosis, self‐mutilatory behaviour and mental retardation. The derivation of mice genetically deficient in this enzyme may help to elucidate the pathogenesis of the neurological abnormality where previously models using drug administration to mimic the disorder have had to suffice.
Biochemistry and molecular biology of chronic granulomatous disease
Authors: Segal A. W. 
Published: June 2005

SummaryThe NADPH oxidase of phagocytic cells is an electron transport chain in the wall of the endocytic vacuole that is activated upon engulfment of the microbe, and is important for its efficient killing and digestion. The oxidase consists of a heterodimeric cytochrome b in the membrane, which is the site of the haem and FAD groups, and two cystolic factors p47‐phox and p67‐phox that appear to activate the system. Absence of this oxidase as a result of defects in each of these specialized proteins causes the syndrome of chronic granulomatous disease (CGD), that is characterized by a profound predisposition to pyogenic infection.
DNA‐based presymptomatic diagnosis of Wilson disease
Authors: Gaffney D. , Walker J. L. , O'Donnell J. G. , Fell G. S. , O'Neill K. F. , Park R. H. R. , Russell R. I. 
Published: June 2005

SummaryInvestigation using DNA markers in a family with Wilson disease revealed that an apparently normal child of 10 years of age with non‐diagnostic copper biochemistry had the disease. The procedure used linked restriction fragment length polymorphic markers. Demonstration of increased liver copper concentration from a liver biopsy confirmed the diagnosis and the child was started on chelation therapy. Two other asymptomatic siblings were shown, using the same techniques, not to have the disease. Similar analysis was carried out on another family with just one index case.
Hereditary tyrosinaemia type II in a consanguineous Ashkenazi Jewish family: Intrafamilial variation in phenotype; absence of parental phenotype effects on the fetus
Authors: Chitayat D. , Balbul A. , Hani V. , Mamer O. A. , Clow C. , Scriver C. R. 
Published: June 2005

SummaryWe describe an Ashkenazi Jewish family in which two adults, offspring of consanguineous parents, have persistent hypertyrosinaemia (770–1110 µmol/L; normal < 110 µmol/L). The metabolic disorder in this family is apparently due to hepatic cytosolic tyrosine aminotransferase deficiency (hereditary tyrosinaemia, type II; McKusick, 276600), because it is associated with the oculocutaneous manifestations of Richner‐Hanhart syndrome. The association of this syndrome with hereditary tyrosinaemia type II is presumed to be constant. It is not in this family. The affected female sib (age 41 years) has hypertyrosinaemia and oculocutaneous signs; the brother (age 39 years) has hypertyrosinaemia but no oculocutaneous disease. Both sibs have two children; none has signs of a metabolic fetopathy. Maternal hypertyrosinaemia and maternal hyperphenylalaninaemia evidently constitute different risk factors for the fetus. Paternal hypertyrosinaemia is apparently not a risk to male infertility.
Tris discriminates between the different α‐glucosidase activities from extracts of human neutrophils
Authors: Ortiz de Apodaca M. Asunción , Fernandez E. , de la Fuente G. 
Published: June 2005

SummaryIn an attempt to detect acid maltase deficiency in neutrophils from patients with type II glycogenosis, without interference from the ‘renal’ α‐glucosidase activity present in these cells, we have evaluated the contribution of the renal component in the total activity measured at pH 4.0 in extracts of human neutrophils. The renal contribution is about 13–25% and renal glucosidase appears to be closely related to the enzyme present on the epithelium of small intestine, which is known to be inhibited by Tris. We have used this compound as a selective inhibitor of the renal component of α‐glucosidase activity measured at pH 4.0 in total extracts of neutrophils. Our results demonstrate that 0.1 mol/L Tris is an inhibitor of the renal α‐glucosidase present in neutrophils and can be used to reduce the interference from this enzyme in assays of acid maltase.
Thiamine transport by erythrocytes and ghosts in thiamine‐responsive megaloblastic anaemia
Authors: Rindi G. , Casirola D. , Poggi V. , De Vizia B. , Patrini C. , Laforenza U. 
Published: June 2005

SummaryA 9‐year study of thiamine metabolism and cellular transport was performed in two patients with thiamine‐responsive megaloblastic anaemia associated with diabetes mellitus and sensorineural deafness, in their relatives, and in age‐matched controls from the same area. The ratios between the content of thiamine and that of its phosphoesters in erythrocytes were within the normal range, whereas the absolute values of thiamine and thiamine compounds were reduced by about 40% as compared to controls. Thiamine pyrophosphokinase activity was about 30% lower than in controls. Thiamine treatment restored the levels of thiamine and thiamine compounds to normal values, whereas kinase was unaffected. Both the saturable (specific, predominant at low, < 2 µmol/L, physiological concentrations of thiamine) and the non‐saturable component of thiamine transport were investigated. Erythrocytes and ghosts from patients exhibited no saturable component, this abnormality being specific for the patients and not shared by their parents. It is concluded that the cells from thiamine‐responsive megaloblastic anaemia patients contain low levels of thiamine compounds, probably due to their inability to take up and retain physiological concentrations of thiamine, as a result of the lack of the saturable, specific component of transport and reduced thiamine pyrophosphokinase.
Decreased selenium intake and low plasma selenium concentrations leading to clinical symptoms in a child with propionic acidaemia
Authors: Yannicelli S. , Hambidge K. M. , Picciano M. F. 
Published: June 2005

SummaryA child with biotin‐non‐responsive propionic acidaemia treated with a propiogenic amino acid‐restricted diet presented with an elevated blood mean corpuscular volume (MCV) of 93.1 fl, indicative of macrocytosis, and unusual hair texture with hypopigmentation. Plasma selenium concentration at this time was subnormal (45.9 µg/L), and calculated dietary selenium intake was 4.7 µg/day. After 4 months of selenium supplementation (50 µg/day) plasma selenium concentration normalized (97.7 µg/L) in conjunction with a reduced MCV (84.0 fl) and a dramatic improvement in hair growth, colour and length. Two additional periods off and on selenium supplementation, of varying time intervals, resulted in similar clinical changes. We conclude that these clinical changes were due to a deficient intake of dietary selenium.
Galactosylcerebrosidase activity in tissues of twitcher mice with and without bone marrow transplantation
Authors: Seller M. J. , Perkins K. J. , Fenson A. H. 
Published: June 2005

AbstractGalactosylcerebrosidase activity was measured and compared in brain, liver, tongue and bone marrow of twitcher (twi/twi) mice, an animal model of human Krabbe's disease, and in normal heterozygotes (twi/+). There was a reduction in enzyme activity in all tissues in twi/twi mice, but the magnitude of the reduction varied, being greatest in the bone marrow (3% of the heterozygote activity). Twitcher mice were transplanted with normal bone marrow cells at birth without prior irradiation, and just over half had a significant increase in their bone marrow enzyme activity, but not in other tissues. The fourfold increase in the enzyme activity was not associated with any improvement in the clinical picture or prolongation of lifespan.
3‐Hydroxy‐3‐methylglutaryl‐coenzyme A lyase deficiency: Biochemical studies and family investigation of four generations
Authors: Barash V. , Mandel H. , Sella S. , Geiger R. 
Published: June 2005

Summary3‐hydroxy‐3‐methyl‐glutaryl‐CoA (HMG‐CoA) lyase activity was determined by the recently described spectrophotometric method of Wanderset al. (1988a) in polymorphonuclear leukocytes and lymphocytes obtained from 33 members of a highly consanguineous Arab‐Bedouin family belonging to four generations. Seven subjects were obligatory heterozygotes (parents and grandparents of three propositi); in seven additional subjects enzyme activity in both cell types was in the heterozygote range. No asymptomatic homozygotes were found. The results support the proposed autosomal recessive mode of inheritance of this disorder.
Dihydropteridine reductase activity in eluates from dried blood spots: Automation of an assay for a national screening service
Authors: Surplice I. M. , Griffiths P. D. , Green A. , Leeming R. J. 
Published: June 2005

SummaryWe describe the automation, using a Cobas Bio centrifugal analyser, of a method for dihydropteridine reductase (DHPR) assay in eluates from dried blood spots. This is used as part of a routine screening service of neonates with hyperphenylalaninaemia in the United Kingdom. Automation reduced reagent volumes and analysis time by about 80% and improved the precision of the assay. Relating DHPR activity to haemoglobin concentration of the eluate further improved the precision of the assay and removed some differences in ‘apparent’ DHPR activity between samples from different countries and different age groups.
Glucose production rates in type 1 glycogen storage disease
Authors: Collins J. E. , Bartlett K. , Leonard J. V. , Aynsley‐Green A. 
Published: June 2005

SummaryGlucose production rates were measured in six patients with glycogen storage disease type 1 (five type 1A, one type 1B) using a primed continuous infusion of either [3‐3H]glucose or [6,6‐2H2]glucose. In four patients exogenous glucose was needed to maintain normoglycaemia. At blood glucose concentrations of 2.3–4.7 mmol/L, the endogenous glucose production rates were between 34 and 100% of that predicted for healthy subjects. No relationship was found between the blood glucose concentration and glucose production rates but there was a positive correlation between that of blood lactate and glucose production rate.The initial steady state was perturbed either by reducing the exogenous glucose infusion rate or by giving intravenous glucagon (20µg/kg) or alanine (0.1–0.2 g/kg). Reducing the exogenous glucose infusion rate had little short term effect on glucose production rate. Intravenous glucagon increased the glucose production rate as well as blood glucose and lactate concentrations. A bolus of alanine (0.2 g/kg) given intravenously increased the glucose production rate and blood glucose concentrations but blood lactate concentrations fell.In four of the patients the studies were repeated under similar conditions and the glucose production rate was higher in all patients. We conclude that the glucose production rate is not fixed but varies with the prevailing metabolic status, a finding that has implications for the treatment of type 1 glycogen storage disease.
Eicosanoid synthesis in children with cholestatic disease
Authors: Dupont J. , Amédée‐Manesme O. , Pepin D. , Chambaz J. 
Published: June 2005

SummaryThe possibility of malabsorption of triglycerides contained in the diets of children with cholestasis suggests a deficiency of essential fatty acids and, therefore, probable effects on eicosanoid metabolism. Children with either biliary atresia (BA) or syndromatic paucity of interlobular bile ducts (PILBD) were evaluated as to plasma and platelet total lipid fatty acid composition and synthesis of prostaglandins (PG) E1, PGE2, PGI2, PGF2, and thromboxane (TXB2) by whole blood incubated at 37°C for 10 min. In both diseases linoleate deficiency was present as shown by low 18:2 fatty acids in plasma lipids. The children with BA had lower plasma arachidonate than controls but normal eicosanoid synthesis except for excess PGI2. Those with PILBD had low platelet arachidonate and were severely deficient in TXB2 synthesis (<10% of controls). Three children with PILBD were fed a supplement of structured triglyceride (Captex 810) intended to provide as much as 10% of energy as linoleate for 2–3 months. Results for these three cases suggested that insufficient linoleate was absorbed to increase plasma linoleate and differences in eicosanoids could not be attributed to linoleate supplementation.
Marfan syndrome: Absence of type I or III collagen structural defects in 25 patients
Authors: Harley V. R. , Chan D. , Rogers J. G. , Cole W. G. 
Published: June 2005

SummaryThe structure and metabolism of type I and III collagens were studied in fibroblast cultures and dermis from 25 unrelated patients including 23 with typical Marfan syndrome and two infants with a very severe clinical form of this syndrome. Electrophoretic analysis of collagen α‐chains, as well as one‐ and two‐dimensional electrophoresis of collagen cyanogen bromide peptides, failed to show any evidence of primary structure defects or overmodification of lysine residues in these collagens. The proportion of hydroxylated prolyl residues in isolated α1(I) chains was also normal. There was a minimal increase in the proportion of type III collagen produced by nine cultures. The findings in this study indicate that the underlying molecular defects in the patients studied are unlikely to involve the structure of the main fibrillar type I and III collagens.
Dietary problems of phenylketonuria: Effect on CNS transmitters and their possible role in behaviour and neuropsychological function
Authors: Güttler F. , Lou H. 
Published: June 2005

AbstractThirty years ago it was observed that the synthesis of serotonin, dopamine and norepinephrine was impaired in untreated phenylketonuria (PKU) as judged either by a decreased concentration in the blood or decreased excretion in the urine of these neurotransmitters, or of their meta10545tes, 5‐hydroxyindoleacetic acid (5‐HIAA) and homovanillic acid (HVA). Fifteen years later, when early treatment of PKU with a phenylalanine restricted diet was routinely introduced, an inverse relationship was found between phenylalanine levels and the urinary excretion of dopamine and serotonin. An inverse relationship between blood phenylalanine levels and cerebrospinal fluid (CSF) concentrations of HVA and 5‐HIAA has repeatedly been reported during the past 10 years. Recently, the effect of the discontinuation of diet in PKU on the synthesis of dopamine, norepinephrine and serotonin has been examined, and the possible relationship between low levels of these neurotransmitters and impaired performance on neuropsychological tests has been evaluated. In some PKU patients the performance on neuropsychological tests of higher integrative function is impaired after discontinuation of diet, especially when blood phenylalanine values exceed 1200 µmol/L, and the patients often complain of lack of concentration and emotional instability. When these patients return to a ‘relaxed’ phenyalanine restricted, tyrosine enriched diet, the impaired neuropsychological and behavioural functions appear to be reversible. One mechanism may involve an impaired synthesis of dopamine and serotonin, as the improvement is accompanied by an increase in dopamine and serotonin excretion and a significant increase in CSF concentrations of HVA and 5‐HIAA. Quite recently it has been observed that supplementation of a free diet with tyrosine (approximately 150 mg/kg) seemed to improve personality, behaviour, reaction time or reaction time variability in patients off diet. Plasma tyrosine and CSF HVA concentrations increased significantly. Plasma phenylalanine levels remained high (>1200 µmol/L). Supplementation of a normal diet with tyrosine and tryptophan may prevent mental and neuropsychological dysfunction following diet discontinuation in PKU.