bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intravenous immune globulin in lysinuric protein intolerance
Authors: Dionisi‐Vici C. , De Felice L. , El Hachem M. , Bottero S. , Rizzo C. , Paoloni A. , Goffredo B. , Sabetta G. , Caniglia M. 
Published: December 2002

AbstractIn addition to systemic manifestations with skeletal, pulmonary, renal, and haematological signs, lysinuric protein intolerance (LPI), a membrane transport defect of cationic amino acids, is often complicated by severe life‐threatening immunological manifestations. A 10‐year‐old boy with LPI who exhibited a severe systemic immunohaematological disease is described here. This patient showed cutaneous lesions similar to the subacute form of systemic lupus erythematosus, severe anaemia and dysproteinaemia, and a marked reduction of circulating T lymphocytes, mainly the CD4+ cells. In vitro bone marrow cell culture studies showed that addition of patient's serum induced macrophage proliferation and inhibited erythroid progenitor cell growth. Treatment with high‐dose intravenous immune globulin resolved most of the clinical and laboratory abnormalities.
Abnormal glutathione conjugation in patients with tyrosinaemia type I
Authors: Mulders T. M. T. , Bergman D. J. W. , Poll‐The B.‐T. , Smit G. P. A. , Breimer D. D. , Mulder G. J. , Duran M. , Smeitink J. A. M. 
Published: December 2002

AbstractPrevious studies have suggested that tyrosinaemia type I may be associated with reduced glutathione availability due to conjugation of tyrosinaemia‐associated reactive intermediates with glutathione. In the present study, the glutathione/glutathione S‐transferase system of two tyrosinaemia patients and three healthy controls were characterized by administering the racemic sedative drug bromisoval, a probe drug for assessing glutathione conjugation activity in vivo. Furthermore, concentrations of glutathione and glutathione S‐trasnferase class alpha (GSTA) isoenzymes as well as the glutathione S‐transferase class mu phenotype were assessed in the blood of six tyrosinaemia patients.The excretion of bromisoval mercapturates in healthy children was comparable to that observed in healthy adults. Tyrosinaemia patients were found to have a very high urinary recovery of bromisoval mercapturates (≥60% of the dose compared to about 30% for healthy, age‐matched children and adults), which could be attributed mainly to a higher urinary excretion of the mercapturate derived from S‐bromisoval. Healthy children and adults predominantly excrete the (R)‐bromisoval mercapturate. The differences in amount excreted as well as in stereoselectivity of the urinary excretion of bromisoval mercapturates in tyrosinaemia patients are possibly related to an increased activity of specific glutathione S‐transferase isoenzymes.Plasma glutathione and blood cell glutathione disulphide concentrations in tyrosinaemia patients were normal. Low blood cell glutathione concentrations were in general found only in two patients with a poor clinical condition. These results indicate that, in contrast to previous suggestions, reduced glutathione availability is not a generalized problem in (stabilized) tyrosinaemia patients.
A novel mutation found in an adrenoleukodystrophy patient who underwent bone marrow transplantation
Authors: Osaka H. , Sekiguchi H. , Inoue K. , Ikuta K. , Sakakihara Y. , Oka A. , Onishi H. , Miyakawa T. , Suzuki K. , Kosaka K. , Matsuyama S. 
Published: December 2002

AbstractWe identified a novel mutation, L322P, in a patient with X‐linked adrenoleukodystrophy (ALD) who underwent bone marrow transplantation (BMT). An identification of the ALD gene mutation enabled us to employ an approach not dependent on the use of radioisotopes for detecting mixed chimerism. This assay could show more than 99.0% of the patient's peripheral white blood cells were replaced by the donor's cells.
Mouse models of genetic disease: New approaches, new paradigms
Authors: Brown S. D. M. 
Published: December 2002

AbstractThe mouse mutant resource is a valuable tool for gene function studies in the post‐genomics era. However, despite a seemingly large catalogue of mouse mutants, it is recognized that we have access to mutations at only a small fraction of the total number of mouse genes. There is a phenotype gap that needs to be narrowed by the implementation of large‐scale, systematic mutagenesis programmes in the mouse. Both genotype‐driven and phenotype‐driven approaches can be employed to recover new mouse mutations. Genotype‐driven approaches include large‐scale genome‐wide mutagenesis by gene trapping in embryonic stem cells. For genotype‐driven approaches, the initial focus is on the characterization of the mutational change to the genome. Identification of the mutated gene is relatively trivial, but the genotype‐driven route provides little indication of the likely phenotypic outcome of the mutation. In contrast, phenotype‐driven approaches employ mutagenesis procedures that emphasize the recovery of novel phenotypes without prior assumptions about the underlying gene or pathway that has been disrupted – although identifying the underlying gene may not be trivial. One phenotype‐driven approach includes chemical mutagenesis using N‐ethyl‐N‐nitrosourea (ENU). ENU mutagenesis programmes are increasingly being brought to bear on increasing the breadth and depth of the mouse mutant resource, and in so doing narrowing the phenotype gap.
Comparative biochemical studies of ATPases in cells from patients with the T8993G or T8993C mitochondrial DNA mutations
Authors: Vázquez‐Memije M. E. , Shanske S. , Santorelli F. M. , Kranz‐Eble P. , DeVivo D. C. , DiMauro S. 
Published: December 2002

AbstractWe performed comparative biochemical studies in cultured fibroblast mitochondria from patients with the T8993G or the T8993C point mutations in the ATPase 6 gene of mitochondrial DNA. We found that ATP production was much more severely decreased in cells from patients with the T8993G mutation than in those from patients with the T8993C mutation. Kinetic studies suggest that both mutations affect only the F0 sector of the mitochondrial ATPase complex. We conclude that these two mutations, which result in the substitution of different amino acids at the same site of the ATPase, result in an enzyme with different biochemical characteristics.
The role of manganese superoxide dismutase in health and disease
Authors: Robinson B. H. 
Published: December 2002

AbstractManganese superoxide dismutase (MnSOD) is the mitochondrial enzyme that disposes of superoxide generated by respiratory chain activity. Of all electrons passing down the mitochondrial respiratory chain, 1–2% are diverted to form superoxide; thus production of hydrogen peroxide occurs at a constant rate due to MnSOD activity. Mice lacking MnSOD develop cardiomyopathy and basal ganglia lesions, have no lipid peroxidation products, but show destruction of enzymes with 4Fe–4S centres. Patients with complex I (NADH‐CoQ oxidoreductase) deficiency show variable hyperinduction of MnSOD that is at least partially dependent on the extent of disturbance of redox state. This in turn appears to result in production of excess hydroxyl radicals, which are damaging to proteins, lipids and DNA. An alternative method of protection from oxygen radicals is employed by complex I‐deficient cell types that do not induce MnSOD in that they show induction of the bcl‐2 protein.
Molecular heterogeneity of Krabbe disease
Authors: Fu L. , Inui K. , Nishigaki T. , Tatsumi N. , Tsukamoto H. , Kokubu C. , Muramatsu T. , Okada S. 
Published: December 2002

AbstractKrabbe disease (globoid cell leukodystrophy) is an autosomal recessive neurodegenerative disorder that affects both the central and peripheral nervous system due to an enzymatic defect of galactocerebrosidase (GALC). Following its cloning, many mutations in the galactocerebrosidase gene have been reported, but the correlation between phenotype and genotype was not clear in many cases. In this study we further investigated the molecular defects in another 10 patients (6 Japanese and 4 non‐Japanese), using cultured skin fibroblasts, and found 10 mutations, of which 8 were novel, including a nonsense mutation (W647X) and 7 missense mutations (G43R, S52F, T262I, Y319C, W410G, R515H, T652R) in the coding region. Some phenotype‐specific mutations were found but the other mutations were private. Mutations reported so far have been distributed over the whole GALC gene and it is difficult to speculate on functional domains of the GALC protein and phenotypically specific regions.
Sphingolipids and cell signalling
Authors: Fredman P. 
Published: December 2002

AbstractThe sphingolipid storage disorders constitute a group of inherited metabolic disorders in which the structure of the stored sphingolipid and the corresponding genetic defect have been established. However, the pathological mechanism(s) behind the disorders has not been fully elucidated. Sphingolipids are known to be recognition molecules involved in intercell communication and altered expression might lead to dyscommunication. The impaired degradation and lysosomal accumulation of specific sphingolipids might influence the metabolism of other molecules and/or intracellular transport, which in turn might alter the distribution of these molecules. However, the progress of these diseases indicates that additional factors, besides the stored sphingolipid itself, might be involved. During the last decade, several sphingolipids have emerged as active participants in intracellular signalling processes such as growth control and apoptosis. Particular interest focused on the sphingolipid metabolites, ceramide and sphingosine, as potential mediators in intracellular events and an altered presence of these metabolites in sphingolipidoses cannot be ruled out. Some sphingolipids have been found to influence cytokine release and thereby might induce immunological processes, which are known to exist in at least one of the sphingolipidoses – Gaucher disease. These processes might already have a pathogenic effect during early development, before significant storage has occurred.
Variable clinical presentation in three patients with 3‐methylglutaconyl‐coenzyme A hydratase deficiency
Authors: Gibson K. M. , Wappner R. S. , Jooste S. , Erasmus E. , Mienie L. J. , Gerlo E. , Desprechins B. , De Meirleir L. 
Published: December 2002

Abstract3‐Methylglutaconyl‐coenzyme A (3‐MG‐CoA) hydratase deficiency (type I 3‐methylglutaconic aciduria), a rare defect of L‐leucine catabolism, has previously been identified in 5 patients (four families). Clinical findings in 3 were mild, with delayed speech development in 2 siblings, and bronchiolitis, mild hyperchloraemic acidosis, and gastro‐oesophageal reflux in a third patient (Narisawa et al 1986; Gibson et al 1992). In two recently described patients, a more severe presentation was observed. The presentation included vomiting, seizures, coma, speech retardation, hepatomegaly, and decerebrate posture in one patient in whom the provisional diagnosis was Reye syndrome (Hou and Wang 1995). In another patient, the clinical picture encompassed psychomotor retardation, failure to thrive, spastic quadriplegia, dystonic involuntary movements in the upper limbs, and bilateral atrophic changes of the basal ganglia (Shoji et al 1996). We present 3 patients with 3‐MG‐CoA hydratase deficiency who also manifested widely differing clinical presentations, bringing to eight the total number of patients with documented 3‐MG‐CoA hydratase deficiency.
The molecular basis of transferase galactosaemia in South African negroids
Authors: Manga N. , Jenkins T. , Jackson H. , Whittaker D. A. , Lane A. B. 
Published: December 2002

AbstractTransferase galactosaemia is an autosomal recessively inherited disorder caused by a deficiency of galactose‐1‐phosphate uridyltransferase (GALT). Manifestations include jaundice, vomiting, cataracts, mental retardation, speech abnormalities and poor growth. The GALT gene has been mapped and sequenced. The S135L mutation accounts for approximately 48% of galactosaemia alleles in African Americans and has been found to account for about 91% of galactosaemia alleles in negroid South African patients which suggested that the mutation had an African origin. We have calculated the S135L allele frequency (±1SE) in a sample of healthy unrelated negroid South Africans to be 0.0067 (±0.0024). The S135L mutation was also detected in negroid populations from other regions of Africa confirming its African origin.
Mutations in the glucose‐6‐phosphatase gene of 53 Italian patients with glycogen storage disease type Ia
Authors: Stroppiano M. , Regis S. , DiRocco M. , Caroli F. , Gandullia P. , Gatti R. 
Published: December 2002

AbstractType Ia glycogen storage disease (GSD1a) is an autosomal recessive metabolic disorder caused by a deficiency in glucose‐6‐phosphatase (G6Pase). Recent cloning of the G6Pase gene and the subsequent identification of several disease‐causing mutations have shown an ethnic molecular heterogeneity. Using SSCP analysis and DNA sequencing, we characterized the G6Pase gene of 53 unrelated Italian patients. The two most common mutations, R83C and Q347X, accounted for 66.9% of the mutant alleles. Eight novel mutations and three rare mutations were identified in 15.7% of disease alleles. These results suggest that a DNA‐based method can be used as an initial screening in Italian patients clinically suspected of having GSD1a, avoiding liver biopsy for enzymatic diagnosis. In particular, a noninvasive diagnosis is a suitable method for the Italian subpopulation coming from Sicily, where the R83C mutation is present in 80% of mutant alleles. Molecular carrier detection and prenatal diagnosis can be provided to GSD1a families with identified mutation in the propositus.
Fasting, postprandial, and post‐methionine‐load homocysteinaemia and methylenetetrahydrofolate reductase polymorphism in vascular disease
Authors: Candito M. , Bedoucha P. , Gibelin P. , Jambou D. , de Franchis R. , Sadoul J.‐L. , Chatel M. , Van Obberghen E. 
Published: December 2002

AbstractHyperhomocysteinaemia is an independent risk factor for cardiovascular disease. The C677T mutation of the methylenetetrahydrofolate reductase (MTHFR) is a common genetic cause of increased homocysteine (HCY) levels. Post‐methionine‐load HCY concentrations allow identification of certain cases of hyperhomocysteinaemia not demonstrated by fasting levels. This study investigated the relationship between MTHFR polymorphism and (1) fasting HCY levels (77 patients); (2) post‐methionine HCY levels (54 patients); and (3) postprandial HCY concentrations (36 patients) in cardiovascular disease. As expected, mean fasting HCY value was higher in the +/+ patients. Moreover, patients who were homozygous for the mutation exhibited significantly increased mean post‐methionine‐load HCY; in contrast, literature results are conflicting. Mean postprandial HCY, which is not known to be increased in controls, was also increased in the (+/+) patients, although the difference did not reach statistical significance, probably owing to the small size of the sample. MTFHR polymorphism is known to be aggravated by a drop in circulating folate. Additional risk factors may be more prevalent in patients with cardiovascular disease.
Both Intra- and Extracellular Ca2+ Participate in the Regulation of the Lateral Diffusion of the PDGF-β2 Receptor
Authors: Höddelius Pia , Lirvall Margareta , Wasteson Åke , Loitto Vesa , Magnusson Karl-Eric 
Published: December 2002

When the receptors for platelet-derived growth factor (PDGF) are activatedthey aggregate, become tyrosine-phosphorylated and elicit a cascade ofdown-stream signals, including mobilization of Ca2+ from intra- andextracellular stores. Receptor mobility in the plane of the membrane isa prerequisite for receptor aggregation and further signalling. Using humanforeskin fibroblasts (AG 1523) and fluorescence recovery afterphotobleaching (FRAP), we therefore assessed the lateral mobilitycharacteristics of PDGF-β2 receptors by their diffusioncoefficient (D), and fraction of mobile receptors (R). This was done oncells stimulated with either normal human serum (NHS) or PDGF underdifferent Ca2+-conditions.
The results suggest that both intra- and extracellular free Ca2+influence the mobility characteristics of the PDGF-β2receptor. Interestingly, the extracellular Ca2+ seems to imposegeneral restrictions on the mobility of receptors, since R increased whenextracellular Ca2+ was quenched with EGTA, whereas intracellularclamping of Ca2+ transients with MABTAM (BAPT/AM) primarily affectedD. When both intra- and extracellular Ca2+ were quenced, D remainedlow and R high, further supporting the proposition that they achievedistinct effects. Inhibition of tyrosine phosphorylation with Erbstatin,partly inhibited the NHS effects and released PDGF-induced receptorimmobilization. Ratio imaging with Fura-2 displayed that both NHS and PDGFinduced changes in intracellular free [Ca2+]. In view of the presentdata it might have important effects on the state of the receptor in themembrane, for instance by regulating its lateral mobility, communicationwith other receptors and signalling functions in the membrane.
Personality profiles of mothers of children with mitochondrial disorders
Authors: Varvogli L. , Waisbren S. E. 
Published: December 2002

AbstractMothers of children with mitochondrial disorders, inherited neurodegenerative diseases, are faced with a frightening diagnosis and numerous demands associated with caring for these children. The psychological profile of mothers whose children carry a mitochondrial disorder is unknown. Forty‐two mothers of children with mitochondrial disorders were interviewed and administered the Minnesota Multiphasic Personality Inventory – Second Edition (MMPI‐2). Fifty‐six per cent of the mothers had scores in the pathological range on three or more scales, most notably on Hypochondriasis, Hysteria and Paranoia scales. The MMPI‐2 profile is associated with situational anxiety and stress or may be associated with carrier status characteristics. Whatever the cause, future studies need to determine whether supportive services can reduce the level of anxiety and stress in mothers of children with these disorders.
Glutaric aciduria type I: From clinical, biochemical and molecular diversity to successful therapy
Authors: Hoffmann G. F. , Zschocke J. 
Published: December 2002

AbstractThe biochemical hallmark of glutaric aciduria type I (GA I) due to glutaryl‐CoA dehydrogenase deficiency is the accumulation of glutaric acid, and to a lesser degree of 3‐hydroxyglutaric and glutaconic acids. Abnormal metabolites vary from gross organic aciduria to only slightly or intermittently elevated or even normal excretion of glutaric acid, making the diagnosis sometimes difficult. Close to 100 pathogenic mutations have been identified in the gene encoding glutaryl‐CoA dehydrogenase. Specific mutations correlate with low or no excretion of glutaric acid, but there appears to be no correlation between genotype and clinical phenotype.GA I causes unique age‐ and location‐specific neuropathological sequelae. Starting in the second half of gestation, maturation of the frontal and temporal cortex is hindered, leading to the characteristic appearance of frontotemporal atrophy. Between 6 and 18 months of age, relatively mild neurological symptoms may become exacerbated by fever or a catabolic state in the course of common infections or routine immunizations, by fasts required for surgery, or by minor head injuries. Putamen and caudate are destroyed, resulting in a permanent movement disorder that is similar to cerebral palsy and ranges from extreme hypotonia to choreoathetosis to rigidity with spasticity. Recently, the underlying pathophysiology could be delineated to an environmentally triggered age‐ and location‐specific overstimulation of the NMDA 2B receptor subtype.Current therapy prevents brain degeneration in more than 90% of affected infants who are treated prospectively. Without treatment, more than 90% of affected children will develop severe neurological disabilities. Recognition of this disorder before the brain has been injured is essential to treatment. GA I may be recognized in routine neonatal screening performed with tandem mass spectrometry by an elevation of glutarylcarnitine. Where this is not done, timely diagnosis depends on the recognition of relatively nonspecific physical findings such as hypotonia, irritability, macrocephaly, on the detection of suggestive abnormalities in neuroimaging and on quantitative urinary organic acid analysis by gas chromatography ‐ mass spectrometry.
D‐2‐Hydroxyglutaric aciduria: Further clinical delineation
Authors: van der Knaap M. S. , Jakobs C. , Hoffmann G. F. , Duran M. , Muntau A. C. , Schweitzer S. , Kelley R. I. , Parrot‐Roulaud F. , Amiel J. , De Lonlay P. , Rabier D. , Eeg‐Olofsson O. 
Published: December 2002

AbstractIt has recently been recognized that D‐2‐hydroxyglutaric aciduria is a distinct neurometabolic disorder with a severe and a mild phenotype. Whereas the clinical and neuroimaging findings of the severe phenotype were homogeneous among the patients, the findings in the mild phenotype were much more variable, leaving the clinical picture poorly defined. We were able to collect the clinical, biochemical and neuroimaging data on an additional 8 patients with D‐2‐hydroxyglutaric aciduria, 4 with the severe and 4 with the mild phenotype. With the new information, it becomes clear that the mild phenotype shares the essential characteristics of the severe phenotype. The most frequent findings, regardless of the clinical phenotype, are epilepsy, hypotonia and psychomotor retardation. Additional findings, mainly occurring in the severe phenotype, are episodic vomiting, cardiomyopathy, inspiratory stridor and apnoeas. The most consistent MRI finding is enlargement of the lateral ventricles, occipital more than frontal. Regardless of the clinical phenotype, early MRI shows in addition subependymal cysts and signs of delayed cerebral maturation. Later MRI may reveal multifocal cerebral white‐matter abnormalities. Two patients had vascular abnormalities, but it is as yet unclear whether these are related to D‐2‐hydroxyglutaric aciduria or are incidental findings.
3‐Methylglutaconic aciduria and hypermethioninaemia in a child with clinical and neuroradiological findings of Leigh disease
Authors: Di Rocco M. , Caruso U. , Moroni I. , Lupino S. , Lamantea E. , Fantasia A. R. , Borrone C. , Gibson K. M. 
Published: December 2002

AbstractWe report on a child with a clinical and neuroradiological picture consistent with Leigh disease and an unusual association of isolated hypermethioninaemia and 3‐methylglutaconic aciduria. A low‐methionine diet normalized both plasma methionine and urine 3‐methylglutaconic acid; a methionine‐loading test led to significant increase of both metabolites. In the skin fibroblasts the activity of 3‐methylglutaconyl‐CoA hydratase was essentially normal. No explanation of this uncommon association of hypermethioninaemia and glutaconic aciduria is available. The possibility of a common transporter for 3‐methylglutaconic acid and methionine is an attractive hypothesis.