bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recent advances in the treatment of cystinosis
Authors: Schneider J. A. , Clark K. F. , Greene A. A. , Reisch J. S. , Markello T. C. , Gahl W. A. , Thoene J. G. , Noonan P. K. , Berry K. A. 
Published: November 2004

SummaryCysteamine bitartrate capsules (Cystagon) have been approved by the US Food and Drug Administration for use in patients with nephropathic cystinosis. Plasma cysteamine concentrations were virtually identical at various times following ingestion of either cysteamine hydrochloride or Cystagon capsules in 24 normal control subjects. A transfer study was done with eight cystinosis patients who had been receiving either cysteamine hydrochloride or phosphocysteamine for many years. The plasma cysteamine concentration was significantly higher 2h after Cystagon and the leukocyte cystine content was significantly lower at all times after Cystagon compared to older forms of the drug. These differences are probably the result of greater patient compliance in taking the capsules compared to the older, liquid forms of the drug. A new method for following the course of renal glomerular deterioration in diseases such as cystinosis has been published recently. This method was used to re‐analyse data on the efficacy of cysteamine treatment and to re‐analyse new data on treating cystinosis patients with either of two doses of cysteamine (1.30 g/m2 per day and 1.95 g/m2 per day). This new method agrees well with other methods and shows that both doses of drug are equally effective in maintaining glomerular function.
The hepatic glycogen storage diseases — problems beyond childhood
Authors: Lee P. J. , Leonard J. V. 
Published: November 2004

SummaryThe introduction of continuous nocturnal enteral glucose feeds and uncooked cornstarch has improved the prognosis for patients with the hepatic glycogen storage diseases. An increasing number of patients are surviving into adulthood in better health, but still at some medical cost. In this review we examine bone mineralization, renal function, hepatic tumours, and vascular endothelial function in GSD I and cardiac function in GSD III. All females over the age of 5 years with GSD I, III, VI and IX had morphologically polycystic ovaries. Thirteen adult GSD I patients have been studied, and been found to have poor bone mineralization and marked renal glomerular and tubular dysfunction. More than half of these patients also had focal hepatic lesions on sonography and yet vascular endothelial function was preserved in the face of hyperlipidaemia. In 12 GSD III patients, one had a focal hepatic lesion and 6 had pronounced left ventricular hypertrophy, although cardiorespiratory function was normal. These data emphasize the multisystem nature of these disorders and highlight the need for careful long‐term follow‐up.
Introduction to the age‐related diagnosis (ARD) index: an age at presentation related index for diagnostic use
Authors: Harkness R. A. , Harkness E. J. 
Published: December 2004

SummaryDevelopment and, therefore, age is important in paediatrics. Diagnostically useful data from this journal has been related to age and organized to form an age‐related diagnostic (ARD) index. The ARD index is designed for non‐expert clinical and laboratory workers to use in the early phases of diagnosis and as an addition to existing diagnostic schemes. Entry to the index is from the age at clinical presentation. Each entry is a sequence starting with clinical and laboratory presentations, clinical course, laboratory key investigations and finally diagnosis with volume and page numbers of the original article, the primary source. Within age groups, entries are grouped by diagnoses with the commonest diagnosis first; this has the effect of roughly but not precisely grouping similar clinical and laboratory findings.
Haplotype distribution at the phenylalanine hydroxylase locus in PKU families from the Moravian area of Czechoslovakia
Authors: Kozák L. , Dvořáková D. , Pijáčková A. , Kamarýt J. 
Published: December 2004

SummaryThe analysis of 21 families affected with classical phenylketonuria (PKU) from the Moravian area of Czechoslovakia has revealed 12 different RFLP haplotypes. Nine and eight haplotypes were associated with the normal and with the mutant alleles, respectively. Most normal alleles are associated with haplotype 1 (42.9%). Almost 80% of all mutant alleles are confined within only three haplotypes (1, 2 and 4). There was a strong association between haplotype 2 and the Czech mutant alleles (61.9% of the mutant alleles compared with 4.8% of the normal alleles). There was linkage disequilibrium between this haplotype and the R408W mutation in exon 12. Two mutant haplotypes 7 were found and in both cases they were tightly linked with G272ter mutation.Our finding is in agreement with observations in other Eastern European countries. These data provide further support for the theories of the spread of the R408W mutation from east to west in European populations.
Heterozygotes for plasmalemmal carnitine transporter defect are at increased risk for valproic acid‐associated impairment of carnitine uptake in cultured human skin fibroblasts
Authors: Tein I. , DiMauro S. , Xie Z. ‐W. , De Vivo D. C. 
Published: November 2004

SummaryOne of the mechanisms by which chronic valproic acid (VPA) therapy induces serum and tissue depletion of carnitine in normal controls is through inhibition of plasmalemmal carnitine uptake (Tein et al 1993). To determine the effect of VPA on proven heterozygotes for the plasmalemmal carnitine transporter defect, we studied this system in cultured human skin fibroblasts with reducedVmaxfor the carnitine transporter usingL‐[3H]carnitine. There was en exponential dose‐dependent decrease in carnitine uptake with increasing VPA concentrations and the relative inhibitory effect was the same for all three carnitine concentrations for a given cell line. Importantly, the lower the maximal velocity of carnitine uptake of the heterozygote, the lower the number of carnitine transporters and the lower the carnitine uptake per given concentration of VPA. The degree of inhibition was also directly proportional to the time of VPA preincubation up to a specific maximal saturation time. The maximal effect of VPA exposure time was reached by 10 days in the control cell line and by 3 days in the two heterozygote lines, probably reflecting earlier saturation. We conclude that patients who are heterozygous for the plasmalemmal carnitine transporter defect are at increased risk for VPA‐associated serum and tissue depletion of carnitine through inhibition of plasmalemmal carnitine uptake.
Metachromatic leukodystrophy among southern Alaskan Eskimos: molecular and genetic studies
Authors: Pastor‐Soler N. M. , Schertz E. M. , Rafi M. A. , de Gala G. , Wenger D. A. 
Published: November 2004

SummaryMetachromatic leukodystrophy (MLD) is an autosomal recessive disorder resulting from the inability to metabolize sulphatide, an important component of myelin. Although there is significant clinical variability between patients, most have the late‐infantile form. It is one of the most common lysosomal disorders involving mental deterioration and is found throughout the world. The great majority of the cases have a deficiency of arylsulphatase A activity. Accurate diagnosis of MLD is complicated by the presence of so‐called pseudodeficiency alleles and the need to receive specimens for biochemical testing within 24–48h of collection. We report the identification of the mutation (a g‐to‐a transition in the first nucleotide of intron 4) in the arylsulphatase A gene causing late‐infantile MLD among the Eskimo population of southern Alaska. As all patients and family members from living and deceased patients had the same mutation, a mutation‐based test was developed to identify patients and carriers that can be done on dried blood spots sent via regular mail service. A possible genetic link between this population and the Navajo Indians of the southwestern United States is proposed.
Phenylketonuric patients decades after diet
Authors: Fisch R. O. , Chang P. ‐N. , Weisberg S. , Guldberg P. , Güttler F. , Tsai M. Y. 
Published: November 2004

SummaryNineteen early‐treated phenylketonuric patients, whose diet was discontinued between 4.5 and 13 years of age, and who have been off the diet for 12–28 years, were reassessed in 1992–93. There was little change in mean IQ between end of diet and follow‐up, less than one IQ point on the average, with no change for any individual exceeding 12 IQ points. Both prior and current IQ correlated slightly negatively with mean phenylalanine (Phe) concentration, and positively with parents' education. The phenylalanine level at follow‐up was significantly lower on average by about 900 µmol/L. Five of the subjects (26%) have evidence of mental disease. However, the data suggest that the discontinuation of the diet did not cause intellectual deterioration. Nonetheless, the patients' intellect cannot be the only consideration for maintenance of diet. The occurrence of psychopathology among phenylketonuric patients and the possible unknown effects of toxic elevation of phenylalanine during their lifetime suggest the need to maintain the diet. The use of DNA for diagnostic and prognostic purposes might assist in decisions about dietary quality and duration, and in anticipation of psychopathology.
Mitochondrial 2‐methylacetoacetyl‐CoA thiolase deficiency: An inborn error of isoleucine and ketone body metabolism
Authors: Søvik O. 
Published: November 2004

SummaryA review is presented of 22 published cases of verified or probable mitochondrial 2‐methylacetoacetyl‐CoA thiolase deficiency, a disorder of isoleucine and ketone body metabolism. The clinical expression, characterized by ketoacidosis, vomiting and lethargy, is highly variable. Typical age of onset is between 6 and 24 months. The disorder, which has been observed in several ethnic groups, is apparently inherited as an autosomal, recessive trait. The prognosis is relatively good if acute episodes of ketoacidosis and dehydration are adequately treated. There is abnormal urinary excretion of 2‐methyl‐3‐hydroxybutyric acid, tiglylglycine, and in some instances also 2‐methyl‐acetoacetic acid. However, such a pattern of organic aciduria has also been found in cases with normal thiolase activity. Genetic complementation analyses have demonstrated considerable heterogeneity. The cDNA for human methyl‐acetoacetyl‐CoA thiolase has been cloned and sequenced. Studies in one patient showed a G‐to‐A substitution at position 1138 of the mRNA, causing 347Ala to Thr change in the mature enzyme. Studies in other patients have shown variable enzyme amount and/or stability.
A possible case of transient hereditary fructose intolerance
Authors: Catto‐Smith A. G. , Adams A. 
Published: November 2004

SummaryA patient is described who presented with the signs and symptoms of hereditary fructose intolerance a few hours after her first fructose challenge. The diagnosis was confirmed by the demonstration of reduced activity of hepatic aldolase B towards fructose‐1‐phosphate. A second liver biopsy 10 months later had normal aldolase B activity towards fructose‐1‐phosphate and a fructose tolerance test was also normal. A possible explanation for these findings is proposed.
The effect of dietary fruits and vegetables on urinary galactitol excretion in galactose‐1‐phosphate uridyltransferase deficiency
Authors: Berry G. T. , Palmieri M. , Gross K. C. , Acosta P. B. , Henstenburg J. A. , Mazur A. , Reynolds R. , Segal S. 
Published: November 2004

SummaryEven on a lactose‐restricted diet, urinary galactitol excretion and erythrocyte galactose‐1‐phosphate levels are persistently elevated in patients with galactose‐1‐phosphate uridyltransferase deficiency. In order to determine the contribution of galactose in dietary fruits and vegetables to this phenomenon, (1) the content of galactose in a lactose‐free diet was directly measured when a galactosaemic patient's diet was specifically enriched in those fruits and vegetables which contain relatively large amounts of free galactose and (2) galactitol excretion was determined during ingestion of this diet for 3 weeks and while on a synthetic diet for 1 week that provided <8 mg galactose/day. For comparison the effect of a 3‐week supplementation of 200 mg galactose/day was determined. The measured intake in total foodstuffs matched the theoretical content of galactose in the patient's diet based on amounts in fruits and vegetables alone, thus supporting the concept that fruits and vegetables are primarily responsible for galactose intake in a lactose‐free diet. All of the dietary manipulations, however, had relatively little effect on metabolite levels, suggesting that endogenous galactose production is primarily responsible for the elevated levels of galactose metabolites routinely detected in patients on lactose‐restricted diets.
The effect of lovastatin on very low‐density lipoprotein apolipoprotein B production by the liver in familial combined hyperlipidaemia
Authors: Cortner J. A. , Bennett M. J. , Le N. ‐A. , Coates P. M. 
Published: November 2004

SummaryOverproduction of very low‐density lipoprotein apolipoprotein B by the liver is a metabolic marker for familial combined hyperlipidaemia, a common inherited disorder of lipoprotein metabolism. Four subjects with familial combined hyperlipidaemia had rates of apolipoprotein B production which were 2–7 times normal, using a protocol in which [15N]nglycine was used to label newly synthesized hepatic proteins. Following 4–6 months of therapy with lovastatin, very low‐density lipoprotein apolipoprotein B production in all four subjects had returned to the normal range. This demonstrates that lovastatin, an inhibitor of cholesterol biosynthesis, acts also to reduce the apparent production rate of apolipoprotein B by the liver.
Molecular basis of phenotype expression in homocystinuria
Authors: Kraus J. P. 
Published: November 2004

SummaryCystathionine β‐synthase (CBS) deficiency is the most common cause of homocystinuria in humans. The human gene maps to chromosome 21q22.3 and encodes the CBS subunit of 551 amino acid residues (63 kDa). CBS, a tetramer of these subunits, binds its two substrates, homocysteine and serine, and three additional ligands: pyridoxal 5′‐phosphate,S‐adenosylmethionine, and haem. Screening for mutations by expressing patient cDNA segments inE. coli permitted us to separate the parental CBS alleles, localize each mutation within one third of the cDNA, and functionally analyse the mutant protein. Using this method we identified the first 14 mutations in homocystinuria. The most common mutation in patients of predominantly ‘Celtic’ origin is the G919A transition which substitutes serine for glycine 307.
Organization of the human genome
Authors: Craig I. W. 
Published: November 2004

SummaryThe human genome contains about 3×109 base pairs which, based on average estimates for the size of coding regions, might suggest an upper limit of about 3 million genes. Evidence from a variety of approaches indicates a much lower figure — in the range 40 000–100 000 genes. Renaturation kinetic analysis reveals the presence of many repetitive elements in the human genome. Some of these are quite simple and highly reiterated, others are more complex and exist in fewer copies. The distribution and function of some of these families and the evolution of complex genomes from simpler ones are discussed.
Dysmorphic disorders — An overview
Authors: Donnai D. 
Published: November 2004

SummaryClinical delineation of dysmorphic syndromes is important for patient management, family counselling and basic research. Productive areas of research in dysmorphology and developmental biology have included the study of the mouse homologies of human disease. Mutations have been identified in both species in highly conserved ‘developmental’ genes, and also because of phenotypic similarity of syndromes. Mosaicism — somatic, germline and placental — involving chromosomal aneuploidy, single gene mutations and functional differences between cell lines is an important cause of malformations and syndromes. Many recurrent pattern malformation syndromes of previously unknown cause have now been found to be due to chromosomal microdeletions. Diagnosis has been greatly aided by the molecular cytogenetic technique of fluorescentin situ hybridization.
Primary hyperoxaluria type 1: Genotypic and phenotypic heterogeneity
Authors: Danpure C. J. , Jennings P. R. , Fryer P. , Purdue P. E. , Allsop J. 
Published: November 2004

SummaryPrimary hyperoxaluria type 1 (PH1) is an autosomal recessive disease caused by a deficiency of the liver‐specific peroxisomal enzyme alanine: glyoxylate aminotransferase (AGT). The disease is notable for its extensive heterogeneity at the clinical, biochemical, enzymic and molecular genetic levels. A study of 116 PH1 patients over the past 8 years has revealed four main enzymic phenotypes: (1) absence of both AGT catalytic activity and immunoreactive AGT protein (≈40% of patients); (2) absence of AGT catalytic activity but presence of immunoreactive protein (≈16% of patients); (3) presence of both AGT catalytic activity and immunoreactive protein (≈41% of patients), in most of which cases the AGT is mistargeted to the mitochondria instead of the peroxisomes; and (4) a variation of the mistargeting phenotype in which AGT is equally distributed between peroxisomes and mitochondria, but in which that in the peroxisomes is aggregated into matrical core‐like structures (≈3% of patients). Various point mutations, all occurring at conserved positions in the coding regions of the AGT gene, have been identified in these patients. The five mutations discussed in the present study, which have been found in individuals manifesting all of the four major enzymic phenotypes, account for the expressed alleles in about half of all Caucasian PH1 patients. The most common mutation found so far leads to a Gly170 → Arg amino acid substitution. This mutation, in combination with a normally occurring Pro11 → Leu polymorphism, appears to be responsible for the unprecedented peroxisome‐to‐mitochondrion mistargeting phenotype.
Variation in mitochondrial DNA levels in muscle from normal controls. Is depletion of mtDNA in patients with mitochondrial myopathy a distinct clinical syndrome?
Authors: Poulton J. , Sewry C. , Potter C. G. , Bougeron T. , Chretien D. , Wijburg F. A. , Morten K. J. , Brown G. 
Published: November 2004

SummaryRecent studies have identified a group of patients with cytochrome oxidase (COX) deficiency presenting in infancy associated with a deficiency of mtDNA in muscle or other affected tissue (Moraes et al 1991). We used a novel approach to compare the level of mitochondrial (mtDNA) compared to nuclear DNA in skeletal muscle from a group of patients and controls, based on dot blots that were hybridized with a mtDNA probe labelled with35S[dCTP] and a reference nuclear DNA probe labelled with [32P]dCTP.The ratio of mtDNA to nuclear DNA varied in samples from different muscles of the same individual. Secondly, fetal muscle had very low levels of mtDNA compared to nuclear DNA, and data from older controls (cross‐sectional rather than sequential) suggest that this increases rapidly over the first 3 months after birth and thereafter more slowly. Four patients with COX deficiency had levels of mtDNA that were below the age‐specific range defined by ‘normal’ quadriceps muscle. The clinical features of two of these patients were similar to earlier case reports of mtDNA depletion. In three patients the clinical course was relatively benign compared to cases that have previously been described.Levels of mtDNA in skeletal muscle from some patients with other forms of muscle disease were also found to be low, suggesting that mtDNA depletion, possibly related to depletion of mitochondria, may be a relatively non‐specific response of muscle to various pathological processes. However, there does appear to be a distinctive group of young patients with reduced cytochrome oxidase activity in muscle, in whom marked mtDNA depletion reflects the primary defect.
Assay of plasmalogens and polyunsaturated fatty acids (PUFA) in erythrocytes and fibroblasts
Authors: Dacremont G. , Vincent G. 
Published: November 2004

SummaryThe direct transesterification method of Lepage and Roy is described as used in our laboratory for the analysis of plasmalogens and polyunsaturated fatty acids in erythrocytes and cultured fibroblasts by gas chromatography. An overview is given of the plasmalogen ratios and docosahexaenoic acid concentrations from controls and patients with different peroxisomal disorders investigated in our laboratory.
Measurement of peroxisomal fatty acid β‐oxidation in cultured human skin fibroblasts
Authors: Wanders R. J. A. , Denis S. , Ruiter J. P. N. , Schutgens R. B. H. , van Roermund C. W. T. , Jacobs B. S. 
Published: November 2004

SummaryOne of the main functions of mammalian peroxisomes is the β‐oxidation of a variety of fatty acids and fatty acid derivatives, including very long‐chain fatty acids. Oxidation of these fatty acids is deficient in a number of different peroxisomal disorders, including the disorders of peroxisome biogenesis (Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease), X‐linked adrenoleukodystrophy and a number of other disorders of peroxisomal β‐oxidation of known and unknown aetiology. Accurate measurement of peroxisomal fatty acid oxidation is of utmost importance for correct postnatal and prenatal diagnosis of these disorders. In this paper we describe a straightforward and accurate assay method to measure the β‐oxidation of palmitic acid (C16:0), hexacosanoic acid (C26:0) and pristanic acid in intact fibroblasts.
Activity measurements of acyl‐CoA oxidases in human liver
Authors: Van Veldhoven P. P. 
Published: November 2004

SummaryPeroxisomal β‐oxidation is involved in the degradation of different fatty acids or fatty acid derivatives including eicosanoids (prostaglandins, leukotrienes, thromboxanes), dicarboxylic fatty acids, very long‐chain fatty acids, pristanic acid, bile acid intermediates (di‐ and trihydroxycoprostanoic acids), and xenobiotics. Separate β‐oxidation systems are probably active inside peroxisomes, each acting on a distinct set of substrates, as suggested by the discovery of multiple acyl‐CoA oxidases.Using specific substrates or selective conditions, we can distinguish in rat liver the action of acyl‐CoA oxidases (type I and II), a pristanoyl‐CoA oxidase and a trihy‐droxycoprostanoyl‐CoA oxidase and, in human liver, of acyl‐CoA oxidase (type I and II) and a branched‐chain acyl‐CoA oxidase. When incubated with suitable CoA‐esters, these different oxidases can be measured in a similar fashion by following fluorimetrically the dimerization of homovanillic acid, catalysed by peroxidase in the presence of hydrogen peroxide. The optimal assay conditions and possible pitfalls in this type of coupled assay are discussed. This knowledge can be used to reveal the existence of peroxisomal disorders in which only one acyl‐CoA oxidase is deficient.
Liver and chorion cytochemistry
Authors: Roels F. , De Prest B. , De Pestel G. 
Published: November 2004

SummaryMicroscopic visualization of peroxisomes in chorionic villus cytotrophoblast and in biopsy and autopsy samples of liver and kidney, the presence of enlarged liver macrophages containing lipid droplets insoluble in acetone and n‐hexane as well as polarizing inclusions formed by stacks of trilamellar sheets are of diagnostic value in peroxisomal disorders. Methods are presented for evaluating these structures by light microscopy; trilamellar inclusions are only detected by electron microscopy. Macrophage features are preserved in archival paraffin blocks. In adrenal cortex, insoluble lipid, polarizing inclusions and trilamellar structures should be looked for. The stains are easily reproducible, and all reagents are commercially available.