bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutation detection in 65 families with a possible diagnosis of ornithine carbamoyltransferase deficiency including 14 novel mutations
Authors: Genet S. , Cranston T. , Middleton‐Price H. R. 
Published: December 2002

AbstractThe high new mutation rate and the wide spectrum of mutations found in patients with ornithine carbamoyltransferase (OCT) deficiency means that direct mutation analysis is essential for providing accurate carrier detection and prenatal diagnosis in affected families. We present our strategy for mutation detection in the OCT gene and summarize the results from 31 families with a confirmed diagnosis and 34 families with a suspected diagnosis of OCT deficiency, and describe 14 previously unreported mutations.
Genetic analysis of phytosterolaemia
Authors: Togo M. , Toda T. , Nguyen L. A. , Kubota S. , Tsukamoto K. , Satoh H. , Hara M. , Iso‐o N. , Noto H. , Kimura S. , Nakahara K. , Seyama Y. , Hashimoto Y. 
Published: December 2002

AbstractTwo women with multiple xanthomas, intermittent arthritis and thrombocytopenia were diagnosed as phytosterolaemia, an autosomal‐recessive lipid storage disease, based on their increased serum concentrations of β‐sitosterol, campesterol and sitostanol. The gene responsible for this disease is located within a distance of 18 cM between microsatellite markers of D2S1788 and D2S1352 at chromosome 2p21. We genotyped the patients and their family members with 16 microsatellite markers around this locus. The results from the homozygosity mapping of one family suggested that the gene was located within the distance of 12.6 cM between D2S2328 and D2S1352. We have shortened the genetic distance by 5.4 cM.
Gene therapy/cell therapy for lysosomal storage disease
Authors: Eto Y. , Ohashi T. 
Published: December 2002

AbstractLysosomal storage diseases (LSD) are considered to be appropriate disorders for gene therapy/cell therapy. We are attempting to treat one of these disorders using a mouse model, the Sly mouse. This is an authentic model for human β‐glucuronidase deficiency, MPS VII. We have carried out two types of experimental protocols; in vivo gene therapy and ex vivo gene therapy using Sly mice. For in vivo gene therapy, we produced a recombinant adenovirus that expresses human β‐glucuronidase and administered this to Sly mice intravenously. The β‐glucuronidase activities in liver and spleen were elevated to 40% and 20%, respectively, of the heterozygote enzyme level at day 16. Expression persisted for at least 35 days. Pathological abnormalities improved in these tissues and urinary glycosaminoglycan excretion was reduced in treated animals. ex vivo gene therapy/cell therapy was carried out using macrophages obtained by cultivation of bone marrow cells. Non‐myeloablated macrophages from normal mice were transplanted into Sly mice, and after 7 days donor cells had populated the liver and spleen. The human β‐glucuronidase (HBG) activity was increased in liver and spleen, although these enzyme activities subsequently fell by 38 days. The pathological improvement in Sly mice was evident at day 38 post transplantation. Furthermore, the macrophages from Sly mice were treated with retrovirus/adenovirus vector expressing HBG activity and the glycosaminoglycan accumulation was markedly decreased after 5 weeks. These data suggest that genetically engineered macrophage transplantation may be a very useful form of ex vivo gene therapy for lysosomal storage diseases. We also discuss the possible treatment of the CNS involvement in lysosomal storage diseases by gene therapy/cell therapy.
Novel mutations in two Japanese cases of glycogen storage disease type IIIa and a review of the literature of the molecular basis of glycogen storage disease type III
Authors: Fukuda T. , Sugie H. , Ito M. 
Published: December 2002

AbstractWe report two novel mutations in two Japanese patients with glycogen storage disease type IIIa (GSD IIIa). In addition, we review the literature on mutations in GSD III to understand better the molecular basis of GSD III. In our first case, the homozygous A‐to‐C mutation at the acceptor site of intron 5 (IVS5–2A>C) was identified. This leads to the skipping of exon 6 and the predicted mutant protein was found to be 68 amino acids shorter than normal. This is the first report of skipping exon 6, which encodes one of the putative active sites, resulting in a profoundly deleterious effect on debrancher activity. In our second case, the homozygous deletion of an A at position 4234 (4234delA) was identified; this induces a frameshift resulting in the appearance of a stop codon at amino acid position 1276 (1276X). In patients with GSD IIIa, several mutations of the debrancher gene located in the C‐terminal region containing putative glycogen binding domains have been identified as well as 4234delA in our second case. On the other hand, specific localization of the mutations within exon 3 was proposed in patients with GSD IIIb.
Cerebral metabolic changes in biotinidase deficiency
Authors: Schürmann M. , Engelbrecht V. , Lohmeier K. , Lenard H. G. , Wendel U. , Gärtner J. 
Published: December 2002

AbstractClinical and metabolic changes in the central nervous system are described in a patient with biotinidase deficiency before and after biotin treatment. Lactate, pyruvate and 3‐hydroxyisovaleric acid as metabolic disease markers were measured in blood, cerebrospinal fluid and brain tissue by biochemical analyses or localized magnetic resonance proton spectroscopy. The patient improved markedly with biotin treatment. Nevertheless, neurological sequelae and abnormal intracerebral lactate concentrations persisted despite normalized metabolic disease markers in extracerebral fluids. Therefore, localized in vivo measurements of intracerebral metabolites may be a valuable tool for elucidating the pathogenesis of biotinidase deficiency.
Effect of plasma α‐tocopherol on leukotriene E4 excretion in genetic vitamin E deficiency
Authors: Kohlschütter A. , Mayatepek E. , Finckh B. , Hübner C. 
Published: December 2002

AbstractStudying the biological effects of vitamin E in humans is difficult because conditions involving vitamin E deficiency are usually associated with chronic multiple pathology. Genetic vitamin E deficiency caused by a deficient α‐tocopherol transport protein offers unique possibilities for study of vitamin E effects since the patients can be studied in good general health. In such a patient we manipulated plasma α‐tocopherol levels in a wide range by varying oral α‐tocopherol supplements and measured urinary leukotriene E4 (LTE4) concentrations. LTE4 excretion proved inversely correlated to plasma α‐tocopherol levels. This strongly suggests that in genetic vitamin E deficiency, α‐tocopherol influences formation of leukotrienes in vivo.
Prevalent mutations in the GALC gene of patients with Krabbe disease of Dutch and other European origin
Authors: Kleijer W. J. , Keulemans J. L. M. , van der Kraan M. , Geilen G. G. , van der Helm R. M. , Rafi M. A. , Luzi P. , Wenger D. A. , Halley D. J. J. , van Diggelen O. P. 
Published: December 2002

AbstractSixty‐four unrelated patients with infantile Krabbe disease (globoid cell leukodystrophy, GLD) of Dutch (n=41) or other European origin (n=23) were screened for the presence of a large 30kb deletion starting in intron 10 (IVS 10del30kb), a base substitution 1538T(T513M) and a polymorphism, 502T. The deletion and the T513M mutation were present in 52% and 8.5%, respectively, of the 82 GALC alleles of the Dutch patients. The 502T polymorphism, which had an allele frequency of 5.3% in a Dutch control panel, occurred in 65% of the GLD alleles. Analysis of patients and both parents in 26 of the families showed that del30kb was invariably associated with 502T. However, 502T was also present on 40% of the GLD alleles with an as yet unidentified mutation, which is 7.5 times higher than its frequency in controls. This suggests that besides del30kb at least one other relatively frequent mutation has arisen on the 502T GALC allele. A relatively high incidence of del30kb was also found in 23 other European (non‐Dutch) patients (allele frequency 35%), but T513M did not occur in this group. Practical examples described in this report illustrate the potential usefulness of mutation analysis in many families with Krabbe disease for heterozygote detection and prenatal diagnosis.
Primary hyperoxaluria type 1: Diagnostic relevance of mutations and polymorphisms in the alanine:glyoxylate aminotransferase gene (AGXT)
Authors: Tarn A. C. , von Schnakenburg C. , Rumsby G. 
Published: December 2002

AbstractPrimary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder of glyoxylate metabolism caused by deficiency of the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). The disease shows considerable phenotypic, enzymatic and genetic heterogeneity. To date, 7 polymorphisms and 11 point mutations have been described in the gene encoding AGT. We report on the prevalence of these polymorphisms and mutations in 79 patients with PH1 with the aim of assessing their diagnostic relevance. A strong association of the C154T, intron 1 insertion and C386T polymorphisms is confirmed and this linkage extends to include the type 1 variant of a polymorphic tandem repeat in intron 4. Only 64 of 158 (40%) PH1 alleles have one of the defined mutations, with the G630A mutation accounting for 39 of these and T853C for 14. Overall only 20 (25%) of the patients studied had the genetic basis of their disease fully explained: 7 were homozygous for the G630A mutation, 5 were homozygous for the T853C mutation, 1 was homozygous for the C819T mutation, and 7 had two different mutations identified and were presumed to be compound heterozygotes. Only the two more frequent G630A and T853C mutations are of general diagnostic relevance for mutation screening. It seems likely that there are a significant number of other mutations, perhaps family‐specific, still to be described. There was no apparent difference in the types of mutations in patients presenting in the first year of life (36%), suggesting that other factors, such as periods of dehydration or urinary tract infections, might contribute more to the clinical manifestation than genotype.
Urinary uracil concentrations are a useful guide to genetic disorders associated with neurological deficits and abnormal pyrimidine metabolism
Authors: Davies P.M. , Fairbanks L.D. , Dulby J.A. , Simmonds H.A. 
Published: December 2002

AbstractElevated urinary uracil concentrations are characteristic of genetic deficiencies of enzymes catalysing the first two steps of the pyrimidine degradative pathway (Van Gennip et al 1993), dihydropyrimidine dehydrogenase (DPD) and dihydropyrimidinase (DHP). DPD is rate limiting for the whole pathway. Homozygotes are detected by the raised levels of uracil and thymine in urine. The pyrimidine synthetic route shares a common intermediate. carbamoyl phosphate, with the urea cycle. In urea‐cycle disorders such as ornithine carbamoyltransferase (OCT) deficiency, orotic aciduria resulting from an increased flux through the pathway has been used to detect hemizygotes or carriers following a protein, or more recently, an allopurinol load (Sebesta et al 1994). This paper demonstrates that uracil may be an even more useful guide to OCT carrier status and compares urinary uracil with concentrations found in genetic pyrimidine defects associated with neurological deficits.
Inherited metabolic diseases affecting the carrier
Authors: Endres W. 
Published: December 2002

AbstractThe objective of this review is to draw attention to those inherited metabolic traits which are potentially harmful also for the carrier, and to outline preventive measures, at least for obligate heterozygotes, i.e. parents of homozygous children. Concerning carriers of food‐dependent abnormalities, early vascular disease in homocystinuria, hyperammonaemic episodes in ornithine transcarbamylase deficiency, presenile cataracts in galactosaemia as well as galactokinase deficiency, spastic paraparesis in X‐linked adrenoleukodystrophy, and HELLP syndrome in mothers of babies with long‐chain 3‐hydroxyacyl‐coenzyme A dehydrogenase deficiency have to be mentioned. In the group of food‐independent disorders, clinical features in carriers may be paraesthesias and corneal dystrophy in Fabry disease, lens clouding in Lowe syndrome, lung and/or liver diseases in α1‐antitrypsin deficiency, and renal stones in cystinuria type II and III. Finally, two monogenic carrier states are known which in pregnant indi‐viduals could possibly afflict the developing fetus, i.e. heterozygosity for galactosaemia and for phenylketonuria. Elevated levels of galactose‐1‐phosphate have been found in red blood cells of infants heterozygous for galactosaemia born to heterozygous mothers. Aspartame in very high doses is reported to increase blood phenylalanine levels in heterozygotes for phenylketonuria, thus being a risk for the fetus of a heterozygous mother. For some of these carrier states preventive measures can be recommended, e.g. restriction of lactose in parents and heterozygous grandparents of children with galactosaemia and galactokinase deficiency as well as transiently in infants heterozygous for galactosaemia, dietary supplementation with monounsaturated fatty acids in symptomatic carriers for X‐linked adrenoleukodystrophy, avoidance of smoking and alcohol in heterozygotes for α1‐antitrypsin deficiency, avoidance of episodes of dehydration in heterozygotes for cystinuria, and restriction of aspartame in p regnant women.
Methylmalonic acidaemia with bilateral globus pallidus involvement: A neuropathological study
Authors: Larnaout A. , Mongalgi M. A. , Kaabachi N. , Khiari D. , Debbabi A. , Mebazza A. , Ben Hamida M. , Hentati F. 
Published: December 2002

AbstractA 16‐month‐old boy was hospitalized because of a 1‐day history of severe ketoacidosis with lethargy, hypotonia, vomiting, and important dyspnoea. Organic acid assay by gas chromatography–mass spectrometry confirmed the diagnosis of methylmalonic acidaemia (MMA). On the sixteenth day, he developed an acute extrapyramidal disorder. The CT scan of the brain disclosed bilaterally symmetric lucency of basal ganglia. He died at 17 months of age. Post‐mortem neuropathological examination, showed severe necrosis with spongiosis, cystic cavitation and numerous lipid‐laden macrophages of the globi pallidi, and mild spongiosis of subthalamic nuclei, mammillary bodies, portion of internal capsule adjacent to globus pallidus, superior cerebellar peduncles and tegmentum of brainstem. Pallidal infarction, a focal ischaemic lesion, demonstrates that ischaemia/energy depletion may be important in the etiology of the neuropathology of MMA.
Bone marrow transplantation for Maroteaux–Lamy syndrome (MPS VI): Long‐term follow‐up
Authors: Herskhovitz E. , Young E. , Rainer J. , Hall C. M. , Lidchi V. , Chong K. , Vellodi A. 
Published: December 2002

AbstractWe describe the results of bone marrow transplantation (BMT) in four patients with mucopolysaccharidosis type VI (MPS VI, McKusick 253200) – Maroteaux–Lamy disease. The indications for transplantation were cardiomyopathy in three patients and severe obstructive sleep apnoea in one. The follow‐up period ranges between 1 and 9 years, and three of the patients are at mainstream schools. In all of the patients the facial features have become less coarse and the cardiac manifestations have improved or remained stable. However, skeletal changes have persisted or even progressed, although posture and joint mobility have improved and all the patients have remained ambulatory and active. BMT appears to prolong survival and improve the quality of life in MPS VI patients, but careful selection of patients is essential.
Lactic acidosis in long‐chain fatty acid β‐oxidation disorders
Authors: Ventura F. V. , Ruiter J. P. N. , IJlst L. , Tavares de Almeida I. , Wanders R. J. A. 
Published: December 2002

AbstractAmong the many disorders of fatty acid β‐oxidation known today, the disorders of long‐chain fatty acid oxidation are the most severe and life‐threatening. One remarkable abnormality, not observed in, for instance, medium‐chain acyl‐CoA dehydrogenase deficiency, is the moderate to severe lactic acidaemia in long‐chain fatty acid β‐oxidation‐deficient patients, suggesting that oxidation of pyruvate is also compromised. In order to understand the underlying basis of the lactic acidaemia in these patients, we have studied the formation of L‐lactate and pyruvate in cultured skin fibroblasts incubated with D‐glucose. All long‐chain fatty acid β‐oxidation‐deficient cell lines studied were found to show a moderate elevation of lactate when compared with control and medium‐chain acyl‐CoA dehydrogenase‐deficient fibroblasts. Interestingly, differences were found between cells deficient in long‐chain 3‐hydroxyacyl‐CoA dehydrogenase and very‐long‐chain acyl‐CoA dehydrogenase, suggesting that saturated acyl‐CoA esters and their 3‐hydroxyacyl‐CoA derivatives affect pyruvate metabolism differently.
Renal clearance of branched‐chain L‐amino and 2‐oxo acids in maple syrup urine disease
Authors: Schadewaldt P. , Hammen> H.‐W. , Ott A.‐C. , Wendel U. 
Published: December 2002

AbstractIn maple syrup urine disease (MSUD), branched‐chain L‐amino (BCAA) and 2‐oxo acids (BCOA) accumulate in body fluids owing to an inherited deficiency of branched‐chain 2‐oxo acid dehydrogenase complex activity. In MSUD, little information is available on the significance of urinary disposal of branched‐chain compounds. We examined the renal clearance of leucine, valine, isoleucine and alloisoleucine, and their corresponding 2‐oxo acids 4‐methyl‐2‐oxopentanoate (KIC), 3‐methyl‐2‐oxobutanoate (KIV), (S)‐ (S‐KMV), and (R)‐3‐methyl‐2‐oxopentanoate (R‐KMV), using pairs of plasma and urine samples (n=63) from 10 patients with classical MSUD. The fractional renal excretion of free BCAA was in the normal range (<0.5%) and indepen‐dent of the plasma concentrations. The excretion of bound (N‐acylated) BCAA was normal and not significantly dependent on the BCAA plasma concentrations. The fractional renal excretion of BCOA was in the order KIC≪KIV<R‐KMV≤S‐KMV (range (%): KIC 0.1–25; KIV 0.14–21.3; S‐KMV 0.26–24.6; R‐KMV 0.1–35.9), significantly correlated with the KIC plasma concentrations, and generally higher than that of the related BCAA. The results show that the renal excretion of free BCAA as well as of the acylated derivatives is negligible. The renal excretion of BCOA, however, to some extent counteracts increases in BCAA concentrations and thus contributes to the lowering of total BCAA pools in MSUD.
Glutaric aciduria type I: Pathomechanisms of neurodegeneration
Authors: Ullrich K. , Flott‐Rahmel B. , Schluff P. , Musshoff U. , Das A. , Lücke T. , Steinfeld R. , Christensen E. , Jakobs C. , Ludolph A. , Neu A. , Röper R. 
Published: December 2002

AbstractIn organotypic corticostriatal and hippocampal slice cultures from rat brain, 3‐hydroxyglutaric acid but not glutaric and glutaconic acids induced neurodegeneration by activation of NMDA receptors. Electrophysiological investigations (Xenopus laevis oocytes expressing glutamate receptors; rat mixed cortex culture) revealed no direct interaction of 3‐hydroxyglutaric acid with glutamate receptors. We speculate that 3‐hydroxyglutaric acid induces a mild energy deprivation that interferes with the voltage‐dependent Mg2+‐block of NMDA receptors.
Quantitative analysis of glucose‐6‐phosphate translocase gene expression in various human tissues and haematopoietic progenitor cells
Authors: Ihara K. , Nomura A. , Hikino S. , Takada H. , Hara T. 
Published: December 2002

AbstractWe investigated the quantitative expression of the human glucose‐6‐phosphate translocase gene (G6PT1) and its splicing variants in human tissues. The G6PT1 gene was strongly expressed in liver, kidney and haematopoietic progenitor cells, which might explain major clinical symptoms such as hepatomegaly, nephromegaly and neutropenia in glycogen storage diseases type Ib. Reverse transcriptase‐mediated PCR amplification of G6PT1 cDNA revealed several splicing variants in tissue‐specific manners. The brain‐specific isoform, which has an additional 22 amino acids between exons 6 and 8, was also identified in heart and skeletal muscle. A new splicing variant, although less prominent in quantity and lacking polypeptide loops corresponding to exons 2 and 3, may have a distinct substrate affinity or specificity in leukocytes and haematopoietic progenitors. In conclusion, the G6PT1 gene was expressed in various tissues, and alternative splicing variants exist in tissue‐specific manners.
Studies of the V94M‐substituted human UDPgalactose‐4‐epimerase enzyme associated with generalized epimerase‐deficiency galactosaemia
Authors: Wohlers T. M. , Fridovich‐Keil J. L. 
Published: December 2002

AbstractImpairment of the human enzyme UDPgalactose 4‐epimerase (hGALE) results in epimerase‐deficiency galactosaemia, an inborn error of metabolism with variable biochemical presentation and clinical outcomes reported to range from benign to severe. Molecular studies of the hGALE loci from patients with epimerase deficiency reveal significant allelic heterogeneity, raising the possibility that variable genotypes may constitute at least one factor contributing to the biochemical and clinical heterogeneity observed. Previously we have identified a single substitution mutation, V94M, present in the homozygous state in all patients genotyped with the severe, generalized form of epimerase‐deficiency galactosaemia. We report here further studies of the V94M‐hGALE enzyme, overexpressed and purified from a null‐background yeast expression system. Our results demonstrate that the mutant protein is impaired relative to the wild‐type enzyme predominantly at the level of Vmax rather than of Km. Studies using UDP‐N‐acetylgalactosamine as a competitor of UDPgalactose further demonstrate that the Km values for these two substrates vary by less than a factor of 3 for both the wild‐type and mutant proteins. Finally, we have explored the impact of the V94M substitution on susceptibility of yeast expressing human GALE to galactose toxicity, including changes in the levels of galactose 1‐phosphate (gal‐1‐P) accumulated in these cells at different times following exposure to galactose. We have observed an inverse correlation between the level of GALE activity expressed in a given culture and the degree of galactose toxicity observed. We have further observed an inverse correlation between the level of GALE activity expressed in a culture and the concentration of gal‐1‐P accumulated in the cells. These data support the hypothesis that elevated levels of gal‐1‐P may underlie the observed toxicity. They further raise the intriguing possibility that yeast may provide a valuable model not only for assessing the impact of given patient mutations on hGALE function, but also for exploring the metabolic imbalance resulting from impaired activity of GALE in living cells.
Coping with domestic violence: Control attributions, dysphoria, and hopelessness
Authors: Clements Caroline M. , Sawhney Daljit K. 
Published: December 2002

AbstractWe investigated the influence of control judgments and coping style on emotional reactions to domestic violence utilizing the framework of hopelessness theory. We assessed abuse severity, control attributions, coping, dysphoric symptoms, and hopelessness in 70 battered women recruited from 12 domestic violence agencies. Respondents reported dysphoria but not hopelessness. Increased reports of dysphoria were associated with higher levels of self‐blame and avoidance coping and lower levels of problem‐focused coping. Increased problem‐focused coping was associated with decreased hopelessness. Perceived control over current abuse was not related to dysphoria. High expectations for control over future events were associated with decreased dysphoria. We discuss our results in terms of their application to attributional accounts of emotional reactions to battering.