bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fetal damage due to maternal phenylketonuria: Effects of dietary treatment and maternal phenylalanine concentrations around the time of conception
Authors: Smith I. , Glossop J. , Beasley M. 
Published: June 2005

SummaryIn 94 infants born to women with PKU, birth weight and head circumference were inversely and linearly related to the mothers' phenylalanine concentrations close to conception; with each 200 µmol/L rise in phenylalanine concentrations, birth weight fell by 98 g and head circumference by 0.46 cm. This relationship was highly significant and appeared to be the same whether or not the mother received a low phenylalanine diet. Even in the 28 infants whose mothers conceived on a strict low phenylalanine diet, birth weights and head circumferences, corrected for sex and gestation, were a little below the population norms (3421 g and 34.7 cm compared with 3600 g and 35.2 cm respectively) although the differences were not statistically significant. Optimal fetal growth occurred only in infants whose mothers had phenylalanine concentrations close to the normal range at conception. Dietary treatment started after conception did not appear to confer any benefit.
Analysis of abnormal urinary metabolites in the newborn period in medium‐chain acyl‐CoA dehydrogenase deficiency
Authors: Bennett M. J. , Coates P. M. , Hale D. E. , Millington D. S. , Pollitt R. J. , Rinaldo P. , Roe C. R. , Tanaka K. 
Published: June 2005

SummaryIn order to determine which are useful early diagnostic markers for medium‐chain acyl‐CoA dehydrogenase (MCAD) deficiency, we have analysed urine from an asymptomatic neonate. Profiling of urinary organic acids followed by peak confirmation by electron impact mass spectrometry revealed a high suberate/adipate ratio (>1.0) and the presence of n‐hexanoylglycine (HG). Acylcarnitine analysis by fast atom bombardment mass spectrometry (FAB‐MS) was inconclusive, but FAB‐MS/MS (tandem mass spectrometry) revealed diagnostic amounts of octanoylcarnitine and hexanoylcarnitine. Quantitative analysis of acylglycines by stable istotope dilution and chemical ionization mass spectrometry revealed a 30‐fold increase in HG and increased suberylglycine, but no increase in 3‐phenylpropionylglycine.
Fatty acid transport in multiple carboxylase deficiency fibroblasts
Authors: Packman S. , Whitney S. 
Published: June 2005

SummaryHolocarboxylase synthetase (HS) and biotinidase deficiencies have been identified as causes of biotin‐responsive multiple carboxylase deficiency. Acetyl‐CoA carboxylase (ACC) deficiency has been shown to occur in multiple carboxylase deficiency, and HS(−) fibroblasts are being employed to investigate compensatory regulatory responses in cells deficient in ACC. In previous studies, biotin starved HS(−) fibroblasts showed a reduced fatty acid content, an abnormal percentage composition of fatty acids, and a preservation of longerchain fatty acid contents of cells. We herein ask whether the mutant cells show compensatory increases in the transport of longer‐chain fatty acids from the medium into fibroblasts. In the present experiments there was no change in the uptake of arachidonate, palmitate or oleate following growth of mutant and control fibroblasts in (+) or (−) biotin conditions. Differential fatty acid uptake from the medium is therefore not a compensatory mechanism in HS(−) cells, and cannot account for the specific changes in fatty acid composition produced by biotin restriction.
Diseases resulting from mitochondrial DNA point mutations
Authors: Wallace D. C. , Lott M. T. , Shoffner J. M. , Brown M. D. 
Published: June 2005

SummaryA number of mitochondrial DNA (mtDNA) mutations have been identified which cause familial, late onset neuromuscular degenerative diseases. These include missense mutations in most of the mtDNA polypeptide genes as well as base substitutions in several tRNA genes. Missense mutations in the mitochondrial electron‐transport genes cause Leber hereditary optic neuropathy. Ten mutations have been associated with this disease, but four at nps 11 178, 3460, 4160 and 15 257 appear sufficient in themselves to cause the disease. One missense mutation in the ATPase 6 gene at np 8993 causes a second phenotype, neurogenic muscle weakness, ataxia and retinitis pigmentosum. Transfer RNA mutations have been identified for myoclonic epilepsy and ragged‐red fibre disease in the tRNALys gene at np 8344 and for the mitochondrial encephalomyopathy, lactic acidosis and stroke‐like episodes syndrome and for maternal mitochondrial myopathy and cardiomyopathy syndrome in the tRNALeu(UUR) gene at nps 3234 and 3260, respectively. Deficiencies in mitochondrial oxidative phosphorylation enzymes have been observed in several common neurodegenerative diseases such as Alzheimer and Parkinson diseases. Perhaps mtDNA mutations play a role in these as well.
Isolation of cDNA sequences around the chromosomal breakpoint in a female with lowe syndrome by direct screening of cDNA libraries with yeast artificial chromosomes
Authors: Okabe I. , Attree O. , Bailey L. C. , Nelson D. L. , Nussbaum R. L. 
Published: June 2005

SummaryThe Lowe oculocerebrorenal syndrome (OCRL; McKusick 309000) is an X‐linked disorder characterized by congenital cataracts, muscular hypotonia, mental retardation, and Fanconi syndrome of the renal tubules. A pair of yeast artificial chromosomes (YACs) that span the Xq25‐q26 translocation breakpoint in a female with OCRL were used as probes to screen cDNA libraries made from bovine lens and human kidney. The methods used to prepare the YACs as probes and to screen the libraries are presented in detail. Two different transcripts were found that map to the region around the Xq25‐q26 breakpoint. These transcripts are now being studied to determine whether one or the other is a candidate gene for OCRL.
Genetic and clinical correlations of Xp21 muscular dystrophy
Authors: Bushby K. M. D. 
Published: June 2005

SummaryWe have investigated over 100 patients with Xp21 muscular dystrophy, drawing together the results of detailed clinical, genetic and dystrophin investigations. A spectrum of disease severity was confirmed, with the most homogeneous clinical groups being at either end of the spectrum, represented by the typical Duchenne and Becker phenotypes. The groups in between showed clinical heterogeneity, and variability in the genetic and dystrophin results. While an out‐of‐frame deletion in association with undetectable dystrophin is most likely to predict the most severe phenotype, and increasing abundance of dystrophin is associated generally with a milder clinical course, no value of dystrophin abundance reliably predicts a particular phenotype. However, deletions of the dystrophin gene involving exons 45–47 and 45–48 especially do seem to be consistently associated with the mildest Becker phenotype. Additional factors must play a role in determining the exact clinical course.
The membrane hypothesis of duchenne muscular dystrophy: Quest for functional evidence
Authors: Hutter O. F. 
Published: June 2005

Summary(1) The location of dystrophin in normal muscle, its molecular structure and associations, characterize it as a component of the submembrane cytoskeleton. When dystrophin is missing the cystoskeleton will therefore be defective, and it has been supposed that this renders the muscle membrane more vulnerable to mechanical damage. With the discovery of animal strains lacking in dystrophin, this hypothesis has been put to experimental tests. Contradictory results have been obtained by workers using different exercise regimens and different indices of fibre damage.(2) Direct measurements of the tensile strength of the membrane have been made on patches of cultured myotubes or isolated muscle fibres, and on sarcolemmal vesicles by pipette aspiration. Neither method has revealed a difference in the tensile strength between normal and dystrophic membrane. The most plausible explanation is that the tensile strength of the membrane is a property more of the lipid bilayer than of the cytoskeleton.(3) In another experimental approach tensile membrane stress has been produced by exposing isolated muscle fibres and myotubes in culture to hypotonic solutions. In such experiments fibres and myotubes lacking dystrophin have been found to lyse more readily than do normal ones. This difference does not conflict with the similarity in tensile strength of normal and dystrophic fibre membranes noted above. Rather, the predisposition to osmotic lysis of dystrophic fibres and myotubes may signify a lower ratio of membrane surface to cell volume, perhaps as a result of loss of some of the spare membrane normally possessed by skeletal muscle fibres and myotubes.(4) In red blood cells the membrane cytoskeleton functions to maintain membrane deformability and stability. Deficiency in spectrin, the main cytoskeletal component, predisposes red cells to cytoskeletal rupture and membrane loss when they experience shear stress. Skeletal muscle fibres, especially long fibres contracting eccentrically, are susceptible to shear stress as a result of uneven contraction along their length. In that event, fibres lacking dystrophin may similarly shed membrane more readily.
Molecular basis of inherited medium‐chain acyl‐CoA dehydrogenase deficiency causing sudden child death
Authors: Kelly D. P. , Hale D. E. , Rutledge S. L. , Ogden M. L. , Whelan A. J. , Zhang Z. , Strauss A. W. 
Published: June 2005

SummaryDeficiency of medium‐chain acyl‐CoA dehydrogenase (MCAD) is an important cause of sudden death in children. The majority of surviving individuals with MCAD deficiency studied to date are homozygous for a single point mutation at bp 985 of the MCAD mRNA (A985G). We have now identified a four‐base‐pair deletion in exon 11 of one allele of the MCAD gene in an American child who died of MCAD deficiency. The deletion mutation results in a frameshift and premature termination codon in the mutant MCAD mRNA. The second mutant allele contained the common point mutation A985G, and thus the proband was a compound heterozygote. Protein immunoblot analysis of the child's liver proteins revealed that the mutant MCAD proteins were barely detectable. Allele‐specific oligonucleotide hybridization analysis performed on amplified exon 11 of the child's MCAD gene clearly identified both mutations. MCAD RFLP analysis of the patient's DNA revealed heterozygosity at the Taq I MCAD RFLP site, thus, the two mutations are associated with different haplotypes. Therefore, we have identified a new mutation in the MCAD gene and have developed a nucleic‐acid‐based screening approach which allows thepost mortem identification of MCAD deficiency.
Azelaic and pimelic acids: Metabolic intermediates or artefacts?
Authors: Bennett M. J. , Ragni M. C. , Hood I. , Hale D. E. 
Published: June 2005

SummaryAzelaic and pimelic acids are excreted in elevated amounts in urine in disorders of mitochondrial β‐oxidation and disorders of peroxisomal β‐oxidation, for which they are of significant diagnostic value. We have detected the presence of azelaic, pimelic and even‐chain‐length dicarboxylic acids (adipic, suberic and sebacic acids) arising artefactually as a result of storage of small sample volumes in plastic containers. Storage of samples for organic acid analysis in glass containers is recommended.
Evaluation of branched‐chain amino acid intake in children with maple syrup urine disease and methylmalonic aciduria
Authors: Parsons H. G. , Carter R. J. , Unrath M. , Snyder F. F. 
Published: June 2005

SummaryThe biochemical and growth responses to dietary branched‐chain amino acid (BCAA) intake were studied in two children; one with a disorder of branched‐chain amino acid metabolism, maple syrup urine disease (MSUD) (McKusick 24860), and another with methylmalonic aciduria (MMA) (McKusick 25100). Biochemical control of MSUD focussed on plasma leucine levels while measurement of plasma ammonia levels was used in MMA. From 0 to 2.75 years both patients exhibited five episodes of toxicity. In each case toxicity was associated with dietary indiscretion or infection. The quantity of protein tolerated was always less in the MMA patient and was approximately 1 g/kg/day. From 1 to 2.75 years each patient's growth velocity approximated their predicted growth channel except during periods of toxicity. In both cases leucine intake, which gave normal growth without toxicity, was always judged to be less than the FAO/WHO recommendations. The BCAA intake of the MMA patient was remarkably stable from 0.5 to 2.75 years and at 2 years of age isoleucine and valine intake approximated the FAO/WHO recommendations. From 2 to 2.75 years BCAA intake (mg/kg/day) of the MSUD patient was less than that of the MMA patient and well below FAO/WHO recommendations. Neuromotor development in both patients is normal.
Retrospective diagnosis of 3‐hydroxydicarboxylic aciduria by analysis of filter paper blood samples
Authors: von Döbeln U. , Venizelos N. , Hagenfeldt L. 
Published: June 2005

SummaryFive patients with 3‐hydroxydicarboxylic aciduria have been investigated. Two of them had elder siblings who had died unexpectedly in early infancy. Stored filter paper blood samples obtained from the patients and their siblings for neonatal screening were retrieved. Elevated levels of 3‐hydroxy fatty acids were observed in the samples from three of the five patients with 3‐hydroxydicarboxylic aciduria and in the samples from both siblings.
Characterization of three new deletions at the 5′ end of the HPRT structural gene
Authors: Wehnert M. , Herrmann F. H. 
Published: June 2005

SummaryIn a panel of seven unrelated HPRT‐deficient patients three partial deletions of the 5′ end of the HPRT structural gene were identified by Southern blot analysis. The deletions could be defined as the loss of exons 1–3, exons 2–3 and exon 3 respectively. In two of the deletion mutations aberrant restriction fragments occurred.
Carrier detection for Sanfilippo A syndrome
Authors: Stone J. , Brimble A. , Pennock C. A. 
Published: June 2005

SummaryLeukocytes from 21 obligate carriers in 12 Sanfilippo A families and 49 normal controls were assayed for heparan sulphamidase (EC 3.10.1.1.) at 55°C. At this assay temperature the results show an absolute distinction between heterozygous carriers and the normal controls.
Maternal phenylketonuria
Authors: Koch R. , Gross Friedman E. , Wenz E. , Jew K. , Crowley C. , Donnell G. 
Published: June 2005

AbstractPregnant women with untreated phenylketonuria (PKU) with blood phenylalanine levels greater than 1200 µmol/L usually give birth to offspring with congenital birth defects, including microcephaly, cardiac defects and mental retardation. According to Mabry and Levy, hyperphenylalaninaemic (HPA) women with blood phenylalanine levels between 600 and 1200 µmol/L also have an increased risk to their offspring. To study this problem further, the National Institute of Child Health and Human Development has established a collaborative study for 7 years to elucidate a proper treatment programme for these women.
Molecular characterization of Duarte‐1 and Duarte‐2 variants of galactose‐1‐phosphate uridyltransferase
Authors: Podskarbi T. , Kohlmetz T. , Gathof B. S. , Kleinlein B. , Bieger W. P. , Gresser U. , Shin Y. S. 
Published: June 2005

SummaryThe N314D polymorphism was found in two different alleles of the galactose‐1‐phosphate uridyltransferase (GALT) gene, Duarte‐1 (D1) and Duarte‐2 (D2). Although both variants have identical electrophoretic mobility and isoelectrofocusing points, the galactose‐1‐phosphate uridyltransferase (GALT) activity varies: D1 alleles showed 110–130% of the normal RBC activity, but D2 alleles only 40–50%. We found that D1 alleles also carried a silent mutation in exon 7 (L218L) in addition to N314D. In contrast, besides N314D, D2 alleles carried two regulatory mutations, G1105C and G1391A, in introns D and E, respectively. In normal and Q188R alleles none of the above four mutations coexisted. However, some galactosaemia alleles with mutations other than Q188R, such as W316X and E340X of exon 10, also carried the N314D mutation. The W316X alleles existed in cis with the intron mutations (G1105C and G1391A), whereas those with E340X are in cis with L218L. In all cases examined, the intron mutations were not found in D1 alleles and no D2 alleles had the silent mutation of L218L. These results suggest that the decrease in the GALT activity in D2 may be due to regulation of the GALT gene expression. The G1105C site may be critical to the function of erythroid transcription factor NF‐E1, since it flanks the core consensus sequence for one of its binding sites. The G1391A mutation may affect another cis‐acting regulatory sequence. Alternatively, both mutations may be involved in an aberrant splice processing, which possibly results in a low level of correctly spliced mRNA.
Protein kinase C activity, phosphate uptake and endogenous substrate phosphorylation are altered in Zellweger syndrome
Authors: Boneh A. 
Published: June 2005

SummaryProtein kinase C (PKC) is a key enzyme in lipid‐mediated signal transduction. Regulation of PKC activation is dependent upon the phospholipid constituents of cellular membranes. PKC is also activated by very long‐chain and long‐chaincis‐unsaturated fatty acids. The present study was undertaken as a first step towards elucidating a possible role for PKC in the pathogenesis of Zellweger syndrome, in which there are both perturbation of plasma membrane phospholipids and accumulation of very long‐chain fatty acids. PKC activity, phosphate uptake and endogenous substrate phosphorylation were examined in intact human skin fibroblasts from Zellweger patients. PKC catalytic activity was increased in the membranous fraction of Zellweger cells compared with control cells, with no apparent translocation of the enzyme from the cytosolic to the membranous compartment. Phosphate uptake was increased in both cytosolic and membranous fractions 2.5‐fold and 4.5‐fold, respectively. Several proteins were extensively phosphorylated in Zellweger cells compared with control cells. These findings indicate that PKC activity is perturbed in Zellweger cells, but the exact role of PKC in altered phosphate uptake and protein phosphorylation and its relevance to the pathogenesis of Zellweger syndrome require further study.
Severe hyperprostaglandin E syndrome with hyperthyroidism — studies of pathogenetic mechanisms
Authors: Fellman V. , Pihko H. , Majander A. , Seyberth H. W. 
Published: June 2005

SummaryHyperprostaglandin E syndrome is a rare disease usually presenting with renal symptoms such as polyuria, polyhydramnios, hypercalciuria, hypokalaemia, and recurrent episodes of extreme fever, diarrhoea, and convulsions. We report a severe variant of this syndrome with obvious pain and prostaglandin E2 (PGE2)‐stimulated hyperthyroidism, an association not previously described. Urinary excretion of PGE2 and its metabolite 7α‐hydroxy‐5,11‐diketotetranorprosta‐1,16‐dioic acid were markedly increased above normal levels (to 53.3 and 1895 ng/h per 1.73 m2, respectively). We studied oxidative capacity of peroxisomes and mitochondria, the sites where PGE2 oxidation takes place. A generalized mitochondrial disease could be ruled out and no deficiency was found in liver peroxisomal oxidases. The basic pathology of hyperprostaglandin E syndrome remains unsolved.
Carrier detection for sanfilippo A syndrome
Authors: Matalon R. , Deanching M. , Marback R. , Michals K. 
Published: June 2005

SummaryIn Sanfillipo A families, sulphamidase activities in leukocytes and cultured fibroblasts determined at 55°C distinguish between heterozygote‐carriers, normal individuals and the homozygotes.
Substrate inhibition of adenosine phosphorylation in adenosine deaminase deficiency and adenosine‐mediated inhibition of PP‐ribose‐P dependent nucleotide synthesis in hypoxanthine phosphoribosyltransferase deficient erythrocytes
Authors: Snyder F. F. , Dyer C. , Seegmiller J. E. , Goldblum R. M. , Mills G. C. , Schmalstieg F. C. 
Published: June 2005

SummaryThe metabolism of adenosine and its effects on phosphoribosylpyrophosphate, PP‐ribose‐P, dependent nucleotide synthesis were studied using erythrocytes from patients with adenosine deaminase and hypoxanthine phosphoribosyltransferase deficiency as models. The phosphorylation of adenosine was progressively inhibited by concentrations of adenosine greater than 1 µmol L−1 for control and ADA deficient erythrocytes. There was essentially no initial rate of phosphorylation at 30 µmol L−1 adenosine. Adenosine, 1 µmol L−1, also caused a 60% reduction in PP‐ribose‐P concentration in ADA deficient erythrocytes. For HPRT deficient erythrocytes in which ADA activity was blocked by coformycin, 10 µmol L−1 inosine stimulated PP‐ribose‐P dependent nucleotide synthesis from adenine, whereas, 10 µmol L−1 adenosine inhibited nucleotide synthesis. These observations suggest that adenosine phosphorylation and PP‐ribose‐P dependent nucleotide synthesis are inhibited under conditions in which adenosine accumulates, such as in hereditary or pharmacologically induced ADA deficiency.
N‐acetylglutamate synthetase deficiency, a second patient
Authors: Bachmann C. , Brandis M. , Weissenbarth‐Riedel E. , Burghard R. , Colombo J. P. 
Published: June 2005

SummaryA second patient withN‐acetylglutamate synthetase deficiency is described. The first symptoms were noted at 6 days of age. The course was lethal despite vigorous treatment. The diagnosis was established after death.
Stable isotope dilution analysis ofN‐acetylaspartic acid in CSF, blood, urine and amniotic fluid: Accurate postnatal diagnosis and the potential for prenatal diagnosis of canavan disease
Authors: Jakobs C. , ten Brink H. J. , Langelaar S. A. , Zee T. , Stellaard F. , Macek M. , Sršňová K. , Sršeň Š. , Kleijer W. J. 
Published: June 2005

SummaryA sensitive and selective analytical technique is described for the determination ofN‐acetylaspartic acid in body fluids using stable isotope dilution in combination with positive chemical ionization mass spectrometry with selected ion monitoring.Control mean and ranges have been established: in urine 19.5 and 6.6–35.4 µmol/mmol creat.; in plasma 0.44 and 0.17–0.81 µmol/L; in cerebrospinal fluid 1.51 and 0.25–2.83 µmol/L; and in amniotic fluid 1.27 and 0.30–2.55 µmol/L.In a patient with Canavan disease,N‐acetylaspartic acid concentration was elevated 80‐fold in urine and 20‐fold in plasma compared to the control means. A subsequent pregnancy of the mother was monitored and theN‐acetylaspartic acid concentration in the amniotic fluid was within the control range and a healthy child was born.
Organic acids in aqueous humour and plasma: Post mortem study in infants and diagnosis of enzymopathies
Authors: Coude M. M. , Charpentier C. , Bonnefont J. P. , Cheron G. , Kamoun P. 
Published: June 2005

SummaryOrganic acids have been determined in aqueous humour and plasma by gas chromatography‐mass spectrometry in 38 cases of infant death and 4 cases of inherited metabolic disease: one had a complex fatty‐acid oxidation disorder with a large urinary excretion of adipic acid, the others had a disorder of propionate catabolism with a large urinary excretion of methylmalonic acid. In each case we found in aqueous humour the abnormal metabolite present in urine. Thus aqueous humour could be a suitable material for retrospective diagnosis of inherited metabolic diseases at autopsy in sudden infant death syndrome.
Long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency
Authors: Przyrembel H. , Jakobs C. , Ijlst L. , de Klerk J. B. C. , Wanders R. J. A. 
Published: June 2005

SummaryA new case of 3‐hydroxyacyl‐CoA dehydrogenase deficiency is described with a relatively benign course.