bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Galactosylcerebrosidase 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

3‐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

We 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

Glucose 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

The 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

The 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

Thirty 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.
Diagnosis in relationship to treatment of hyperphenylalaninaemia
Authors: Blaskovics M. E.
Published: June 2005

PKU is not a single simply defined entity. It is part of a spectrum of the hyperphenylalaninaemias. Natural protein loading studies with uniform Phe equivalents are simple, and they are an inexpensive and safe way to determine or catagorize the types of hyperphenylalaninaemias (excluding defects of biopterin). Evidence from the US PKU Collaborative Study indicates that all patients with PKU do not require indefinite or prolonged restrictive dietary therapy to maintain normal intellectual functioning. Although there are as yet no absolute criteria, it appears that the milder forms of PKU may need treatment for a shorter period of time.
Problems related to diet management of maternal phenylketonuria
Authors: Acosta P. B. , Stepnick‐Gropper S.
Published: June 2005

Provision of nutritionally complete elemental diets for pregnant women with PKU requires greater knowledge of ‘conditionally’ essential nutrient requirements than is presently available as well as application of known information. Formulation of elemental products needs to be improved to enhance aroma and taste and to decrease osmolality. Designers of the metal and vitamin components should keep in mind that a major portion (70–80%) of most of these nutrients must be obtained from the elemental products. Thus deletion of suspected essential minerals or vitamins could cause serious deficiencies. On the other hand, knowledge of appropriate ratios that make for improved trace metal absorption should be applied. Clinical nutritionists need to assist patients in selection of foods that are low in binding substances and provide ‘conditionally’ essential nutrients in adequate amounts. Closer cooperation between clinical nutritionists, nutrition scientists and food technologists should result in improved elemental products for care of pregnant women with PKU.
Presentation of the data of the Italian registry for oculocutaneous tyrosinaemia
Authors: Fois A. , Borgogni P. , Cioni M. , Molinelli M. , Frezzotti R. , Bardelli A. M. , Lasorella G. , Barberi L. , Durand P. , Di Rocco M. , Romano C. , Parini R. , Corbetta C. , Giovannini M. , Riva E. , Balato N. , Sartorio R. , Mollica F. , Zammarchi E. , Battini M. L.
Published: June 2005

Conclusions

Type II tyrosinaemia in Italy has no regional preponderance. Neuromotor retardation and/or microcephaly seem to be correlated with the higher values of tyrosine. Enzyme studies have been refused in all patients. Treatment with a low tyrosine diet has been successful when accepted: since in many patients the diagnosis was made rather late, it is not possible to evaluate the results of the diet for the prevention of neuromotor retardation.
Studies on the molecular defect in phenylketonuria and hyperphenylalaninaemia using antibodies against phenylalanine hydroxylase
Authors: Bartholomé K. , Dresel A.
Published: June 2005

Monospecific antibodies against human phenylalanine hydroxylase were prepared. Liver extract of 10 patients with phenylketonuria (PKU) and of two patients with hyperphenylalaninaemia were examined for reactivity toward the antibodies in crossed immunoelectrophoresis. In all patients phenylalanine hydroxylase could be detected. In nine out of 10 patients with PKU the mutant enzyme did not differ from the wild type enzyme with respect to the electrophoretic mobility. In one case the mutant enzyme had a more negative charge. In the patients with hyperphenylalaninaemia the enzyme of one patient had normal electrophoretic mobility and the enzyme of the other differed from the normal enzyme. No difference could be shown in heterozygotes for PKU.
Turnover of the fast components of myelin and myelin proteins in experimental hyperphenylalaninaemia. Relevance to termination of dietary treatment in human phenylketonuria
Authors: Hommes F. A. , Eller A. G. , Taylor E. H.
Published: June 2005

The turnover of myelin and of myelin protein fractions has been measured in the central nervous system of rats who were placed on a hyperphenylalaninaemia‐inducing diet (3%L‐phenylalanine and 0.12%p‐chlorophenylalanine added to the normal laboratory chow) when they were 25 days of age. A considerably increased turnover of the fast component of myelin and of myelin protein fractions was observed, which was not found in weight‐matched controls or in controls fed the normal laboratory chow supplemented with 0.12%p‐chlorophenylalanine. The increased turnover is therefore due to the hyperphenylalaninaemic condition and not due to the slow‐down in growth or the presence ofp‐chlorophenylalanine. Furthermore, an inhibition of myelin synthesis due to the hyperphenylalaninaemic condition has been observed.

Since these effects on myelin metabolism can be demonstrated to occur even when the brain has matured considerably, prudence should be exercised in considering the termination of the dietary treatment of patients with phenylketonuria.
Carrier detection in ornithine transcarbamylase deficiency
Authors: Haan E. A. , Danks D. M. , Grimes A. , Hoogenraad N. J.
Published: June 2005

We have studied six known heterozygotes for ornithine transcarbamylase (McKusick 31125; OTC) deficiency. All had abnormal results when tested by measurement of urine orotic acid after protein loading. Duodenal mucosa OTC assay detected fewer of the known heterozygotes but was a useful supplementary test. Urine orotic acid excretion after protein loading is influenced by age and results from women being tested must be compared with those from controls of appropriate age.
Decreased transport of ornithine across the inner mitochondrial membrane as a cause of hyperornithinaemia
Authors: Hommes F. A. , Ho C. K. , Roesel R. A. , Coryell M. E. , Gordon B. A.
Published: June 2005

Hyperornithinaemia due to a transport defect of ornithine across the inner mitochondrial membrane was demonstrated in three patients by measuring ornithine uptake by fibroblast mitochondria. Particulate compartments and soluble cytoplasm of fibroblasts were separated by a slight modification of the digitonin method of Zuurendonk and Tager. Patient's fibroblast pellet fraction contained significantly less radioactivity than control fibroblast pellet fraction after incubation of fibroblasts with [14C]‐ornithine. Since neither of the patients was deficient in ornithine‐δ‐oxoacid aminotransferase, we concluded that in these hyperornithinaemia patients a defect exists for transport of ornithine across the inner mitochondrial membrane. The exact nature of this transport defect remains to be elucidated.
Stimulation of ketogenesis by propionate in isolated rat hepatocytes: An explanation for ketosis associated with propionic acidaemia and methylmalonic acidaemia?
Authors: Rosario P. , Medina J. M.
Published: June 2005

The effect of propionate on ketone body production from oleate and octanoate in isolated rat hepatocytes was studied. Propionate (5 mmol/l) stimulated ketogenesis from oleate and octanoate, although the effect was more pronounced when octanoate was used as substrate. Propionate decreased CO2 production from fatty acids, suggesting that propionate inhibited the oxidation of free fatty acid carbons through the tricarboxylic acid cycle. Our results suggest that propionate enhanced ketogenesis as a consequence of the decrease in the rate of the tricarboxylic acid cycle, caused by propionate and/or its derivatives. The stimulation of ketogenesis caused by propionate is discussed as the possible cause of ketosis associated with propionic acidaemia and methylmalonic acidaemia.
Annotation Molecular genetics of methylenetetrahydrofolate reductase deficiency
Authors: Rozen R.
Published: June 2005

In severe MTHFR deficiency with neonatal or adolescent onset, 9 rare mutations have been identified. In mild MTHFR deficiency with thermolabile enzyme, a single common mutation (an alanine‐to‐valine substitution) is involved, but a genetic‐nutrient interactive effect is required to produce mild hyperhomocysteinaemia. This interactive effect has been proposed to be a risk factor for arteriosclerosis and for neural‐tube defects. Large‐scale studies are required for confirmation of the role of MTHFR in these multifactorial processes as well as to assess its role in other folate‐dependent disorders.
Haemostatic variables in phenylketonuric children under dietary treatment
Authors: Schulpis K. H. , Platokouki H. , Papakonstantinou E. D. , Adamtziki E. , Bargeliotis A. , Aronis S.
Published: June 2005

Classical phenylketonuria (PKU) (McKusick 261600) is an inborn error of metabolism treated by a controlled low‐phenylalanine (Phe) diet started as soon as possible in the first days of life. Such a diet can be achieved with vegetable protein and can be considered non‐atherogenic because of the reduction of animal products. Thirty patients with PKU were classified into two groups according to their annual mean Phe levels. Their daily protein intake was largely replaced by PKU2 Milupa which contains a mixture of amino acids. The product has no phenylalanine or fat of any kind. Thirty‐eight (38) individuals of comparable age were used as controls. Group A (n=15) had good compliance with the special diet (Phe mean 192±115 µmol/L); group B (n=15) did not strictly adhere to the diet (Phe mean 595±263 µmol/L). Certain haemostatic components (factors I, VII, VIII, and X, antithrombin III, protein C, and plasminogen) and lipid variables (cholesterol, triglycerides, high‐density lipoprotein, low‐density lipoprotein, very‐low‐density lipoprotein) as well as Phe levels were estimated. All the haemostatic factors studied were found within the normal range with the exception of a significant reduction in protein C in both groups of PKU patients. Furthermore, a statistically significant reduction in factor VII and X concentrations was observed in patients on strict diet. Cholesterol and low‐density lipoprotein concentrations were significantly lower in PKU children compared to normal controls. It is suggested that even though the special diet of PKU children, especially in group A, is rich in vegetables, the reduced fat intake might have impaired the absorption of vitamin K and its delivery to the site of synthesis of vitamin K‐dependent haemostatic factors.
Removal of branched‐chain amino acids andα‐ketoisocaproate by haemofiltration and haemodiafiltration
Authors: Gouyon J. B. , Semama D. , Prévot A. , Desgres J.
Published: June 2005

Venovenous haemofiltration (VVHF) and haemodiafiltration (VVHDF) were performed with a neonatal haemo(dia)filter (Miniflow 10, Hospal) on 8 anaesthetized rabbits infused with branched‐chain amino acids (leucine, isoleucine and valine) andα‐ketoisocaproate. The branched‐chain amino acids (BCAA) andα‐ketoisocaproate blood levels were close to those previously observed in neonates with maple syrup urine disease when extracorporeal blood purification was required. VVHF and VVHDF performances were assessed with two different blood flows ( and 16.6 ml/min). VVHDF was performed with four dialysate flow rates ( and 3.0 L/h).

Within each period, clearances of the three BCAA were strictly similar. BCAA clearances obtained by VVHF were similar to ultrafiltration rates (respectively, 0.78±0.14 and 1.79±0.28 ml/min at high and low;p<0.05). Theα‐ketoisocaproate clearances obtained by VVHF were 0.39±0.17 and 0.92±0.43 ml/min at low and high (not significantly different).

Whatever the value, the VVHDF procedures always allowed higher BCAA andα‐ketoisocaproate clearances as compared with the corresponding VVHF period with similar. BCAA clearances obtained by VVHDF with a 0.5 L/h dialysate flow were 4.1±0.5 and 5.4±0.5 mL/min at low and high, respectively. The concurrentα‐ketoisocaproate clearances were 2.5±0.8 and 2.9±1.0 ml/min.
Stable‐isotope selected‐ion monitoring quantification of methylmalonic acid in dried filter‐paper urine samples
Authors: Parnet J. M. , Divry P. , Vianey‐Saban C. , Mathieu M.
Published: June 2005

Urea and creatinine were measured by Kodak Ektachem methods and methylmalonic acid by stable‐isotope gas chromatography—mass spectrometry in 24 urine samples from patients with methylmalonic acidaemia. For each sample analyses were performed both directly on the liquid urine and on an aliquot which had been blotted onto filter paper and dried. There was good correlation between the methylmalonate/creatinine ratios in liquid and dried urine (r2=0.983). Urine dried on filter paper can be used advantageously for monitoring treatment in patients with this disorder.
ALDP expression in fibroblasts of patients with X‐linked adrenoleukodystrophy
Authors: Kemp S. , Mooyer P. A. W. , Bolhuis P. A. , van Geel B. M. , Mandel J. L. , Barth P. G. , Aubourg P. , Wanders R. J. A.
Published: June 2005

The adrenoleukodystrophy gene encodes a peroxisomal integral membrane protein (ALDP) consisting of 745 amino acids with a molecular weight of 75 kDa. ALDP expression was studied in fibroblasts from 24 male ALD patients from 17 unrelated ALD kindreds. In four kindreds an identical 2‐base‐pair deletion was found. We report the absence of ALDP in 12 kindreds carrying nonsense mutations, frame shifts or amino acid substitutions in the carboxy terminus of ALDP, together accounting for 71% of the ALD kindreds. ALDP was present in five kindreds (29%) with amino acid substitutions in the amino terminal half of the protein; in two of these kindreds ALDP was present although at a reduced level. The absence of truncated proteins suggests that the carboxy terminus has a function in the stabilization of ALDP.
Phospholipids accumulation in mucolipidosis IV cultured fibroblasts
Authors: Bargal R. , Bach G.
Published: June 2005

Cultured fibroblasts from mucolipidosis IV patients accumulated phospholipids when compared to normal controls or cells from other genotypes. The major stored compounds were identified as phosphatidylcholine, phosphatidylethanolamine and to a larger extent lysophosphatidylcholine and lysobisphosphatidic acid. Pulse chase experiments of32P‐labelled phospholipids showed increased retention of these compounds in the mucolipidosis IV lines throughout the pulse and chase periods. Phospholipase A1, A2, C, D and lysophospholipase showed normal activity in the mucolipidosis IV lines and thus the metabolic cause for this storage remains to be identified.
Evidence for both endogenous and exogenous sources of the sphingomyelin storage in lymphoid cell lines from patients with Niemann‐Pick disease types A and B
Authors: Levade T. , Salvayre R. , Maret A. , Douste‐Blazy L.
Published: June 2005

Epstein‐Barr virus‐transformed lymphoid cell lines from normal individuals and from patients with Niemann‐Pick disease types A, B or C were subjected to various culture conditions in order to study the source of the characteristic lysosomal storage of sphingomyelin observed in the tissues of Niemann‐Pick patients. The culture medium was supplemented with a serum substitute devoid of lipoproteins or with one of the following lipid sources: fetal calf serum, human low‐density lipoprotein (LDL), or human high‐density lipoprotein (HDL). Storage of sphingomyelin was demonstrated under all tested culture conditions in cells deficient in acid sphingomyelinase (Niemann‐Pick disease types A and B). In contrast, the sphingomyelin concentration in the lymphoid cell line from a Niemann‐Pick type C patient (not deficient in sphingomyelinase) was normal. After more than 30 days in a medium devoid of sphingomyelin, the Niemann‐Pick types A and B lymphoid cell lines showed accumulation of sphingomyelin about twice control. The concentration was higher when cells were grown in a medium supplemented with lipids, particularly human LDL or HDL. These results are consistent with the hypothesis that both exogenous and endogenous sphingomyelins participate in the lysosomal storage observed in lymphoid cell lines from patients with Niemann‐Pick disease types A and B.
Biochemical studies on prolidase in sera from control, patients with prolidase deficiency and their mother
Authors: Ohhashi T. , Ohno T. , Arata J. , Kodama H.
Published: June 2005

Prolidase activity in serum from normal subjects and the mother of two patients was readily detected without adding Mn2+ to the assay, and the activity was increased by addition of Mn2+ to the assay or preincubation with Mn2+. However, the activity in serum from patients with prolidase deficiency against gly‐pro, leu‐pro and val‐pro could not be detected irrespective of Mn2+ conditions and activity against met‐pro, ala‐pro and phe‐pro also showed a marked reduction compared to controls. Both normal and the patients' mother's prolidase activity against gly‐pro was reduced about 20% at 60°C compared to the activity at 37°C, but the addition of Mn2+ at 55°C increased the activity about 1.8‐fold, whereas prolidase activity of patients could not be increased by the addition of Mn2+. The addition of Co2+ increased prolidase activity in serum from control and the patients' mother but did not increase the heat stability. These results indicate that prolidase in serum from patients with prolidase deficiency is altered rather than markedly reduced in amount.
Abetalipoproteinaemia in adults: Role of vitamin therapy
Authors: MacGilchrist A. J. , Mills P. R. , Noble M. , Foulds W. S. , Simpson J. A. , Watkinson G.
Published: June 2005

The retinal and neurological complications of abetalipoproteinaemia may be preventable by replacing vitamins A and E from an early age, but their role in adult presentations is less clear. Two adult females with abetalipoproteinaemia have received 8 and 10 years respectively of replacement therapy with vitamins A, E and linoleic acid. In Case 1, visual function improved objectively on commencing therapy but has subsequently deteriorated and her neuropathy has slowly progressed. The rate of progression of neurological impairment in Case 2 was slowed but not halted by therapy, and her severe visual disturbance was unaffected. Replacement by fat soluble vitamins has only a limited role in the management of abetalipoproteinaemia once irreversible neurological/retinal damage has occurred.
Amniotic fluid glycoasparagines in fetal aspartylglycosaminuria
Authors: Mononen I. , Kaartinen V. , Mononen T.
Published: June 2005

Midterm amniotic fluid samples from one pregnancy with the fetus affected by aspartylglycosaminuria and from 11 normal pregnancies were analysed for glycoasparagines accumulating in urine in aspartylglycosaminuria. The aspartylglucosamine concentration in the affected pregnancy was about five times higher than in the controls, but the absolute value was very low being only about one‐thousandth of that in urine in aspartylglycosaminuria and one‐tenth of that in urine samples from normal adults. In total monosaccharide analysis, only galactose content in the affected amniotic fluid was slightly elevated compared to controls, indicating that higher glycoasparagines typical of urine in aspartylglycosaminuria were not accumulated in significant amounts. The data demonstrate that the analysis of glycoasparagines in amniotic fluid is not likely to permit reliable prenatal diagnosis of aspartylglycosaminuria.
Fatal lactic acidosis due to deficiency of E1 component of the pyruvate dehydrogenase complex
Authors: Birch‐Machin M. A. , Shepherd I. M. , Solomon M. , Yeaman S. J. , Gardner‐Medwin D. , Sherratt H. S. A. , Lindsay J. G. , Aynsley‐Green A. , Turnbull D. M.
Published: June 2005

Pyruvate dehydrogenase complex deficiency is thought to be a common cause of lactic acidosis. We report a patient with lactic acidosis and intermittent weakness. The rate of oxidation of pyruvate by intact skeletal muscle and liver mitochondrial fractions was impaired and pyruvate dehydrogenase complex (PDC) activity was low. The amounts of immunoreactive dihydrolipoyl transacetylase and dihydrolipoyl dehydrogenase in liver and skeletal muscle mitochondrial fractions from the patient were normal. However, there were markedly lower concentrations of both theα andβ subunits of the E1 component of PDC.
Fifteen years' experience with 212 hyperammonaemic cases at a Metabolic Unit
Authors: Tokatli A. , Coşkun T. , Özalp İ
Published: June 2005

Two hundred and twelve cases with hyperammonaemia, diagnosed at the Metabolic Unit of Hacettepe Children's Hospital over the past 15 years, were evaluated both clinically and biochemically.
Allele‐specific amplification of genomic DNA for detection of deletion mutations: Identification of a French‐Canadian tay‐sachs mutation
Authors: Kaplan F. , Boulay B. , Bayleran J. , Hechtman P.
Published: June 2005

A rapid and efficient method for the detection of a 7.6‐kb deletion in theβ‐hexosaminidase Aα‐subunit gene, a mutant allele causing Tay‐Sachs disease in French Canadians, is described. The protocol involves PCR (polymerase chain reaction) amplification of target sequences on normal and mutant chromosomes. Three amplification primers, a single 5′ primer complementary to normal and mutant DNA templates and two 3′ primers specific for normal and mutant DNA templates are required. The primers direct amplification of two unique fragments (normal and mutant) that are easily separated by gel electrophoresis. Allele‐specific oligonucleotide hybridization using normal and mutant probes to genomic DNA samples from normal, heterozygous and homozygous individuals confirms these results and is consistent with results of genotypic classification of individuals using Southern analysis. The method is applicable to detection of deletion mutations in cases where some deletion‐flanking sequence is known.
Type I hereditary tyrosinaemia: Presentation of 11 cases
Authors: Coşkun T. , Özalp İ. , Koçak N. , Yüce A. , Çaglar M. , Berger R.
Published: June 2005

Diagnostic information is supplied for the early detection of subacute and chronic forms of type I tyrosinaemia.
Chronic inflammatory bowel disease in glycogen storage disease type 1B
Authors: Sanderson I. R. , Bisset W. M. , Milla P. J. , Leonard J. V.
Published: June 2005

Two children with glycogen storage disease type 1B developed chronic inflammatory bowel disease. The first, a 7‐year‐old boy, had ileitis and later developed perianal disease. The second developed colitis by the age of 9 years; in both the features were consistent with Crohn disease. The children had neutropenia and neutrophil mobility defects characteristic of GSD‐1B. It is suggested that these neutrophil abnormalities are important in the pathogenesis of the bowel inflammation.
Primary hyperoxaluria type I: Ultrastructural observations in liver biopsies
Authors: Iancu T. C. , Danpure C. J.
Published: June 2005

The liver ultrastructure of four patients with the peroxisomal disease primary hyperoxaluria type I has been investigated. In all cases, peroxisomes of normal appearance were present in the parenchymal cells, except that they were somewhat reduced in number and size. In all patients, conspicuous lipofuscin was present, presumably resulting from the various metabolic disturbances to which the livers were subjected during the course of their disease. Considerable hepatocyte iron overloading was found in the three patients who had been haemodialysed and/or had blood transfusion. Whether the relatively mild peroxisomal abnormalities (as compared to other peroxisomal diseases, such as Zellweger's syndrome) found in these hyperoxaluric patients are related directly to the peroxisomal deficiency of alanine:glyoxylate aminotransferase, or whether they are a secondary phenomenon, resulting from the consequent metabolic disturbance, remains to be elucidated.
Alterations in cholesterol metabolism in cultured fibroblasts from patients with Niemann‐Pick disease type C
Authors: Mazière C. , Mazière J. C. , Mora L. , Lageron A. , Polonovski C. , Polonovski J.
Published: June 2005

Cholesterol synthesis, esterification and efflux were investigated in cultured fibroblasts from patients with Niemann‐Pick disease type C. Sterol synthesis from sodium acetate was markedly increased in the two Niemann‐Pick disease type C strains as compared to controls, either in the presence or absence of exogenous cholesterol supply by low‐density lipoproteins. By contrast, cholesterol esterification was about 2–3‐fold reduced when measured by oleic acid incorporation into cholesteryl esters and 10–15‐fold reduced when measured with labelled free cholesterol as precursor, although acylcoenzyme‐A: cholesterol acyltransferase activity was normal when studiedin vitro on cell homogenates. Chase experiments with14C‐cholesterol demonstrated that the rate of cholesterol efflux was decreased by about 3–4‐fold in fibroblasts from patients with Niemann‐Pick disease type C. These results provide further evidence for alterations of sterol metabolism in Niemann‐Pick disease type C and support the hypothesis of a trapping of exogenous cholesterol, which cannot enter the regulatory intracellular pools.
Hyperammonaemia and lactic acidosis in a patient with pyruvate dehydrogenase deficiency
Authors: Brown G. K. , Scholem R. D. , Hunt S. M. , Harrison J. R. , Pollard A. C.
Published: June 2005

A patient who presented in the newborn period with severe lactic acidosis and hyperammonaemia has been shown to have a specific defect in the pyruvate dehydrogenase complex. The secondary inhibition of ureagenesis in this patient appears to be due to a functional deficiency of carbamyl phosphate synthetase.
Urinary organic acids in succinic semialdehyde dehydrogenase deficiency: Evidence of α‐oxidation of 4‐hydroxybutyric acid, interaction of succinic semialdehyde with pyruvate dehydrogenase and possible secondary inhibition of mitochondrial β‐oxidation
Authors: Brown G. K. , Cromby C. H. , Manning N. J. , Pollitt R. J.
Published: June 2005

In addition to the previously reported abnormalities, urine extracts from three cases of succinic semialdehyde dehydrogenase deficiency have shown consistently increased amounts of 2,4‐dihydroxybutric acid, and its lactone, and 3‐hydroxypropionic acid, metabolites related to the α‐oxidation of 4‐hydroxybutyric acid.Threo‐ anderythro‐4,5‐dihydroxyhexanoic acids have also been identified for the first time and probably arise from the reaction of succinic semialdehyde with an intermediate in the pyruvate dehydrogenase pathway. Adipic acid excretion is also consistently raised, suggesting secondary interference with mitochondrial β‐oxidation. The presence of these metabolites could be a source of diagnostic confusion.
Amniotic fluid propionylcarnitine in methylmalonic aciduria
Authors: Penn D. , Schmidt‐Sommerfeld E. , Jakobs C. , Bieber L. L.
Published: June 2005

Amniotic fluid samples from pregnancies complicated by foetal methylmalonic aciduria and from metabolically normal pregnancies were obtained at 16–18 weeks of gestation and analysed for total, free and acylcarnitine and individual carnitine esters. The amniotic fluid concentrations of total acylcarnitine and propionylcarnitine were higher in pregnancies with methylmalonic aciduria than in normal pregnancies. The predominant carnitine ester was propionylcarnitine in the methylmalonic aciduria group and acetylcarnitine in the normal group. These findings suggest that in methylmalonic aciduria, abnormalities of carnitine metabolism already occur early in gestation. The amount of propionylcarnitine in amniotic fluid may be useful as an additional indicator of foetal methylmalonic aciduria
Urinary D‐4‐hydroxyphenyllactate, D‐phenyllactate and D‐2‐hydroxyisocaproate, abnormalities of bacterial origin
Authors: Spaapen L. J. M. , Ketting D. , Wadman S. K. , Bruinvis L. , Duran M.
Published: June 2005

Analysis of urinary organic acids in patients admitted for screening for inborn errors of metabolism incidentally revealed the presence of abnormal amounts of 4‐hydroxyphenyllactate (4‐HPLA) and phenyllactate (PLA). These compounds are found in tyrosinaemia and phenylketonuria but in our patients such disorders could not be established. By means of configuration analysis it was shown that these 2‐hydroxyacids consisted partly of theD‐enantiomers, pointing to a bacterial origin. Endogenously formed urinary 2‐hydroxyacids in tyrosinaemia or phenylketonuria consisted of only theL‐enantiomers. Furthermore, the urine of a patient with an established short bowel syndrome contained a wide variety of bacterial amino acid metabolites, including 2‐hydroxyisocaproic acid (2‐HICA). In this case 2‐HICA occurred predominantly in theD‐form whereas in the urine of a patient with maple syrup urine disease this compound appeared to have theL‐configuration.
Increased urinary excretion of putrescine in hyperargininaemia
Authors: Kato T. , Sano M. , Mizutani N. , Hayakawa C.
Published: June 2005

A 4‐year‐old boy with hyperargininaemia had an increased urinary excretion of putrescine which was exaggerated with oral ornithine supplementation. It seems unlikely that putrescine was overproduced within the gut, because a loading with a single oral dose of ornithine showed that the intestinal ornithine absorption in the patient was normal. An acceleration of extramitochondrial ornithine metabolism due to impaired mitochondrial ornithine uptake may have caused the hyperexcretion of putrescine.
Cerebrotendinous xanthomatosis: a defect in cellular sterol biosynthetic control
Authors: Barron J. L. , Maxwell J. U. , Rutherfoord G. S.
Published: June 2005

A mentally retarded woman with tendon xanthomata and normal serum cholesterol concentration was found to have raised cholestanol concentrations in the serum and in a xanthoma. This confirmed the diagnosis of cerebrotendinous xanthomatosis (CBX). No specific lipoprotein fraction was found to transport cholestanol. For the first time cultured fibroblasts from a patient with CBX were found to accumulate cholestanol.
Treatment of hyperargininaemia due to arginase deficiency with a chemically defined diet
Authors: Cederbaum S. D. , Moedjono S. J. , Shaw K. N. F. , Carter M. , Naylor E. , Walzer M.
Published: June 2005

A brother and sister aged 11 and 17 years have been reported previously to have hyperargininaemia and arginase deficiency: they were treated with a semi‐synthetic diet consisting of fat, carbohydrate, minerals, vitamins and essential amino acids in amounts equivalent to 0.55–0.65 g protein kg−1 day−1 for 2 years. Plasma arginine levels fell from 0.50–0.90 µmol/l to 0.13–0.30 µmol/l (normal range 0.02–0.15). Increased concentrations of arginine in the cerebrospinal fluid (CSF) fell from 0.069–0.098 µmol/l to 0.040–0.056 µmol/l (normal mean ± SD=0.020±0.006). Dibasic aminoaciduria returned to normal within 1 week. Substitution of the keto‐acid analogues of five essential amino acids in the formula lowered arginine concentrations further, but proved to be unpalatable. Urinary concentrations of orotic acid, uridine and uracil fell toward normal but remained increased, even when the plasma ammonia concentration was measured as normal. Both patients showed a stable clinical improvement.
Zinc status and growth of children undergoing treatment for phenylketonuria
Authors: Acosta P. B. , Fernhoff P. M. , Warshaw H. S. , Elsas L. J. , Hambidge K. M. , Ernest A. , McCabe E. R. B.
Published: June 2005

Children with phenylketonuria (PKU) are treated with semi‐synthetic diets restricted in phenylalanine. Low‐phenylalanine or phenylalanine‐free formulae provide the majority of protein and energy in the diet while phenylalanine requirements are met by low‐protein natural foods. Because of the restriction of natural protein sources in this diet, the study assessed the zinc nutrition of 22 treated children with PKU (aged from 1 month to 8 1/2 years) and correlated linear growth with zinc status.

The mean (±SE) plasma zinc concentration of the PKU population was 66.6±3.3 µg/dl. The mean (±SE) hair zinc concentration was 70.2±11.5 µg/g. The mean plasma and hair zinc concentrations of the PKU population were significantly different (p<0.05) when compared with mean (±SE) normal values of 84.2±2.9 µg/dl and 130.7±8.3 µg/g, respectively. The mean (±SD) dietary zinc intake of 10 PKU patients was 8.56±2.68 mg/day. No significant differences (p<0.123) were found when the mean zinc intake was compared with National Academy of Sciences Recommended Dietary Allowance for age of 10 mg/day. No significant correlations were found when plasma and hair zinc concentrations were plotted with height percentiles. Further studies are required to assess the effects of zinc supplementation and the bioavailability of zinc from low‐phenylalanine diets.
Normal hydroxylation of proline in collagen synthesized by skin fibroblasts from a patient with prolidase deficiency
Authors: Royce P. M. , Danks D. M.
Published: June 2005

The extent of hydroxylation of proline in collagen synthesized and secreted into the culture medium by skin fibroblasts derived from a patient with prolidase deficiency has been examined and found to be normal. It would seem likely that to a considerable extent the urinary proline‐containing dipeptides apparent in this condition are derived from sources other than collagen.
Cell genetic studies on propionyl‐CoA carboxylase deficient cell lines
Authors: van Leeuwen G. H. , de Vrieze G. , Gimpel J. A. , Huisjes H. J. , Hommes F. A.
Published: June 2005

Thirteen propionyl‐CoA carboxylase (PCC)‐deficient fibroblast lines were analysed for complementation by examining the incorporation of [14C]propionate into trichloroacetic‐acid insoluble cellular macromolecules of polyethylene‐glycol‐dimethyl‐sulphoxide induced heterokaryons formed by fusion of mutant cell lines. Corrections for variations in the rate of protein synthesis of the heterokaryons and individual cell lines was made by measuring the incorporation of [3H]lysine, added simultaneously with the labelled propionate.

Two distinct complementation groups were found in this sample of PCC‐deficient cell lines. Evidence for intragenic complementation was not obtained.
Dietary treatment and biochemical studies on a neonatal case of propionyl‐CoA carboxylase deficiency
Authors: Del Valle J. A. , Merinero B. , Jiménez A. , García M. J. , Ugarte M. , Omeñaca F. , Neustadt G. , Quero J.
Published: June 2005

The case of a patient with neonatal propionic acidaemia is reported. Despite an initially favourable response to the administration of an artificial formula, the patient finally died when 9.5 months old. Protein tolerance never exceeded 1.3 g kg−1 day−1. During the remission periods, when ingesting the formula, 3‐hydroxypropionic acid was excreted alone or together with tiglylglycine and/or methylcitrate. In a period of ketoacidosis, in addition to these three metabolites and those of ketoacidosis, elevations of 2‐methyl‐3‐oxovaleric acid, propionylglycine and 2‐methyl‐3‐hydroxybutyric acid were found. A severe deficiency of propionyl‐CoA carboxylase in cultured fibroblasts was detected; biotin, when added to the fibroblasts culture media, did not stimulate this enzyme activity. The effectiveness of the administered formula is discussed.
Carrier detection in glutaric aciduria type I using interleukin‐2‐dependent cultured lymphocytes
Authors: Seargeant L. E. , Chudley A. E. , Dilling L. A. , Mallory C. J. , Haworth J. C.
Published: June 2005

Cultured interleukin 2 (IL‐2)‐dependent leukocytes from 13 patients with glutaric aciduria type I, 12 obligate carriers, 105 family members and 31 normal controls were assayed for glutaryl‐CoA dehydrogenase activity. Of the 13 affected patients, 10 (all Ojibway Indian) had residual enzyme activity (2–13% of control) and 3 patients (all non‐Indian) had undetectable enzyme activity. There was partial overlap between the distribution of enzyme activity in obligate heterozygotes and in normal controls (mean values±SD: 6.29±0.94 and 10.75±2.58 nmol/h per mg protein respectively). Using an arbitrary cutoff level of <7 nmol/h per mg protein as presumptive evidence of carrier status, the observed frequency of carriers did not differ significantly from that expected from theira priori risk of carrier status. Thirteen per cent of the family members had inconclusive status (activity between 7 and 8.5 nmol/h per mg protein). The method appears suitable for carrier detection, although definitive carrier assignment awaits identification of the mutation(s) responsible for glutaric aciduria type I.
Characterization of phosphofructokinase‐deficient canine erythrocytes
Authors: Harvey J. W. , Pate M. G. , Mhaskar Y. , Dunaway G. A.
Published: June 2005

Dogs homozygously affected with muscle‐type phosphofructokinase (PFK) deficiency had about 20% of normal erythrocyte PFK activity and exhibited a compensated haemolytic anaemia. Erythrocyte glucose‐6‐phosphate and fructose‐6‐phosphate concentrations were increased and dihydroxyacetone phosphate and 2,3‐bisphosphoglycerate values were below normal in affected dogs. Other intermediates distal to the PFK step were not significantly below normal and fructose‐1,6‐bisphosphate was even above normal. Erythrocyte ATP was higher than normal in affected dogs owing to the reticulocytes present. Abnormal adenylate metabolism was demonstrated by low ATP/AMP and ADP/AMP ratios and the inability to maintain ATP content when affected erythrocytes were incubated with cyanide. Glucose‐1,6‐bisphosphate content was normal, and fructose‐2,6‐bisphosphate content in affected canine erythrocytes was higher than normal. Studies of erythrocyte PFK isozymes revealed altered enzyme kinetic properties in affected dogs which appeared to be due to the loss of the M‐type subunit.
Plasma lipoproteins and monocyte‐macrophages in a peroxisome‐deficient system: Study of a patient with infantile refsum disease
Authors: Mandel H. , Berant M. , Meiron D. , Aizin A. , Oiknine J. , Brook J. G. , Aviram M.
Published: June 2005

Hypocholesterolaemia in infantile Refsum disease (IRD) may link peroxisomes and lipoprotein metabolism. In our patient, plasma cholesterol levels were reduced to 26% and 29% of control in LDL and HDL fractions, respectively. Plasma apolipoproteins B‐100 and A‐I levels were 52% and 66% of controls, respectively. In the kindred, plasma cholesterol concentration was 61–73% of controls. The HDL‐cholesterol/apo A‐I ratios were: patient 0.12; kindred 0.17; controls 0.28.

Analysis of the IRD patient's lipoprotein revealed compositional abnormalities in all fractions. The patient's LDL demonstrated a substantial reduction in its lipid‐to‐protein ratio. Alterations in plasma lipoproteins affect their interaction with macrophages. Upon incubation of the patient's LDL with J‐774 macrophages, its cellular uptake, measured as cholesterol esterification rate, was only 66% of a control rate. The abnormal LDL of the IRD patient showed also only 25% of control susceptibility toin vitrooxidation. Studies of cellular cholesterol metabolism in the patient's monocyte‐derived macrophages (MDM) showed 57% increased cholesterol esterification rate in comparison to normal MDM. The possible link between lipoprotein abnormalities and monocyte‐macrophage cholesterol metabolism is discussed.