bluuebunny/crossref_metadata_2025_split huggingface dataset:
Signals on proteins, intracellular targeting and inborn errors of organellar metabolism
Authors: Tager J. M. , Aerts J. M. F. G. , van den Bogert C. , Wanders R. J. A. 
Published: November 2004

SummaryNewly synthesized polypeptides contain signals that direct them to the appropriate intracellular organelles and the organelles contain receptors that recognize the signals. Protein synthesis occurs either on free ribosomes or on ribosomes bound to the endoplasmic reticulum. The proteins synthesized on bound ribosomes are co‐translationally translocated into the lumen of the endoplasmic reticulum and contain or acquire targeting information for retention in the endoplasmic reticulum or for sorting to lysosomes and other compartments of the secretory and endocytic pathways. Proteins synthesized on free ribosomes remain in the cytosol or contain signals for import into the nucleus, mitochondria or peroxisomes. The nature of the targeting signals and the mechanisms of import are discussed briefly. Examples are given of inborn errors of metabolism caused by incorrect or impaired incorporation of proteins into mitochondria, lysosomes or peroxisomes.
Peroxisomal disorders: A review
Authors: Fournier B. , Smeitink J. A. M. , Dorland L. , Berger R. , Saudubray J. M. , Poll‐The B. T. 
Published: November 2004

SummaryUntil recently peroxisomal disorders were considered to be extremely rare and the diagnostic procedures available for postanatal and prenatal diagnosis were not widely known. At present, 17 human disorders are linked to peroxisomal dysfunction. The clinical, biochemical and morphological peroxisome heterogeneity described in the different diseases illustrate that only combined analysis of all the different approaches will lead to a correct diagnosis and a coherent pathophysiological model to guide ongoing research. With the study of human peroxisomal diseasese, advances have been gained as to the function of the peroxisome in normal and pathological conditions. Genetic analysis of peroxisome biogenesis and research on peroxisomal targeting signals are now in progress. Peroxisomal disorders are usually classified according to the degree of biochemical impairment. In this paper, a tentative classification of peroxisomal disorders will be proposed, based on the degree of biochemical abnormalities combined with new data obtained on whether or not defective peroxisome assembly is involved: (1) disorders with peroxisome assembly deficiencies; (2) disorders with single enzyme deficiencies.The clinical onset and the major symptoms of the various disorders, and the recently discovered findings are discussed.
Modifying exogenous glucocerebrosidase for effective replacement therapy in Gaucher disease
Authors: Brady R. O. , Murray G. J. , Barton N. W. 
Published: November 2004

SummaryImportant therapeutic principles were established in developing effective enzyme replacement therapy for patients with Gaucher disease. The background and sequence of the investigations that led to effective delivery of exogenous glucocerebrosidase to the lipid‐storing macrophages in patients with Guacher disease are described. The principle of targeting the intravenously injected enzyme to the mannose lectin on the surface of these cells by engineering the glycoform of the enzyme is a useful model of an essential requirement for effective enzyme therapy. Similar strategies are expected to be effective for the treatment of a number of hereditary metabolic disorders of humans.
Impaired ketogenesis in fructose‐1,6‐bisphosphatase deficiency: a pitfall in the investigation of hypoglycaemia
Authors: Morris A. A. M. , Deshpande S. , Ward‐Platt M. P. , Whitfield A. E. , Aynsley‐Green A. , Leonard J. V. , Pourfarzam M. , Bartlett K. 
Published: November 2004

SummaryIntermediary metabolite concentrations were measured in blood during fasting in two patients with fructose‐1,6‐bisphosphatase deficiency. Hypoglycaemia was accompanied by markedly raised levels of plasma free fatty acids, without the expected degree of ketosis. This suggests that there is secondary impairment of ketogenesis in this condition, and could lead to diagnostic confusion.
An HPLC assay for detection of elevated urinaryS‐sulphocysteine, a metabolic marker of sulphite oxidase deficiency
Authors: Johnson J. L. , Rajagopalan K. V. 
Published: November 2004

SummarySulphite oxidase deficiency occurs in man in two forms, as the isolated deficiency and as a syndrome of combined molybdoenzyme deficiency. This latter pleiotropic condition has as its underlying cause a defect in the synthesis of the molybdenum cofactor required for the activity of all molybdoenzymes in humans. Difficulties in diagnosis of sulphite oxidase deficiency are often encountered. A new method for detection of a key diagnostic metabolite,S‐sulphocysteine, is outlined. The procedure is based on precolumn derivatization of urinary amino acids with dimethylaminoazobenzene sulphonyl chloride (Dabsyl‐Cl) and resolution of the modifiedS‐sulphocysteine by reversed‐phase HPLC. A number of affected patients and control individuals with similar clinical symptoms have been studied, and a clear demarcation between the two groups has been noted.
Tyrosinaemia type 1 and glutathione synthetase deficiency: two disorders with reduced hepatic thiol group concentrations and a liver 4‐fumarylacetoacetate hydrolase deficiency
Authors: Lloyd A. J. , Gray R. G. F. , Green A. 
Published: November 2004

SummaryThiol groups are important components of proteins and their oxidation can lead to a substantial loss of protein function. Patients with two apparently unrelated inborn errors of metabolism, tyrosinaemia type 1 and glutathione synthetase deficiency, have been reported to show reduced cell glutathione concentrations. We have found that not only glutathione but also protein thiol concentrations are reduced in the liver in tyrosinaemia type 1 patients. We also report a case of glutathione synthetase deficiency with a substantial deficiency of liver 4‐fumarylacetoacetate hydrolase and provide evidence that glutathione, or some small‐molecular‐weight thiol, is essential for maintaining stability of this enzymein vitro. Our results suggest that the availability of thiol groups may modify the phenotype of tyrosinaemia type 1 and that liver 4‐fumarylacetoacetate hydrolase deficiency may be a secondary complicating factor in some forms of glutathione synthetase deficiency.
A modified spectrophotometric assay for porphobilinogen deaminase: its application in the detection of both carriers and patients with acute intermittent porphyria
Authors: Vázquez‐Prado J. , Sánchez‐Anzaldo F. J. , Ruiz‐Argüelles G. J. , Marín‐López E. , Lobato‐Mendizábal E. 
Published: November 2004

SummaryA spectrophotometric method for porphobilinogen deaminase assay in erythrocytes is described. This test is determinant for the definite diagnosis of acute intermittent porphyria. In the method described, δ‐aminolevulinic acid is used as substrate. Mercaptoethanol and zinc ions are introduced to maintain δ‐aminolevulinic acid dehydratase in optimal conditions and to guarantee thein vitro production of porphobilinogen. An incubation temperature of 45°C leads to the production of uroporphyrins, which are measured spectrophotometrically at 405 nm, giving reproducible results. The assay can be performed easily in any clinical laboratory and is valuable for detecting both patients and carriers of acute intermittent porphyria.
Clinical approach to inherited peroxisomal disorders
Authors: Poggi‐Travert F. , Fournier B. , Poll‐The B. T. , Saudubray J. ‐M. 
Published: November 2004

SummaryAt least 21 genetic disorders have now been found that are linked to peroxisomal dysfunction. Whatever the genetic defect might be, peroxisomal disorders should be considered in various clinical conditions, dependent on the age of onset.The prototype of peroxisomal disorders is represented by ‘classical’ Zellweger syndrome (ZS) which is the most severe disorder combining all the characteristic symptoms. ZS is characterized by the association of errors of morphogenesis, severe neurological dysfunction, neurosensory defects, regressive changes, hepatodigestive involvement with failure to thrive, usually early death, and absence of recognizable liver peroxisomes. Other peroxisomal disorders (pseudo‐Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), pseudo‐neonatal adrenoleukodystrophy, rhizomelic chondrodysplasia punctata (RCDP), and hyperpipecolic acidaemia) share some of these symptoms, but with varying organ involvement, severity of dysfunction, and duration of survival. The diagnosis should not cause difficulty when all the characteristic manifestations are present.Depending on the main presenting sign, peroxisomal disorders in neonates should be suspected in two categories of circumstances: polymalformative syndrome with craniofacial dysmorphism, and severe neurological dysfunction. During the first 6 months of life, the predominant symptoms may be hepatomegaly, prolonged jaundice, liver failure, anorexia, vomiting and diarrhoea leading to failure to thrive resembling a malabsorption syndrome; severe psychomotor retardation, hearing loss and ocular abnormalities become evident. Beyond 4 years of age, behavioural changes, intellectual deterioration, visual impairment and gait abnormalities may be the presenting symptoms.Independently of the clinical symptoms and age of onset, most peroxisomal disorders described so far can be clinically screened by recordings of electroretinogram, visual‐evoked responses, and brain auditory‐evoked responses, which are almost always abnormal. Nine of the 17 peroxisomal disorders with neurological involvement are associated with an accumulation of very long‐chain fatty acids (VLCFA), which suggests that assay of plasma VLCFA should be used as a primary test. However, assays of plasma phytanic acid and plasma/urine bile acid intermediates should also be performed in view of the recent reports of atypical chondrodysplasia variants (without rhizomelic shortening) and isolated trihydroxycholestanoic aciduria. The differential diagnoses in various clinical conditions and age periods are discussed.
DNA diagnosis of X‐linked adrenoleukodystrophy
Authors: Seneca S. , Lissens W. 
Published: November 2004

SummaryThe X‐linked adrenoleukodystrophy (ALD) gene was identified recently and is predicted to encode a 745‐amino‐acid peroxisomal membrane protein. Strategies have been designed for the search for mutations in the ALD gene in patients. Several mutations have now been found and it seems that many different mutations are responsible for ALD. There is no straightforward correlation between genotype and phenotype since the same mutation can cause different ALD phenotypes in the same family. However, once a mutation has been found in a family, it can be traced in all at‐risk individuals of that family, both post‐ and prenatally, without the need for very long‐chain fatty acid (VLCFA) analysis. Segregation analysis with extragenic and intragenic polymorphisms may remain useful in families where mutation analysis is not possible for practical reasons; VLCFA analysis and measurement of the peroxisomal β‐oxidation with C26:0 fatty acid as a substrate will remain the alternative. We also briefly discuss the possibilities of DNA diagnosis for other peroxisomal disorders.
Histochemistry of peroxisomal enzyme activities: A tool in the diagnosis of Zellweger syndrome
Authors: Frederiks W. M. , Bosch K. S. , Ankum M. , Wanders R. J. A. 
Published: November 2004

SummaryThe localization of the activity of the peroxisomal enzymesD‐amino acid oxidase and hydroxyacid oxidase was studied at the light‐microscopical level in livers and kidneys of control subjects and patients with Zellweger syndrome, an inherited disease characterized by a lack of intact peroxisomes.D‐Amino acid oxidase and hydroxyacid oxidase activities were demonstrated in unfixed cryostat sections with the cerium‐diaminobenzidine‐cobalt‐hydrogen peroxide procedure, in which cerium ions capture hydrogen peroxide, the product of both enzymes. In a second step reaction decomposition of cerium perhydroxide gives rise to a diaminobenzidine polymer complexed with cobalt ions.D‐Amino acid oxidase and hydroxyacid oxidase activities were found in peroxisomes of liver parenchymal cells, and onlyD‐amino acid oxidase in peroxisomes of proximal tubular cells of kidneys of control humans. The activities of these enzymes were not detectable in livers and kidneys of Zellweger patients. It is concluded that the cerium‐diaminobenzidine‐cobalt‐hydrogen peroxide procedure enables the demonstration of peroxisomal enzyme activities in human tissues at the light‐microscopical level and is an important tool in detecting patients with Zellweger syndrome.
Identification of a new missense mutation in Japanese phenylketonuric patients
Authors: Goebel‐Schreiner B. , Schreiner R. 
Published: November 2004

SummaryA new missense mutation in the phenylalanine hydroxylase (PAH) gene was identified in 20/30 members of the families of 10 unrelated Japanese phenylketonuria (PKU) patients from Kyushu island. The point mutation was present in 20 of 40 mutant alleles. This was proved by DNA sequence analysis after polymerase chain reaction (PCR) amplification and allele‐specific oligonucleotide (ASO) hybridization. This point mutation, an A to G transition at the first base of codon 276 in exon 7, resulted in an amino acid substitution. Methionine was replaced by valine and the mutation was found to be associated with restriction fragment length polymorphism (RFLP) haplotype 4 in the investigated patients. The mutation was not found in 24 unrelated Caucasian patients from different countries. These findings may indicate a founder effect in the transmission of the mutation.
Diagnosis and prevention of lysosomal storage diseases in Russia
Authors: Krasnopolskaya K. D. , Mirenburg T. V. , Aronovich E. L. , Lebedeva T. V. , Odinokova O. N. , Demina N. A. , Kozlova V. M. , Kuznetsov M. I. 
Published: November 2004

SummaryA special programme for the diagnosis and prevention of lysosomal storage diseases (LSD) was developed in the former USSR. All the patients from 814 families at risk were investigated using biochemical techniques. In total, 363 patients with mucopolysaccharidoses (MPS), mucolipidoses, glycoproteinoses, sphingolipidoses and other LSD were diagnosed; 55 families at risk sought prenatal diagnosis and 67 fetuses were investigated for MPS (types I, II, IIIA and IIIB, VI), Tay‐Sachs disease, Sandhoff disease, GM1‐gangliosidosis, metachromatic leukodystrophy, mannosidosis, Gaucher disease and multiple sulphatidosis; 17 affected fetuses were diagnosed and aborted. There was an ethnic distribution of different lysosomal storage diseases in the former USSR.
Hereditary tyrosinaemia type I: A long‐term study of the relationship between the urinary excretions of succinylacetone and δ‐aminolevulinic acid
Authors: Schierbeek H. , Beukeveld G. J. J. , van Faassen H. , van Spronsen F. J. , Bijsterveld K. , Venekamp‐Hoolsema E. E. A. , Wolthers B. G. , Smit G. P. A. 
Published: November 2004

SummaryPatients with hereditary tyrosinaemia type I (HT) excrete large amounts of succinylacetone (SA) in urine. Owing to structural resemblance of SA to δ‐aminolevulinic acid (ALA), SA inhibits the second enzyme in the pathway for haeme biosynthesis, porphobilinogen synthase, resulting in increased urinary ALA excretion. We investigated the relationship between urinary SA and ALA excretions of two patients with different forms of HT (late‐infantile and juvenile). In both patients the urinary SA and ALA excretions showed a more or less inverse correlation. The patient with the early‐infantile form of HT had a relatively greater increase in urinary SA and ALA excretions in comparison to the patient with the juvenile form of HT. A possible explanation for this unexpected inverse correlation between the urinary excretion of SA and ALA might be a lack of intramitochondrial glycine, a substrate for δ‐aminolevulinic acid synthesis. It has been reported previously that high concentrations of SA reversibly and competitively inhibit the transport of glycine through membranes.
NormalN‐oligosaccharyltransferase activity in fibroblasts from patients with carbohydrate‐deficient glycoprotein syndrome
Authors: Knauer R. , Lehle L. , Hanefeld F. , von Figura K. 
Published: November 2004

SummaryTheN‐oligosaccharyltransferase activity was found to be normal in fibroblasts from five patients with the carbohydrate‐deficient glycoprotein syndrome type I and type III using an assay based on dolichyldiphosphoryl‐N‐N′‐diacetylchitobiose as donor and a hexapeptide as acceptor substrate.
Personality disorder in young women with treated phenylketonuria
Authors: Waisbren S. E. , Zaff J. 
Published: November 2004

SummaryTwenty‐eight young women with phenylketonuria (PKU) attending a Maternal PKU Summer Camp were interviewed and administered a personality inventory, the Minnesota Multiphasic Personality Inventory (MMPI). The 12 young women who were either late‐treated (treatment initiated after 90 days) or who had terminated the diet for a period of at least 5 years (the extended exposure group) were compared to the 16 women who were early‐treated and had remained continuously on diet (the continuously treated group). Although the mean blood phenylalanine and tyrosine concentrations at the camp for the two groups were comparable (973±344 and 1033±284 µmol/L for phenylalanine and 43±16 and 40±25 µmol/L for tyrosine), the women in the extended exposure group evidenced significantly greater psychopathology as measured by the MMPI and self‐report; thought disorder and mood disturbances were associated with diet termination in PKU.
Severity of mutation in the phenylalanine hydroxylase gene influences phenylalanine metabolism in phenylketonuria and hyperphenylalaninaemia heterozygotes
Authors: Svensson E. , Iselius L. , Hagenfeldt L. 
Published: November 2004

SummaryWe examined whether the degree of residual activity from the mutant phenylalanine hydroxylase (PAH) allele affected phenylalanine metabolism in heterozygotes for phenylketonuria (PKU) or non‐PKU hyperphenylalaninaemia (HPA). Discriminant analysis was carried out to find the function of fasting plasma concentrations of phenylalanine (PHE) and tyrosine (TYR) that best separated carriers from non‐carriers. This function (0.103TYR −0.214PHECORR −4.499) was subsequently used as the dependent variable, with thein vitro activity of the expressed mutant PAH as the independent variable, in a regression analysis performed on heterozygotes for mutations that had been studied in a eukaryotic cell expression system. This analysis showed a significant correlation (r=0.40,n=140,p<0.001), although there was a wide spread of values within each of the two major groups of carriers and a considerable overlap between the groups. We conclude that the severity of the mutation, as determined byin vitro expression analysis, in the mutant PAH gene is reflected in the biochemical phenotype of heterozygotes. This result emphasizes the relevance of the cell expression system used for establishing the relative severities of most mutations at the PAH locus. Differences in the activities from the carried mutant PAH allele on phenylalanine metabolism in heterozygotes are, however, small compared to the activity from the normal PAH allele and are easily obscured by other factors leading to inter‐ or intra‐individual variation in phenylalanine metabolism. Fasting plasma concentrations of phenylalanine and tyrosine thus can not be used to predict the severity of the carried PAH mutation in individual PKU or HPA heterozygotes.
Inborn errors of amino acid metabolism in North India
Authors: Kaur Manjeet , Das Prasad Ganesh , Verma Ishwar Chander 
Published: November 2004

SummaryWe screened 2560 referred cases for inborn errors of amino acid metabolism by chemical tests and thin‐layer chromatography of urine/plasma. In 62(2.4%) cases, eleven inherited Mendelian disorders of amino acids were identified. The four commonest disorders were homocystinuria, alcaptonuria, maple syrup urine disease and nonketotic hyperglycinaemia. Ornithinaemia was detected in two cases (0.08%), and phenylketonuria and cystinuria in two cases each (0.08%). Generalized hyperaminoacidurias were found in 90 (3.52%) subjects. The frequency pattern of the various amino acid disorders in North India was found to be remarkably different from that observed in the West.
Biochemical evidence for the requirement of continuous glucose therapy in young adults with type 1 glycogen storage disease
Authors: Wolfsdorf J. I. , Crigler J. F. 
Published: November 2004

SummaryTo determine whether patients with GSD‐1 need nocturnal glucose therapy after completing physical growth and development, studies were performed on two consecutive nights. On the first night uncooked cornstarch (UCS) was given at the calculated glucose production rate at 21:00 h and 02:00 h. On the second night UCS was given at 21:00 h but omitted at 02:00 h. Six GSD‐1 patients, aged 17.2–20.9 years, previously treated with continuous glucose therapy were studied. Measurements were made of plasma glucose (PG), serum insulin, growth hormone, cortisol, plasma glucagon (n=4), and blood lactate at 30–60‐min intervals. Serum uric acid, cholesterol, and triglycerides were measured at 21:00 h and 07:00 h, and serum FFA at 21:00 h, 02:00 h and 07:00 h on the first night and immediately before treatment for hypoglycaemia on the second night.For five hours after UCS at 21:00 h, mean PG, serum insulin and blood lactate concentrations were similar on the two nights. With UCS at 02:00 h, mean PG concentrations were ≥4.1 mmol/L from 02:00 to 07:00 h. Without UCS at 02:00 h, in all subjects PG concentrations fell to <2.5 mmol/L after 6.5–8.5 h and mean blood lactate concentration increased to 7.4±3.0 mmol/L.Young adults with GSD‐1 developed hypoglycaemia and hyperlactataemia after a relatively brief period without exogenous glucose and, therefore, need to continue nocturnal glucose therapy to prevent fasting hypoglycaemia.
Molecular basis for the phenotypical diversity of phenylketonuria and related hyperphenylalaninaemias
Authors: Güttler F. , Guldberg P. , Henriksen K. F. , Mikkelsen I. , Olsen B. , Lou H. 
Published: November 2004

ConclusionPhenylalanine hydroxylase deficiency results in a fairly continuous spectrum of metabolic phenotypes, which can now be predicted by means of molecular analysis. Methods for direct detection of previously identified mutations and mutation scanning techniques (SSCP and DGGE) have facilitated genotyping of the hyperphenylalaninaemic neonate. Genotyping will confirm that the hyperphenylalaninaemic neonate has PAH deficiency and not a BH4‐deficient form of hyperphenylalaninaemia or acquired hyperphenylalaninaemia. Genotyping will also distinguish between non‐PKU HPA neonates and PKU patients. Finally, genotyping predicts the metabolic phenotype, facilitating optimal dietary therapy from the neonatal period.A possible relationship between mutation genotype and the ultimate prognosis of PKU (MRI changes, cognitive development), and the question of whether the maternal genotype and the mutant allele of her offspring may influence pregnancy outcome are challenges for future studies.
Extracellular and cerebrospinal fluids
Authors: Segal M. B. 
Published: November 2004

SummaryThe mechanism of formation of extracellular fluid is first described, followed by an explanation of the relation between osmotic force, reflection coefficient and molecular size. The possible mechanism of brain extracellular fluid formation is then proposed in relation to the restriction offered by the blood‐brain barrier.The functions and compositions of cerebrospinal fluid (CSF) are then described followed by sections on the process of formation of CSF, the nonelectrolytes and proteins in CSF, the drainage mechanisms and protein synthesis by the choroid plexus.