bluuebunny/crossref_metadata_2025_split huggingface dataset:
X‐linked adrenoleukodystrophy: Biochemical diagnosis and enzyme defect
Authors: Wanders R. J. A. , van Roermund C. W. T. , Lageweg W. , Jakobs B. S. , Schutgens R. B. H. , Nijenhuis A. A. , Tager J. M. 
Published: June 2005

SummaryThe adrenoleukodystrophies refer to three genetically distinct disorders all characterized by the accumulation of very long‐chain fatty acids. In this paper we will review the biochemical aspects of these leukodystrophies with particular emphasis on the methods used to measure very long‐chain fatty acid levels in plasma and their reliability. Furthermore, we will concentrate on the primary defect in the X‐linked form of adrenoleukodystrophy.
Adrenoleukodystrophy: Phenotypic variability and implications for therapy
Authors: Moser H. W. , Moser A. B. , Smith K. D. , Bergin A. , Borel J. , Shankroff J. , Stine O. C. , Merette C. , Ott J. , Krivit W. , Shapiro E. 
Published: June 2005

SummaryX‐linked adrenoleukodystrophy (ALD) is a relatively common disorder that shows a great deal of phenotypic variability. Approximately half of the patients have the rapidly progressive childhood cerebral form that is associated with an inflammatory response in brain and leads to total disability or death during the first decade. Twenty five per cent or more of the patients have adrenomyeloneuropathy (AMN), a form that progresses slowly, involves the spinal cord mainly, shows little or no inflammatory response, manifests in adulthood, and is compatible with a near‐normal life span. The two forms of the disease occur frequently within the same kindreds and nuclear families. Segregation analysis based on 3862 individuals in 89 kindreds points to the existence of an autosomal modifier locus with a likelihood ratio of 20:1. In addition, we present preliminary results of three types of therapy. Two hundred and four patients have received a dietary regimen that combines the administration of oils containing mono‐unsaturated fatty acids (oleic and erucic) with the restricted intake of very long‐chain fatty acids. This regimen normalizes the levels of satured very long‐chain fatty acids in plasma within 4 weeks. It appears to improve peripheral nerve function in patients with AMN, and a large‐scale trial is in progress to determine whether it can prevent the onset of neurological involvement in patients who have the biochemical abnormality of ALD but are neurologically intact. We report early results of bone marrow transplantation in 14 patients. There is encouraging but still preliminary evidence that transplantation can arrest the progression of the disease in patients with mild neurological involvement. There is urgent need to develop methods to combat the rapid progression of the cerebral forms of the disease, which so far has resisted therapeutic intervention, including immunosuppression or the administration of immunoglobulin.
The molecular basis of X‐linked immunodeficiency disease
Authors: Kinnon C. , Levinsky R. 
Published: June 2005

SummaryThe molecular bases of the X‐linked immunodeficiency diseases remain largely undetermined. Two of the genes involved in these diseases have been isolated, namely the genes for X‐linked chronic granulomatous disease and properdin deficiency, and substantial progress has now been made in identifying the genes which are defective in the other five diseases, Wiskott‐Aldrich syndrome, X‐linked severe combined immunodeficiency, X‐linked agammaglobulinaemia, X‐linked hyper‐IgM and X‐linked lymphoproliferative syndrome. We review here the nature of the diseases, progress made in identifying and isolating the genes involved and the prospects for improved prenatal detection, carrier status determination and treatment of these life‐threatening conditions.
Gene analysis of mennonite maple syrup urine disease kindred using primer‐specified restriction map modification
Authors: Mitsubuchi H. , Matsuda I. , Nobukuni Y. , Heidenreich R. , Indo Y. , Endo F. , Mallee J. , Segal S. 
Published: June 2005

SummaryMaple syrup urine disease (MSUD) is an autosomal recessive inherited disease due to a deficiency of any of the subunits, E1α, E1β or E2, of the branched‐chain α‐ketoacid dehydrogenase complex (BCKDH). A large Mennonite kindred of MSUD has been studied in Pennsylvania, USA. In the present investigation, genomes from 70 members, including 12 patients belonging to eight different Mennonite MSUD pedigrees, were examined for possible abnormalities in the E1α gene of BCKDH, by primer‐specified restriction map modification. A T‐to‐A substitution which generates an asparagine in place of a tyrosine at amino acid 394 of the mature E1α subunit was present in both alleles in all the patients and in a single allele in all obligate carriers and several siblings. We describe a new technique for rapid and easy detection of the mutant gene in this population. These family studies provide additional evidence that Mennonite MSUD is caused by a missense mutation of the E1α gene of BCKDH.
Persistent hypermethioninaemia with dominant inheritance
Authors: Blom H. J. , Davidson A. J. , Finkelstein J. D. , Luder A. S. , Bernardini I. , Martin J. J. , Tangerman A. , Trijbels J. M. F. , Mudd S. H. , Goodman S. I. , Gahl W. A. 
Published: June 2005

SummaryA clinically benign form of persistent hypermethioninaemia with probable dominant inheritance was demonstrated in three generations of one family. Plasma methionine concentrations were between 87 and 475 µmol/L (normal mean 26 µmol/L; range 10–40 µmol/L); urinary methionine and homocystine concentrations were normal. Plasma homocystine, cystathionine, cystine and tyrosine were virtually normal. The concentrations in serum and urine of metabolites formed by the methionine transamination pathway were normal or moderately elevated. Methionine loading of two affected family members revealed a diminished ability to catabolize methionine, but the activities of methionine adenosyltransferase and cystathionine β‐synthase were not decreased in fibroblasts from four affected family members. Fibroblast methylenetetrahydrofolate reductase activity and its inhibition byS‐adenosylmethionine were also normal, indicating normal regulation ofN5‐methyltetrahydrofolate‐dependent homocysteine remethylation. Serum folate concentrations were not increased.The findings in this family differ from those previously described for known defects of methionine degradation. Since the hepatic and fibroblast isoenzymes of methionine adenosyltransferase differ in their genetic control, this family's biochemical findings appear consistent with a mutation in the structural gene for the hepatic methionine adenosyltransferase isoenzyme.
3‐Methylglutaconic aciduria: A marker for as yet unspecified disorders and the relevance of prenatal diagnosis in a ‘new’ type (‘type 4’)
Authors: Chitayat D. , Chemke J. , Gibson K. M. , Mamer O. A. , Kronick J. B. , McGill J. J. , Rosenblatt B. , Sweetman L. , Scriver C. R. 
Published: June 2005

SummaryThe Mendelian disorder known as 3‐methylgutaconic aciduria (McKusick 250950) gives evidence of allelic and locus heterogeneity. Type 1 has a mild clinical phenotype and confirmed 3‐methylgutaconyl‐CoA hydratase deficiency; inheritance is autosomal recessive. Other forms have major clinical manifestations and subdivide into X‐linked (type 2), a form in Iraqi Jews with optic atrophy (so‐called type 3); and untyped (putative autosomal recessive) forms without identified enzyme defects. In the latter, 3‐methylglutaconic aciduria may simply be a marker for another metabolic disorder.We describe a male proband with 3‐methylglutaconic aciduria designated here as ‘type 4’ (autosomal recessive, with severe psychomotor phenotype and cerebellar dysgenesis). He is the offspring of Italian consanguineous parents. Born with congenital malformations, he has been followed for 18 years, showing profound developmental delay and cerebellar dysgenesis. Measures of hydratase activity in cultured fibroblasts from the proband and 11 additional patients (two with type 1 disease, 9 with either type 2 or an unspecified form) revealed deficient enzyme activity in type 1 cases and normal activity in the proband and the other 11 cases. Two of the untyped cases probably have 3‐methylglutaconic aciduria of the type described here.Prenatal diagnosis in the form described here may be feasible by analysis of amniotic fluid metabolites in pregnancies at risk if the mother does not entirely remove elevated concentrations. A female sibling of the proband had normal metabolite values in amniotic fluid. Postnatal follow‐up confirmed absence of the disease. We give the normal values for amniotic fluid and results on these additional fetuses at risk (none affected).
Myelin turnover in hyperphenylalaninaemia. A re‐evaluation with the HPH‐5 mouse
Authors: Hommes F. A. , Moss L. 
Published: June 2005

SummaryMyelin turnover has been studied in the 25‐day‐old HPH‐5 mouse, a phenylalanine hydroxylase‐deficient mouse mutant. The half‐life of the fast component of myelin decreased from 15 days in control mice to 4.5 days at blood phenylalanine levels of 2.5 mmol/L. The slow component of myelin seems also to be affected by the high phenylalanine level. These observations confirm similar observations obtained with chemically induced models of hyperphenylalaninaemia and are therefore due to the hyperphenylalaninaemiaper se, independently of the inhibitors of phenylalanine hydroxylase. An intermediate blood level of phenylalanine (0.7 mmol/L) likewise seems to interfere with myelin metabolism, although to a lesser degree.
Diminished concentration of the NF‐H subunit of neurofilaments in cerebral cortex of rats chronically treated with proline, methylmalonate and phenylalanine plus α‐methylphenylalanine
Authors: Rubin M. A. , Wannmacher C. M. D. , Valente G. B. , Camargo M. M. , Pureur R. P. 
Published: June 2005

SummaryWistar rats from the same litter were randomly divided into four groups and received subcutaneously from the 6th to 28th daypost partum one of the following drugs:l‐proline, methylmalonate,l‐phenylalanine plus α‐methylphenylalanine, or equivalent volumes of 0.9% (w/v) saline (controls). On day 30, the animals were killed, the brain was removed and the cerebral cortex and cerebellum was immediately dissected.Total intermediate filament fraction (IF) was obtained from cerebral cortex and cerebellum by using a high‐salt phosphate‐buffered solution supplemented by 1% Triton X‐100. The pellet contained the bulk of the IF proteins. Following SDS‐polyacrylamide gel electrophoresis, these proteins were identified as the 200, 150 and 68 kD subunits of neurofilaments (NF‐H, NF‐M and NF‐L, respectively), the 66 kDa associated protein, the 57 kDa intermediate filament‐like protein and the 52 kDa glial fibrillary acidic protein (GFAP). They were further scanned through densitometry from enriched fractions of controls and of animals treated with the various drugs in order to determine the effects of the treatments on their concentration. Our results showed that the concentration of IF protein in cerebellum was not affected by the treatments, whereas chronic administration of all drugs significantly decreased NF‐H subunit concentration in rat cerebral cortex.
3‐Hydroxy‐3‐methylglutaryl‐coenzyme A lyase deficiency: A review
Authors: Wysocki S. J. , Hähnel R. 
Published: June 2005

AbstractChildren with 3‐hydroxy‐3‐methylglutaryl‐CoA lyase deficiency (HMG‐CoA‐LD; McKusick 24645), have inherited two areas of metabolic weakness. Firstly, they are unable to metabolize fully the carbon skeleton of leucine, and secondly, they cannot make ketone bodies in response to prolonged fasting. In the first year of life infants with HMG‐CoA‐LD run a high risk of developing severe hypoglycaemia which can lead to death if prompt intervention does not occur. The metabolic crisis develops when the infant is first introduced to dietary protein soon after birth, or later, when a reduced intake of glucose, often during a viral infection, results in a drain on the infant's circulating glucose levels. However, where diets are adequately adjusted to limit protein and fat intake, the metabolic handicaps of individuals with HMG‐CoA‐LD are not exposed and they are virtually symptomless. As children with HMG‐CoA‐LD grow older the incidence of hypoglycaemic attacks diminishes and they usually develop normally. This article reviews literature on cases of HMG‐CoA‐LD and interprets data on altered metabolism in these children.
Tetrahydrobiopterin non‐responsiveness in dihydropteridine reductase deficiency is associated with the presence of mutant protein
Authors: Cotton R. G. H. , Jennings I. , Bracco G. , Ponzone A. , Guardamagna O. 
Published: June 2005

AbstractCorrelation of the response to a load of tetrahydrobiopterin (BH4) in dihydropterin reductase (DHPR) deficient patients to the type of mutation in these patients has led to the conclusion that 4 patients without mutant DHPR molecules in their cells respond to the BH4 load, whereas 3 patients with mutant DHPR in their cells do not respond. Intravenous injection of BH4 in 1 of the cases not responding to BH4 again showed no response.
Treatment of chronic congenital lactic acidosis by oral administration of dichloroacetate
Authors: Kuroda Y. , Ito M. , Toshima K. , Takeda E. , Naito E. , Hwang T. J. , Hashimoto T. , Miyao M. , Masuda M. , Yamashita K. , Adachi T. , Suzuki Y. , Nishiyama K. 
Published: June 2005

AbstractSodium dichloroacetate (DCA) was administered orally at a dose of 50 mg per kg body weight twice or three times per day to a newborn infant with lactic acidosis of unknown cause (patient 1) and to a 15‐year‐old boy with mitochondrial encephalomyopathy associated with lactic acidosis (patient 2). In patient 1, during treatment with DCA, DCA accumulated in the blood judging from the findings that the urinary excretion of DCA increased cumulatively and the blood lactate level rapidly decreased to the normal range. In patient 2, the blood DCA level gradually increased during treatment to a concentration of 250 µgml−1 and the blood lactate level decreased and was maintained within the normal range. DCA was detected in the brain (25 µg g tissue−1) and the liver, kidney and muscle (33.8, 33.8 and 26.3 µg g tissue−1, respectively) obtained at autopsy of patient 1, and in the cerebrospinal fluid of patient 2 at a concentration of 125 µg ml−1 when the blood concentration was 250 µg ml−1. The lactate levels in the cerebrospinal fluid decreased from 7 and 4mmoll−1 to 2.4 and 2.6 mmoll−1 in patients 1 and 2, respectively. Thus DCA may be useful in clinical treatment of chronic congenital lactic acidosis because it seems to cross the blood‐brain barrier. However, it must be given at non‐toxic doses, determined by monitoring the concentrations of lactate and DCA in the blood, because orally administered DCA tends to accumulate in tissues.
Kinetic abnormalities of carbamyl phosphate synthetase‐I in a case of congenital hyperammonaemia
Authors: Qureshi I. A. , Letarte J. , Ouellet R. , Lemieux B. , Cathelineau L. 
Published: June 2005

AbstractA sensitive direct colourimetric method has been employed to measure kinetic parameters and pH dependence of carbamyl phosphate synthetase‐I, in a liver sample from a 2 1/2‐month‐old girl, who died from complications of a late‐developing congenital hyperammonaemia. The residual activity of carbamyl phosphate synthetase‐I was 25%, whereas other urea cycle enzymes were within normal range. ApparentKm for ammonium ion (0.73 mmol/L) was significantly increased (normal range 0.24–0.51).Km for bicarbonate ion was normal, whileKm for NAG showed a slight variation from normal. The pH dependence curve of the patient's enzyme was flat, as compared to two controls showing pH optima at 7.8. Radial immunodiffusion (Mancini) of the abnormal enzyme against human enzyme antiserum gave a cross‐reacting material of 10–20%. The methodological approach presented can be used to characterize abnormal enzymes in cases of partial deficiency with only 100–200 mg of liver tissue.
Lysosomal protein degradation in experimental hyperphenylalaninaemia
Authors: Schröter J. , Schott K. ‐J. , Purtill M. ‐A. , Neuhoff V. 
Published: June 2005

AbstractThe influence of α‐methylphenylalanine‐induced hyperphenylalaninaemia (HYP) on the lysosomal protein degradation system in brain and liver of suckling rats was investigated. In both tissues cathepsind andl activities, measured at 5, 10 and 15 days post partum (p.p.), exhibited no differences between experimental and control animals.N‐Acetyl‐β‐d‐glucosaminidase (NAGase) activity in brain, measured at 10 and 15 days p.p., was not affected by HYP either. The release of valine and lysine from liver and brain homogenates respectively, serving as a measure for the lysosomal content of degradable proteins, was not influenced by HYP. Lysosomal integrity during incubation of homogenate was monitored by the recovery of NAGase activity in the cytosolic supernatant, and by the relative NAGase activity in total homogenates in the absence of the lysosome disrupting detergent Triton X‐100. In conclusion, experimental HYP appears unlikely to influence the lysosomal protein degradation system in brain and liver of suckling rats.
On the mechanism ofl‐alloisoleucine formation: Studies on a healthy subject and in fibroblasts from normals and patients with maple syrup urine disease
Authors: Schadewaldt P. , Hammen H. ‐W. , Dalle‐Feste C. , Wendel U. 
Published: June 2005

Summaryl‐Alloisoleucine formation froml‐isoleucine was studiedin vitro andin vivo. When a healthy subject was loaded withl‐isoleucine, plasma levels ofl‐isoleucine and 3‐methyl‐2‐oxopentanoate (KMV), as well asl‐alloisoleucine, increased. Peak values were reached successively and were in the orderl‐isoleucine > > KMV > >l‐alloisoleucine. Metabolic clearance ofl‐isoleucine and KMV was rapid; clearance ofl‐alloisoleucine was considerably delayed. When human skin fibroblast cultures were challenged withl‐isoleucine, KMV accumulated at a gradually decreased rate, whereasl‐alloisoleucine accumulated at a gradually accelerated rate. KMV andl‐alloisoleucine formation were related and depended on thel‐isoleucine concentration applied. In cell lines derived from MSUD patients (classical form), metabolite formation was only about 2‐fold higher than in control strains. The relatively small difference between normal and MSUD fibroblastsin vitro as opposed to the striking differences between healthy subjects and MSUD patientsin vivo are discussed with respect to the significance of physiological mechanisms participating in the formation and degradation ofl‐alloisoleucine in man.
The effect of plasma valine, isoleucine and leucine on the control of the flux through tyrosine‐ and tryptophan‐hydroxylase in the brain
Authors: Hommes F. A. , Lee J. S. 
Published: June 2005

SummaryThe effect of increasing blood levels of valine, isoleucine and leucine on the fluxes through tyrosine and tryptophan hydroxylase in brain has been calculated and analysed in terms of flux control coefficients. It is concluded that any beneficial effect of increasing the concentration of these amino acids in phenylketonuria patients is not due to a decrease in brain phenylalanine or an improved neurotransmitter synthesis through tyrosine or tryptophan hydroxylase.
Quantitative analysis of disaccharides in the urine ofβ‐mannosidosis patients
Authors: Tjoa S. , Wenger D. A. , Fennessey P. V. 
Published: June 2005

SummaryUntil recently, there have not been any confirmed reports ofβ‐mannosidase deficiency in man. We have now analysed urine from two patients with confirmedβ‐mannosidase deficiency and have found Man‐β(1–4)GlcNAc concentrations of 65 and 73 mg/mmol creatinine. These levels are at least 12 times higher than those found in patients with other lysosomal storage diseases. The method we report for this analysis requires only 0.1 ml of urine and uses a gas chromatograph, area ratio, calibration curve for the quantitative analysis.
Muscle cell cultures in Menkes' disease: Copper accumulation in myotubes
Authors: van den Berg G. J. , Kroon J. J. , Wijburg F. A. , Sinjorgo K. M. C. , Herzberg N. H. , Bolhuis P. A. 
Published: June 2005

SummaryWe present64Cu uptake studies in cultured muscle cells from a one‐year‐old patient with Menkes' disease. The cultured muscle cells from the patient showed a five‐fold higher64Cu uptake than control muscle cells. Copper uptake in muscle cells was of the same magnitude as that found in fibroblasts from the patient and also from other Menkes' patients. The copper content of a muscle biopsy from the patient was twice that of a control biopsy. The enhanced uptake is probably copper specific, since zinc uptake was unaltered in both muscle cells and fibroblasts from the patient.Cytochrome c oxidase in the muscle of the patient was reduced to one‐third of the value for controls, which is in agreement with the hypothesis that in Menkes' disease copper accumulates in a biologically non‐active form. However, in cultured muscle cells and fibroblasts from the patient the cytochrome c oxidase activity was in the normal range, probably because of the relatively large amount of copper already available in the culture medium.
Gyrate atrophy of the choroid and retina: 3 cases in one Italian family
Authors: Fois A. , Borgogni P. , Cioni M. , Mancini G. M. S. , Molinelli M. , Pizzetti M. , Bardelli A. M. , Biangini L. , Barberi L. , Malpassi C. , Harms E. , Kleijer W. J. 
Published: June 2005

ConclusionsOur study reports the first comprehensive evaluation of HOGA in an Italian family, and is thus intended to alert Italian ophthalmologists and paediatricians to this potentially treatable condition in children with even apparently mild visual disturbances. The typical fundoscopic findings make diagnosis possible. Extensive epidemiological investigations could be justified to determine the incidence of this disorder in Italy.
Four cases of hyperphenylalaninaemia: Studies during pregnancy and of the offspring produced
Authors: Koch R. , Blaskovics M. 
Published: June 2005

AbstractFour cases of variant hyperphenylalaninaemia during pregnancy are presented. Babies born to mothers with blood phenylalanine concentrations of 4–8 mg/dl were normal and did not exhibit significant microcephaly, although one did have a major congenital anomaly (exstrophy of the bladder). The mother with blood phenylalanine concentrations of 6–12 mg/dl during pregnancy delivered three of four infants with mild microcephaly but normal intellectual function. The data suggest that phenylalanine concentrations of 4–8 mg/dl are reasonable and desirable during pregnancy in hyperphenylalaninaemic women. Furthermore, the data do not support or refute the justification hypothesis of Bessmanet al.
The use of deuterated phenylalanine for thein vivo assay of phenylalanine hydroxylase activity in children
Authors: Matalon R. , Matthews D. E. , Michals K. , Bier D. 
Published: June 2005

AbstractFifteen children, five with phenylketonuria (PKU), five with hyperphenylalaninaemia, and five phenotypically normal but at risk of being carriers for PKU, were given [ring2H5]phenylalanine orally in amounts ranging from 75 mg/kg to 10 mg/kg. Plama was assayed for [2H5]phenylalanine and [2H4]tyrosine at hourly intervals, the amino acids being measured as theN‐acetyl, n‐propyl esters by gas chromatography‐mass spectroscopy. The results obtained were calculated as the log of the ratio [2H5]phenylalanine: [2H4]tyrosine in the plasma. The five patients with PKU had ratios of infinity because no [2H4]tyrosine was measured in their plasma during the experimental period. The patients with hyperphenylalaninaemia had log ratios over 2.00 throughout the assay period. Among the five normal children three are considered to be carriers for PKU as the logarithms of the [2H5]phenylalanine: [2H4]tyrosine ratios were 1.77, 1.73, and 1.33 and remained over 1.00 during the assay period. The other children had log ratios of 1.16 and 1.00 at the first hour which dropped below 1.00 subsequently, suggesting normal activity of phenylalanine hydroxylase.