bluuebunny/crossref_metadata_2025 huggingface dataset:
Inborn errors of metabolism in Singapore
Authors: Tan I. K. , Chio L. F. , Loh F. C. , Wee S. C. , Ng I. , Teo S. H. , Yong Y. P. , Chan D. , Chow W. C. , Ho P. S. , Lim K. W. , Goh A. , Pratibha A. , Kumar P. , Wong Y. S.
Published: November 2004

Between 1992 and 1994 the Paediatric Metabolic Centre screened 403 patients for inherited metabolic disease. Seventeen patients were diagnosed, including 7 with organic acidurias, 5 with mucopolysaccharidoses, 2 with amino acid disorders, 2 with carbohydrate disorders and 1 with hyperlipidaemia. The ethnic distribution of disorders in Singapore is compared with incidences reported by others in this part of the world. It is likely that further studies will indicate which diagnostic or screening tests would best serve this community.
Review: The immunochemical analysis of enzyme from mucopolysaccharidoses patients
Authors: Brooks D. A.
Published: November 2004

The immunochemical analysis of enzyme from mucopolysaccharidoses (MPS) patients is aimed at defining the level and nature of the enzymically deficient protein produced by specific gene mutations. Immunochemical techniques allow purification of enzyme, characterization of the composite molecular species, measurement of cellular protein content, investigation of protein biosynthesis, determination of subcellular distribution, as well as information on protein structure and folding. This review focuses on the application of immunochemical techniques to the study of the aberrant protein produced in skin fibroblast cells derived from MPS patients. The analysis of enzyme protein has been applied to phenotype expression within single enzyme deficiency disorders. It is proposed that reliable prediction of MPS patient phenotype may require a combined approach utilizing immunochemical, biochemical, cell biological and gene analysis. However, this review will address the structure and nature of the protein produced in cells from MPS patients, the biological activity of this protein, and the incorporation of the protein into, and location within, subcellular fractions.
Biochemical and immunological characterization of X‐linked ichthyosis
Authors: Fan X. , Petruschka L. , Wulff K. , Grimm U. , Herrmann F. H.
Published: November 2004

An immunoquantification protocol based on an enzyme‐linked immunosorbent assay was developed to measure the abundance of the microsomal enzyme steroid sulphatase (STS). The two‐step sandwich immunoassay is sufficiently sensitive to detect 100–200 pg purified steroid sulphatase in a 50‐µl sample. The steroid sulphatase content in fibroblast, leukocyte and placental extracts correlates with the steroid sulphatase activity in these extracts. No steroid sulphatase protein was found in approximately 350 µg plasma proteins from a normal person. In three of four X‐linked ichthyosis patients a complete gene deletion was found by Southern hybridization with the full‐length STS cDNA as probe. Neither steroid sulphatase protein nor enzymatic activity was found in fibroblast extracts of these three patients. In a fibroblast extract of another X‐linked ichthyosis patient, which had a normal Southern blotting pattern, no immunoreactive protein was detected. Residual activity of steroid sulphatase was also not found after prolonged incubation of this fibroblast extract with the natural substrate oestrone sulphate.
Tissue distribution of mutant mitochondrial DNA in mitochondrial myopathy, encephalopathy, lactic acidosis and stroke‐like episodes (MELAS)
Authors: Shoji Y. , Sato W. , Hayasaka K. , Takada G.
Published: November 2004

We analysed the distribution of mutant mitochondrial DNA (mtDNA) with A‐to‐G substitution mutation of tRNALeu(UUR) in various autopsied tissues from a patient with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke‐like episodes (MELAS). There was no significant difference in the proportion (76–86%) of mutant mtDNA in many tissues, except in the lung and spleen. Unequal partitioning of mtDNA in somatic cells appears less prominent than that in germ cells.
Membrane‐bound sorbitol dehydrogenase in human red blood cells. Studies in normal subjects and in enzyme‐deficient subjects with congenital cataracts
Authors: Alvarez A. , Martínez A. , Ibarra B. , Medina C. , Bracamontes M. , Perea J. , Vaca G.
Published: November 2004

Membrane‐bound and soluble forms of erythrocyte sorbitol dehydrogenase (SORD) activity are compared in normal individuals. Both isoenzymes showed similar properties. In a family with red cell SORD deficiency and congenital cataracts,Km values for sorbitol and NAD+ as well as the effect of the enzymatic deficiency on sorbitol accumulation in red cells incubated in high‐glucose or high‐fructose media were determined. In SORD‐deficient patients, the enzymatic deficiency was observed in both crude haemolysate and SORD‐M preparations with sorbitol, galactitol, xylitol or ribitol as substrates. The mutation responsible for SORD deficiency did not modify theKm for sorbitol and NAD+. Finally, SORD deficiency produced a significant increase of sorbitol accumulation in red cells incubated in high‐concentration glucose media and a significant decrease when the cells were incubated in high‐concentration fructose media.
Impaired hexose uptake by diploid skin fibroblasts from galactosaemic patients. Connection with cell growth and amino acid metabolism, and possible bearing on late‐onset clinical symptoms
Authors: Wolfrom C. , Raynaud N. , Kadhom N. , Poggi J. , Soni T. , Gautier M.
Published: November 2004

In skin fibroblasts of patients presenting with galactosaemia, either from galactose 1‐phosphate uridyltransferase or galactokinase deficiency, a deficit in extracellular glucose utilization was observed. This deficit was constant over 3 weeks of continuous cell growth in a medium containing 5.5 mmol/L glucose as the only hexose, and homologous serum. Levels of glucose utilization by deficient skin fibroblasts were stable at about 65–70% of the glucose utilization of control normal skin fibroblasts. Cell morphology was normal, and cell growth was subnormal during this period. However, the energy provision appeared sufficient for cellular needs since cell growth in this glucose medium was observed not to depend on the presence of extracellular glutamine. In contrast, glutamine was required for growth of galactosaemic fibroblasts cultured in medium containing 5.5 mmol/L galactose. If expressed in many cell types, this impaired glucose uptake would be expected seriously to damage highly glucose‐dependent tissues such as the central nervous system. This might be of relevance to the persistent neurological damage observed in many galactosaemic patients in spite of their compliance with an early strict galactose‐free diet.
Identification ofN‐acetyl‐α‐aminoadipic acid in the urine of a patient with α‐aminoadipic and α‐ketoadipic aciduria
Authors: Takechi T. , Okada T. , Wakiguchi H. , Morita H. , Kurashige T. , Sugahara K. , Kodama H.
Published: November 2004

A 3.5‐year‐old Japanese boy with a mild speech disturbance excreted a large amount of α‐aminoadipic acid into the urine. The amino acid analysis using an amino acid analyser confirmed the presence of α‐aminoadipic acid in both urine and plasma.

We detected α‐aminoadipic acid in the hydrolysate of the effluent and washwater fraction through cation exchange resin. This suggested the presence of acetylated derivatives and we identifiedN‐acetyl‐α‐aminoadipic acid using liquid chromatography‐atmospheric pressure ionization mass spectrometry (LC‐API‐MS). The concentrations of α‐aminoadipic acid andN‐acetyl‐α‐aminoadipic acid in the urine of a patient with α‐aminoadipic aciduria were 376.9 nmol/mg creatinine and 18.1 nmol/mg creatinine, respectively. We also detected α‐ketoadipic acid in the urine of this patient using LC‐API‐MS.
Genetic imprinting in the mouse: Implications for gene regulation
Authors: Cattanach B. M. , Jones J.
Published: November 2004

Genetic imprinting specifies a germline marking that subsequently results in the repression of one or other parental allele at some point in development. Genetic manipulations to generate maternal and paternal duplications of specific chromosome regions have been used to screen almost the entire mouse genome for evidence of imprinting. As a result, 15 imprinting effects involving 10 regions on 6 different chromosomes have been detected that range from early embryonic lethalities to various growth and developmental defects seen only after birth. Genes with important roles in development therefore appear to be involved. Diverse studies have identified four imprinted genes, all of which show monoallelic expression in some, but not necessarily all, tissues. A correlation with methylation is indicated but the pattern of methylation is not consistent for each of the genes; methylation is therefore unlikely to be the imprinting signal. Methods being used to identify further imprinted genes are summarized and some of the difficulties posed are indicated.
Relevance of the Human Genome Project to inherited metabolic disease
Authors: Burn J.
Published: November 2004

The Human Genome Project is an international effort to identify the complete structure of the human genome. HUGO, the Human Genome Organization, facilitates international cooperation and exchange of information while the Genome Data Base will act as the on‐line information retrieval and storage system for the huge amount of information being accumulated. The clinical register MIM (Mendelian Inheritance in Man) established by Victor McKusick is now an on‐line resource that will allow biochemists working with inborn errors of metabolism to access the rapidly expanding body of knowledge. Biochemical and molecular genetics are complementary and should draw together to find solutions to the academic and clinical problems posed by inborn errors of metabolism.
Molecular pathology of 21‐hydroxylase deficiency
Authors: Strachan T.
Published: November 2004

Steroid 21‐hydroxylase deficiency is a recessively inherited disorder of adrenal steroidogenesis. Different clinical variants map to a single geneCYP21B, which maps within the HLA complex and is located about 30 kb proximal to a very closely related 21‐hydroxylase pseudogene,CYP21A. The two CYP21 genes are located on highly homologous tandemly repeated 30 kb units, facilitating interlocus sequence exchanges. One type of exchange, unequal crossover, can result inCYP21B gene deletion or replacement of a large segment of theCYP21B gene by the analogous segment of theCYP21A gene. Gene conversion‐like mechanisms can result in replacement of a very small segment ofCYP21B by the analogousCYP21A sequence, thereby introducing a deleteriousCYP21A‐specific mutation. The vast majority of point mutation alleles seem to be accounted for by only a few of the mutations copied fromCYP21A and can be assayed by ASO hybridization or allele‐specific amplification assays of selectively amplifiedCYP21B gene sequences. Genotype‐phenotype correlations are largely as expected: mutations resulting in no or severely curtailed gene expression are associated with severe clinical phenotypes; those resulting in significant residual enzyme activity are associated with milder clinical phenotypes.
Metabolic disorders of embryogenesis
Authors: Brown G. K.
Published: November 2004

Prevention of major physical malformations would represent a significant reduction in the burden of mortality and morbidity in infants and young children. However, preventive and therapeutic approaches must be based on a clear understanding of underlying pathogenic mechanisms. While it is estimated that single gene defects account for up to 10% of cases of major malformation, relatively few of these have been identified and analysed in detail. The recognition of characteristic patterns of developmental anomalies associated with specific enzyme defects has highlighted the important role of the metabolic environment in normal development and offers the possibility of correlating biochemical abnormalities with particular teratogenic effects. Once it is generally appreciated that some forms of structural malformation have a specific biochemical basis, metabolic studies should be performed more often in patients with major developmental anomalies. This should lead to identification of other examples of diseases of this type and the elucidation of molecular mechanisms of human teratogenesis.
Characterization of the mutations in the glucose‐6‐phosphatase gene in Israeli patients with glycogen storage disease type 1a: R83C in six Jews and a novel V166G mutation in a Muslim Arab
Authors: Parvari R. , Moses S. , Hershkovitz E. , Carmi R. , Bashan N.
Published: November 2004

Glycogen storage disease type 1a (GSD 1a), an autosomal recessive disease, is caused by the inactivity of glucose‐6‐phosphatase, the gene of which has been recently cloned. We report on the missense mutation C → T at nucleotide 326 of the G6Pase gene, causing the change of the Arg codon at position 83 into a Cys codon, as the single mutation detected in six Jewish patients. This finding suggests that this mutation might be prevalent among the Jewish population. A new missense mutation T → G at nucleotide 576 resulting in V166G was found in an Arab Muslim patient. These families may benefit now from pre‐ and postnatal diagnosis by analysis of DNA from blood and amniotic fluid or chorionic villus cells rather than liver biopsy. No mutations in the G6Pase gene were detected in two GSD 1b patients.
Abnormal α‐aminoadipic acid excretion in a newborn with a defect in platelet aggregation and antenatal cerebral haemorrhage
Authors: Candito M. , Richelme C. , Parvy P. , Dageville C. , Appert A. , Bekri S. , Rabier D. , Chambon P. , Mariani R. , Kamoun P.
Published: November 2004

α‐Aminoadipic acid (αAA) is an intermediate in lysine metabolism. We report a new case with αAA excess in urine and plasma, without α‐ketoadipic acid, in a full‐term male child born to unrelated parents; he presented at 24h of life with seizures that failed to respond to phenobarbital, clonazepam, and Vigabatrin and death occurred on the 38th day of life. Brain imaging suggested antenatal haemorrhage. Small quantities of αAA were also detected in the blood and urine of both parents and a healthy brother, all three of whom exhibited the same defect in platelet aggregation as the deceased child. Both parents had decreased levels of plasma neopterin, a finding that might be related to the immunodeficiency described in other cases.
A new neonatal case ofN‐acetylglutamate synthase deficiency treated by carbamylglutamate
Authors: Guffon N. , Vianey‐Saban C. , Bourgeois J. , Rabier D. , Colombo J. P. , Guibaud P.
Published: November 2004

N‐Acetylglutamate synthase (NAGS) deficiency is a rare, autosomal recessive urea‐cycle disease. Its clinical presentation is not different from the other hereditary hyperammonaemias. We report a new neonatal case with hyperammonaemic coma. A test by carbamylglutamate was performed at 25 days of life. Since then, the child was treated by carbamylglutamate three or four times a day with a total dose of 80–100 mg/kg per day. Today, the boy is 1 year old. He receives carbamylglutamate 200 mg four times a day. He has normal somatic and neurological development and good metabolic balance.
Plasma lysosomal enzyme levels in patients with motor neuron disease
Authors: Michelakakis H. , Papadimitriou A. , Divaris R. , Mavridou I. , Dimitriou E.
Published: November 2004

β‐Hexosaminidase and acid‐α‐mannosidase were estimated in 17 adult patients with motor neuron disease. Normal plasma levels of β‐hexosaminidase ((A+B) and A) were found in all patients studied. Plasma acid α‐mannosidase levels were normal in all but two patients with the spinal muscular atrophy type of the disorder. In addition, altered biochemical properties of acid α‐mannosidase (i.e.Km, thermal stability) were found in the low‐activity cases.
Pre‐ and postnatal diagnosis of peroxisomal disorders using stable‐isotope dilution gas chromatography ‐ mass spectrometry
Authors: Verhoeven N. M. , Kulik W. , van den Heuvel C. M. M. , Jakobs C.
Published: November 2004

Quantitative analysis of the following peroxisomal metabolites is reported: very long‐chain fatty acids (VLCFA), pipecolic acid, bile acid intermediates, phytanic and pristanic acid, in plasma, urine, cerebrospinal fluid (CSF), blood spots collected at neonatal screening and amniotic fluid. An overview is given of the concentrations of these metabolites in body fluids from control subjects and all patients investigated so far in this laboratory. The method of choice is gas chromatography — mass spectrometry (GC‐MS) with electron capture detection, combined with the use of stable‐isotope‐labelled internal standards
Polyunsaturated fatty acids in the developing human brain, erythrocytes and plasma in peroxisomal disease: therapeutic implications
Authors: Martinez M.
Published: November 2004

Patients with Zellweger syndrome and related peroxisomal disorders have profound changes in the polyunsaturated fatty acid (PUFA) patterns in brain and other tissues, with a constant decrease in docosahexaenoic acid (DHA, 22:6ω3) concentration. Arachidonic acid (AA, 20:4ω6) concentration is normal or increased and linoleic acid (LA, 18:2ω6) is increased in the brain of Zellweger patients. In the retina of these patients, the levels of DHA are extremely low. Since these alterations are reflected elsewhere, they can be detectedin vivo in patients with generalized peroxisomal disorders by measuring the PUFA content of plasma and erythrocytes, which show very low concentrations of DHA. The concentration of AA is low in plasma in generalized peroxisomal patients, although it is within normal limits in erythrocytes. Patients with X‐linked adrenoleukodystrophy (X‐ALD) or adrenomyeloneuropathy (AMN) have a normal DHA and AA content in both plasma and erythrocytes, unless they receive extremely low‐PUFA diets.

Given the probable role of DHA deficiency in the pathogenesis of Zellweger syndrome (ZS), it is important to normalize concentrations of DHA, at least in blood, in an attempt to correct the DHA deficiency in brain. DHA ethyl ester was given orally to two infants with a peroxisome deficiency disorder for a year, and some favourable biochemical changes were produced in erythrocytes and plasma. Normalization of the DHA concentrations in erythrocytes was obtained in about 2 months, and the ratios 26:0/22:0 and 26:1/22:0 decreased markedly in plasma in the two patients. The plasmalogen ratio 18:0 dimethyl acetal/18:0 in erythrocytes increased to virtually normal values in both patients. There was a clear clinical improvement in the two patients, which paralleled the increase in blood DHA. The concentrations of AA and other PUFAs were closely monitored and, when necessary, AA was added to the diet. Such a DHA therapy, given under close biochemical and clinical control, and accompanied by a diet rich in other long‐chain PUFA, is strongly recommended in all patients with peroxisomal disorders in whom a DHA deficiency is detected in blood.
Measurement of very long‐chain fatty acids, phytanic and pristanic acid in plasma and cultured fibroblasts by gas chromatography
Authors: Dacremont G. , Cocquyt G. , Vincent G.
Published: November 2004

Two methods are described, both currently used in our laboratory, for the quantitative analysis of very long‐chain fatty acids, phytanic acid and pristanic acid in plasma and cultured fibroblasts by gas‐liquid chromatography. The first method is based on the procedure developed by Moser and Moser (1991) and the second is based on the method of Onkenhout and colleagues (1989), which is an application of the original method of Lepage and Roy for plasma and fibroblasts. A survey is given of the concentrations of very long‐chain fatty acids, pristanic and phytanic acid in plasma and fibroblasts from control subjects and all patients investigated so far in our laboratory.
Measurement of dihydroxyacetone‐phosphate acyltransferase (DHAPAT) in chorionic villous samples, blood cells and cultured cells
Authors: Wanders R. J. A. , Ofman R. , Romeijn G. J. , Schutgens R. B. H. , Mooijer P. A. W. , Dekker C. , van den Bosch H.
Published: November 2004

Dihydroxyacetone‐phosphate acyltransferase (DHAPAT) is a peroxisomal enzyme catalysing the first step in ether‐phospholipid biosynthesis. DHAPAT is deficient in cells from patients suffering from a variety of peroxisomal disorders. Accurate measurement of the activity of this enzyme is of great importance, especially since it is a central parameter in the prenatal diagnosis of the disorders of peroxisome biogenesis, rhizomelic chondrodysplasia punctata and DHAPAT‐deficiency. We describe a straightforward and accurate assay allowing the activity of DHAPAT to be measured reliably in chorionic villus samples, blood cells, cultured skin fibroblasts, cultured chorionic villus fibroblasts and cultured amniocytes.
Immunoblot analysis of peroxisomal proteins in liver and fibroblasts from patients
Authors: Wanders R. J. A. , Dekker C. , Ofman R. , Schutgens R. B. H. , Mooijer P.
Published: November 2004

Identification of a patient as suffering from a peroxisomal disorder usually starts by the finding of elevated very long‐chain fatty acids in plasma and/or serum. This is followed by more detailed studies in blood, fibroblasts and tissues, including immunoblot analysis. Indeed, immunoblot analysis has become a valuable tool in the correct diagnosis and assignment of individual patients, except for X‐linked adrenoleukodystrophy (X‐ALD). We describe a simple immunoblotting procedure applicable to liver and fibroblast homo‐genates using antibodies raised against catalase and the three β‐oxidation enzyme proteins acyl‐CoA oxidase I, bifunctional protein and peroxisomal thiolase. The same procedure can also be used for chorionic villus biopsy specimens and has now become the method of choice for the prenatal diagnosis of Zellweger syndrome (and other disorders of peroxisome biogenesis) and rhizomelic chondrodysplasia punctata.
Secondary alterations of human hepatocellular peroxisomes
Authors: De Craemer D.
Published: November 2004

The morphological and morphometric characteristics of peroxisomes in normal human liver and the peroxisomal alterations in the liver of patients with acquired or congenital non‐peroxisomal diseases are reviewed. Secondary peroxisomal changes are observed in steatosis, hepatitis and cirrhosis induced by various agents (viruses, alcohol, drugs, etc.), in cholestasis, in hepatomas, in extrahepatic cancer with or without liver metastasis, in extrahepatic inflammatory processes, in metabolic disorders affecting metabolism of carbohydrates, lipids and lipoproteins, glycoproteins, amino acids, bilirubin or copper, and in altered thyroid hormone levels. They are recognized as a proliferation of peroxisomes (increased in number and to a lesser extent in surface density and volume density) often accompanied by a minor reduction in size (at most to 68% of the mean diameter in control livers) but very rarely by an increase in mean peroxisomal diameter, and as proliferation‐related changes in shape (tails, gastruloid cisternae, funnel‐like constrictions, elongation, protrusions) in at least a few of the peroxisomes. These secondary alterations of the peroxisomes are clearly distinguishable from the primary changes in peroxisomes observed in the liver of patients with congenital peroxisomal disorders.
A fluorimetric assay for succinic semialdehyde dehydrogenase activity suitable for prenatal diagnosis of the enzyme deficiency
Authors: Thorburn D. R. , Thompson G. N. , Howells D. W.
Published: November 2004

Succinic semialdehyde dehydrogenase (SSAD) is an enzyme involved in the turnover of the neurotransmitter 4‐aminobutyrate (GABA). Deficiency of SSAD results in developmental delay, ataxia, seizures and 4‐hydroxybutyric aciduria. We have developed a simple fluorimetric assay for the enzyme and applied it to measurement of SSAD activity in a range of cell types often used for prenatal and postnatal diagnosis of enzyme defects. Lymphocytes from children with SSAD deficiency were found to have <5% of the activity found in lymphocytes from normal children. Heterozygotes are asymptomatic and have intermediate enzyme activities. Although SSAD activity has been detected previously in uncultured chorionic villi, we found that SSAD was not expressed in cultured chorionic villus cells nor in some fibroblast‐like amniocytes from control fetuses. Lymphocytes from fetal blood and non‐fibroblastic amniocytes have high SSAD activities, and should be suitable for prenatal diagnosis of SSAD deficiency.
The effect of hyperphenylalaninaemia on the muscarinic acetylcholine receptor in the HPH‐5 mouse brain
Authors: Hommes F. A.
Published: November 2004

Previous studies on the effect of hyperphenylalaninaemia on the development of the muscarinic acetylcholine receptor in the cerebrum of the rat, using α‐methylphenylalanine‐induced hyperphenylalaninaemia, have shown a gradual and steady decrease in the number of binding sites for this neurotransmitter. The HPH‐5 mouse, a phenylalanine hydroxylase mutant, can be hyperphenylalaninaemic without the use of a hydroxylase inhibitor. By employing quantitative autoradiography using [3H]quinuclinidylbenzilate to label muscarinic acetylcholine receptors, a refined analysis of this decrease in neurotransmitter binding sites can be made. The decrease was confirmed and is therefore due to the hyperphenylalaninaemiaper se and not to the use of the inhibitor. Various areas of the brain reacted differently to hyperphenylalaninaemia, from no change (putamen) to a gradual decrease (external layer of the olfactory bulb, parietal, occipital and cingulate areas of the cerebral cortex, CA1 and CA3 layer of the hippocampus) to a decrease preceded by a transient increase (frontal area of the cerebral cortex, caudate nucleus).

The extent of these changes depends on the duration of exposure to hyperphenylalaninaemia as well as on the degree of brain maturation, but can even be observed in the brain of the adult mouse on a hyperphenylalaninaemic regimen for 11 days.

Since the hippocampus has been shown to be involved in the long‐term storage of information, damage to this structure by hyperphenylalaninaemia may provide a clue to the global mental retardation observed in untreated PKU.
Carbonic anhydrase II deficiency in three unrelated Japanese patients
Authors: Aramaki S. , Yoshida I. , Yoshino M. , Kondo M. , Sato Y. , Noda K. , Jo R. , Okue A. , Sai N. , Yamashita F.
Published: November 2004

Three Japanese patients with carbonic anhydrase II (CAII) deficiency from three families were described. The parents of one patient were unrelated, the parents of each of the other two patients were first cousins. All the patients had renal tubular acidosis, osteopetrosis, symmetrical cerebral calcification and mental retardation. They exhibited poor activity and poor appetite in the neonatal period, and then developed psychomotor retardation. Two of them were diagnosed as having osteopetrosis at 10 months and 36 years of age, respectively, and the other as having osteomalacia at 28 years of age. All patients had recurrent episodes of muscle weakness. The CAII enzyme activity and protein levels in red blood cells in each of the three patients were deficient. Their parents exhibited approximately 50% normal levels of CAII activity and protein.

This is the first report of patients with CAII deficiency in the Japanese population.
Long‐term clinical progress in bone marrow transplanted mucopolysaccharidosis type I patients with a defined genotype
Authors: Hopwood J. J. , Vellodi A. , Scott H. S. , Morris C. P. , Litjens T. , Clements P. R. , Brooks D. A. , Cooper A. , Wraith J. E.
Published: November 2004

Two mucopolysaccharidosis type I (MPS‐I) patients, subjected to bone marrow transplantation (BMT) more than 10 years ago, have recently had their α‐L‐iduronidase genotypes defined. Both patients, homozygous for the relatively common W402X mutation, received BMT when they were 14 and 11 months of age, and are now 12 and 14 years old, respectively. Untreated MPS‐I patients, homozygous for W402X, have an extremely severe clinical phenotype with rapid clinical deterioration and death before 6 years of age. The 12‐year‐old patient, with limited mobility, is coping well at school, while the other patient is wheelchair‐bound with severe disability in his lower limbs, and attends a school for the physically handicapped. Both patients have less than normal intelligence with slowly continuing losses. A third MPS‐I patients, diagnosed at the age of 6 months, was felt, prior to BMT at 14 months, to have a severe phenotype. Twelve years post‐BMT, he is ambulatory, albeit with restricted movement, and has normal intelligence. This patient did not have a defined MPS‐I genotype and had α‐L‐iduronidase protein and activity consistent with a less severe outcome than the first two patients. We conclude that BMT has significantly slowed down the clinical regression of the W402X phenotype. We propose that if further gains are to be made, BMT should be performed within the first few months of life. Early diagnosis is therefore essential.
A novel mtDNA deletion in an infant with Pearson syndrome
Authors: Kapsa R. , Thompson G. N. , Thorburn D. R. , Dahl H. ‐H. M. , Marzuki S. , Byrne E. , Blok R. B.
Published: November 2004

Pearson syndrome is a multisystem mitochondrial disorder of infancy that is associated with deletions in the mitochondrial DNA (mtDNA) genome. We report a study on a male infant with Pearson syndrome. Assessment of oxidative phosphorylation activity indicated combined respiratory‐chain defects in muscle, liver and fibroblasts; in particular, activity of complex I was reduced. Analysis of the patient's mtDNA identified a novel heteroplasmic 2.461 kb deletion, present at levels greater than 50% of the total mtDNA in the tissues examined. The deletion spanned nucleotides 10368 to 12828 and was flanked by a 3 bp GCC direct repeat sequence. Gene sequences affected are subunits 3, 4, 4L and 5 of complex I, and tRNAs for arginine, histidine, serine and leucine. Our findings correlate with the multiorgan involvement observed in Pearson syndrome.
Brain magnetic resonance imaging in children with optimally controlled hyperphenylalaninaemia
Authors: Toft P. B. , Lou H. C. , Krägeloh‐Mann I. , Andresen J. , Güttler F. , Guldberg P. , Henriksen O.
Published: November 2004

This study was undertaken to investigate whether the white‐matter changes on MRI and the EEG abnormalities detectable in treated adolescents and adults with hyperphenylalaninaemia (HPA) can be detected in younger children on an optimally controlled diet. The study included 17 children, 7–12 years of age, with HPA. The MRI of five healthy children were included in the blind evaluation of the MR images. According to mutation genotype and dietary tolerance of phenylalanine, 9 patients have severe HPA and 8 have moderate HPA, all requiring dietary treatment. Mild white‐matter hyperintensity was detected in 1 of the 5 healthy children and in 10 of 17 patients. EEG was abnormal in 2 patients. This group of children was compared with a previously reported group of adolescents with HPA who had been treated according to the same dietary regimen. MRI changes and EEG abnormalities were significantly less frequent in the group of children than in the group of adolescents. It is suggested that the more frequent MRI changes and EEG abnormalities seen in adolescents are related to the fact that a relaxation of the dietary treatment after the age of 8 years is often accepted.
Long‐chain 3‐hydroxyacyl‐CoA dehydrogenase in chorionic villi, fetal liver and fibroblasts and prenatal diagnosis of 3‐hydroxyacyl‐CoA dehydrogenase deficiency
Authors: von Döbeln U. , Venizelos N. , Westgren M. , Hagenfeldt L.
Published: November 2004

Prenatal diagnosis of long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency was performed by analysis of the enzyme activity in a chorionic villus biopsy obtained in the 10th week of pregnancy. The diagnosis was confirmed in liver tissue and cultured fibroblasts from the aborted fetus.
The investigation of respiratory chain disorders in heart using endomyocardial biopsies
Authors: Rustin P. , Lebidois J. , Chretien D. , Bourgeron T. , Piechaud J. ‐F. , Rötig A. , Sidi D. , Munnich A.
Published: November 2004

Conclusion

Hitherto, cardiomyopathy has never been reported as the presenting symptom of a mitochondrial disorder. Although it appears premature to conclude as to the prevalence of defects of oxidative phosphorylation in hypertrophic cardiomyopathies, this study demonstrates that such defects should be regarded as a potential cause of idiopathic hypertrophic cardiomyopathy in early infancy. While an abnormal redox status in plasma and widespread multitissue defects support the diagnosis of mitochondrial cardiomyopathy, normal results in such investigations do not preclude the possibility of heart‐specific respiratory chain defect and should prompt one to carry outin vivo investigations on endomyocardial biopsies.
The blood‐brain barrier: Cellular basis
Authors: Janzer R. C.
Published: November 2004

Perfusion experiments with horseradish peroxidase have established that the morphological substrate of the blood‐brain barrier is represented by microvascular endothelial cells. They are characterized by complexly arranged tight junctions and a very low rate of transcytotic vesicular transport. They express transport enzymes, carrier systems and brain endothelial cell‐specific molecules of unknown function not expressed by any other endothelial cell population. These blood‐brain barrier properties are not intrinsic to these cells but are inducible by the surrounding brain tissue. Type I astrocytes injected into the anterior eye chamber of the rat or onto the chick chorioallantoic membrane are able to induce a host‐derived angiogenesis and some blood‐brain barrier properties in endothelial cells of non‐neural origin. Recently we have shown that this cellular interaction is due to the secretion of a soluble astrocyte derived factor(s). Astrocytes are also implicated in the maintenance, functional regulation and the repair of the blood‐brain barrier. Complex interactions between other constituents of the microenvironment surrounding the endothelial cells, such as the basement membrane, pericytes, nerve endings, microglial cells and the extracellular fluid, take place and are required for the proper functioning of the blood‐brain barrier, which in addition is regionally different as reflected by endothelial cell heterogeneity.
Abnormalities of biogenic amine metabolism
Authors: Hyland K.
Published: November 2004

The term biogenic amine is an umbrella term that encompasses all amines with an origin in biological processes. This review will be restricted to the biogenic amine abnormalities that affect the metabolism of serotonin and the catecholamines. The synthesis and catabolism of these neurotransmitters are outlined, and a summary is given of the neurological details, biochemical features, and treatment of the inborn errors that primarily affect their metabolism. An idea is also developed that proposes that abnormalities of biogenic amine metabolism are far more common than is currently considered, and that the search for these problems may be appropriate in any neonate or infant who presents with neurological problems of unknown origin.
Excitotoxicity, energy metabolism and neurodegeneration
Authors: Ludolph A. C. , Riepe M. , Ullrich K.
Published: November 2004

There is increasing evidence that the neurotoxic effects of excitatory amino acids and their analogues are part of the pathogenesis of neuronal degeneration in acute and chronic neurological disease. Recent studies indicate that activation of excitatory amino acid receptors is also induced in the mechanism of neuronal damage induced by impairment of cellular energy metabolism. This article briefly summarizes the evidence for the presence of such a mechanism and discusses metabolic diseases in which excitatory amino acids alone or in combination with energy deficiency could play a pathogenetic role. In these and other metabolic diseases, antagonists to excitatory amino acid receptors may offer a therapeutic opportunity; however, there are potential limits that may prevent chronic use.
An introduction to the molecular basis of inherited myelin diseases
Authors: Matthieu J. ‐M.
Published: November 2004

The myelin sheath is an extension of a plasma membrane tightly wrapped around axons. It facilitates conduction while conserving space and energy. Myelin is characterized by a high lipid content (80% of dry weight). Most myelin proteins are unique to that structure and some of them are restricted to the central or peripheral nervous system. In this review a few examples of inherited metabolic disorders affecting the oligodendrocyte and/or the Schwann cells are presented. Emphasis is placed on mutations in animals that represent invaluable models for investigating the molecular mechanisms of inherited myelin diseases in humans.
Biochemical pathogenesis of subacute combined degeneration of the spinal cord and brain
Authors: Surtees R.
Published: November 2004

In humans, subacute combined degeneration of the spinal cord and brain, a primary demyelinating disease, is caused by cobalamin or methyltetrahydrofolate deficiency. Experimental studies into its pathogenesis suggest that dysfunction of the methyl‐transfer pathway may be the cause. Compelling evidence for this comes from the study of inborn errors of cobalamin metabolism where deficiency of methylcobalamin, but not deoxyadenosylcobalamin, is associated with demyelination. Recent studies have focused upon inborn errors of the methyl‐transfer pathway. Cerebrospinal fluid concentrations of metabolites of the methyl‐transfer pathway have been measured in humans with sequential errors of the pathway and correlated with demyelination demonstrated on magnetic resonance imaging of the brain. This has provided new data suggesting that deficiency ofS‐adenosylmethionine is critical to the development of demyelination in cobalamin deficiency.
The role of the Southern Ocean in global processes: an earth system science approach
Authors: BUSALACCHI ANTONIO J.
Published: November 2004

The Southern Ocean is unique among the world's oceans in its linkage across the other major ocean basins, its rich and unusual marine ecosystem, and its interaction between the physical climate system and the biogeochemistry of the region. This paper provides an overview and conclusions of a meeting at the Royal Society in London in which an Earth System Science approach was taken to our present and future understanding of the Southern Ocean. A brief summary of what Southern Ocean science has achieved to date, challenges that need to be confronted, and the key questions for the future within an Earth System Science approach are provided.
Air-sea gas exchange in Antarctic waters
Authors: LISS PETER S. , CHUCK ADELE L. , TURNER SUZANNE M. , WATSON ANDREW J.
Published: November 2004

The flux of gases between the atmosphere and the oceans can be calculated from the product of the concentration difference across the sea surface and a kinetic term, often called a transfer velocity. The transfer velocity is frequently parameterized in terms of wind speed, although the actual exchange process is also affected by waves, bubbles, wind fetch, and less certainly by surfactants and chemical reactivity. There is currently an uncertainty of about a factor of two in using the wind speed parameterization. In view of the windiness of the Southern Ocean, transfer velocities will often be high, although there are few published in situ measurements of transfer rates made in the region. Data for gas concentration fields in the Southern Ocean are generally sparse compared to other better studied oceanic areas. In this paper we discuss what is known for the region for carbon dioxide, including the oceanic sink for man-made inputs to the atmosphere; dimethyl sulphide, where there appears to be a substantial source, which has the potential for a significant climatic effect due to the low particulate loading in the region; and organo-halogen and alkyl nitrate gases, where marine emissions may play an important role in controlling the oxidation capacity of the Antarctic atmosphere.
Bottom-up versus top-down control in phytoplankton of the Southern Ocean
Authors: SMITH WALKER O. , LANCELOT CHRISTIANE
Published: November 2004

Oceanic phytoplankton communities are a mixture of various algal functional groups, all of which are of different sizes, have variable physiologies, and interact differently with disparate herbivores. We suggest that polar plankton communities, and specifically the larger phytoplankton of Southern Ocean HNLC (high nutrient, low chlorophyll) systems, are controlled primarily by bottom-up processes, but that smaller (pico- and nanoplankton) reach an equilibrium that is set simultaneously by light, iron and grazing by microzooplankton. Thus Southern Ocean phytoplankton conforms to the “ecumenical iron hypothesis”, albeit with the further addition of light as an environmental control. Examples of bottom-up controls include iron availability, irradiance regulation (either by the incident surface irradiance as controlled by season and sea ice cover, or by the effects of vertical turbulence and mixed layer depths), and macronutrient availability (silicic acid and nitrate). While the contribution of various phytoplankton taxa varies spatially and temporally within the Antarctic, we suggest that this is largely due to the specific responses of the important functional groups to the patterns of physical forcing and micronutrient inputs, rather than to changes in controls by small and large grazers. Examples of abiotic and biotic controls are examined from representative regions of the Antarctic, including continental shelf regions and open ocean HNLC systems. Results from models further support our contention that bottom-up control of large forms is paramount in the Southern Ocean, but top-down controls play an important part in regulating the equilibrium standing stocks of smaller taxa. If bottom-up control is indeed universal in the Antarctic, then it has profound implications for the understanding of interannual variability, food web structure, and population dynamics of higher trophic levels in both the present and past Southern Ocean.
The role of grazing in structuring Southern Ocean pelagic ecosystems and biogeochemical cycles
Authors: SMETACEK VICTOR , ASSMY PHILIPP , HENJES JOACHIM
Published: November 2004

This review examines the links between pelagic ecology and ocean biogeochemistry with an emphasis on the role of the Southern Ocean in global cycling of carbon and silica. The structure and functioning of pelagic ecosystems is determined by the relationship between growth and mortality of its species populations. Whereas the key role of iron supply in conditioning the growth environment of land-remote oceans is now emerging, the factors shaping the mortality environment are still poorly understood. This paper addresses the role of grazing as a selective force operating on the structure and functioning of pelagic ecosystems within the larger conceptual framework of evolutionary ecology. That mortality due to grazing decreases with increasing cell size is widely taken for granted. We examine the impact of this principle across the range of size classes occupied by Southern Ocean plankton and show that relatively few species play crucial roles in the trophic structure and biogeochemical cycles of the Southern Ocean. Under iron-sufficient conditions, high growth rates of weakly silicified diatoms and Phaeocystis result in build-up of blooms that fuel “the food chain of the giants” (diatoms-krill-whales) and drive the carbon pump. In contrast, high grazing pressure of small copepods and salps on the regenerating microbial communities characteristic of the iron-limited Southern Ocean results in accumulation of large, heavily silicified diatoms that drive the silicon pump. The hypotheses we derive from field observations can be tested with in situ iron fertilization experiments.
Retinoids: potential in cancer prevention and therapy
Authors: Clarke Nicole , Germain Pierre , Altucci Lucia , Gronemeyer Hinrich
Published: November 2004

Retinoids (derivatives of vitamin A) are signalling molecules that play important roles in cell growth, differentiation and death. Retinoids act through two types of receptors – retinoic acid receptors (RARα, RARβ and RARγ) and retinoid X receptors (RXRα, RXRβ and RXRγ) – which themselves act as ligand-dependent transcription factors. Retinoids are of special interest in cancer research owing to their antiproliferative and cancer-preventative properties. They have been used successfully to cure acute promyelocytic leukaemia (APL) and can suppress carcinogenesis in a variety of tissue types (e.g. skin, lung, breast and oral cancers). Extensive research efforts have been dedicated to elucidating the molecular and cellular networks that are induced by retinoids, and this has recently yielded novel insights into how retinoids can both prevent and combat cancer.
Accelerating seismic release from a self‐correcting stochastic model
Authors: Jaumé Steven C. , Bebbington Mark S.
Published: November 2004

We investigate the conditions under which the “stress‐release model,” a stochastic version of the elastic rebound model, produces synthetic earthquake sequences characterized by Accelerating Seismic Release (ASR). In this model, the level, or “stress,” of the process accumulates linearly with time through tectonic input and decreases as the result of earthquakes. These “stress drops” correspond to some power of the energy released in the earthquakes, either E0.5 (Benioff strain) or E (seismic moment). Earthquakes occur in a point process with rate controlled by the level of the process. We hypothesize that the critical factor in the appearance of ASR is the manner in which the event sizes depend on the level of the process. This is modeled by the square root of energy released following either a tapered Pareto or truncated Gutenberg‐Richter distribution, with maximum earthquake size controlled by a “tail‐off” or “truncation” point. As the tail‐off point becomes large, so does the average size, corresponding to an “acceleration to criticality” of the system. We found that those cases where the underlying level of the process corresponded to accumulated seismic moment produced numerous ASR sequences, whereas those cases using accumulated Benioff strain as the level did not. These results suggest that the occurrence of ASR is strongly dependent on how large earthquakes affect the dynamics of the fault system in which they are embedded, and hopefully provide some insight into the mechanics of acceleration to criticality, i.e., on the possible causes of occurrence/nonoccurrence of ASR.
Weathering controls on mechanisms of carbon storage in grassland soils
Authors: Masiello C. A. , Chadwick O. A. , Southon J. , Torn M. S. , Harden J. W.
Published: November 2004

On a sequence of soils developed under similar vegetation, temperature, and precipitation conditions, but with variations in mineralogical properties, we use organic carbon and 14C inventories to examine mineral protection of soil organic carbon. In these soils, 14C data indicate that the creation of slow‐cycling carbon can be modeled as occurring through reaction of organic ligands with Al3+ and Fe3+ cations in the upper horizons, followed by sorption to amorphous inorganic Al compounds at depth. Only one of these processes, the chelation of Al3+ and Fe3+ by organic ligands, is linked to large carbon stocks. Organic ligands stabilized by this process traverse the soil column as dissolved organic carbon (both from surface horizons and root exudates). At our moist grassland site, this chelation and transport process is very strongly correlated with the storage and long‐term stabilization of soil organic carbon. Our 14C results show that the mechanisms of organic carbon transport and storage at this site follow a classic model previously believed to only be significant in a single soil order (Spodosols), and closely related to the presence of forests. The presence of this process in the grassland Alfisol, Inceptisol, and Mollisol soils of this chronosequence suggests that this process is a more significant control on organic carbon storage than previously thought.