bluuebunny/crossref_metadata_2025_split huggingface dataset:
Missense mutations in codon 225 of ornithine transcarbamylase (OTC) result in decreased amounts of OTC protein: A hypothesis on the molecular mechanism of the OTC deficiency
Authors: García‐Pérez M. A. , Climent C. , Briones P. , Vilaseca M. A. , Rodés M. , Rubio V. 
Published: December 2002

AbstractMutations P225L and P225R were identified in codon 225 of the gene for ornithine transcarbamylase (OTC) in two patients with the neonatal form of OTC deficiency. The mutations occur at a CpG dinucleotide and eliminate a unique MspI restriction site in exon 7 of the OTC gene. They do not alter existing splice sites or create new sites, as judged from the nucleotide sequence. Both mutations are associated with undetectable levels of OTC antigen in liver homogenates, and with either complete lack of OTC activity (P225R mutation) or very small residual activity (0.15% of normal in the P225L mutation). The residual activity observed with P225L exhibits normal pH dependence, little or no increases in the Km values for ornithine and carbamoyl phosphate and normal stability at either 37°C or, in the presence of 0.66 mol/L urea, at 0°C. The latter conditions were used to examine whether the P225L mutation favours dissociation of the active OTC trimer. Given the normal stability and lack of tendency to dissociation of the mutant enzyme, it appears likely that the dramatic reduction in the level of OTC protein is due to inefficient conversion of the mutant OTC precursor polypeptide (pOTC) into the correctly localized, appropriately folded, mature enzyme trimer, suggesting degradation of pOTC in transit to the mitochondria.
Alternative pathway therapy for urea cycle disorders
Authors: Feillet F. , Leonard J. V. 
Published: December 2002

AbstractIn man the major pathway for the disposal of waste nitrogen is the urea cycle; in inborn errors of this pathway, nitrogen flux is reduced. As a result there is accumulation of ammonia and glutamine with disordered metabolism of other amino acids. Nitrogen homeostasis can be restored in these patients with a low‐protein diet combined with compounds that create alternative pathways for nitrogen excretion. The introduction of these compounds has been a major advance in the management of these inborn errors and as a result the outcome, particularly for those treated early, has improved.
Diagnosis and management of glutaric aciduria type I
Authors: Barić I. , Zschocke J. , Christensen E. , Duran M. , Goodman S. I. , Leonard J. V. , Müller E. , Morton D. H. , Superti‐Furga A. , Hoffmann G. F. 
Published: December 2002

AbstractGlutaric aciduria type I (GA1) is a preventable cause of acute brain damage in early childhood, leading to a severe dystonic‐dyskinetic disorder that is similar to cerebral palsy and ranges from extreme hypotonia to choreoathetosis to rigidity with spasticity. Degeneration of the putamen and caudate typically occurs between 6 and 18 months of age and is probably linked to changes in metabolic demand caused by normal maturational changes and superimposed catabolic stress. Recognition of this biochemical disorder before the brain has been injured is essential to outcome. Diagnosis depends upon the recognition of relatively nonspecific physical findings such as hypotonia, irritability and macrocephaly, and on performance of urine organic acid quantification by gas chromatography–mass spectrometry or selective searches of urine or blood specimens by tandem mass spectrometry for glutarylcarnitine. The diagnosis may also be suggested by characteristic findings on neuroimaging. In selected patients diagnosis can only be reached by enzyme assay. Specific current management by the authors of this paper includes pharmacological doses of L‐carnitine, as well as dietary protein restriction. Metabolic decompensation must be treated aggressively to avoid permanent brain damage. Multicentre studies are needed to establish best methods of diagnosis and optimal therapy of this disorder.
Effects of hyperammonaemia on brain function
Authors: Butterworth R. F. 
Published: December 2002

AbstractNeuropsychiatric symptoms of hyperammonaemia include alterations of mood and personality, cognitive impairment, ataxia, convulsions and coma. The nature and severity of CNS dysfunction depend upon the aetiology and degree of hyperammonaemia, its acuteness of onset and the age of the patient. Neuropathological studies reveal Alzheimer type II astrocytosis in the adult hyperammonaemic patient, whereas hyperammonaemia in the infant resulting from congenital urea cycle disorders or Reye syndrome is accompanied by cerebral atrophy, neuronal loss and cerebral oedema. Several electrophysiological and biochemical mechanisms have been proposed to explain the deleterious effects of ammonia on CNS function. Such mechanisms include direct effects of the ammonium ion on excitatory and inhibitory neurotransmission and a deficit in cerebral energy metabolism due to ammonia‐induced inhibition of α‐ketoglutarate dehydrogenase. In addition, ammonia has been shown to interfere with normal processes of uptake, storage and release of various neurotransmitters. Ammonia disrupts monoamine storage, inhibits the high‐affinity uptake of glutamate by both astrocytic and neuronal elements and activates ‘peripheral‐type’ benzodiazepine receptors leading to the potential synthesis of neuroactive steroids in brain. On the basis of these actions, it has been proposed that ammonia disrupts neuron‐astrocyte trafficking of amino acids and monoamines in brain. The increased formation of brain glutamine in hyperammonaemic syndromes could be responsible for the phenomenon of brain oedema in these disorders. Therapies aimed at either decreasing ammonia production in the gastrointestinal tract or increasing ammonia removal by liver or skeletal muscle are the mainstay in the prevention and treatment of the CNS consequences of hyperammonaemia. New therapeutic approaches aimed at correction of the neurotransmitter and cerebral energy deficits in these syndromes could hold promise for the future.
Mutation of ornithine transcarbamylase (H136R) in a girl with severe intermittent orotic aciduria but normal enzyme activity
Authors: Vella S. , Steiner F. , Schlumbom V. , Zurbrügg R. , Wiesmann U. N. , Schaffner T. , Wermuth B. 
Published: December 2002

AbstractOrnithine transcarbamylase deficiency shows X‐linked inheritance with partial dominant expression in carrier females. We studied a girl with intermittent severe orotic aciduria and mild hyperammonaemia despite apparently normal enzyme activity in the liver. Sequence analysis of all 10 exons of the ornithine transcarbamylase gene revealed a novel a → G exchange (A502G) in exon 5 which changes His‐136 to arginine in the ornithine transcarbamylase protein. Km values for carbamyl phosphate and ornithine determined in the patient's liver were comparable to those of wild‐type enzyme but, unlike the wild‐type enzyme, the mutant enzyme was unstable upon freezing and thawing. Electron microscopy revealed several giant mitochondria with paracrystalline inclusions. The results are compatible with the assumption that the mutant enzyme cannot form a functional complex with carbamyl phosphate synthetase and the ornithine carrier, resulting in decreased availability of substrates and diminished enzyme activity in vivo.
The human nuclear‐encoded acyl carrier subunit (NDUFAB1) of the mitochondrial complex I in human pathology
Authors: Triepels R. , Smeitink J. , Loeffen J. , Smeets R. , Buskens C. , Trijbels F. , van den Heuvel L. 
Published: December 2002

AbstractWe present the cDNA sequence of the human mitochondrial acyl carrier protein NDUFAB1, a nuclear‐encoded subunit of complex I of the mitochondrial respiratory chain. We obtained the NDUFAB1 cDNA using the cDNA sequence of the bovine mitochondrial acyl carrier protein. The human cDNA contains two putative translation initiation codons. The human NDUFAB1 protein contains a phosphopantetheine attachment site (DLGLDSLDQVEIIMAM), unique for acyl carrier proteins, and an EF‐hand calcium binding domain (DIDAEKLMCPQEI). Transcripts of this gene are found in a wide range of human tissues. The highest expression levels were observed, in descending order, in adult heart, skeletal muscle and fetal heart. We subjected NDUFAB1 fibroblast cDNA of 20 patients with an isolated enzymatic complex I deficiency to mutational detection. No mutations in the NDUFAB1 open reading frame were observed. Future studies will answer whether mutations in the NDUFAB1 promoter or transcription elements are responsible for the observed complex I deficiency.
Tyrosinaemia type I and NTBC (2‐(2‐nitro‐4‐trifluoromethylbenzoyl)‐1,3‐cyclohexanedione)
Authors: Holme E. , Lindstedt S. 
Published: December 2002

AbstractIn tyrosinaemia type I (McKusick 276700), fatal liver disease results either because of liver failure during infancy or early childhood or because of development of hepatocellular carcinoma during childhood or adolescence. This is caused by toxic metabolites which accumulate because of deficiency of fumarylacetoacetase, the last enzyme in the tyrosine catabolic pathway. NTBC is a potent inhibitor of 4‐hydroxyphenylpyruvate dioxygenase and has been shown to efficiently prevent tyrosine degradation, and production of succinylacetone, in patients with tyrosinaemia. Since the first trial of NTBC treatment for tyrosinaemia type I in 1991, over 220 patients have been treated by the drug using a protocol which includes regular follow‐up with reports of clinical and laboratory investigations to the study centre in Gothenburg, where additional analysis of critical variables is done on regularly collected samples. The course of the disease in patients with acute tyrosinaemia has changed dramatically. Only 10% of the patients have not clinically responded to NTBC treatment. In half of these patients, successful liver transplantation has been performed which has further reduced the mortality rate during infancy to 5%. The international NTBC study has now been going for 5 years and data have emerged that indicate a decreased risk for early development of hepatocellular carcinoma in patients who started treatment at an early age. There are now 101 patients aged 2–8 years who have started NTBC treatment before 2 years of age, and no cancer has developed after 2 years of age among these patients. However, there is no safe age with respect to occurrence of liver cancer, which has been recognized at diagnosis at 1 year of age in one patient and after a few months of treatment in an infant who was given NTBC at 5 months of age.
3‐Methylglutaconic aciduria type I: Clinical heterogeneity as a neurometabolic disease
Authors: Shoji Y. , Takahashi T. , Sawaishi Y. , Ishida A. , Matsumori M. , Shoji Ya. , Enoki M. , Watanabe H. , Takada G. 
Published: December 2002

Abstract3‐Methylglutaconic (3‐MGC) aciduria with 3‐methylglutaconyl‐CoA hydratase deficiency (3‐MGC aciduria type I) is a rare inherited metabolic disease of L‐leucine catabolism. We describe a 9‐month‐old Japanese boy with this disorder who showed progressive neurological impairments presented as quadriplegia, athetoid movements and severe psychomotor retardation from 4 months of age. This finding indicates the existence of clinical heterogeneity in 3‐MGC aciduria type I, suggesting it may present as a neurometabolic disease.
Murine mucopolysaccharidosis type VII: The impact of therapies on the clinical course and pathology in a murine model of lysosomal storage disease
Authors: Vogler C. , Sands M. S. , Galvin N. , Levy B. , Thorpe C. , Barker J. , Sly W. S. 
Published: December 2002

AbstractMurine mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by a recessively inherited deficiency of the lysosomal enzyme β‐glucuronidase. Affected mice have clinical, biochemical and pathological findings similar to those seen in humans with MPS VII (Sly syndrome), including growth retardation, facial dysmorphism, deafness, behavioural deficits and widespread glycosaminoglycan storage in lysosomes in the viscera, skeleton and brain. This mouse model is a useful tool for the evaluation of the effectiveness and experimental therapies for the MPS disorders. Syngeneic bone marrow transplantation performed in newborn MPS VII animals – before clinical evidence of disease is pronounced – prolongs life, improves hearing and bone growth, and prevents lysosomal storage in many sites, but does not correct the central nervous system disease. Enzyme therapy with β‐glucuronidase from the first days of life does reduce lysosomal storage in the brain in murine MPS VII. The enzyme‐replaced mice also have reduced visceral lysosomal storage, impressive normalization of their phenotype and an improved life span. The effectiveness of gene therapy for the treatment of lysosomal storage disease has also been tested using the MPS VII model. When transplanted into MPS VII mice, syngeneic haematopoietic stem cells or mouse skin fibroblasts infected with retrovirus expressing β‐glucuronidase decreased storage, but only in the liver and spleen. Injection of an adenovirus vector expressing β‐glucuronidase into the vitreous of the MPS VII mice reduced storage in the retinal pigment epithelium and corneal endothelium. Intravenous administration of the adenovirus vector transduced with the β‐glucuronidase gene reduced liver and spleen storage and, when instilled into the cerebral ventricles, this viral vector caused β‐glucuronidase production in epithelial cells lining the ventricles. Recently, retroviral vector‐corrected MPS VII fibroblasts secreting high levels of β‐glucuronidase were engrafted directly into the brains of adult MPS VII mice with resultant reduction in storage in neurons and glia adjacent to the grafts. Future efforts aimed at prolonging expression of the β‐glucuronidase gene by viral vectors and more precisely directing the therapeutic effect to the skeleton and brain will be important in optimizing treatments for murine MPS VII and extending the results of such therapies to humans with MPS.
Compromised fatty acid oxidation in mitochondrial disorders
Authors: Hagenfeldt L. 
Published: December 2002

AbstractMeasurement of palmitate oxidation by the tritium release method in cultured fibroblasts or in lymphocytes detects patients with mitochondrial β‐oxidation disorders and in addition many patients with dysfunction of the respiratory chain. The clinical presentation and studies of metabolite levels in serum and urine are valuable in the differential diagnosis between these two groups of disorders.
4,5‐Dimethyl‐3‐hydroxy‐2[5H]‐furanone (sotolone) — The odour of maple syrup urine disease
Authors: Podebrad F. , Heil M. , Reichert S. , Mosandl A. , Sewell A. C. , Böhles H. 
Published: December 2002

AbstractMaple syrup urine disease is an autosomal recessive inherited disorder of branched‐chain amino acid metabolism due to deficiency of the branched‐chain α‐keto acid dehydrogenase complex. The disease was originally named after the characteristic sweet aroma, reminiscent of maple syrup, present in the body fluids of affected patients. Until now, the substance responsible for the odour has not been positively identified. Using enantioselective multidimensional gas chromatography‐mass spectrometry (enantio‐MDGC‐MS), we could demonstrate that 4,5‐dimethyl‐3‐hydroxy‐2[5H]‐furanone (sotolone), a well‐known flavour impact compound present in fenugreek and lovage, was present in urine from seven patients with maple syrup urine disease. Urine samples from healthy control persons lacked sotolone. We have shown that sotolone is responsible for the characteristic odour of maple syrup urine disease and, since maple syrup also contains sotolone, the naming of this disease appears to be correct.
The human NADH:ubiquinone oxidoreductase NDUFS5 (15kDa) subunit: cDNA cloning, chromosomal localization, tissue distribution and the absence of mutations in isolated complex I‐deficient patients
Authors: Loeffen J. , Smeets R. , Smeitink J. , Triepels R. , Sengers R. , Trijbels F. , van den Heuvel L. 
Published: December 2002

AbstractWe have cloned the cDNA of the NDUFS5 subunit (15 kDa) of the human mitochondrial respiratory chain complex NADH:ubiquinone oxidoreductase (complex I). The open reading frame consists of 321 base‐pairs, coding for 106 amino acids, with a calculated molecular mass of 12.5 kDa. There is an 81.0% identity with the bovine equivalent on cDNA level and 74.5% identity on amino acid basis. PCR analysis of rodent–human somatic cell hybrids revealed that the human NDUFS5 gene maps to chromosome 1. The NDUFS5 mRNA is expressed ubiquitously in human tissues, with a relative higher expression in human heart, skeletal muscle, liver, kidney and fetal heart. A mutation detection study of twenty isolated enzymatic complex I‐deficient patients revealed no mutations, nor polymorphisms.
Dietary management of long‐chain 3‐hydroxyacyl‐CoA dehydrogenase deficiency (LCHADD). A case report and survey
Authors: Gillingham M. , Van Calcar S. , Ney D. , Wolff J. , Harding C. 
Published: December 2002

AbstractCurrent dietary management of long‐chain 3‐hydroxyacyl‐CoA dehydrogenase (LCHAD; long‐chain‐(S)‐3‐hydroxyacyl‐CoA:NAD+ oxido‐reductase, EC 1.1.1.211) deficiency (LCHADD) is based on avoiding fasting, andminimizing energy production from long‐chain fatty acids. We report the effects of various dietary manipulations on plasma and urinary laboratory values in a child with LCHADD. In our patient, a diet restricted to 9% of total energy from long‐chain fatty acids and administration of 1.5g medium‐chain triglyceride oil per kg body weight normalized plasma acylcarnitine and lactate levels, but dicarboxylic acid excretion remained approximately ten times normal. Plasma docosahexaenoic acid (DHA, 22:6n−3) was consistentlylow over a 2‐year period; DHA deficiency may be related to the development of pigmentary retinopathy seen in this patient population. We also conducted a survey of metabolic physicians who treat children with LCHADD to determine current dietary interventions employed and the effects of these interventions on symptoms of this disease. Survey results indicate that a diet low in long‐chain fatty acids, supplemented with medium‐chain triclyceride oil, decreased the incidence of hypoketotic hypoglycaemia, and improved hypotonia, hepatomegaly, cardiomyopathy, and lactic acidosis. However, dietary treatment did not appear to effect peripheral neuropathy, pigmentary retinopathy or myoglobinuria.
Homocystinuria due to cystathionine β‐synthase deficiency in Ireland: 25 years' experience of a newborn screened and treated population with reference to clinical outcome and biochemical control
Authors: Yap S. , Naughten E. 
Published: December 2002

AbstractHomocystinuria (HCU) due to cystathionine β‐synthase deficiency (Mudd et al 1964) was independently described by Gerritsen and colleagues (USA) and Carson and colleagues (Northern Ireland) in 1962. The worldwide frequency of HCU has been reported as 1 in 344 000, while that in Ireland is much higher at 1 in 65 000, based on newborn screening and cases detected clinically. The national newborn screening programme for HCU in Ireland was started in 1971 using the bacterial inhibition assay. A total of 1.58 million newborn infants have been screened over a 25‐year period up to 1996. Twenty‐five HCU cases were diagnosed, 21 of whom were identified on screening. The remaining four HCU cases were missed and presented clinically; three of these were breast‐fed and one was pyridoxine responsive. Twenty‐four HCU cases were pyridoxine nonresponsive. Once the status of pyridoxine responsiveness was identified, all pyridoxine nonresponsive cases, but one, were started on a low methionine, cystine‐enhanced diet supplemented with pyridoxine, vitamin B12 and folate. Dietary treatment commenced within 6 weeks of birth (range 8–42 days) for those cases detected by screening, while for the late‐detected cases treatment was started upon presentation and diagnosis. Biochemical control was monitored measuring deproteinized plasma methionine, free homocystine and cystine at least once a month. Review of the clinical outcome of the 25 HCU cases with 365.7 patient‐years of treatment revealed no HCU‐related complications in 18 screened, dietary‐treated cases. Fifteen of these had lifetime medians of free homocystine ≤11 μmol/L (range 4–11). The remaining three cases with higher lifetime medians of free homocystine (18, 18 and 48 μmol/L) have developed increasing myopia recently. Among the three screened non‐dietary‐compliant cases, two have ectopia lentis, one has osteoporosis and two have mental handicap. Of the four cases missed on screening, three presented with ectopia lentis after the age of 2 years. There were no thromboembolic events in any of the 25 HCU cases. The lifetime medians for methionine ranged from 47 to 134 μmol/L. The Irish HCU clinical outcome data suggest that newborn screening, early commencement of dietary treatment and a lifetime median of free homocystine of ≤11 μmol/L had significantly reduced the probability of developing complications when it was compared to the untreated HCU data (Mudd et al 1985).
Cholesterol and oxygenated cholesterol concentrations are markedly elevated in peripheral tissue but not in brain from mice with the Niemann–Pick type C phenotype
Authors: Tint G. S. , Pentchev P. , Xu G. , Batta A. K. , Shefer S. , Salen G. , Honda A. 
Published: December 2002

AbstractNiemann–Pick disease type C (NP‐C) is a rare genetic disorder characterized by progressive neurodegeneration, frequent developmental delay and early death. Tissues of affected individuals accumulate large quantities of free cholesterol in lysosomes. Because cytotoxic oxygenated derivatives of cholesterol are known to form readily when cholesterol concentrations are elevated, we searched for these compounds in liver, kidney, spleen and brain from mice with the NP‐C phenotype. In order of abundance, we identified 7α‐ and 7β‐hydroxycholesterol, 5α,6α‐epoxycholestan‐3β‐ol, 4β‐hydroxycholesterol, cholest‐4‐en‐3β,7α‐diol and cholest‐4‐en‐3β,6β‐diol in most tissue samples. Cholesterol concentrations in affected mice were increased 3‐fold in kidney and 7‐ to 8‐fold in spleen and liver compared to controls (all p<0.001) but were unchanged in brain. Although oxysterol levels were markedly elevated in non‐brain tissue, the oxysterol and cholesterol concentrations increased proportionally so that oxysterols expressed as percentage of total sterols were the same for all animals (0.34±0.19% averaged over all organs in affected animals vs 0.40±0.42% in control mice). In contrast to peripheral tissue, we could not detect any increase in either absolute or relative oxysterol levels in the brains of affected and control mice (49±61 vs 53±43 μg/g wet weight and 0.45±0.52 vs 0.47±0.37%, respectively). Thus, brain sterols are normal in NP‐C mice and it is unlikely that an accumulation of cytotoxic oxygenated derivatives of cholesterol could account for the progressive neuropathology seen in the disease.