bluuebunny/crossref_metadata_2025_split huggingface dataset:
The fragile X syndrome
Authors: Hoogeveen A. T. , Oostra B. A. 
Published: December 2002

AbstractThe fragile X syndrome is caused by the amplification of a polymorphic CGG repeat in the 5′ untranslated region of the FMR1 gene and is the most common form of inherited mental retardation. When the repeat is amplified beyond 200 repeat units, the repeat and the FMR1 promoter region are methylated. As a result of this methylation the gene is silenced and no FMR1 gene product (FMRP) is translated. The lack of expression of FMRP in the fragile X syndrome causes the fragile X phenotype. A mouse model for the fragile X syndrome (knockout for FMRP) has been generated to study the pathological mechanisms leading to the symptoms seen in fragile X patients. FMRP is widely expressed in different tissues and localized predominantly in the cytoplasm associated with the 60S ribosomal subunit. The protein has RNA binding properties and possibly shuttles between cytoplasm and nucleus. The target signals necessary for this intracellular transport, like a nuclear location signal and a nuclear export signal, are present in FMRP. FMRP is also able to bind to other proteins by using specific sequence domains present in the protein. The coiled‐coil structures formed by these domains are known to be involved in protein‐protein interaction. In this review we postulate that FMRP is involved in the transport of RNA and/or proteins from the nucleus to the cytoplasm.
Inborn errors of signal transduction: Mutations in G proteins and G protein‐coupled receptors as a cause of disease
Authors: Spiegel A. M. 
Published: December 2002

AbstractA vast array of neurotransmitters, polypeptide hormones and other extracellular signalling molecules utilize G protein‐coupled pathways for transmembrane signalling. In recent years, mutations in G protein‐coupled receptors and in G protein α subunits have been identified as the cause of a variety of human diseases. Both loss and gain of function mutations have been described in disorders such as Albright hereditary osteodystrophy, nephrogenic diabetes insipidus, McCune‐Albright syndrome, and familial male precocious puberty. Identification of mutations in G protein‐coupled receptors and in G proteins in human diseases has provided unique insights into G protein‐coupled signal transduction, has important implications for diagnosis and potentially for treatment, and should stimulate the search for additional defects in G protein‐coupled signal transduction in other diseases.
Commentary: Neonatal onset in fatty acid oxidation disorders: How can we minimize morbidity and mortality?
Authors: Riudor E. 
Published: December 2002

AbstractNeonatal onset is one of the most severe forms of presentation in inborn errors of metabolism. In mitochondrial fatty acid oxidation disorders, neonatal onset is more frequent than commonly supposed, with high morbidity and mortality. Presentations include hypoketotic hypoglycaemia, which may be difficult to assess in the neonate because of its relative immaturity, metabolic acidosis, liver, muscle and/or cardiac involvement and even sudden death. In many cases diagnosed with a fatty acid oxidation defect a previous sibling had died suddenly in the neonatal period, emphasizing the severity of the neonatal presentation. Neonatal presentation has been described in the majority of fatty acid oxidation defects, as reviewed by Pollitt (1995) and Stanley (1995).
Glycogen storage disease type 1a in three siblings with the G270V mutation
Authors: Parvari R. , Isam J. , Moses S. W. 
Published: December 2002

AbstractGlycogen storage disease type 1a (von Gierke disease, GSD1a) is caused by the deficiency of microsomal glucose‐6‐phosphatase (G6Pase) activity. The cloning of G6Pase cDNA and characterization of the human G6Pase gene enabled the identification of the mutations causing GSD1a. Here we report on the clinical and biochemical features of three GSD1a siblings of a Muslim Arab family with a G270V mutation. Two older patients presented with an unusually mild clinical and biochemical course.
From toxicological problem to therapeutic use: The discovery of the mode of action of 2‐(2‐nitro‐4‐trifluoromethylbenzoyl)‐1,3‐cyclohexanedione (NTBC), its toxicology and development as a drug
Authors: Lock E. A. , Ellis M. K. , Gaskin P. , Robinson M. , Auton T. R. , Provan W. M. , Smith L. L. , Prisbylla M. P. , Mutter L. C. , Lee D. L. 
Published: December 2002

AbstractNTBC is a triketone with herbicidal activity that has been shown to have a novel mode of action by inhibiting the enzyme 4‐hydroxyphenylpyruvate dioxygenase in plants. Early studies on the toxicity of this compound found that rats treated with NTBC developed corneal lesions. Investigations aimed at understanding the mechanistic basis for the ocular toxicity discovered that the rats developed tyrosinaemia and excreted large amounts of 4‐hydroxyphenylpyruvate and 4‐hydroxyphenyllactate, owing to inhibition of the hepatic enzyme 4‐hydroxyphenylpyruvate dioxygenase. The corneal lesions resemble those seen when rats are fed a diet supplemented with tyrosine, leading us to conclude that the ocular toxicity seen with NTBC is a consequence of a marked and sustained tyrosinaemia. Studies in collaboration with Professor Sven Lindstedt showed that NTBC was a potent inhibitor of purified human liver 4‐hydroxyphenylpyruvate dioxygenase. This interaction lead to the concept of using NTBC to treat patients with tyrosinaemia type 1, to block or reduce the formation of toxic metabolites such as succinylacetoacetate in the liver. Zeneca Agrochemicals and Zeneca Pharmaceuticals made NTBC available for clinical use and, with the approval of the Swedish Medical Products Agency, a seriously ill child with an acute form of tyrosinaemia type 1 was successfully treated in February 1991. Subsequently, other children with this inborn error of metabolism in Sweden and other countries have been treated with NTBC. The drug is now available to those in need via Swedish Orphan AB.
One‐methyl group metabolism in non‐ketotic hyperglycinaemia: Mildly elevated cerebrospinal fluid homocysteine levels
Authors: Van Hove J. L. K. , Lazeyras F. , Zeisel S. H. , Bottiglieri T. , Hyland K. , Charles H. C. , Gray L. , Jaeken J. , Kahler S. G. 
Published: December 2002

AbstractNon‐ketotic hyperglycinaemia (NKH) is a rare, severe brain disease caused by deficient glycine cleavage enzyme complex activity resulting in elevated glycine concentrations. Recent experience suggests that factors in addition to glycine kinetics are involved in its pathogenesis. The glycine cleavage reaction through the formation of methylenetetrahydrofolate is an important one‐methyl group donor. A deficiency in one‐methyl group metabolites, in particular of choline, has been hypothesized in NKH. We investigated metabolites involved in one‐methyl group metabolism in plasma and CSF of 8 patients with NKH, and monitored the effect of treatment with choline in one patient. Plasma and CSF choline and phosphatidylcholine concentrations were normal, except for a low plasma choline in the single neonate studied. Choline treatment did not change brain choline content, and was not associated with clinical or radiological improvement. Methionine concentrations and, in one‐patient, S‐adenosylmethionine and 5‐methyltetrahydrofolate concentrations were normal in CSF. Homocysteine concentrations in CSF, however, were slightly but consistently elevated in all four patients examined, but cysteine, cysteinylglycine and glutathione were normal. Serine is important in the transfer of one‐methyl groups from mitochondria to cytosol. Serine concentrations were normal in plasma and CSF, but dropped to below normal in CSF in three patients on benzoate treatment. These observations add to our understanding of the complex metabolic disturbances in NKH.
Animal models of lysosomal disease: An overview
Authors: Suzuki K. , Månsson J.‐E. 
Published: December 2002

AbstractThe relative rarity of human lysosomal disorders, extremely heterogeneous genetic background and ethical restrictions make well‐controlled studies difficult with human patients. Genetically authentic animal models complement human patients with their ready availability, homogeneous genetic background and the relatively flexible experimental designs. Spontaneous animal models of human lysosomal disorders are rare, particularly among small laboratory animals. However, the homologous recombination and embryonic stem cell technology has so far enabled us to duplicate almost all known human sphingolipidoses, two mucopolysaccharidoses and aspartylglycosaminuria in mice and more disorders are expected in the near future. This technology also allows generation of mouse mutants that are not known or are highly unlikely to exist in humans, such as ‘double‐knockouts’. Studies of lysosomal disease have come to the half‐way turning point of the marathon race from clincopathological descriptions, identification of affected compounds, enzymology, to the present gene‐level inquiries. The animal models will play an important role in our long journey from nucleic acids back to biology. While the utility of these mouse models is obvious, species differences in the brain development and metabolic pathways must be always remembered if the ultimate goal of the study is application to human patients. After all, the mouse is not human.
Renal transplantation in a patient with methylmalonic acidaemia
Authors: Van Calcar S. C. , Harding C. O. , Lyne P. , Hogan K. , Banerjee R. , Sollinger H. , Rieselbach R. E. , Wolff J. A. 
Published: December 2002

AbstractRenal insufficiency is frequently reported in mutase‐deficient methylmalonic acidaemia. We present a case report of a patient with mut– methylmalonic acidaemia who developed chronic tubulointerstitial nephropathy during adolescence. At 24 years of age, she developed end‐stage renal failure and underwent renal transplantation. Both plasma and urine methylmalonic acid levels decreased significantly with improved renal function following transplantation. Complications included cyclosporin toxicity and development of diabetes. Renal, metabolic, and clinical status remained improved at 3 years after the kidney transplant.
Diffuse leukodystrophy in an infant with cytochrome‐c oxidase deficiency
Authors: Harpey J‐P. , Heron D. , Prudent M. , Charpentier C. , Rustin P. , Ponsot G. , Cormier‐Daire V. 
Published: December 2002

AbstractA 25‐month‐old boy, born to consanguineous parents, had progressive spastic tetraplegia, and increased signal of the white matter on cerebral T2‐weighted magnetic resonance imaging indicative of diffuse leukodystrophy. Elevated blood and cerebrospinal fluid lactate levels pointed to a respiratory chain defect. Cytochrome‐c oxidase deficiency was demonstrated in cultured skin fibroblasts and skeletal muscle. This report extends the phenotype of COX deficiency in infancy. Systematic study of blood and CSF lactate should be carried out in every infant with leukodystrophy.
A simple screening test for fatty acid oxidation defects using whole‐blood palmitate oxidation
Authors: Seargeant L. E. , Balachandra K. , Mallory C. , Dilling L. A. , Greenberg C. R. 
Published: December 2002

AbstractWe report that measurement of whole‐blood palmitate oxidation is a rapid and inexpensive screening test for fatty acid oxidation defects. The assay has been adapted from published assays using cultured fibroblasts or isolated white blood cells. Micro whole‐blood samples are incubated with tritiated palmitic acid as substrate. The tritiated water produced is proportional to the mitochondrial β‐oxidation of palmitic acid. Patients with confirmed β‐oxidation defects show low whole‐blood palmitate oxidation.
Transcobalamin II deficiency with methylmalonic aciduria in three sisters
Authors: Bibi H. , Gelman‐Kohan Z. , Baumgartner E. R. , Rosenblatt D. S. 
Published: December 2002

AbstractTranscobalamin II (TC II) is a plasma protein that binds vitamin B12 (cobalamin, Cbl) and facilitates cellular Cbl uptake by receptor‐mediated endocytosis. In autosomal recessive TC II deficiency, intracellular Cbl deficiency results in an early onset of megaloblastic anaemia that may be accompanied by neurological abnormalities. Inadequate treatment may lead to neurological abnormalities. We describe three sisters, the daughters of first cousins of Moroccan origin, with TC II deficiency requiring continuous and long‐term vitamin B12 treatment. The diagnosis was suspected from the finding of low unsaturated vitamin B12 binding capacity and confirmed by absence of detectable TC II by radioimmunoassay and by inability of cultured fibroblasts to synthesize TC II.
Artefactual pyruvate and 2‐oxobutyrate produced by trimethylsilylation of methylmalonic and ethylmalonic acids in the presence of oxygen
Authors: Mamer O. A. , Choiniere L. , Boismenu D. , Lepine F. 
Published: December 2002

AbstractTrimethylsilylation of methylmalonic and ethylmalonic acids in the presence of headspace atmospheric oxygen is shown to produce the trimethylsilyl derivatives of pyruvic and 2‐oxobutyric acids, along with 2‐hydroxy‐2‐methylmalonic and 2‐hydroxy‐2‐ethylmalonic acids, respectively. This may lead to overestimation of these keto acids, if they were not oximated in the original sample, and the mistaken reporting of the 2‐hydroxymalonates.
A review of biochemical and molecular genetic aspects of tyrosine hydroxylase deficiency including a novel mutation (291delC)
Authors: Wevers R. A. , de Rijk‐van Andel J. F. , Bräutigam C. , Geurtz B. , van den Heuvel L. P. W. J. , Steenbergen‐Spanjers G. C. H. , Smeitink J. A. M. , Hoffmann G. F. , Gabreëls F. J. M. 
Published: December 2002

AbstractAn overview is given of the current knowledge on the human tyrosine hydroxylase gene and on the biochemical aspects of diagnosing defects in this gene. Diagnostic biochemical findings are described in four cases of genetically confirmed tyrosine hydroxylase deficiency. Decreased CSF levels of homovanillic acid (HVA) and 3‐methoxy‐4‐hydroxyphenylethyleneglycol (MHPG), together with normal pterin and CSF tyrosine and 5‐hydroxyindoleacetic acid (5‐HIAA) concentrations are the diagnostic hallmarks of tyrosine hydroxylase deficiency. At the metabolite level the diagnosis can only be made reliably in CSF. Strict adherence to a standardized lumbar puncture protocol and adequate reference values are essential for diagnosis of this “new” treatable neurometabolic disorder. Measurements of HVA, vanillylmandelic acid (VMA) or catecholamines in urine are not relevant for diagnosing tyrosine hydroxylase deficiency. The diagnosis should be considered in all children with unexplained hypokinesia and other extrapyramidal symptoms. Three of our patients are homozygous for a mutation in exon 6 (698G>A) of the tyrosine hydroxylase gene and one patient was compound heterozygous for the same mutation and a novel truncating mutation in exon 3 (291delC).
Adolescent myopathic presentation in two sisters with very long‐chain acyl‐CoA dehydrogenase deficiency
Authors: Merinero B. , Pascual Pascual S. I. , Pérez‐Cerdá C. , Gangoiti J. , Castro M. , Garcia M. J. , Pascual Castroviejo I. , Vianey‐Saban C. , Andresen B. , Gregersen N. , Ugarte M. 
Published: December 2002

AbstractTwo sisters were investigated at the ages of 20 and 13 years owing to persistently increased serum creatine kinase and recurrent episodes of rhabdomyolysis after emotional stress in the older and myalgias in the younger. The finding of increased levels of cis‐5‐tetradecenoic acid (C14:1) in plasma, severe hypocarnitinaemia and the absence of a pathological dicarboxylic aciduria in both sisters suggested a very long‐chain acyl‐CoA dehydrogenase (VLCAD) deficiency. Reduced [1‐14C]palmitate oxidation and deficient mitochondrial VLCAD activity in fibroblasts were found. Mutation analysis revealed compound heterozygosity for Asp365His and Arg410His changes. This late‐onset, milder clinical presentation differs from the other two more severe infantile phenotypes described, since there is no hypoglycaemia or cardiac disease. Fatty acid oxidation defects should be investigated in all cases with rhabdomyolysis beginning in adolescence or early adulthood.
Urinary organic acid screening in children with developmental language delay
Authors: Michelson M. , Harel S. , Gutman A. , Lerman‐Sagie T. 
Published: December 2002

AbstractThe prevalence of 3‐methylglutaconic aciduria was evaluated among children with developmental language disorders. A urine specimen was obtained from 40 children referred for developmental language delay to the Tel‐Aviv Child Development Center during 12/96–6/97 and from 50 age‐matched controls. Urine organic acids were analysed by gas chromatography–mass spectrometry. Urinary 3‐methylglutaconic acid was quantified. A mildly increased excretion of 3‐methylglutaconic acid was found in 8 children with developmental language delay. The combined excretion of 3‐methylglutaconic and 3‐methylglutaric acid was increased in 9 patients. There were no differences in the excretion of other organic acids. The patients with elevated 3‐methylglutaconic acid did not differ from the other patients with developmentallanguage disorders in any of the parameters evaluated. Mildly elevated urinary levels of 3‐methylglutaconic acid may be a marker of a still undefined metabolic disorder presenting with developmental language delay. A further study in large groups of children with different developmental disorders is mandatory.
Genomics, mutations and the Internet: The naming and use of parts
Authors: Scriver C. R. , Nowacki P. M. 
Published: December 2002

AbstractMutations are the source of genetic variation and diversity; by their effect, some are neutral, others are pathogenic. In contemporary genetics, mutations appear at the interface between genomics (structural and functional) and genetics (heredity), where they serve gene discovery and mapping (genomics) and generate challenges to modify their phenotypic effects (medical genetics). Assuming the human genome harbours 80000 transcribed genes each possessing at least 100 different (germline) alleles in a typical population, how then to record and recover data on at least 8 million human alleles? Bioinformatics is the essential resource to create the corresponding accessible digital libraries (genomic and locus‐specific mutation databases) for this purpose, a goal to which The HUGO Mutation Database Initiative (Science 279: 10–11, 1998) aspires. Guidelines now exist for naming alleles (Hum Mutat 11: 1–3, 1998). The principles behind the practice are illustrated by PAHdb (http://www.mcgill.ca/pahdb), a prototype locus‐specific mutation database (NAR 26: 220–225, 1998), and by prototype genomic mutation databases (HGMD (NAR 26: 285–287, 1998), http://www.uwcm.ac.uk/uwcm/mg/hgmd0.html; the EBI mutation database, http://www2.ebi.ac.uk/mutations/; and OMIM, http://www.ncbi.nlm.nih.gov/Omim.html).
Population newborn screening for inherited metabolic disease: Current UK perspectives
Authors: Green A. , Pollitt R. J. 
Published: December 2002

AbstractSome of the generally accepted criteria for screening programmes are inappropriate for newborn metabolic screening as they ignore the family dimension and the importance of timely genetic information. Uncritical application of such criteria creates special difficulties for screening by tandem mass spectrometry, which can detect a range diseases with widely different natural histories and responsiveness to treatment. Further difficulties arise from increasing demands for direct proof of the effects of screening on long‐term morbidity and mortality. The randomized controlled trial is held to be the gold standard, but for ethical and practical reasons it will be impossible to achieve for such relatively rare diseases. This approach also oversimplifies the complex matrix of costs and benefits of newborn metabolic screening. A more workable approach could involve Bayesian synthesis, combining quantitative performance data from carefully designed prospective pilot studies of screening with existing experience of the natural history, diagnosis, and management of the individual disorders concerned.
Towards metabolic sink therapy for mut methylmalonic acidaemia: Correction of methylmalonyl‐CoA mutase deficiency in T lymphocytes from a mut methylmalonic acidaemia child by retroviral‐mediated gene transfer
Authors: Chang C.‐C. , Hsiao K.‐J. , Lee Y.‐M. , Lin C.‐M. 
Published: December 2002

AbstractThe pathology associated with mut methylmalonic acidaemia (MMA) is caused by systemic accumulation of methylmalonate. Therefore, removal of methylmalonate from the circulation of affected individuals by an engineered metabolic system is proposed as a potential treatment. The haematopoietic cell is a potential site for such a metabolic system because of its direct contact with the accumulated metabolite and the demonstrated safety and ease in utilizing this cell. In this study, we assessed the feasibility of developing a haematopoietic cell‐based methylmalonate sink by analysing propionate/methylmalonate metabolism in a variety of haematopoietic cells. The results show that propionate metabolism and methylmalonyl‐CoA mutase (MCM) activity are intact in primary T cells, EBV‐B cells, and CD34+ haematopoietic stem cell‐derived granulocytes, whereas they are defective in those from a mut MMA child. Moreover, normal T and EBV‐B cells clear methylmalonate from the medium at a significant rate. Transduction of MCM‐deficient T cells with a recombinant retrovirus encoding the human MCM cDNA results in correction of propionate metabolism. These results establish the basis for developing haematopoietic cell‐based metabolic sink therapy for mut MMA by T lymphocyte/haematopoietic stem cell‐directed gene transfer.
High plasma leucine concentrations without neurological symptoms in a patient with classical maple syrup urine disease
Authors: Skladal D. , Grissenauer G. , Konstantopoulou V. , Felker S. , Sperl W. 
Published: December 2002

AbstractIt has been found that the amino acid analyser used in this study systematically overestimated plasma leucine at high concentrations. The concentration reported as 2249 μmol/L had a true value of 1430 μmol/L and leucine values reported as >2000 μmol/L were approximately 1500 μmol/L.
Short‐term effect of captopril on microalbuminuria in children with glycogen storage disease type Ia
Authors: Özen H. , Ciliv G. , Koçak N. , Saltik İ. N. , Yüce A. , Gürakan F. 
Published: December 2002

AbstractEarly signs of renal dysfunction in glycogen storage disease type Ia (GSD Ia) are glomerular hyperfiltration and proteinuria. In a non‐randomized study, the effect of captopril on the improvement of proteinuria in GSD Ia patients with microalbuminuria was investigated. A positive effect has been shown for the insulin‐dependent diabetes mellitus patients. Microalbuminuria was defined as albumin/creatinine ratio (mg/mmol) more than 2.5 in spot urine. Nineteen (52.7%) out of 36 patients had microalbuminuria, and 8 patients received captopril at a dose of 1mg/kg per day. Microalbuminuria was evaluated periodically during the follow‐up period. Of the captopril‐treated patients, one was lost to follow‐up. In the remaining 7 patients, urinary albumin excretion normalized in 3 patients (42.9%) and decreased at least by 50% in another 3 patients (42.8%) after 6 months of treatment. One patient, who was the oldest, did not have any benefit. In untreated patients, only two patients had a decrease in microalbuminuria of more than 50%. Patients with microalbuminuria had significantly higher blood lactate (p<0.05) and plasma triglyceride (p<0.01) concentrations and significantly lower blood bicarbonate concentration (p<0.05) than those patients without it. Additionally, the patients with microalbuminuria had been diagnosed earlier than those without microalbuminuria (p<0.05). Patients with microalbuminuria have more severe clinical and laboratory findings than those without microalbuminuria. Captopril at a dose of 1 mg/kg per day seems to be effective in at least 50% of GSD Ia patients with microalbuminuria.