bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutational analyses in four Japanese families with X‐linked liver phosphorylase kinase deficiency type 1
Authors: Hirono H. , Shoji Y. , Takahashi T. , Sato W. , Takeda E. , Nishijo T. , Kuroda Y. , Nishigaki T. , Inui K. , Takada G. 
Published: December 2002

AbstractWe analysed the gene of the human α‐subunit of liver phosphorylase kinase (PHKA2) in four Japanese families with X‐linked liver phosphorylase kinase deficiency type 1 by RT‐PCR followed by PCR–single‐strand conformation polymorphism and direct DNA sequencing. In this study, two novel mutations (Y116D and 2675A→G) and one mutation previously reported (P1205L) were identified, revealing molecular heterogeneity in Japanese patients. Considering the dissimilarity in phenotype among our patients even with an identical mutation in the PHKA2 gene, it seems that each genetic deficiency in this gene may not be the only factor to determine the clinical heterogeneity in this disease.
Biochemical monitoring of the treatment in paediatric patients with mitochondrial disease
Authors: Artuch R. , Vilaseca M. A. , Pineda M. 
Published: December 2002

AbstractTreatment strategies in mitochondrial diseases consist of several drugs that diminish the deleterious effects of the abnormal respiratory chain function, reduce the presence of toxic agents or correct deficiencies in essential cofactors. In this study we evaluated the monitoring of tocopherol, carnitine and ubiquinone concentrations in a group of paediatric patients during a follow‐up period of 18 months and the response to treatment of these patients by means of the determination of blood lactate, plasma alanine and oxygen consumption by lymphocytes in relation to the clinical status of the patients. Tocopherol, carnitine and ubiquinone concentrations were easily corrected with therapy. Blood lactate proved the best biochemical tool to assess the response to treatment in paediatric patients. According to our results, improvement or stabilization of the clinical course seems to be more related to the biochemical or molecular defect than to the effectiveness of the treatment.
4‐Aminobutyrate aminotransferase (GABA‐transaminase) deficiency
Authors: Medina‐Kauwe L. K. , Tobin A. J. , De Meirleir L. , Jaeken J. , Jakobs C. , Nyhan W. L. , Gibson K. M. 
Published: December 2002

Abstract4‐Aminobutyrate aminotransferase (GABA‐transaminase, GABA‐T, EC 2.6.1.19) deficiency (McKusick 137150), an inborn error of GABA degradation, has until now been documented in only a single Flemish child. Compared to the other defects of GABA degradation, succinic semialdehyde dehydrogenase (SSADH, EC 1.2.1.24) deficiency with >150 patients (McKusick 271980) and pyridoxine‐dependent seizures with >100 patients ('putative'glutamic acid decarboxylase (GAD, EC 4.1.1.15) deficiency; McKusick 266100), GABA‐T deficiency is very rare. We present a summary of the clinical, biochemical, enzymatic and molecular findings on the index proband, and a recently identified second patient, with GABA‐T deficiency. The phenotype in both included psychomotor retardation, hypotonia, hyperreflexia, lethargy, refractory seizures and electroencephalographic abnormalities. In an effort to elucidate the molecular basis of GABA‐T deficiency, we isolated and characterized a 1.5kb cDNA encoding human GABA‐T, in addition to a 41kb genomic clone which encompassed the GABA‐T coding region. Standard methods of cloning and sequencing revealed an A‐to‐G transition at nucleotide 754 of the coding region in lymphoblast cDNAs derived from the index proband. This mutation resulted in substitution of an invariant arginine at amino acid 220 by lysine. Expression of the mutant in E. coli, followed by isolation and enzymatic characterization of the recombinant protein, revealed an enzyme whose Vmax was reduced to 25% of wild‐type activity. The patient and father were heterozygous for this allele; the second allele in the patient remains unidentified. Genomic Southern analysis revealed that the second proband most likely harbours a deletion in the 3′region of the GABA‐T gene.
Spinal muscular atrophy
Authors: Talbot K. 
Published: December 2002

AbstractSpinal muscular atrophy is a common cause of disability in childhood and is characterized by weakness and wasting of voluntary muscle. It is frequently fatal. The gene for this disorder has been identified as the SMN gene and is part of a highly complex duplicated region of chromosome 5 that is subject to a high rate of gene deletion and gene conversion. The severity of muscle weakness correlates with the amount of full‐length SMN protein produced. Molecular genetic studies support a model in which patients are compound heterozygotes of deleted and converted alleles that predicts a progressively decreasing amount of protein product with severity of muscle weakness. The function of SMN is beginning to be understood and it appears to be involved in ribonucleoprotein biogenesis and thus indirectly in post‐transcriptional processing of mRNA. There are theoretical grounds for motor neurons having a cell‐specific vulnerability to disturbances of mRNA processing and transport and these are briefly reviewed.
Chloramphenicol and Ampicillin-Induced Changes in Rat Hepatic Esterase and Amidase Activities
Authors: Farombi E. Olatunde , Nwankwo Joseph O. , Wara Sanusi H. , Odutola Bankole , Emerole Godwin O. 
Published: December 2002

The influence of ampicillin and chloramphenicol administered intraperitoneallysingly or in combination on the protein content and the activities of hepaticsterase and amidase have been investigated in rats. The results have beencompared to the effects of phenobarbitone (inducer) andp-nitrophenyl-phosphate (inhibitor) of hepatic hydrolases.
Ampicillin pretreatment reduced protein level and amidase activity by3.5% each but caused a significant increase (8.1%) in total esteraseactivity compared to controls. Chloramphenicol treatment caused an overalldecrease in protein level, esterase and amidase activities respectively by11%, 11%, and 35% over controls.
Combined administration of both drugs resulted in a decrease in protein,esterase and amidase activities by 11.5%, 12.5%, and 41.2% respectively,thus mimicking the effects obtained with chloramphenicol alone.
The changes induced by administration of the drugs particularly incombination on the constituent enzymes of rat hepatic hydrolases may affectthe ability of the body to deal with exposure to environmental chemicals ifextrapolated to man.
Long‐term outcome of liver transplantation in patients with glycogen storage disease type Ia
Authors: Faivre L. , Houssin D. , Valayer J. , Brouard J. , Hadchouel M. , Bernard O. 
Published: December 2002

AbstractLiver transplantation may be indicated in patients with GSD type Ia when dietary treatment fails or when hepatic adenomas develop, because they carry a risk of liver cancer or severe intratumoral haemorrhage. Published reports on the results of liver transplantation in patients with GSD Ia include 10 patients and provide little information on long‐term outcome. In particular, it is not known whether liver transplantation prevents renal failure due to focal segmental glomerulosclerosis. We report here on 3 patients with GSD Ia in whom liver transplantation was performed at 15, 17 and 23 years of age because of multiple hepatic adenomas in all 3 patients with a fear of malignant transformation, and of poor metabolic balance and severe growth retardationin the youngest one. Renal function was normal in all patients. During the 6–8 years following transplantation, the quality of life has initially greatly improved, with none of the previous dietary restraints and a spectacular increase in height. However, long‐term complications included chronic hepatitis C in one patient, gouty attacks in another and focal segmental glomerulosclerosis with progressive renal insufficiency in the third. These results: (1) confirm that liver transplantation restores a normal metabolic balance in patients with GSD Ia, allows catch‐up growth and improves the quality of life; (2) suggest that liver transplantation may be considered in teenagers with unresectable multiple adenomas because of a lack of clear‐cut criteria to detect malignant transformation early; and (3) suggest that liver transplantation does not prevent focal segmental glomerulosclerosis associated with GSD Ia.
Recognition and management of fatty acid oxidation defects: A series of 107 patients
Authors: Saudubray J. M. , Martin D. , De Lonlay P. , Touati G. , Poggi‐Travert F. , Bonnet D. , Jouvet P. , Boutron M. , Slama A. , Vianey‐Saban C. , Bonnefont J. P. , Rabier D. , Kamoun P. , Brivet M. 
Published: December 2002

AbstractIn a personal series of 107 patients, we describe clinical presentations, methods of recognition and therapeutic management of inherited fatty acid oxidation (FAO) defects. As a whole, FAO disorders appear very severe: among the 107 patients, only 57 are still living. Including 47 siblings who died early in infancy, in total 97 patients died, of whom 30% died within the first week of life and 69% before 1 year. Twenty‐eight patients presented in the neonatal period with sudden death, heart beat disorders, or neurological distress with various metabolic disturbances. Hepatic presentations were observed in 73% of patients (steatosis, hypoketotic hypoglycaemia, hepatomegaly, Reye syndrome). True hepatic failure was rare (10%); cholestasis was observed in one patient with LCHAD deficiency. Cardiac presentations were observed in 51% of patients: 67% patients presented with cardiomyopathy, mostly hypertrophic, and 47% of patients had heart beat disorders with various conduction abnormalities and arrhythmias responsible for collapse, near‐miss and sudden unexpected death. All enzymatic blocks affecting FAO except CPT I and MCAD were found associated with cardiac signs. Muscular signs were observed in 51% of patients (of whom 64% had myalgias or paroxysmal myoglobinuria, and 29% had progressive proximal myopathy). Chronic neurologic presentation was rare, except in LCHAD deficiency (retinitis pigmentosa and peripheral neuropathy). Renal presentation (tubulopathy) and transient renal failure were observed in 27% of patients. The diagnosis of FAO disorders is generally based on the plasma acylcarnitine profile determined by FAB‐MS/MS from simple blood spots collected on a Guthrie card. Urinary organic acid profile and total and free plasma carnitine can also be very helpful, mostly in acute attacks. If there is no significant disturbance between attacks, the diagnosis is based upon a long‐chain fatty acid loading test, fasting test, and in vitro studies of fatty acid oxidation on fresh lymphocytes or cultured fibroblasts. Treatment includes avoiding fasting or catabolism, suppressing lipolysis, and carnitine supplementation. The long‐term dietary therapy aims to prevent periods of fasting and restrict long‐chain fatty acid intake with supplementation of medium‐chain triglycerides. Despite these therapeutic measures, the long‐term prognosis remains uncertain.
The neuronal ceroid‐lipofuscinoses (Batten disease): A new class of lysosomal storage diseases
Authors: Bennett M. J. , Hofmann S. L. 
Published: December 2002

AbstractThe neuronal ceroid‐lipofuscinoses (Batten disease) are a group of severe neurodegenerative disorders characterized clinically by visual loss, seizures and psychomotor degeneration, and pathologically by loss of neurons and lysosomal accumulation of autofluorescent storage material resembling ageing pigment. To date, eight genetic loci have been identified (CLN1‐8). Four CLN genes have been isolated (CLN1, CLN2, CLN3 and CLN5) and their gene products have been characterized. CLN1 is a lysosomal palmitoyl‐protein thioesterase (PPT) and CLN2 is a lysosomal pepstatin‐insensitive peptidase. CLN3 and CLN5 are proteins with multiple membrane‐spanning regions and have no homologies to other proteins that would suggest their function. The CLN3 protein is associated with lysosomal membranes and the intracellular location of the CLN5 protein is unknown. Therefore, there is ample evidence that the neuronal ceroid‐lipofuscinoses represent a new class of lysosomal storage disorders.
A rapid screening procedure for the diagnosis of peroxisomal disorders: Quantification of very long‐chain fatty acids, as dimethylaminoethyl esters, in plasma and blood spots, by electrospray tandem mass spectrometry
Authors: Johnson D. W. 
Published: December 2002

AbstractA rapid method with potential to screen for many of the peroxisomal disorders using 5μl of plasma or a 3‐mm blood spot (3.6μl blood impregnated on filter paper) is described. Fatty acids are liberated from plasma or blood spots and converted to dimethylaminoethyl esters. Trideuterated fatty acids, added as internal standards, are used to quantify eicosanoic (C20:0), docosanoic (C22:0), tetracosanoic (C24:0) and hexacosanoic (C26:0) acids by electrospray tandem mass spectrometry. The C26:0/C22:0 and C24:0/C22:0 ratios are significantly greater in the plasma of patients with peroxisomal disorders compared to controls. The C20:0/C22:0 ratio is elevated in the plasma of peroxisomal patients who accumulate phytanic acid. Blood spots collected from four peroxisomal patients between 2 and 10 days after birth and stored for up to 17 years, were shown to give between 33% and 233% higher C26:0/C22:0 ratios compared to age‐matched controls.
Differentiation of hair growth cycle from scalp hair roots for the diagnosis of glucose‐6‐phosphate dehydrogenase deficiency in neonates
Authors: Lin S.‐Y. , Niu D.‐M. , Li M.‐J. , Tu C.‐P. , Lin H.‐L. 
Published: December 2002

AbstractHair analysis can be used as a screening tool in the diagnosis of genetic diseases. The scalp hair roots of 67 normal neonates and 39 neonates with glucose‐6‐phosphate dehydrogenase (G6PD) deficiency were analysed using Fourier transform infrared (FT‐IR) microspectroscopy to differentiate the stages of the hair growth cycle and to diagnose the genetic disorder on the basis of spectral differences. We have demonstrated that FT‐IR microspectroscopy is a rapid and effective noninvasive diagnostic method to differentiate scalp hair roots of normal neonates into the anagen, catagen or telogen phases of the hair growth cycle, using IR spectral differences within the 3000–2800 cm−1 region and the IR peak area ratio of 2854 cm−1/2873 cm−1 or 1084 cm−1/amide II band (p<0.001). Moreover, G6PD‐deficient neonates could be accurately diagnosed from telogen phase hair roots owing to significant differences in IR peak area ratios of 2854 cm−1/2873 −1 or 1084 cm−1/amide II band compared to normal values in healthy neonates. The result suggests that the application of FT‐IR microspectroscopy may be capable not only of differentiating the hair growth cycle into anagen, categen or telogen phases but also of detecting G6PD deficiency. Hair root analysis promises to be a useful complement to serum and urine analysis in the diagnosis of genetic diseases.
Sequence variations in the NDUFA1 gene encoding a subunit of complex I of the respiratory chain
Authors: Wittig I. , Augstein P. , Brown G. K. , Fujii T. , Rötig A. , Rustin P. , Munnich A. , Seibel P. , Thorburn D. , Wissinger B. , Tamboom K. , Metspalu A. , Lamantea E. , Zeviani M. , Wehnert M. S. 
Published: December 2002

AbstractNDUFA1 is one of the 36 nuclear genes encoding subunits of the mitochondrial complex I involved in the respiratory chain. The human NDUFA1 has been cloned, completely sequenced and mapped to Xq24. In the present study, we searched for sequence variations in NDUFA1 as causative defects in complex I deficiency using genomic DNA of 152 patients with various clinical phenotypes. The patient sample consisted of 54 patients (46 male and 8 female) with Leber heriditary optic neuropathy (LHON) from 48 unrelated families from Germany and 98 patients (72 male and 26 female) with biochemically proven complex I deficiency including Leigh syndrome. Patient DNA was used to amplify all three exons, including the exon/intron boundaries and the promoter region of NDUFA1 for heteroduplex analysis and direct sequencing. In the 152 patients tested, no mutation was found that could be related to any of the disease phenotypes included. However, three single‐nucleotide polymorphisms (SNPs) located in the promoter region (SNP G/C at nt −71 and SNP T/C at nt −189) and in intron 1 (SNP T/G nt 1454) were discovered. Allele frequencies of the SNPs were estimated in a German and Estonian control population and compared to complex I‐deficient patients. There was no significant difference between the control population, the LHON patients, or the severely affected patients with complex I deficiency, excluding an association of the polymorphisms with the diseases. Our results suggest that mutations in NDUFA1 do not cause the gender difference observed in clinically severe and complex phenotypes with complex I deficiency.
Dietary therapy in two patients with a mild form of sulphite oxidase deficiency. Evidence for clinical and biological improvement
Authors: Touati G. , Rusthoven E. , Depondt E. , Dorche C. , Duran M. , Heron B. , Rabier D. , Russo M. , Saudubray J. M. 
Published: December 2002

AbstractWe report an attempt at dietetic therapy in two unrelated patients with isolated sulphite oxidase deficiency, with a mild clinical course and late onset of symptoms. In case 1, disease started at 15 months with an acute crisis of agitation, unexplained crying and restlessness following otitis. Case 2 was diagnosed at 10 months when she presented with slight motor delay and dislocation of lenses. In both cases, sulphite oxidase activity measured in fibroblasts was undetectable. Therapy consisted of a diet low in protein from natural foods (daily methionine intake 130–150 mg) and a synthetic amino acid mixture (50 g per day) without cystine and methionine (Xmet, Cys Maxamaid, SHS International Ltd). A comparison of clinical and biochemical parameters was made between the period before treatment and after 2 years of treatment. Restriction in protein and sulphur amino acids brought about a dramatic decrease of urinary thiosulphate and S‐sulphocysteine. It also brought about a generalized hypoaminoacidaemia with a low plasma methionine and cystine in both patients. Furthermore, both patients grew normally with no signs of neurological deterioration, and there was evidence of progress in psychomotor development.
Pharmacological and genetic modifications of somatic cholesterol do not substantially alter the course of CNS disease in Niemann–Pick C mice
Authors: Erickson R. P. , Garver W. S. , Camargo F. , Hossian G. S. , Heidenreich R. A. 
Published: December 2002

AbstractNiemann–Pick type C (NPC) is a neurodegenerative disorder with somatically altered cholesterol metabolism. The NPC1 gene has recently been cloned and shown to have sequences shared with known sterol‐sensing proteins. We have used a mouse model with a disrupted Npc1 gene to study two cholesterol‐lowering drugs (nifedipine and probucol) and the effects of introducing a null mutation in the low‐density lipoprotein receptor (LDLR). Although these treatments significantly ameliorated liver cholesterol storage, little effect on the onset of neurological symptoms was found.
Three cases of intravenous sodium benzoate and sodium phenylacetate toxicity occurring in the treatment of acute hyperammonaemia
Authors: Praphanproj V. , Boyadjiev S. A. , Waber L. J. , Brusilow S. W. , Geraghty M. T. 
Published: December 2002

AbstractIntravenous sodium benzoate and sodium phenylacetate have been used successfully in the treatment of acute hyperammonaemia in patients with urea cycle disorders. They provide alternative pathways for waste nitrogen disposal and help maintain nitrogen homeostasis. However, we report three patients with hyperammonaemia who received inappropriate doses of intravenous sodium benzoate and sodium phenylacetate that resulted in severe complications. Ambiguous medical prescriptions and inadequate cross‐checking of drug dosage by physicians, nurses and pharmacists were the main causes of these incidents. All the patients presented with alteration in mental status, Kussmaul respiration and a partially compensated metabolic acidosis with an increased anion gap. Two patients developed cerebral oedema and hypotension and died. The third survived after haemodialysis. Plasma levels of benzoate and phenylacetate were excessively high. The possible mechanisms of toxicity, management and safety measures are discussed.
Reduction of large neutral amino acid concentrations in plasma and CSF of patients with maple syrup urine disease during crises
Authors: Wajner M. , Coelho D. M. , Barschak A. G. , Araújo P. R. , Pires R. F. , Lulhier F. L. G. , Vargas C. R. 
Published: December 2002

AbstractNeurological dysfunction is common in patients with maple syrup urine disease (MSUD). However, the mechanisms underlying the neuropathology of this disorder are poorly understood. We determined the concentrations of all amino acids in plasma of patients with MSUD during crises (with severe CNS symptoms) and after recovery in the hope of detecting possible alterations of these levels during metabolic decompensation. Blood samples obtained from 11 children with MSUD aged 1 month to 7 years and from 10 age‐matched controls (5 months to 6 years) with no evidence of metabolic disease were examined for their amino acid content by high‐performance liquid chromatography. We observed that leucine, isoleucine and valine concentrations were respectively 30, 9 and 3 times higher than normal values, whereas the concentrations of the large neutral amino acids (LNAA) phenylalanine, tyrosine, tryptophan and methionine were significantly lower during metabolic decompensation as compared to the controls. In addition, concentrations of leucine, but not of valine or isoleucine, were inversely related to the LNAA concentrations in plasma. The concentrations of these amino acids in plasma returned to normal values when patients were clinically well. CSF amino acid concentrations also showed decreased amounts of LNAA and increased concentrations of branched‐chain amino acids. It is possible that the decrease in plasma concentrations of LNAA may lead to a deficit of these essential amino acids in the brain as well as of their products such as proteins and neurotransmitters, a fact that might be related to the neurological dysfunction of MSUD.
Inborn errors of metabolism and pregnancy
Authors: Walter J. H. 
Published: December 2002

AbstractAn increasing number of women with inborn errors of metabolism are now reaching child‐bearing age. For certain disorders there are maternal risks associated with pregnancy. These may be related to an increased likelihood of metabolic decompensation (e.g. disorders of the urea cycle) or to increased stress to systems already compromised by disease (e.g. cardiomyopathy in GSD III). Detrimental effects upon the fetus may also be caused by maternal disease, as occurs with phenylketonuria, or from medication used to treat the mother's condition. Less commonly, fetal inborn errors may adversely effect the mother's health – e.g. fetal long‐chain acyl‐CoA dehydrogenase deficiency and the maternal HELLP syndrome (haemolysis, elevated liver enzymes and low platelets) and AFLP (acute fatty liver of pregnancy). Because of the rarity of individual disorders, our knowledge of risks associated with pregnancy is limited. Even for more common inborn errors such as phenylketonuria, there remain a number of questions that have not been fully answered.