bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lysosomal enzyme activities in serum and leukocytes from patients with carbohydrate‐deficient glycoprotein syndrome type IA (phosphomannomutase deficiency)
Authors: Barone R. , Carchon H. , Jansen E. , Pavone L. , Fiumara A. , Bosshard N. U. , Gitzelmann R. , Jaeken J. 
Published: December 2002

AbstractFrom 10 patients with carbohydrate‐deficient glycoprotein (CDG) syndrome due to phosphomannomutase (PMM) deficiency, out of 10 lysosomal enzymes, 7 enzyme activities were measured in serum and 9 in leukocytes. In serum there was a 2‐fold to 4‐fold increase in activity of β‐glucuronidase, β‐hexosaminidase, β‐galactosidase, and arylsulphatase A. In leukocytes, however, several enzymes had reduced activity, particularly α‐fucosidase, β‐glucuronidase and α‐mannosidase. These abnormalities could result from missorting, defective reuptake and/or reduced stability of the enzymes due to the defective glycosylation.
Succinic semialdehyde dehydrogenase deficiency: low excretion of metabolites in a neonate
Authors: Pitt J. J. , Hawkins R. , Cleary M. , Eggington M. , Thorburn D. R. , Warwick L. 
Published: December 2002

AbstractA neonate at risk for succinic semialdehyde dehydrogenase deficiency was investigated on day 1. The urine level of 4‐hydroxybutyrate was only slightly elevated (23 µmol/mmol of creatinine; controls 1.6‐14, n=18). This value was considerably less than those found for older children with succinic semialdehyde dehydrogenase deficiency and made interpretation of the result uncertain. The diagnosis of succinic semialdehyde dehydrogenase deficiency was confirmed by enzyme assay, and repeat urine testing showed a steady increase in the level of 4‐hydroxybutrate to 359 µmol/mmol at 6 months.
Clinical heterogeneity and prognosis in combined methylmalonic aciduria and homocystinuria (cblC)
Authors: Rosenblatt D. S. , Aspler A. L. , Shevell M. I. , Pletcher B. A. , Fenton W. A. , Seashore M. R. 
Published: December 2002

AbstractThe clbC form of methylmalonic acidaemia is a rare and poorly understood condition which results from impaired biosynthesis of methylcobalamin and adenosylcobalamin. The consequent functional deficiencies of methylmalonyl‐CoA mutase and methionine synthase produce both methylmalonic aciduria and homocystinuria. Systemic symptoms and neurological decompensation comprise the clinical phenotype. In an effort to clarify the phenotype and prognosis, we obtained clinical information on 50 patients with methylmalonic acidaemia whose cells had been assigned to the cblC complementation group. We identified two distinct phenotypes; they differed in age of onset, presence of systemic symptoms, type of neurological symptoms, and outcome after diagnosis and treatment. Forty‐four patients presented in the first year of life. Feeding difficulties, neurological dysfunction (hypotonia, seizures, developmental delay), and ophthalmological and haematological abnormalities characterized their clinical picture. About one‐quarter of those patients died. Survival was associated with neurological impairment; only one infant was neurologically intact at follow‐up. Onset in childhood, in contrast, was associated with less severe haematological abnormalities, largely involving the red cell series. Extrapyramidal signs, dementia, delirium or psychosis characterized the neurological findings. Survival, with mild to moderate disability in some, was typical in patients with later onset. Treatment in both groups included hydroxycobalamin, betaine and carnitine; complete normalization of biochemical parameters was rare.
A longitudinal study of cognitive functioning in patients with classical galactosaemia, including a cohort treated with oral uridine
Authors: Manis F. R. , Cohn L. B. , McBride‐Chang C. , Wolff J. A. , Kaufman F. R. 
Published: December 2002

AbstractExisting longitudinal data on patients with classical galactosaemia suggests that neurocognitive functioning is impaired and, in isolated case reports, may show a decline in performance over time. The present study explored whether there are long‐term changes in cognitive abilities in patients with galactosaemia and whether oral uridine can improve neurocognitive performance. Thirty‐five patients (18 males, 17 females), 29 of whom received oral uridine powder at 150 mg/kg per day (divided dose, three times daily), were evaluated over a 2‐5‐year period with the Woodcock‐Johnson Revised Cognitive Abilities Test, three academic achievement tests, and the Beery Test of Visual Motor Integration. Results showed that the uridine cohort and a comparison group that received only dietary restriction made small gains in cognitive performance over the treatment period and the size of the gains did not differ significantly. Seven subjects who started uridine prior to the age of 14 months did not differ significantly in their cognitive test scores at an average age of 3.5 years from a group of older children who had begun treatment at 4.5 years of age. These results provide no support for any developmental or uridine‐treatment‐related change in cognitive functioning for this sample of galactosaemic subjects.
Identification of a common mutation (R245H) in Sanfilippo A patients from the Netherlands
Authors: Weber B. , van de Kamp J. J. P. , Kleijer W. J. , Guo X.‐H. , Blanch L. , van Diggelen O. P. , Wevers R. , Poorthuis B. J. H. M. , Hopwood J. J. 
Published: December 2002

AbstractWe have identified a common mutation (R245H) in the sulphamidase gene of Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA, MPS IIIA) patients from The Netherlands. Allele‐specific oligonucleotide hybridization was used to determine the incidence of this mutation in 45 unrelated MPS IIIA patients from different regions of The Netherlands. R245H was present in 51 alleles, representing 56.7% of the total allelic population. Of 39 patients, for whom we have uniform clinical details, 13 MPS IIIA patients who were homozygous for this common mutation had a more uniform but severe clinical phenotype than the remaining 21 or 5 patients, containing respectively one or no R245H alleles. The R245H allele had a higher prevalence in western rather than eastern regions of The Netherlands.
Human α‐galactosidase A: High plasma activity expressed by the ‐30G→A allele
Authors: Fitzmaurice T.F. , Desnick R.J. , Bishop D.F. 
Published: December 2002

AbstractHuman α‐galactosidase A (EC 3.2.1.22; α‐Gal A) is the lysosomal exoglycosidase responsible for the hydrolysis of terminal α‐galactosyl residues from glycoconjugates and is the defective enzyme causing Fabry disease (McKusick 301500). An unsually elevated level of plasma α‐Gal A activity (>2.5 times the normal mean) was detected in two unrelated normal males and the elevated activities were inherited as X‐linked traits in their families. Sequencing of the α‐Gal A coding region, intron/exon boundaries and 5′‐flanking region from the proband identified a single mutation, a G→A transition 30 nt upstream from the initiation of translation codon in exon 1. The ‐30G→A mutation occurred in a putative NFκB/Ets consensus binding site that was recently shown to inhibit protein binding to the 5′‐untranslated region of the gene, providing a possible explanation for its high activity. To further characterize the mutation, the mRNA and protein expressed by this variant allele were studied. Purified plasma and lymphoblast α‐Gal A activity from individuals with the ‐30G→A mutation had normal physical and kinetic properites. In vitro translation of mRNAs from the cloned normal and high plasma activity alleles resulted in similar levels of α‐Gal A protein, indicating that this mutation did not enhance translation. These findings suggest that the ‐30G→A mutation in the 5′‐untranslated region of the α‐Gal A gene enhances transcription, presumably by interfering with the binding of negatively‐acting transcription factors which normally decrease α‐Gal A expression in various cells. Preliminary studies of the frequency of the ‐30G→A mutation in 395 unrelated normal males of mixed ancestry revealed two additional unrelated individuals who had high plasma enzymatic activity and the mutation, confirming the effect of this mutation on enzyme expression and suggesting that about 0.5% of normal individuals have high plasma α‐Gal A activity due to this variant allele.
The association between haematological manifestation and mtDNA deletions in Pearson syndrome
Authors: Muraki K. , Nishimura S. , Goto Y. , Nonaka I. , Sakura N. , Ueda K. 
Published: December 2002

AbstractWe studied the proportion of deleted mitochondrial DNA in blood cells from patients with Pearson syndrome. Patient 1 is a 17‐year‐old female with Kearns‐Sayre syndrome who survived Pearson syndrome. Patient 2 is a 5‐year‐old boy with Pearson syndrome who recovered from refractory anaemia but continues to have thrombocytopenia and neutropenia. Patient 3 is a female neonate who died with severe acidosis and pancytopenia at 14 days of age. Southern blot analysis was performed with total DNA from three patients' blood cells and two samples of bone marrow cells from one patient. In peripheral blood, patients with a higher proportion of deleted mitochondrial DNA had lower blood cell counts. In patient 2, the percentage of mutant mitochondrial DNA in bone marrow cells decreased as anaemia improved. This indicates that the proportion of deleted mitochondrial DNA in peripheral blood and in bone narrow has a tendency to correlate to the severity of haematological manifestation.
Pregnancy in a woman with maple syrup urine disease
Authors: Grÿnewald S. , Hinrichs F. , Wendel U. 
Published: December 2002

AbstractWe present the favourable outcome of a pregnancy in a woman with maple syrup urine disease. Keeping the maternal plasma levels of the branched‐chain amino acids between 100 and 300 µmol/L is compatible with delivery of a normal infant. Leucine tolerance increased progressively from the 22nd week of gestation from 350 to 2100 mg/day. The risk of metabolic decompensation in the postpartum period can be minimized by careful monitoring of the mother after delivery.
Fulminant Leigh syndrome and sudden unexpected death in a family with the T9176C mutation of the mitochondrial ATPase 6 gene
Authors: Dionisi‐Vici C. , Seneca S. , Zeviani M. , Fariello G. , Rimoldi M. , Bertini E. , De Meirleir L. 
Published: December 2002

AbstractWe report an Italian family in which the T‐to‐C point mutation at nucleotide 9176 of the mitochondrial adenosine triphosphate synthetase (mtATPase) 6 gene is associated with an early‐onset fulminant form of Leigh syndrome and with sudden unexpected death in two siblings, respectively. Polymerase chain reaction single‐strand conformation polymorphism (PCR‐SSCP) analysis and direct sequencing revealed that the mutation was homoplasmic in mitochondrial DNA of the proband. The T9176C mutation changes a highly conserved leucine to a proline in subunit 6 of the mtATPase gene and is maternally inherited, but the maternal relatives are asymptomatic. This point mutation was initially described in two brothers with bilateral striatal necrosis, a milder variant of Leigh syndrome.
The allopurinol load test lacks specificity for primary urea cycle defects but may indicate unrecognized mitochondrial disease
Authors: Bonham J. R. , Guthrie P. , Downing M. , Allen J. C. , Tanner M. S. , Sharrard M. , Rittey C. , Land J. M. , Fensom A. , O'Neill D. , Duley J. A. , Fairbanks L. D. 
Published: December 2002

AbstractThirty‐three children ranging from 2 weeks to 12 years of age were selected for allopurinol loading, 16 on the basis of an increased urinary orotate excretion detected by routine organic acid analysis (group A), and 17 for clinical reasons suggesting a urea cycle defect (group B). The allopurinol load test proved positive in 13 of 16 patients from group A, mean peak orotate 64.0μmol/mmol creatinine (upper limit of reference range, 13.2) and 11 of 17 patients from group B, mean peak orotate 41.0μmol/mmol creatinine (upper limit of reference range, 13.2). Thorough investigation of these patients including urinary and plasma amino acid analysis and, in 17 cases, liver biopsy for histology and measurement of ornithine carbamyltransferase (OCT) and carbamyl‐phosphate synthetase (CPS) activity failed to identify any evidence of a urea cycle disorder. However, muscle biopsies performed in 11 patients showed some evidence of mitochondrial disease in four cases, two defined on the basis of reduced respiratory chain enzyme activity and two on the basis of mtDNA abnormalities. These findings indicate that an increased excretion of orotate in sick children may not be uncommon and that a positive allopurinol load test result may not indicate a specific inherited urea cycle defect. In addition, these results raise the interesting possibility that defective ureagenesis may be a feature of mitochondrial disease in some individuals.
Glycosphingolipid degradation and animal models of GM2‐gangliosidoses
Authors: Kolter T. , Sandhoff K. 
Published: December 2002

AbstractGlycosphingolipids form cell type‐specific patterns on the surface of eukaryotic cells. Degradation of glycosphingolipids requires endocytic membrane flow of plasma membrane‐derived glycosphingolipids into the lysosomes as the digesting organelles. The inherited deficiencies of lysosomal hydrolases and of sphingolipid activator proteins both give rise to sphingolipid storage diseases. Recent research has focused on the mechanisms leading to selective membrane degradation in the lysosomes and on the mechanism and physiological function of sphingolipid activator proteins. The GM2‐degrading system is a paradigm for activator protein‐dependent lysosomal degradation. Three polypeptide chains contribute to the in vivo degradation of ganglioside GM2: the α‐ and β‐chains of the β‐hexosaminidases and the GM2 activator. Mouse models of Tay–Sachs disease (α‐chain deficiency), Sandhoff disease (β‐chain deficiency) and GM2 activator deficiency have been described. While the phenotypes of these variants of GM2‐gangliosidoses are only slightly different in humans, the animal models show drastic differences in severity and course of the diseases. The reason for this is the specificity of sialidase, which is different between mouse and human. A double‐knockout mouse lacking β‐hexosaminidases A, B and S shows a phenotype of mucopolysaccharidosis and gangliosidosis. A substrate deprivation approach to therapy is discussed with respect to animal models of the GM2‐gangliosidoses.
Diagnosis of isovaleric acidaemia by tandem mass spectrometry: False positive result due to pivaloylcarnitine in a newborn screening programme
Authors: Abdenur J. E. , Chamoles N. A. , Guinle A. E. , Schenone A. B. , Fuertes A. N. J. 
Published: December 2002

AbstractTandem mass spectrometric analysis of acylcarnitines and amino acids has been applied in newborn screening programmes for the detection of several inborn errors of metabolism. We report a false positive result for isovaleric acidaemia in a newborn screening programme using this method. The newborn screening sample showed a very prominent signal corresponding to the mass of isovalerylcarnitine. Repeat samples (age 6 days) of blood and urine showed similar results. However, urine organic acids were normal. Acylcarnitine analysis in blood, breast milk and urine of the mother also showed a prominent signal of the same mass. Gas chromatography–mass spectrometry of the methyl esters demonstrated that the signal in the patient's urine was due to the presence of pivaloylcarnitine, which is isomeric with isovalerylcarnitine. The patient's mother was receiving an antibiotic containing a derivative of pivalic acid to treat a urinary tract infection. Follow‐up samples in the patient and the mother confirmed a decrease in the levels of pivaloylcarnitine, concomitant with the discontinuation of the treatment.We conclude that pivaloylcarnitine can give a false positive result for isovaleric acidaemia in newborns whose mothers are on treatment with pivoxilsulbactam‐containing antibiotics.
Hunter disease in the Spanish population: Molecular analysis in 31 families
Authors: Gort L. , Chabás A. , Coll M. J. 
Published: December 2002

AbstractMucopolysaccharidosis type II (Hunter disease) is an X‐linked disorder due to deficiency of the lysosomal enzyme iduronate 2‐sulphatase. Here we report an update of molecular studies in 31 Spanish families with Hunter disease. We found a total of 22 novel small mutations (7 reported previously by our group), and 4 large deletions or rearrangements. Particularly relevant are two mutations, one showing an alternatively spliced product although the normal splice site is conserved; the other mutation results in an amino acid change that most likely modifies regulation of expression of the IDS gene. Except for large gene alterations and for the G374sp mutation already described, we could not establish a clear phenotype–genotype correlation. Mutation G374sp is the point mutation most frequent in our population (10%) and is always associated with mild phenotype. Our molecular analyses carried out in a relatively large series of patients with Hunter disease contribute to the identification of new mutations and reinforce the conclusions drawn in other populations about the genotype–phenotype correlation and the gene distribution of mutations.
Severe skeletal complications in Japanese patients with type 1 Gaucher disease
Authors: Ida H. , Rennert O. M. , Kato S. , Ueda T. , Oishi K. , Maekawa K. , Eto Y. 
Published: December 2002

AbstractTo better characterize skeletal complications in Japanese patients with type 1 Gaucher disease (GD), we performed genotyping and clinical and radiological analysis of 35 patients, the vast majority of this population, Skeletal complications tend to be very common, severe and rapidly progressive in Japanese patients with type 1 GD. Twenty (57%) of these patients manifested end points of severe bone disease including avascular necrosis, pathological fracture and/or bone crisis. Mean time from presentation/diagnosis of GD until presentation of this involvement was 3 years 6 months±4 years 1 month. Prevalence of severe bone disease is significantly higher in splenectomized than in non‐splenectomized patients – 81% (17/21) versus 21% (3/14) (p=0.0007, Fisher's exact test). Four (29%) of 14 patients receiving enzyme replacement therapy (ERT) or bone marrow transplantation (BMT) manifested severe bone involvement for the first time during or after treatment. All cases occurred in children in whom ERT doses had been lowered after only brief administration of higher starting doses (n=3) or partial donor marrow engraftment resulted in low glucocerebrosidase (GCR) activity (n=1). These observations suggest that splenectomy may correlate with accelerated skeletal deterioration with severe skeletal disease, at least in patients with severe phenotypic expression. They also suggest that it is important that sufficient GCR is available in paediatric patients with severe phenotypic expression. Hence ERT dosages should be based on disease severity and on age, with sustained administration of full doses in patients at greater risk of important skeletal complications.
Variables influencing parental perception of inherited metabolic diseases before and after genetic counselling
Authors: Saleem R. , Gofin R. , Ben‐Neriah Z. , Boneh A. 
Published: December 2002

AbstractThe present study was undertaken to characterize the variables that influence parental perception of metabolic disorders and their genetic origin before and after genetic counselling, the effect of counselling on parental attitudes towards prenatal diagnosis and pregnancy termination, and the factors affecting parental coping with burden.Parents of children with metabolic diseases from 32 Arab‐Muslim families were interviewed, answering a pre‐structured questionnaire. These interviews indicate the following. (1) Traditional belief and religious commitment are more important determinants than education in parental perception of inherited metabolic diseases. (2) The number of affected children has a greater impact on parental evaluation of the burden than the number of healthy children. The social component, i.e. the way families are viewed by society, is the most significant factor of the burden. (3) Parents use different techniques to divide responsibility regarding reproduction. Having a healthy child and the availability of prenatal diagnosis and pregnancy termination were the two most important factors in parental reproductive decision making. In the absence of a healthy child and when the burden was perceived as too heavy, parents tended ‘not to decide’. (4) Parental attitude to pregnancy termination was dependent on two factors: religious commitment (leading to objection) and severity of disease (leading to flexibility and approval). (5) In almost all families, genetic counselling altered parental perception of the disease and its hereditary origin.We conclude that genetic counselling and population education may be helpful in the prevention of consanguineous marriages and in family planning, even in a society that values traditional beliefs very highly.
Pilot study of screening for Wilson disease using dried blood spots obtained from children seen at outpatient clinics
Authors: Ohura T. , Abukawa D. , Shiraishi H. , Yamaguchi A. , Arashima S. , Hiyamuta S. , Tada K. , Iinuma K. 
Published: December 2002

AbstractWilson disease (WD) is an autosomal recessive disorder of copper accumulation leading to liver and/or brain damage. In this paper, we describe the results of a pilot study of screening for WD using ceruloplasmin determinations in dried blood samples. Specimens were collected from children aged 1 to 6 years who were seen at local paediatric outpatient clinics in the Miyagi Prefecture. We measured ceruloplasmin (CP) concentrations in 2789 children using an enzyme‐linked immunosorbent assay. The mean value was 12.4±3.95 mg/dl blood. Among these children, we identified two (case 1, male, 2 years old; case 2, female, 3 years old) with markedly reduced CP concentrations. Apart from low serum copper concentrations, their biochemical findings were almost normal, as were growth and development. To confirm the diagnosis, we analysed the WD gene and detected A803T/2871delC mutations in case 1 and R778L/G1035V mutations in case 2. We conclude that these children were presymptomatic WD patients. The CP level in dried blood samples from children aged 1 to 6 years appears to be a reliable marker for early detection of WD.
Therapeutic trials in the murine model of hereditary tyrosinaemia type I: A progress report
Authors: Grompe M. , Overturf K. , Al‐Dhalimy M. , Finegold M. 
Published: December 2002

AbstractWe have studied a knockout mouse with fumarylacetoacetate hydrolase (FAH) deficiency as a model of human hereditary tyrosinaemia type I (HT1). These mice have a phenotype very similar to the human disease, which is characterized by acute hepatic failure, renal tubular disease and hepatocarcinoma. We have previously reported on the efficacy of 2‐(2‐nitro‐4‐trifluoromethylbenzyol)‐1,3‐cyclohexanedione (NTBC) in preventing acute liver disease in HT1 mice. Here we present a progress report on long‐term follow up (>1 year) of high‐dose NTBC therapy in combination with tyrosine restriction. In vivo retroviral gene therapy was also effective in abolishing the acute liver failure of HT1. Retrovirally treated mice remained completely healthy and active for 12 months after retroviral gene transfer. However, hepatocarcinoma developed in 2/3 treated animals after 1 year. Southern blot analysis showed that the tumours did not arise from retrovirally transduced hepatocytes but from non‐corrected FAH‐deficient cells. These results highlight the extreme danger for tumour formation in HT1 and indicate the need for improved gene therapy that leads to the elimination of endogenous FAH‐deficient liver cells.