bluuebunny/crossref_metadata_2025 huggingface dataset:
The Relation of Perceived Neighborhood Danger to Childhood Aggression: A Test of Mediating Mechanisms
Authors: Colder Craig R. , Mott Joshua , Levy Susan , Flay Brian
Published: December 2002

In the current study, two mediational mechanisms, parenting practices and children's beliefs about aggression, were hypothesized to account for the relationship between perceived neighborhood danger and childhood aggression. Using structural equation modeling, data were analyzed from an inner‐city school‐based sample of 732 predominantly African American 5th graders. Results suggested that perceived neighborhood danger was associated with strong positive beliefs about aggression, which in turn was associated with high levels of aggression. The hypothesized mediating role of parenting practices (restrictive discipline, parental monitoring, and parental involvement) on the relation between perceived neighborhood danger and child aggression was not supported. However, the current findings suggest that children's positive beliefs about aggression mediated the relationship between restrictive discipline and aggression. Directions for future research are discussed.
Investing in Children, Families, and Communities: Challenges foran Interdivisional Public Policy Collaboration
Authors: Solarz Andrea L.
Published: December 2002

An interdivisional collaboration to foster the development of strengths‐based policies for children, youth, families, and communities is described. The initiative includes (1) producing a book that integrates scholarly research and policy; (2) developing materials for policymakers to use, including a policy‐oriented summary of the book; (3) enhancing the capacities of the divisions to communicate with and influence policymakers; and (4) taking action steps to influence policymakers. During the process of developing these products, a number of tensions emerged between the academically‐based and policy‐based authors of the book, many of which centered around how the information should be presented and, in particular, how to formulate and present policy recommendations. Tensions fell into four general categories: understanding the appropriate scope for recommendations, using the right language, understanding the kind of information that is needed, and understanding the bottom line. The author concludes by urging psychologists to become adept at understanding and participating in the public policymaking process.
Transforming Community Psychology
Authors: Riger Stephanie
Published: December 2002

Community psychology has made great strides in including context when understanding people in their environments. While continuing to consider context, we need to expand our conceptualization of the individual in community settings. I propose 3 principles: (1) focus our research on people, not programs; (2) consider multiple dimensions of people's experience; and (3) conceptualize people as agentic and not simply as reactors to the environmental press. I illustrate those principles with research on domestic violence and welfare reform. In doing so, I call attention both to the way in which aspects of people's lives intersect with community settings, and to the embeddedness of people's lives (and community settings) in larger social structures.
Dextromethorphan in nonketotic hyperglycinaemia: metabolic variation confounds the dose‐response relationship
Authors: Arnold G. L. , Griebel M. L. , Valentine J. L. , Koroma D. M. , Kearns G. L.
Published: December 2002

Nonketotic hyperglycinaemia (NKH) is an inborn error of the glycine cleavage system resulting in seizures and mental retardation. Two prior reports noted an anticonvulsant effect from high‐dose dextromethorphan (DM) in this disorder, although the two reported patients demonstrated widely disparate DM requirements and drug levels. We report two children with NKH who also demonstrated disparate and variable DM metabolism which markedly influenced the dose‐concentration‐response relationship. Levels of DM and its primary metabolite dextrorphan (DX) were utilized to guide DM therapy and exhibited patterns reflective of the extensive and poor metabolizer phenotypes for CYP2D6, the cytochrome P450 isoform responsible for DM metabolism. In the patient who appeared to represent the extensive metabolizer (EM) phenotype, treatment with the non‐specific cytochrome P450 inhibitor cimetidine was required to reduce biotransformation of DM to DX and, thus, to increase DM plasma concentrations. In the patient with the apparent poor metabolizer (PM) phenotype, a change in the DM preparation to a sustained‐release form and increase in the dosing interval was required to lower DM plasma concentrations. These cases demonstrate the importance of CYP2D6 phenotype in providing safe and effective DM therapy to patients with NKH.
Hepatic porphyrias in children
Authors: Elder G. H.
Published: December 2002

Clinically overt hepatic porphyria is uncommon in children. The autosomal dominant acute hepatic porphyrias, acute intermittent porphyria (AIP), variegate porphyria (VP) and hereditary coproporphyria (HCP), are rarely present before puberty. Identification of asymptomatic children who have inherited these disorders is an important aspect of the management of the disease in their families and requires either enzymatic or DNA methods. Homozygous variants of AIP, VP and HCP usually present in early childhood and have phenotypes of variable severity. Mutational analysis is currently elucidating the relationship between these disorders and their autosomal dominant counterparts. 5‐Aminolaevulinate dehydratase deficiency porphyria is a rare, autosomal recessive acute porphyria that may present at any age. Two cutaneous hepatic porphyrias are seen in children. Porphyria cutanea tarda (PCT), although mainly an adult disease, has been reported in young children with the autosomal dominant (type II) form of the disorder. Hepatoerythropoietic porphyria usually develops before the age of 2 years; patients are homo‐ or heteroallelic for uroporphyrinogen decarboxylase mutations, at least one of which is known to cause type II PCT.
Biochemical characterization of the S135L allele of galactose‐1‐phosphate uridylyltransferase associated with galactosaemia
Authors: Wells L. , Fridovich‐Keil J. L.
Published: December 2002

Impairment of the human enzyme galactose‐1‐phosphate uridylyltransferase (GALT) results in the potentially lethal disorder galactosaemia. The S135L mutation, which accounts for almost 50% of the GALT alleles in galactosaemia patients of African‐American descent, has been associated with activities ranging from null to wild‐type by different investigators examining cell lysates representing different tissues or model systems. Because of the crude nature of the lysates examined, however, and the absence of quantitative measures concerning GALT abundance in most of those lysates, the available data do not distinguish between differences in GALT enzyme expression/abundance, specific activity, or kinetic constants in these different tissues or systems. In an effort to overcome this uncertainty and investigate the biochemical impact of the S135L substitution on human GALT function under defined conditions, we have overexpressed both wildtype and S135L‐mutant GALT sequences in a null‐background yeast expression system, and purified both proteins to near homogeneity. Abundance of the wild‐type and mutant proteins in crude yeast lysates differed by ~2‐fold. Kinetic studies of the purified proteins, however, demonstrated that although Km values differed by <2‐fold, specific activities differed by 10‐fold. Temperature‐activity profiles revealed no significant differences, and coprecipitation studies demonstrated that S135L‐hGALT subunits remained competent to self‐associate in vivo. We conclude that the S135L substitution causes either steric or electrochemical changes sufficiently close to the active site in human GALT to result in partial impairment of the transferase reaction.
Liver transplantation for the treatment of urea cycle disorders
Authors: Whitington P. F. , Alonso E. M. , Boyle J. T. , Molleston J. P. , Rosenthal P. , Emond J. C. , Millis J. M.
Published: December 2002

The principal goal of therapy when liver transplantation is used for the treatment of metabolic disease is to correct the metabolic error. By doing so, liver transplantation eliminates the hepatic and peripheral consequences of the error. Inborn errors involving the urea cycle appear on theoretical grounds to be amenable to treatment using liver transplantation and, indeed, published data demonstrate that this approach to therapy can be successful. The purpose of this study is to examine the outcome of liver transplantation done for the indication of urea cycle defects in a large group of patients. The first goal of the study is to determine with certainty that liver transplantation corrects hyperammonaemia and halts the progress of disease. A second goal is to determine the extent of neurological recovery in children previously injured by hyperammonaemia. The final goal is to understand whether the quality of life is improved and medical expense is reduced by transplantation. The study involved a survey of major transplantation centres. Four centres provided data about 16 patients, 14 of whom were alive 11 months to 6 years after transplantation. The results demonstrate that liver transplantation resulted in correction of hyperammonaemia in all patients. The neurological outcome after transplantation correlated closely with the condition prior to transplantation. This population of patients has had relatively few problems in the long term related to the liver transplant itself. The quality of life seems to be much improved, but further study will be needed to confirm this. Limited data involving two patients show a reduction in the cost of care. We conclude from our experience that liver transplantation can be an effective treatment for children with urea cycle defects.
Evaluation of gene therapy for citrullinaemia using murine and bovine models
Authors: Patejunas G. , Lee B. , Dennis J. A. , Healy P. J. , Reeds P. J. , Yu H. , Frazer M. , Mull B. , Warman A. W. , Beaudet A. L. , O'Brien W. E.
Published: December 2002

Citrullinaemia is an autosomal recessive disorder caused by the deficiency of argininosuccinate synthase. The deficiency of this enzyme results in an interruption in the urea cycle and the inability to dispose of excess ammonia derived from the metabolism of protein. The only treatment for this disorder has been dietary restriction of protein and supplementation with medications allowing for alternative excretion of excess nitrogen. Gene therapy offers the possibility of a long‐term cure for disorders like citrullinaemia by expressing the deficient gene in the target organ. We have explored the use of adenoviral vectors as a treatment modality for citrullinaemia in two animal models, a naturally occurring bovine model and a murine model created by molecular mutagenesis. Mice treated with adenoviral vectors expressing argininosuccinate synthase lived significantly longer than untreated animals (11 days vs 1 day); however, the animals did not exhibit normal weight gain during the experiment, indicating that the therapeutic effectiveness of the transducing virus was suboptimal. It is speculated that part of the failure to observe better clinical outcome might be due to the deficiency of arginine. In the bovine model, the use of adenoviral vectors did not result in any change in the clinical condition of the animals or in the level of plasma ammonia. However, the use of15N isotopic ammonia allowed us to assess the flux of nitrogen through the urea cycle during the experiment. These studies revealed a significant increase in the flux through the urea cycle following administration of adenoviral vectors expressing argininosuccinate synthase. We conclude that the use of adenoviral vectors in the treatment of citrullinaemia is a viable approach to therapy but that it will be necessary to increase the level of transduction and to increase the level of enzyme produced from the recombinant viral vector. Future experiments will be designed to address these issues.
Mitochondrial abnormalities of liver in two children with citrullinaemia
Authors: Zamora S. A. , Pinto A. , Scott R. B. , Parsons H. G.
Published: December 2002

Citrullinaemia is a rare inborn error of urea‐cycle metabolism. Two affected children are reported in whom progressive metabolic instability suggested the possibility of hepatopathy or an ongoing hepatic mitochondrial injury. A percutaneous liver biopsy was performed in each patient. Electron‐microscopic findings were similar in both cases. Approximately 20% of the mitochondria were abnormally enlarged with paracrystalline inclusions and electron‐dense bodies of different sizes and shapes present in the matrix. The specificity of these findings is discussed in the context of previous reports of ultrastructural abnormalities in the hepatocytes of patients with inborn errors of the urea cycle. It is speculated that the mitochondrial abnormalities in citrullinaemia may be related to the accumulation of citrulline in the mitochondria which may eventually manifest as metabolic instability.
Kennedy disease
Authors: Fischbeck K. H.
Published: December 2002

Kennedy disease is a disorder with progressive motor neuron degeneration that is caused by trinucleotide repeat expansion in the androgen receptor gene. The disease mechanism likely involves toxicity of an expanded polyglutamine tract in the androgen receptor protein. This mechanism is probably shared by other neurodegenerative disorders with polyglutamine expansion, including Huntington disease. Attempts at reproducing the Kennedy disease phenotype by introducing the expanded androgen receptor into cultured neuronal cells and transgenic animals have thus far been unsuccessful, but recently developed model systems with other expanded polyglutamine constructs should allow the pathogenesis of these diseases to be elucidated.
Primary adrenal insufficiency in a child with a mitochondrial DNA deletion
Authors: Bruno C. , Minetti C. , Tang Y. , Magalhães P. J. , Santorelli F. M. , Shanske S. , Bado M. , Cordone G. , Gatti R. , DiMauro S.
Published: December 2002

Mitochondrial disorders can affect any organ system, but certain tissues, such as skeletal muscle, heart, and brain are more susceptible to oxidative phosphorylation defects because of their high energy requirements. Endocrinological manifestations, especially diabetes mellitus, are common but they rarely dominate the clinical picture. We describe a 5‐year‐old girl who died of primary adrenal insufficiency with a mitochondrial disease. Biochemical studies in muscle showed decreased respiratory chain enzyme activities. We detected a novel 7.0 kb mtDNA deletion in muscle from the proband, but not in her mother's white blood cells. Our findings further enlarge the spectrum of clinical presentation associated with mitochondrial DNA deletions.
Long‐chain polyunsaturated fatty acids in plasma and erythrocyte membrane lipids of children with phenylketonuria after controlled linoleic acid intake
Authors: Pöge A. P. , Bäumann K. , Müller E. , Leichsenring M. , Schmidt H. , Bremer H. J.
Published: December 2002

It has been reported that children with classical phenylketonuria (PKU) have reduced levels of arachidonic acid (AA, 20:4 n–6) and docosahexaenoic acid (DHA, 22:6 n–3) in plasma and membrane phospholipids compared to controls and may therefore require supplementation. However, it is not established that these changes are specific for PKU. They may as well be attributed to the specific composition of a largely vegetarian diet used for dietary PKU treatment. We therefore investigated the fatty acid composition of plasma phospholipids (PL), plasma cholesterol esters (CE), red blood cell phosphatidylcholine (PC), and red blood cell phosphatidylethanolamine (PE) in two groups of PKU patients including 8 children between 1 and 6 years (group A), 9 adolescents between 11 and 18 years (group B), and 20 age‐matched healthy controls. Group A had good dietary control (median plasma phenylalanine 272 μmol/L during the last 6 months before phospholipid analysis) while median phenylalanine in group B was 714 μmol/L (p<0.001). When compared to age‐matched controls, group A showed significantly lower DHA levels in PE (4.21 vs 5.85 weight% (wt%), p<0.01), in PC (1.02 vs 1.25 wt%, p<0.05) and in CE (0.25 vs 0.54 wt%, p<0.05). There was no significant difference of DHA between group B and controls. AA levels were similar in phospholipids of all groups. We conclude that reduced levels of long‐chain polyunsaturated fatty acids in PKU patients occur only in those patients with strict dietary therapy with respect to n–3 fatty acids, most probably caused by reduced intake of n–3 fatty acids.
Clinical heterogeneity and molecular mechanisms in inborn muscle AMP deaminase deficiency
Authors: Gross M.
Published: December 2002

Lack of the muscle‐specific isoform of AMP deaminase (myoadenylate deaminase deficiency) can cause a metabolic myopathy, with exercise‐induced muscle symptoms such as early fatigue, cramps and/or myalgia. It is the most common muscle enzyme defect in man, found in about 2‐3% of all muscle biopsies. The genetic basis of the inherited defect is the nonsense mutation C34‐T in the AMPD1 gene encoding myoadenylate deaminase. The mutation results in a premature stop of the enzyme synthesis. In a healthy German population, the frequency of the mutant allele was 0.1, and 1 % of this population is expected to be homozygous for the mutation. In people with muscle symptoms, the allele frequency was significantly higher (0.145). The correlation between allele frequency and muscle symptoms underscores the clinical significance of this defect. However, the vast majority of homozygous subjects do not develop a metabolic myopathy. This clinical heterogeneity may be due to molecular genetic factors such as alternative splicing of the exon harbouring the mutation, or due to metabolic conditions such as pathways compensating for the defect. The real basis for the high percentage of asymptomatic homozygous subjects remains to be revealed.
The effect of fasting, long‐chain triglyceride load and carnitine load on plasma long‐chain acylcarnitine levels in mitochondrial very long‐chain acyl‐CoA dehydrogenase deficiency
Authors: Costa C. G. , Dorland L. , Tavares de Almeida I. , Jakobs C. , Duran M. , Poll‐The B. T.
Published: December 2002

We studied a 10‐year‐old patient with very long‐chain acyl‐CoAdehydrogenase (VLCAD) deficiency who was originally (mis)diagnosed ashaving systemic carnitine deficiency. He was subjected to a fasting test, a long‐chain triglyceride (LCT) loading test (1.5 g/kg) and an intravenous carnitine clearance test (0.25 μmol/kg per min). Plasma acylcarnitines were analysed using a quantitative GC‐CI‐MS method. During fasting, all long‐chain acylcarnitines with a chain length of C14and higher (especially C14:1) increased dramatically. Total plasma long‐chain acylcarnitine reached a concentration of 28.6 μmol/L. LCT loading resulted in a moderate increase, mainly of the C18esters. The carnitine infusion, which led to a supranormal plasma free carnitine concentration, gave only a slight but generalized rise of long‐chain acylcarnitines. Although only one patient could be tested, the results suggest that the accumulation of potentially toxic long‐chain acylcarnitines in VLCAD deficiency is provoked by fasting, LCT loading and carnitine supplementation. Therapy should be adjusted accordingly.
Mutation analysis in the iduronate‐2‐sulphatase gene in 43 Japanese patients with mucopolysaccharidosis type II (Hunter disease)
Authors: Isogai K. , Sukegawa K. , Tomatsu S. , Fukao T. , Song X‐Q. , Yamada Y. , Fukuda S. , Orii T. , Kondo N.
Published: December 2002

Our series of studies on Hunter disease in Japanese patients showed allelic heterogeneity of IDS gene mutations, genotype/phenotype correlation and racial differences in distribution of mutations. Twenty‐five different small mutations have been characterized. Small mutations in the Japanese population are widely distributed through the IDS gene, although some mutations were unevenly concentrated on exon 5 (28%) and on exon 9 (24%). Mutations were seen at the same codon 468 in exon 9 in 5 patients. These findings are in good agreement with data on other ethnic groups. Two unique mutations linked to a severe phenotype were apparently associated with aberrant splicings; one was a point mutation within exon 3 (P86L), partially activating a cryptic splice acceptor site at 28 bp downstream from the mutation site within exon 3 and producing a 44‐base truncated mRNA, and the other was a point mutation at the consensus sequence of the splice donor site of intron 2, causing exon 2 skipping.
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

Mutations 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

In 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

Glutaric 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

Neuropsychiatric 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

Ornithine 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

We 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

In 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

3‐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

Murine 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

Measurement 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

Maple 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

We 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

Current 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

Homocystinuria (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

Niemann–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.
Successful pregnancy outcome in a woman with argininosuccinate lyase deficiency
Authors: Mardach M. R. , Roe K. , Cederbaum S. D.
Published: December 2002

Argininosuccinic aciduria (ASAD) is caused by deficiency of the fourth enzyme of the urea cycle, argininosuccinic acid lyase (EC 4.3.2.1; McKusick 207900). It results in the accumulation of large amounts of argininosuccinic acid in tissues and all the body fluids (Brusilow and Horwich 1995). The disorder may vary in severity from neonatal hyperammonaemia, which if untreated is fatal, to a biochemical abnormality without apparent clinical sequelae (Brusilow and Horwich 1995). A number of patients survive to adulthood and an increasing number have normal or near normal intelligence (Brusilow and Horwich 1995). There are, however, few reports of pregnancy outcome in women affected with this condition. Those available suggest that the offspring may not be at risk for development delay (Ward et al 1990; Worthington et al 1996). We report here the birth of two children to a woman affected with this disorder. Both were entirely normal developmentally as judged by formal testing. It supports the notion that this condition may not be embryotoxic due either to the inherent nontoxic nature of argininosuccinate or to its failure to cross the placenta in adequate amounts.
Benefits of normalizing plasma phenylalanine: Impact on behaviour and health. A case report
Authors: Williams K.
Published: December 2002

An elderly man with mental retardation who had never received dietary treatment for his phenylketonuria was placed on a phenylalanine‐restricted diet. Social skills and walking gait improved and a new interest in the objects in his environment developed spontaneously. A 2‐year analysis of diet, blood plasma phenylalanine levels and behavioural state indicated that small differences in phenylalanine intake impacted his well‐being. Of significant note, leg tremor and spasm that precipitated severe self‐injury were only reversible when plasma blood phenylalanine concentrations were titrated to near normal ranges and daily phenylalanine intake was strictly controlled. This case may offer a potential explanation for some of the late treatment failures that have been reported and suggest new avenues to explore in the late treatment of PKU.
Holocarboxylase synthetase deficiency: Report of a case with onset in late infancy
Authors: Touma E. , Suormala T. , Baumgartner E. R. , Gerbaka B. , Ogier de Baulny H. , Loiselet J.
Published: December 2002

A case of holocarboxylase synthetase (HCS) deficiency of late‐infantile onset is presented and compared with the common manifestations in previously reported patients. Our patient had her first episode at 20 months followed by recurrent episodes of metabolic acidosis with ketolactic acidosis responding dramatically to a short trial of biotin and thiamin. The main clinical findings were metabolic acidosis with alteration in consciousness and respiration, which are in accordance with findings in earlier reported patients with both neonatal‐onset and infantile‐onset forms of HCS deficiency. The diagnosis of HCS deficiency was made only at the age of 5.5 years during a metabolic work‐up when organic acid analysis was performed. This revealed elevated urinary excretion of the characteristic metabolites, 3‐hydroxypropionate, 3‐hydroxyisovalerate and methylcitrate, suggesting multiple carboxylase deficiency (MCD). MCD was demonstrated in fibroblasts of our patient, but only when the cells were grown in a medium with a very low biotin concentration of10−10mol/L. Kinetic studies of reactivation of deficient propionyl‐CoA carboxylase activity with biotin in intact fibroblasts revealed a mildly decreased reactivation rate and only a 3–5 times higher biotin requirement as compared with controls. These findings are in accordance with a mild form of HCS deficiency.This child responded to 10mg/day of biotin with normal lymphocyte carboxylase activities and adequate school performance at 10 years of age.