bluuebunny/crossref_metadata_2025_split huggingface dataset:
A clinical biochemist's view of the investigation of suspected inherited metabolic disease
Authors: Blom W. , Huijmans J. G. M. , van den Berg G. B. 
Published: June 2005

SummaryThe necessity for a multi‐disciplinary approach to the study of genetic disease is discussed. The progress of laboratory investigation programmes made it not feasible and inefficient to run a full metabolic investigation programme in every new patient suspected of inherited metabolic disease. An application form for metabolic investigation is described, which can be used to collect clinical information relevant to metabolic disease. On the basis of the patient's clinical information, selection criteria are given to decide which laboratory investigation programme has to be performed in the individual patient. A full metabolic laboratory investigation programme is described and illustrated with some examples of abnormal metabolite patterns. Diagnostic results over a 2‐year period are presented.
Genetic aspects of prenatal diagnosis
Authors: Connor J. M. 
Published: June 2005

SummaryWith improved control of environmental agents, genetic conditions are now a major cause of residual handicap and mortality in all age groups. Primary prevention of this diverse group of over 5000 distinct disorders is not yet possible and effective therapy is, as yet, available for very few. Hence, the present emphasis on prevention is directed towards the identification and testing of pregnancies at risk in order to allow the option of early selective termination of pregnancy. Although over 400 distinct conditions have already been successfully prenatally diagnosed, the identification of at‐risk pregnancies on the basis of a positive family history alone can identify only a minority of affected pregnancies. In contrast, genetic screening during (or before) pregnancy offers a real prospect for detection of a majority of affected pregnancies and hence for reducing the birth frequency of serious genetic conditions. This is exemplified by the impact of the maternal serum α‐fetoprotein screening programme for neural tube defects and is under active development for autosomal aneuploidies and certain other major congenital malformations. These screening programmes will result in a reduced frequency of mental and physical handicap in the community but their implementation will require a comprehensive team approach with supraregional (or national) funding and co‐ordination.
Prenatal and perinatal diagnosis of peroxisomal disorders
Authors: Schutgens R. B. H. , Schrakamp G. , Wanders R. J. A. , Heymans H. S. A. , Tager J. M. , van den Bosch H. 
Published: June 2005

SummaryPeroxisomes play an essential role in human cellular metabolism. Peroxisomal disorders, a group of genetic diseases caused by peroxisomal dysfunction, can be classified into three groups: (1) disorders of peroxisome biogenesis with a generalized loss of peroxisomal functions (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease, hyperpipecolic acidaemia); (2) disorders with a loss of multiple peroxisomal functions (rhizomelic chondrodysplasia punctata and Zellweger‐like syndrome; (3) disorders with loss of a single peroxisomal function (X‐linked adrenoleukodystrophy, peroxisomal thiolase deficiency, bifunctional protein deficiency, acyl‐CoA oxidase deficiency, classic Refsum disease, hyperoxaluria type I and acatalasaemia). Prenatal diagnosis is indicated in all these genetic disorders with the exception of classic Refsum disease, most types of hyperoxaluria type I and acatalasaemia.A variety of techniques is available now for the prenatal diagnosis of peroxisomal disorders in the first or second trimester of gestation. Prenatal diagnosis was performed by us in 70 pregnancies at risk for a disorder of peroxisome biogenesis, three for rhizomelic chondrodysplasia punctata, four for X‐linked adrenoleukodystrophy and two for a defect in peroxisomal β‐oxidation. Fourteen affected fetuses were identified; no false negative cases were obtained.
Prenatal diagnosis of disorders of galactose metabolism
Authors: Holton J. B. , Allen J. T. , Gillett M. G. 
Published: June 2005

SummaryOf three clinically significant galactose disorders, there is only a real need and experience of prenatal diagnosis in classical galactosaemia. Prenatal diagnosis for this disorder may be carried out by galactose‐1‐phosphate uridyl transferase assay in cultured amniotic fluid cells or in chorionic villus biopsies and by galactitol estimation in amniotic fluid supernatant. Although the long‐term outcome of patients treated on a galactose‐restricted diet is recognized to be unsatisfactory, prenatal diagnosis is only rarely performed with a view to terminating the affected pregnancy.
Disorders of mitochondrial β‐oxidation: Prenatal and early postnatal diagnosis and their relevance to Reye's syndrome and sudden infant death
Authors: Pollitt R. J. 
Published: June 2005

SummaryThere are still many problems with the diagnosis and classification of inherited disorders of mitochondrial β‐oxidation. At present only the acyl‐CoA dehydrogenase step of the β‐oxidation spiral has been explored in any detail and a large number of patients have disorders that cannot be properly characterized. β‐Oxidation defects may present in a wide variety of ways, the most dramatic being acute encephalopathy with hepatic involvement (atypical Reye's syndrome) or ‘sudden’ death. Investigations may include urinary and plasma organic acids, metabolic stress tests and assays of overall metabolic pathways or of specific enzymes in cultured fibroblasts, lymphocytes, or other material. Early postnatal diagnosis presents particular difficulties but in medium‐chain acyl‐CoA dehydrogenase deficiency the diagnosis may be apparent from careful examination of urine. There is as yet little general experience in prenatal diagnosis of this group of disorders except for glutaric aciduria type II. Single prenatal diagnoses of medium‐chain acyl‐CoA dehydrogenase deficiency and of an incompletely characterized defect of medium‐chain fatty acid oxidation have been performed.
The control of 5‐hydroxytryptamine and dopamine synthesis in the brain: A theoretical approach
Authors: Hommes F. A. , Lee J. S. 
Published: June 2005

SummaryThe transport of the eight amino acids (phenylalanine, tyrosine, tryptophan, valine, leucine, isoleucine, histidine and methionine) using the large neutral amino acid transporter of the blood‐brain barrier (BBB) has been calculated using published kinetic data. The fate of the amino acids has been followed from blood to interstitial space, to cell and through metabolism which included, for tyrosine and tryptophan, the hydroxylases. The system was analysed in terms of flux control coefficients. Since the summation theorem did not hold, the system clearly behaved as a non‐homogeneous system. At physiological levels of these eight amino acids, the largest contribution to the control of the flux of tyrosine is given by the hydroxylase step, followed by the diffusional component of the transport across the BBB. For tryptophan it is the hydroxylase step, followed by the carrier‐mediated transport across the BBB. For the other amino acids it is the metabolism, followed by the diffusional component of the BBB transport.These parameters for tyrosine and tryptophan were determined at increased levels of blood phenylalanine, tyrosine or histidine. The flux through tryptophan hydroxylase can be affected by high blood levels of tyrosine and histidine to values also observed in hyperphenylalaninaemia. Since hypertyrosinaemia (type II) and hyperhistidinaemia are not associated with mental retardation, it is concluded that interference with transport across the BBB of tyrosine and tryptophan, as well as the flux through tryptophan hydroxylase leading to the synthesis of 5‐hydroxytryptamine, do not contribute to the cause of permanent brain dysfunction in hyperphenylalaninaemia.It can be calculated that addition of tyrosine to the diet to raise the blood tyrosine level in phenylketonuria patients may have a beneficial effect for the synthesis of neurotransmitters derived from tyrosine.
Results of newborn screening for galactose metabolic disorders
Authors: Inoue B. , Hata M. , Ichiba Y. , Wada H. , Misumi H. , Mori T. 
Published: June 2005

SummaryA screening strategy has been used which uses the Paigen and Beutler methods for the determination of galactose and galactose‐1‐phosphate. A blood spot test for epimerase has also been developed. In the last 10 years, 265019 samples from newborns have been tested by these methods. Among the 154 screening positives, we have detected seven cases of epimerase‐deficient galactosaemia (Type III), seven cases of Duarte/galactosaemia heterozygotes, 48 cases of other various types of heterozygotes, four cases of persistent hypergalactosaemia, three cases of hepatitis and one case of congenital atresia of the bile duct. These results indicate that our screening system has effectively detected the infants with galactose metabolic disorders.
Immunoquantification of the low abundance lysosomal enzymeN‐acetylgalactosamine 4‐sulphatase
Authors: Brooks D. A. , McCourt P. A. G. , Gibson G. J. , Hopwood J. J. 
Published: June 2005

SummaryThe low abundance lysosomal enzymeN‐acetylgalactosamine 4‐sulphatase (4‐sulphatase) has been quantified using a microimmunopurification step and a monoclonal‐based ELISA detection system. The assay is similar in principle to a two‐site ELISA but uses a single monoclonal antibody against one epitope to bind 4‐sulphatase in two separate assay steps. The sensitivity of this assay is sufficient to allow the quantification of 4‐sulphatase in human cultured skin fibroblasts derived from normal controls and patients deficient in 4‐sulphatase activity (mucopolysaccharidosis type VI or Maroteaux‐Lamy syndrome). The results obtained suggest a range of mucopolysaccharidosis type VI or 4‐sulphatase deficient mutants, from those expressing little or no quantifiable 4‐sulphatase protein to those examples with quantifiable levels of 4‐sulphatase protein which is enzymically inactive. Phenotypic variability in patients with a 4‐sulphatase deficiency may therefore be partially attributed to a range of protein expressions. The method should allow the determination of 4‐sulphatase specific activity in mucopolysaccharidosis type VI patients.
International database of tetrahydrobiopterin deficiencies
Authors: Blau N. , Barnes I. , Dhondt J. L. 
Published: June 2005

SummaryApproximately 2% of newborns with hyperphenylalaninaemia are deficient in tetrahydrobiopterin. Selective screening must be performed in all instances where hyperphenylalaninaemia is detected by neonatal screening. In the last 20 years, 308 patients with tetrahydrobiopterin deficiencies have been recognized as a result of screening carried out, worldwide, in Departments of Paediatrics. Of these 308 patients, 181 suffered from 6‐pyruvoyltetrahydropterin synthase deficiency, 92 from dihydropteridine reductase deficiency, 13 from pterin‐4a‐carbinolamine dehydratase deficiency, 12 from GTP cyclohydrolase I deficiency, and 10 are still unclassified. In the BIODEF database we have tabulated the most common clinical and laboratory data related to hyperphenylalaninaemia and tetrahydrobiopterin deficiencies. Additionally, there are data regarding treatment, outcome, and DNA analysis. Preliminary evaluation reveals that the degree of hyperphenylalaninaemia can vary from normal to 2500 µmol/L. Analyses of pterins in urine and measurement of dihydropteridine reductase activity from Guthrie cards are absolutely essential tests for accurate diagnosis. There is a regional (demographic) variation in the frequency of tetrahydrobiopterin deficiencies indicating the highest incidence in Saudi Arabia, probably a consequence of the high consanguinity rate.
Clinical and laboratory findings in four patients with the non‐progressive hepatic form of type IV glycogen storage disease
Authors: McConkie‐Rosell A. , Wilson C. , Piccoli D. A. , Boyle J. , De Clue T. , Kishnani P. , Shen J.‐J. , Boney A. , Brown B. , Chen Y. T. 
Published: June 2005

SummaryThe classic clinical presentation for type IV glycogen storage disease (branching enzyme deficiency, GSD IV) is hepatosplenomegaly with failure to thrive occurring in the first 18 months of life, followed by progressive liver failure and death by age 5 years. Although there have been two patients without apparent liver progression previously reported, no long‐term follow‐up clinical data have been available. We present here the clinical spectrum of the non‐progressive liver form of GSD IV in four patients, and long‐term follow‐up of the oldest identified patients (ages 13 and 20 years). None has developed progressive liver cirrhosis, skeletal muscle, cardiac or neurological involvement, and none has been transplanted. Branching enzyme activity was also measured in cultured skin fibroblasts from patients with the classic liver progressive, the early neonatal fatal, and the non‐progressive hepatic presentations of GSD IV. The residual branching enzyme activity in the patients without progression was not distinguishable from the other forms and could not be used to predict the clinical course. Our data indicate that GSD IV does not always necessitate hepatic transplantation and that caution should be used when counselling patients regarding the prognosis of GSD IV. Patients should be carefully monitored for evidence of progression before recommending liver transplantation.
Detection of defective 3β‐hydroxysterol Δ7‐reductase activity in cultured human fibroblasts: a method for the diagnosis of Smith‐Lemli‐Opitz syndrome
Authors: Lund E. , Starck L. , Venizelos N. 
Published: June 2005

SummaryPatients with the autosomal recessive disorder Smith‐Lemli‐Opitz syndrome (SLO) have recently been shown to have markedly increased tissue levels of certain cholesterol biosynthesis intermediates, most notably 7‐dehydrocholesterol. The findings strongly suggest a block in the step that catalyses reduction of 7‐dehydrocholesterol to cholesterol. The accumulation of 7‐dehydrocholesterol can generally easily be detected in serum by gas chromatography‐mass spectrometry. However, it could not be totally ruled out that SLO patients with less severe enzyme defects could escape detection by this method. A more direct way of diagnosing a defect in 7‐dehydrocholesterol reduction would be to assay the conversion of 7‐dehydrocholesterol to cholesterol in cultured fibroblasts from patients with suspected SLO.In the present work, an assay for the conversion of [3H]lathosterol to [3H]‐cholesterol in cultured human fibroblasts is described. Lathosterol is the immediate precursor of 7‐dehydrocholesterol in the cholesterol biosynthetic pathway and was chosen for the assay instead of 7‐dehydrocholesterol owing to the difficulty in preparation and handling of the latter compound. Fibroblasts from control subjects converted [3H]lathosterol to [3H]cholesterol efficiently, whereas in fibroblasts from SLO patients the conversion did not go beyond 7‐dehydrocholesterol. It is concluded that the present method is useful for the diagnosis of SLO.
Single base deletion in exon 7 of the glycosylasparaginase gene causes a mild form of aspartylglycosaminuria in a patient of Mauritian origin
Authors: Park H. , Rossiter M. , Fensom A. H. , Winchester B. , Aronson N. N. 
Published: June 2005

SummaryAspartylglycosaminuria (AGU) is a lysosomal storage disorder of glycoprotein degradation caused by deficiency of glycosylasparaginase (GA). A deletion mutation was found in a mildly affected AGU patient whose parents are first‐cousins of Mauritian origin. One bp deletion at position 787 or 788 (ΔT788) in exon 7 of the GA gene resulted in a frameshift and produced an immediate stop codon. The resulting truncated polypeptide was defective in its post‐translational proteolytic processing and remained as a single chain (36 kDa) with no GA activity.
Tandem mass spectrometry: A new method for acylcarnitine profiling with potential for neonatal screening for inborn errors of metabolism
Authors: Millington D. S. , Kodo N. , Norwood D. L. , Roe C. R. 
Published: June 2005

ConclusionA method for analysis of acylcarnitines in blood at physiological concentrations has been developed. Preliminary results from umbilical cord blood and neonatal blood spotted onto Guthrie cards are encouraging. This method will detect up to at least eight inherited metabolic disorders which exhibit diagnostic acylcarnitine profiles, including medium‐chain acyl‐CoA dehydrogenase deficiency. The speed and simplicity of the method permit automation with existing technology, and could enable routine neonatal screening to be carried out in an efficient and cost‐effective manner.
Respiratory‐chain and pyruvate metabolism defects: Italian collaborative survey on 72 patients
Authors: Caruso U. , Adami A. , Bertini E. , Burlina A. B. , Carnevale F. , Cerone R. , Dionisi‐Vici C. , Giordano G. , Leuzzi E. , Parenti G. , Savasta S. , Uziel G. , Zeviani M. 
Published: June 2005

ConclusionsThe results of this survey show that respiratory‐chain and pyruvate metabolism defects are rather frequent diseases in Italy. The clinical presentation, as well as the age of onset, is widely heterogeneous, mainly with respect to respiratory‐chain defects; unusual and new phenotypes have been described. Even the biochemical profile is variable, including rare associations with different biochemical abnormalities. In our experience, the accurate evaluation of urine organic acid would appear compulsory in all patients in whom a respiratory‐chain or pyruvate metabolism defect is suspected.The true number of affected patients in Italy is certainly higher than reported here: several other patients were reported with strongly suggestive clinical and biochemical features, but still without defined diagnosis, owing to work being in progress or to the known diagnostic difficulties connected with this group of diseases.Finally, our experience emphasizes that collaborative studies on rare disorders are effective, exchanging experiences and increasing knowledge.
Glucose metabolism in fibroblasts from patients with erythrocyte hexokinase deficiency
Authors: Magnani M. , Chiarantini L. , Stocchi V. , Dachà M. , Fornaini G. 
Published: June 2005

AbstractFour different hexokinase (HK) isoenzymes are distributed in different proportions in human tissues. Fibroblasts contain HK type I as the predominant glucose phosphorylating activity, the same isoenzyme that predominates in red blood cells (RBC). We have established cell lines from two patients homozygous for RBC HK deficiency but carrying different mutations. In one case (HK‐Melzo) the residual RBC enzyme shows a marked heat instability but possesses normal kinetic and regulatory properties; in the other (HK‐Napoli), the enzyme is characterized by an increased Ki for glucose‐1,6‐diphosphate. These properties are also retained by the fibroblasts' hexokinase. Glucose utilization by cultured fibroblasts from these patients was markedly reduced in the cell lines where HK deficiency was more pronounced. However, cells with only 30% HK activity retained their full ability to utilize glucose in the hexose monophosphate pathway. This was shown to be true not only under basal conditions but also in the presence of oxidative agents such as methylene blue. Significant reduction of the ATP level was also found in HK‐Melzo fibroblasts. Thus, HK deficiency is associated with reduced glucose utilization and normal hexose monophosphate shunt rates. Results previously obtained on RBC support similar conclusions.
Gonadal function in patients with galactosaemia
Authors: Kaufman F. R. , Donnell G. N. , Roe T. F. , Kogut M. D. 
Published: June 2005

AbstractGonadal function was followed in 26 females and 12 males with galactosaemia due to deficiency of the enzyme galactose‐1‐phosphate (Gal‐1‐P) uridyl transferase over a 4 year period. Gonadal function was normal in males, but all females except two had evidence of acquired ovarian failure. Twelve females with ovarian failure documented at the beginning of this study continued to have either primary or secondary amenorrhoea on follow‐up. Five of six patients, who previously had normal gonadal function developed either hypergonadotrophic hypogonadism or an abnormal response to gonadotrophin‐releasing hormone (LRH) indicative of acquired ovarian damage. Seven of eight female patients, 1–12 years of age, who were evaluated for the first time had an exaggerated release of gonadotrophins during LRH stimulation tests diagnostic of gonadal insufficiency. The pathogenesis of ovarian failure remains unknown, but it appears likely that galactose or Gal‐1‐P is toxic to the ovary. The source of galactose metabolites, which may begin to accumulate prenatally and continue to damage the gonad in the postnatal period, is likely to be derived from the diet and from the endogenous synthesis of Gal‐1‐P from glucose via a variety of metabolic pathways. The testis appears to be relatively resistant to the effects of abnormal galactose metabolism.
Non‐ketotic hyperglycinaemia due to a deficiency of T‐protein in the glycine cleavage system in liver and brain
Authors: Schutgens R. B. H. , Ket J. L. , Hayasaka K. , Tada K. 
Published: June 2005

AbstractNon‐ketotic hyperglycinaemia was diagnosed in a girl at 3 weeks of age because of the typical clinical presentation, the elevated glycine concentration in urine, plasma and especially in cerebrospinal fluid and the normal profile of organic acids in urine. An EEG showed the typical burst suppression pattern. Therapeutic approaches with either pyridoxine (50 mg d−1) alone or in combination with N5formyltetrahydrofolate (3×3 mg d−1) or with strychnine (0.3 mg per kg body weight) did not result in improvement.In postmortem liver and brain of the patient the overall activity of the glycine cleavage system was deficient; examination of the activity of the individual components of the glycine cleavage system in the tissues revealed that the activity of the T‐protein was undetectable, whereas that of the other components and of lipoamide dehydrogenase was normal.
Intracerebral paraventricular hyperdensities: A new CT sign in Krabbe globoid cell leukodystrophy
Authors: Feanny S. J. , Chuang S. H. , Becker L. E. , Clarke J. T. R. 
Published: June 2005

AbstractComputer‐assisted tomographic (CT) scanning showed intracranial paraventricular calcification in two out of six patients with enzymatically and/or histologically confirmed Krabbe globoid cell leukodystrophy (GLD) 1–5 months after the onset of symptoms of the disease.
The effect ofd‐(+)‐glucosamine on levels of freeN‐acetylneuraminic acid and UDP‐N‐acetylhexosamines in infantile sialic acid storage disease (ISSD) fibroblasts
Authors: Paschke E. , Höfler G. , Roscher A. 
Published: June 2005

AbstractAn impairment in the regulation ofN‐acetylneuraminic acid (NANA) biosynthesis might potentially contribute to accumulation of free NANA in fibroblasts of patients with sialic acid storage disease (ISSD). By the use of a glucosamine loading test an increase in uridine‐diphosphate‐N‐acetyl‐hexosamines (UDP‐HexNAc) but not in free NANA was found. NANA biosynthesis therefore appears to be under normal regulatory control in ISSD.