bluuebunny/crossref_metadata_2025_split huggingface dataset:
Familial isolated vitamin E deficiency. Extensive study of a large family with a 5‐year therapeutic follow‐up
Authors: Amiel J. , Maziere J. C. , Beucler I. , Koenig M. , Reutenauer L. , Loux N. , Bonnefont D. , Féo C. , Landrieu P. 
Published: November 2004

SummaryA major neurological deterioration, beginning with ataxia, led to the diagnosis of familial vitamin E deficiency in a girl. Based upon vitamin E determinations, 4/8 members of the (consanguineous) sibship were considered to be homozygous. Homozygosity was also found for the alleles of six markers linked to theAVED locus, recently identified in similar Tunisian or Sicilian families on chromosome 8q. Measures of vitamin E in lipoprotein fractions and in liver biopsy after vitamin E oral load suggested that free diffusion of vitamin E between the different compartments was possible and even increased. However, a high‐affinity ligand seemed to be lacking, either in the hepatic recycling of vitamin E or in both the hepatic and the other vitamin E compartments. The 5‐year substitutive treatment was successful only in the pre‐ or paucisymptomatic patients. Serum vitamin E must be measured in any unexplained progressive ataxia.
Diagnosis of Zellweger syndrome by analysis of very long‐chain fatty acids in stored blood spots collected at neonatal screening
Authors: Jakobs C. , van den Heuvel C. M. M. , Stellaard F. , Largillière C. , Skovby F. , Christensen E. 
Published: November 2004

SummaryZellweger syndrome was diagnosedpost mortem by determining the very long‐chain fatty acids in a blood spot collected at neonatal screening.
Skin fibroblast carnitine uptake in secondary carnitine deficiency disorders
Authors: Tein I. , De Vivo D. C. , Ranucci D. , DiMauro S. 
Published: November 2004

SummarySkin fibroblast carnitine uptake studies may identify and differentiate primary and secondary carnitine deficiency disorders. To confirm the specificity of these studies in differentiating primary from secondary carnitine deficiency disorders, we have studied carnitine uptake in the cultured skin fibroblasts from 5 children who have various enzymatic defects in intramitochondrial β‐oxidation including short‐chain, medium‐chain and long‐chain acyl‐CoA dehydrogenase and short‐chainl‐3‐hydroxyacyl‐CoA dehydrogenase deficiencies, and in 4 children with cytochrome oxidase deficiency. Carnitine uptake was normal in the intramitochondrial β‐oxidation cases, suggesting other mechanisms for their carnitine deficiency. Therefore, intramitochondrial β‐oxidation defects associated with carnitine deficiency can be differentiated from primary carnitine deficiency not only by the presence of an abnormal dicarboxylic aciduria but by normal skin fibroblast carnitine uptake. In contrast to these findings, carnitine uptake in the cultured skin fibroblasts of four children with secondary carnitine deficiency due to cytochrome oxidase deficiency demonstrated a partial decrease in the maximal velocity of uptake (20–47% controlVmax), similar to that observed in the primary carnitine deficiency heterozygotes. We propose that this observation may be due to a generalized decrease in intracellular ATP, thus decreasing the efficiency of the energy‐ and sodium‐dependent carnitine transporter. We conclude that carnitine uptake studies in cultured skin fibroblasts will contribute to an understanding of the mechanisms of carnitine depletion in the primary and secondary carnitine deficiency disorders.
Inhibition of succinate dehydrogenase and β‐hydroxybutyrate dehydrogenase activities by methylmalonate in brain and liver of developing rats
Authors: Dutra J. C. , Dutra‐Filho C. S. , Cardozo S. E. C. , Wannmacher C. M. D. , Sarkis J. J. F. , Wajner M. 
Published: November 2004

SummaryThe effects of methylmalonate (MMA) on succinate dehydrogenase (SDH) and β‐hydroxybutyrate dehydrogenase (HBDH) activities in brain and liver of 15‐day‐old rats were studied. The apparentKm of SDH for succinate was 0.45 mmol/L in brain and 0.34 mmol/L in liver. MMA inhibited the enzyme activity in both tissues withKi values of 4.5 mmol/L and 2.3 mmol/L in brain and liver, respectively, and the inhibition was of the reversible competitive type. The calculatedKm for HBDH with β‐hydroxybutyrate as substrate was 1.26 mmol/L in brain and 0.36 mmol/L in liver. MMA inhibited the enzyme with aKi value of 0.015 mmol/L in brain and 0.275 mmol/L in liver. These results are probably relevant to our understanding of cerebral metabolism in methylmalonic acidaemic children, especially during ketoacidotic and hypoglycaemic crises, and may be related to the pathogenesis of cerebral dysfunction of methylmalonic acidaemia.
Molecular genetics of metachromatic leukodystrophy
Authors: Gieselmann V. , Polten A. , Kreysing J. , von Figura K. 
Published: November 2004

SummaryMetachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulphatase A. The disease is characterized by a progressive demyelination that causes a variety of neurological symptoms. Patients die within a few years after the age of onset. Clinically the disease is heterogeneous and according to the age of onset three different forms can be distinguished. The gene of arylsulphatase A has been cloned and several mutations causing metachromatic leukodystrophy have been characterized. The distribution of these alleles among patients with different clinical forms of the disease has revealed a genotype‐phenotype correlation. A major determinant of the clinical phenotype is the residual enzyme activity that it associated with a particular genotype. Homozygosity for alleles that do not allow the synthesis of arylsulphatase A polypeptides causes the most severe form of disease, whereas homozygosity for alleles that encode arylsulphatase A with low residual enzyme activity is found in the mild late‐onset forms of disease. A substantial arylsulphatase A deficiency can also be found in healthy individuals at high frequency. This phenomenon has been termed pseudodeficiency. It is often difficult to distinguish whether an arylsulphatase A deficiency is due to metachromatic leukodystrophy or harmless pseudodeficiency. The characterization of the mutations causing pseudodeficiency has allowed the detection of the pseudodeficiency allele in the DNA of probands and has thus improved the diagnosis and genetic counselling for metachromatic leukodystrophy.
Tetrahydrobiopterin deficiency and brain nitric oxide synthase in thehph1 mouse
Authors: Brand M. P. , Heales S. J. R. , Land J. M. , Clark J. B. 
Published: November 2004

SummaryTetrahydrobiopterin (BH4) is the cofactor for the aromatic amino acid monoxygenase group of enzymes and for all known isoforms of nitric oxide synthase (NOS). Inborn errors of BH4 metabolism lead to hyperphenylalaninaemia and impaired catecholamine and serotonin turnover. The effects of BH4 deficiency on brain nitric oxide (NO) metabolism are not known. In this study we have used thehph‐1 mouse, which displays GTP cyclohydrolase deficiency, to study the effects of BH4 deficiency on brain NOS. In the presence of exogenous BH4, NOS specific activity was virtually identical in the control andhph‐1 preparations. However, omission of BH4 from the reaction buffer led to a significant 20% loss of activity in thehph‐1 preparations only. TheKm for arginine was virtually identical for the control andhph‐1 NOS when BH4 was present in the reaction buffer. In the absence of cofactor, theKm for arginine was 3‐fold greater for control and 5‐fold greater forhph‐1 preparations. It is concluded that (a) BH4 does not regulate the intracellular concentration of brain NOS; (b) less binding of BH4 to NOS occurs in BH4 deficiency states; (c) BH4 has a potent effect on the affinity of NOS for arginine; and (d) the availability of arginine for NOS activity may become severely limiting in BH4 deficiency states. Since, in the presence of suboptimal concentrations of BH4 or arginine, NOS may additionally form oxygen free‐radicals, it is postulated that in severe BH4 deficiency states NO formation is impaired and the central nervous system is subjected to increased oxidative stress.
Immunocytochemical localization of peroxisomal proteins in human liver and kidney
Authors: Espeel M. , Van Limbergen G. 
Published: November 2004

SummaryThe sample preparation and immunocytochemical methods for investigating the presence and subcellular localization of peroxisomal proteins (catalase, the three β‐oxidation enzymes, alanine: glyoxylate aminotransferase and a peroxisomal membrane protein) in human liver biopsies are described. We present a protocol for immunolabelling on ultrathin and semithin sections from the same tissue block, with protein A‐colloidal gold as a reporter system. For this purpose, the tissue is embedded in Unicryl, a hydrophilic acrylic resin that is cured by ultraviolet illumination at 2°C. The limitations and possibilities of the methods are discussed together with methodological problems. Cryostat sections of prefixed material should be used for the visualization by light microscopy of cytoplasmic catalase. It is emphasized that immunolabelling for catalase in formalin‐fixed archival liver samples and in liver autopsy tissue (in the latter also for the peroxisomal β‐oxidation enzymes) permits visualization of peroxisomes; this can be helpful in diagnosing an index case retrospectively.
Applications of a new fluorimetric enzyme assay for the diagnosis of aspartylglucosaminuria
Authors: Vozyi Ya. V. , Keulemans J. L. M. , Lleijer W. J. , Aula P. , Gray G. R. , van Diggelen O. P. 
Published: November 2004

SummaryL‐Aspartic acid‐β‐7‐amido‐4‐methylcoumarin is a sensitive and specific fluorogenic substrate for lysosomal glycoasparaginase (aspartylgluco‐saminidase). Fibroblasts and leukocytes from 8 patients with aspartylglucosaminuria, showed 1–7% of the mean normal glycoasparaginase activity. Heterozygotes showed intermediate activities. Glycoasparaginase activity in chorionic villi, cultured trophoblasts, cultured amniotic fluid cells and amniotic fluid was readily detectable, indicating that prenatal analysis of aspartylglucosaminuria should be possible with this assay. β‐Aspartyl‐4‐methylumbelliferone was synthesized but this potential substrate can not be used to assay glycoasparaginase since it hydrolyses spontaneously.
A fluorimetric enzyme assay for the diagnosis of Sanfilippo disease type D (MPS IIID)
Authors: He Wang , Voznyi Ya. V. , Boer A. M. , Kleijer W. J. , van Diggelen O. P. 
Published: November 2004

Summary4‐Methylumbelliferyl‐α‐N‐acetylglucosamine 6‐sulphate was synthesized and shown to be a substrate for the lysosomalN‐acetylglucosamine‐6‐sulphate sulphatase (GlcNAc‐6S sulphatase). Fibroblasts and leukocytes from 3 different Sanfilippo D patients showed <1% of mean normal GlcNAc‐6S sulphatase activity. The enzymatic liberation of the fluorochrome from 4‐methyl‐umbelliferyl‐α‐N‐acetylglucosamine 6‐sulphate requires the sequential action of the GlcNAc‐6S sulphatase and α‐N‐acetylglucosaminidase. A normal level of α‐N‐acetylglucosaminidase activity was insufficient to complete the hydrolysis of the reaction intermediate 4‐methylumbelliferyl‐α‐N‐acetylgluco‐saminide formed by the GlcNAc‐6S sulphatase. A second incubation in the presence of excess α‐N‐acetyglucosaminidase is needed to avoid underestimation of the GlcNAc‐6S sulphatase activity.
Possible β‐mannosidosis chimera. Altered expression of metabolic perturbations
Authors: Jones M. Z. , Cavanagh K. T. , Kranich R. , Traviss C. , Fujita Y. , Ohta M. , Matsuura F. 
Published: November 2004

SummaryAn aberrant β‐mannosidosis phenotype in a 5‐month‐old triplet goat kid was characterized by a late postnatal onset of mild neurological symptoms. Necropsy examination revealed relatively normal myelination; however, the distribution of cytoplasmic vacuolation in the kidney and brain was similar to that observed in neonatal β‐mannosidosis. Variable engraftment of donor stem cells, resulting from transplacental transfusion of stem cells from a normal sibling during the immunotolerant period, may have modified the expected severe β‐mannosidosis phenotype. This investigation was designed to determine the effects of a possible chimeric state on organ‐specific metabolic perturbations. Residual β‐mannosidase enzyme activity was found in plasma, kidney, liver and spleen but not in brain. Other lysosomal enzyme activities were comparable to normal values. Immunoreactive β‐mannosidase was estimated to be less than 10% of normal levels. Kidney, brain grey matter and brain white matter contained 33%, 12% and 4%, respectively, of the oligosaccharides expected in the organs of β‐mannosidosis animals. There were no detectable oligosaccharides or cytoplasmic vacuolation in the liver or spleen. Studies of this possible chimera provided preliminary evidence for the efficacy of prenatal treatment of early‐onset neurodegenerative disorders.
Mucolipidosis IV fibroblasts synthesize normal amounts of hyaluronic acid
Authors: Goldin E. , Imai Y. , Kaneski C. R. , Pentchev P. G. , Brady R. O. , Hascall V. C. 
Published: November 2004

SummaryMucolipidosis IV (ML IV) (McKusick 252650) is an autosomal recessive metabolic disorder that displays signs of both lipid and mucopolysaccharide (glycosaminoglycan) storage. It has been reported that fibroblasts from ML IV patients exhibit abnormally high synthesis of hyaluronic acid in culture. In our search for a biochemical marker that will enable positive identification of ML IV, we studied glycosaminoglycan synthesis in fibroblast cultures from patients with this disease. ML IV and normal control fibroblasts were incubated with [3H]glucosamine and [35S]sulphate. Labelled glycosaminoglycans were extracted from the cell layer and medium. Chondroitin sulphate and hyaluronic acid were determined by analysis of disaccharides after digestion with chondroitinase ABC. Synthesis of neither of these two glycosaminoglycans differed significantly between control and ML IV fibroblasts. Synthesis of hyaluronic acid was nearly linear for 24 h, with mean calculated values of 11.7 ± 1.4 and 14.4 ± 1.6 pg/cell per 24 h in control and ML IV cultures respectively. The variability within the two groups is attributed primarily to population variability and possibly to culture density. These experiments exclude the possibility that a general metabolic defect in hyaluronic acid synthesis is responsible for the ML IV phenotype, nor can such a defect be used as a diagnostic tool for the disease.
Menstrual cycle and gonadal steroid effects on symptomatic hyperammonaemia of urea‐cycle‐based and idiopathic aetiologies
Authors: Grody W. W. , Chang R. J. , Panagiotis N. M. , Matz D. , Cederbaum S. D. 
Published: November 2004

SummaryWe report two female patients, one with a known inborn error of ureagenesis and the other of unknown cause, in whom recurrent, transient episodes of severe hyperammonaemia increased in frequency and severity with sexual maturity and parturition. Both responded to ovarian steroids administered continuously to suppress ovulation and menstruation, and ultimately to simple hysterectomy. These studies suggest a new therapeutic approach to defective ureagenesis in female patients and a relationship between ammonia production or disposal and the menstrual cycle.
Characterization of a point mutation in the pyruvate dehydrogenase E1α gene from two boys with primary lactic acidaemia
Authors: Awata H. , Endo F. , Tanoue A. , Kitano A. , Matsuda I. 
Published: November 2004

SummaryWe report here a novel mutation in the codon for amino acid 263 resulting in the change from arginine to glutamine in the pyruvate dehydrogenase (PDH) E1α gene, in two boys with primary lactic acidaemia, from independent families. The mutation changes an amino acid located between the two serine residues which are the sites of phosphorylation of the subunit protein. In one family, the mutation wasde novo and in the other it was transmitted from mother to son. The amino acid substitution may affect function of the PDH complex via phosphorylation and dephosphorylation of the E1α subunit. Derangement in the regulation of activity of the PDH complex may explain the primary lactic acidaemia in the patients.
Increased urine concentration of subunit c of mitochondrial ATP synthase in neuronal ceroid lipofuscinoses patients
Authors: Wisniewski K. E. , Golabek A. A. , Kida E. 
Published: November 2004

SummaryIn searching for an easily available diagnostic test for the neuronal ceroid lipofuscinoses (NCL), we screened urine collected from 8 late‐infantile and 12 juvenile NCL cases, 8 obligate heterozygotes, and 16 controls for the presence of subunit c of mitochondrial ATP synthase. Subunit c is a component of the storage material in brain and other tissues of various forms of NCL, apart from the infantile form. Using Western blot analysis and the ELISA technique, we have found significantly higher levels of subunit c in the urine of late‐infantile and some juvenile patients. This finding may have clinical application in developing a diagnostic test for NCL.
Phytanic acid α‐oxidase deficiency (Refsum disease) presenting in infancy
Authors: Herbert M. A. , Clayton P. T. 
Published: November 2004

SummaryThis report describes a patient with high serum phytanic acid concentration due to phytanic acid α‐oxidase deficiency (classical Refsum disease). He presented unusually early, hypotonia and developmental delay being apparent by 7 months. A generalized peroxisomal disorder (so‐called ‘infantile Refsum disease’) was excluded by analyses of pristanic acid, very long‐chain fatty acids, bile acids and plasmalogen synthesis. The early presentation raises the possibility ofin utero exposure to phytanate.
Cerebrospinal fluid amino acids, purines and pyrimidines as a tool in the study of metabolic brain diseases
Authors: Gerrits G. P. J. M. , Monnens L. A. H. , Gabreëls F. J. M. , De Abreu R. A. , Koster A. , Trijbels J. M. F. 
Published: November 2004

SummaryAfter establishing more extended reference values for amino acids, purines and pyrimidines in cerebrospinal fluid (CSF) in infancy and childhood, we studied 1250 CSF‐aliquots from patients who were undergoing a diagnostic lumbar puncture for diverse clinical indications. Our primary aim was to answer the question whether determination of the concentration of amino acids, purines and pyrimidines in CSF is a useful tool in screening for metabolic disorders in children with unexplained mental retardation.In unexplained mental retardation (95 patients) we observed varying abnormalities of CSF. These were reproducible in only 2 patients (a decrease of homocarnosine in combination with two unidentified compounds). Striking abnormalities in pyrimidine content which are limited to CSF are found in argininosuccinic aciduria and uraemia. In uraemia a general decrease in amino acids in CSF and increase of γ‐aminobutyric acid (GABA) was observed.The results obtained indicate that determination of amino acids, purines and pyrimidines in CSF is only of limited value in the diagnosis of unexplained mental retardation.
The inherited leukodystrophies: A clinical overview
Authors: Aicardi J. 
Published: November 2004

SummaryThe leukodystrophies are degenerative diseases that involve primarily the white matter of the brain. The most common leukodystrophies result from known disturbances in the synthesis or catabolism of myelin such as a block in the catabolism of sulphatides and of galactocerebrosides, respectively, in metachromatic leukodystrophy and in Krabbe disease, or from synthesis of an abnormal proteolipid protein in Pelizaeus‐Merzbacher disease. The cause of white matter involvement in other leukodystrophies remains unknown even though metabolic anomalies, such as accumulation of acetylaspartic acid in Canavan disease, have been demonstrated.Common clinical features of the leukodystrophies include neurological deterioration following a period of normal development, predominant involvement of motor function at least initially, and absence of convulsions or myoclonus. Imaging — especially magnetic resonance — shows changes in density or signal from central white matter.Most leukodystrophies feature suggestive symptoms and signs such as effects on peripheral nerves' myelin in Krabbe disease and metachromatic leukodystrophy, or X‐linked inheritance and slow deterioration in Pelizaeus‐Merzbacher disease.Therapy of the leukodystrophies is purely symptomatic in most cases. Trials of bone marrow transplantation are being pursued for metachromatic leukodystrophy and adrenoleukodystrophy.
Canavan disease: Biochemical and molecular studies
Authors: Matalon R. , Kaul R. , Michals K. 
Published: November 2004

SummaryDeficiency of the enzyme aspartoacylase and the accumulation ofN‐acetylaspartic acid lead to a severe leukodystrophy and spongy degeneration of the brain, Canavan disease (McKusick 271900). Since our discovery in 1988 of the defect in Canavan disease, 144 patients with Canavan disease have been diagnosed in our laboratory. Most of these children are of Ashkenazi Jewish extraction. The level of enzyme activity can be used for carrier testing. Prenatal diagnosis has been difficult using the enzyme assay owing to the low activity of aspartoacylase in cultured chorionic villus samples or amniocytes. The determination ofN‐acetylaspartic acid in the amniotic fluid is another parameter for diagnosis; however, the levels may not always be elevated.Bovine and human aspartoacylase have been purified in our laboratory. Bovine and human cDNA and genomic clones have been isolated and six exons have been localized. This information is being used for the study of Canavan disease at the molecular level.
Inborn errors and demyelination: MRI and the diagnosis of white matter disease
Authors: Kendall B. E. 
Published: November 2004

SummaryThe progress and extent of myelination can be assessed using magnetic resonance imaging (MRI). Myelination is delayed or diminished in several inherited metabolic abnormalities presenting in early life. Only minimal myelination of the CNS occurs in Pelizaeus‐Merzbacher disease. Dysmyelination tends to produce fairly symmetrical lesions affecting white matter. In many mitochondrial enzyme and some lysosomal defects, the grey matter is also involved. The appearances and in particular the distribution on MRI and/or CT are characteristic in some conditions and the diagnosis is limited in others. Demyelination due to inflammatory disorders typically causes multifocal white matter lesions, recurrent in multiple sclerosis, monophasic in acute disseminated encephalomyelitis, extending in progressive multifocal leukoencephalopathy and classically involving the pons or corpus callosum in myelinolysis. Hypoxic ischaemic lesions may be metabolically induced and simulate primary demyelinating disorders. Mitochondrial enzyme defects in particular may present with stroke‐like appearances. In many of these conditions, diagnosis is biochemical, but imaging has a significant role in suggesting the diagnosis, and documenting progression, response to therapy or complications.