bluuebunny/crossref_metadata_2025_split huggingface dataset:
Disorders of mitochondrial long‐chain fatty acid oxidation
Authors: Pollitt R. J. 
Published: November 2004

SummaryThe oxidation of long‐chain fatty acids requires a series of enzymes which are located in or on the mitochondrial membranes. These include carnitine palmitoyltransferases I and II, a carnitine‐acylcarnitine translocase and, newly discovered, very long‐chain acyl‐CoA dehydrogenase and the mitochondrial trifunctional protein. These last two chain‐shorten acyl‐CoA esters to the point where they can be transferred to the more soluble medium‐ and short‐chain‐specific enzymes within the mitochondrial matrix. The disorders of long‐chain fatty acid oxidation show a rather similar range of clinical and biochemical features, though with different emphasis in the different conditions. Patients with severe defects usually present early with acute attacks of hypoketotic hypoglycaemia and impaired liver function, or with cardiomyopathy or cardiac arrhythmia. In milder variants, skeletal myopathy with intermittent myoglobinuria develops later in life. 3‐Hydroxyacyl‐CoA dehydrogenase deficiency is unusual in producing peripheral neuropathy and retinitis pigmentosa. Treatment is based on the avoidance of fasting and replacement of normal dietary fat by medium‐chain triglyceride, the medium‐chain fatty acids entering the mitochondria in a carnitine‐independent manner and bypassing the long‐chain part of the spiral. Diagnosis must ultimately be based on direct assay of the enzyme involved, but preliminary indicators may come from determination of carnitine and intermediate metabolites in plasma, urinary organic acid profiling, and radioisotopic screening assays with lymphocytes or cultured fibroblasts.
Treatment of cystic fibrosis based on understanding CFTR
Authors: Smith A. E. 
Published: November 2004

SummaryIn the five years since the gene associated with cystic fibrosis was isolated, rapid progress has been made in understanding the structure and function of CFTR, the gene product. Based on the knowledge that CFTR is a cAMP‐regulated chloride channel in the apical surface of epithelia in many tissues, new approaches to treating CF disease have emerged. These include development of agents to open alternative chloride channels, to relocate mutant CFTR, which commonly is mislocalized because of a trafficking defect, and to deliver CFTR using protein or gene therapy. Although the underlying basis of each of these approaches is now well understood, major practical problems face each of them. Nevertheless, it is difficult not to be optimistic that new therapies will emerge.
Carrier screening in the community
Authors: Brock D. J. H. 
Published: November 2004

SummaryA number of different models of cystic fibrosis (CF) carrier screening have now been tested in pilot trials. Apart from opportunistic and cascade testing (which are strictly speaking not true forms of screening), the major programmes have been directed either to young adults in primary care or to pregnant women in antenatal clinics. Only in the latter form of screening has sufficient data been collected to allow conclusions to be reached on the optimum mode of delivery. It seems very probable that when CF carrier screening passes into routine service, it will be the antenatal couple model that is used.
Glycine andl‐carnitine therapy in 3‐methylcrotonyl‐CoA carboxylase deficiency
Authors: Rutledge S. L. , Berry G. T. , Stanley C. A. , van Hove J. L. K. , Millington D. 
Published: November 2004

SummaryGenetic deficiency of 3‐methylcrotonyl‐CoA carboxylase (3‐MCC) is a rare inborn error of leucine metabolism producing an organic acidaemia. With accumulation of 3‐methylcrotonyl‐CoA, there is increased production of 3‐hydroxyisovaleric acid, the glycine conjugate (3‐methylcrotonylglycine), and the carnitine conjugate (3‐hydroxyisovalerylcarnitine). These conjugates represent endogenous detoxification products. We studied excretion rates of these conjugates at baseline and with glycine and carnitine therapy in an 8‐year‐old girl with 3‐MCC deficiency. Her preadmission diet was continued. Plasma and urine samples were obtained after 24h of each of the following:l‐carnitine 100mg/kg per day and glycine 100, 175 and 250mg/kg per day. Plasma and urinary carnitine levels were reduced by 80% and 50%, respectively with abnormal urinary excretion patterns. These normalized with carnitine therapy. Acylcarnitine excretion increased with carnitine therapy. The glycine conjugate, 3‐methylcrotonylglycine (3‐MCG), was the major metabolite excreted at all times and its excretion increased with glycine therapy. Clearly, in 3‐MCC deficiency the available glycine and carnitine pools are not sufficient to meet the potential for conjugation of accumulated metabolites, suggesting a possible therapeutic role for glycine and carnitine therapy in this disorder.
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

SummaryBetween 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

SummaryThe 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

SummaryAn 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

SummaryWe 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

SummaryMembrane‐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

SummaryIn 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

SummaryA 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

SummaryGenetic 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

SummaryThe 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

SummarySteroid 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

SummaryPrevention 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

SummaryGlycogen 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

Summaryα‐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

SummaryN‐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

Summaryβ‐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

SummaryQuantitative 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

SummaryPatients 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.