bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myotonic dystrophy: Molecular and cellular consequences of expanded DNA repeats are elusive
Authors: Strong P. N. , Brewster B. S. 
Published: December 2002

AbstractThe mutation in the myotonic dystrophy (DM) gene is an expansion in a triplet (CTG)n repeat in the 3′ untranslated region of a novel gene that partially encodes a serine‐threonine protein kinase (DMPK), with closest sequence homology to a small subgroup of protein kinases involved in the control of proliferation and cell shape. Expansion of the repeat correlates reasonably well with disease severity and offers a plausible molecular explanation for the previously contentious issue of anticipation. There is considerable heterogeneity in CTG expansion size in different tissues of affected individuals. The consensus of data from many laboratories indicates that DMPK mRNA is most probably downregulated as a consequence of the repeat expansion. Two polypeptides (68/78 kDa) have been shown to be absent in mouse knockout mutants and therefore can be considered as bona fide gene products. Previous data suggesting that 52‐55 kDa polypeptides were likely candidates, have been firmly ruled out at the same time. Further results from studies of knockout and overexpressing transgenic mice indicate that neither simple loss nor gain of DMPK expression is sufficient to account for the DM clinical phenotype. One of the most pressing questions now being addressed is how expansion of the CTG repeat within the DMPK gene affects gene expression, not only of DMPK, but of all genes at the 19q13.3 locus: is DMPK actually responsible for the clinical phenotype seen in DM? The identification of both immediate upstream and downstream human genes (59 and DMRHP, respectively) has been an important first step to answering these questions. Only when these matters have been dealt with can one reasonably expect to start to delineate the different metabolic and signalling pathways responsible for the diverse phenotypes that make up the complex clinical picture of DM.
The success of dietary protein restriction in alkaptonuria patients is age‐dependent
Authors: de Haas V. , Carbasius Weber E. C. , de Klerk J. B. C. , Bakker H. D. , Smit G. P. A. , Huijbers W. A. R. , Duran M. , Poll‐The B. T. 
Published: December 2002

AbstractAlkaptonuria is characterized by an increased urinary excretion of homogentisic acid, pigmentation of cartilage and connective tissues, and ultimately the development of inflammatory arthropathy. Various diets low in protein have been designed to decrease homogentisic acid excretion and to prevent the ochronotic pigmentation and arthritic lesions. However, limited information is available on the long‐term beneficial effects of these diets. We reviewed the medical records of 16 patients aged 3–27 years (4>18 years) to ascertain the age of diagnosis, growth, development, social behaviour, signs of complications and longitudinal dietary compliance. The diagnosis of alkaptonuria was made at an average age of 1.4 years (2 months–4 years); following the diagnosis all patients were prescribed a diet with a protein content of 1.5 g/kg per day. All patients showed normal growth and development, and no major complications of the disease. Behavioural problems associated with poor dietary compliance emerged as the main problem. Dietary compliance decreased progressively with age. The effect of dietary protein restriction in homogentisic acid excretion was studied by fixing the amounts of protein in the diet at 1 g/kg per day and 3.5–5 g/kg per day during 8 days. Twelve patients, aged 4–27 years, participated in the investigation. Protein restriction resulted in a significantly lower excretion of homogentisic acid in the urine of children younger than 12 years (p<0.01), whereas this effect was less obvious for adolescent and adult patients. The results suggest that restriction of protein intake may have a beneficial effect on alkaptonuric children; but continuation of this regimen to older age seems questionable and not practical.
Mutant CuZn superoxide dismutase in motor neuron disease
Authors: Gurney M. E. , Liu R. , Althaus J. S. , Hall E. D. , Becker D. A. 
Published: December 2002

AbstractCuZn superoxide dismutase (CuZn SOD) is one of several antioxidant enzymes that defend the cell against damage by oxygen free radicals. Mutations of the SOD1 gene encoding CuZn SOD are found in patients with familial amyotrophic lateral sclerosis (FALS), a progressive and fatal paralytic disease that is caused by the death of motor neurons in cortex, brainstem and spinal cord. The disease can be reproduced in transgenic mice by expression of mutant human CuZn SOD. Recent studies both in vitro and in vivo suggest that the effect of mutation is to enhance the generation of oxygen radicals by the mutant enzyme. Thus, mutation converts a protective, antioxidant enzyme into a destructive, prooxidant form that catalyses free radical damage to which motor neurons are selectively vulnerable. Recent studies of neuroprotective agents in the FALS model show that inhibition of oxidative mechanisms (copper chelation therapy, dietary antioxidants, and coexpression of bcl‐2) delays disease onset but does not extend disease duration. In contrast, inhibition of glutamatergic or apoptotic mechanisms (riluzole, gabapentin, and coexpression of an inhibitor of caspase‐1) has no effect on disease onset but extends survival by increasing the duration of symptomatic disease. Thus, neuroprotective agents differentially target the processes underlying disease initiation and propagation.
The metabolism of phytanic acid and pristanic acid in man: A review
Authors: Verhoeven N. M. , Wanders R. J. A. , Poll‐The B. T. , Saudubray J.‐M. , Jakobs C. 
Published: December 2002

AbstractThe branched‐chain fatty acid phytanic acid is a constituent of the diet, present in diary products, meat and fish. Degradation of this fatty acid in the human body is preceded by activation to phytanoyl‐CoA and starts withone cycle of α‐oxidation. Intermediates in this pathway are 2‐hydroxy‐phytanoyl‐CoA and pristanal; the product is pristanic acid. After activation, pristanic acid is degraded by peroxisomal β‐oxidation. Several disorders havebeen described in which phytanic acid accumulates, in some cases in combination with pristanic acid. In classical Refsum disease, the enzyme that converts phytanoyl‐CoA into 2‐hydroxyphytanoyl‐CoA – phytanoyl‐CoA hydroxylase – is deficient, resulting in highly elevated levels of phytanic acid in blood and tissues. Also in rhizomelic chondrodysplasia punctata, phytanic acid accumulates, owing to a deficiency in the peroxisomal import of proteins with a peroxisomal targeting sequence type 2. In patients affected with generalized peroxisomal disorders, degradation of both phytanic acid and pristanic acid is impaired owing to absence of functional peroxisomes. In bifunctional protein deficiency, the disturbed oxidation of pristanic acid results in elevated levels of this fatty acid and a secondary elevation of phytanic acid. In addition, several variant peroxisomal disorders with unknown aetiology have been described in which phytanic acid and/or pristanic acid accumulate. This review describes the discovery of phytanic acid and pristanic acid and the initial attempts to elucidate the origins and fates of these fatty acids. The current knowledge on the α‐oxidation and β‐oxidation of these branched‐chain fatty acids is summarized. The disorders in which phytanic acid and/or pristanic acid accumulate are described and some remarks are made on the pathogenic mechanisms of elevated levels of phytanic acid and pristanic acid.
Menkes disease: Underlying genetic defect and new diagnostic possibilities
Authors: Tümer Z. , Horn N. 
Published: December 2002

AbstractCloning of the gene defective in the X‐linked neurodegenerative disorder Menkes disease led to a cascade of new findings. Besides giving a better understanding of the intracellular copper homeostasis, these findings had important consequences from a clinical point of view. Today the underlying genetic defect has been described in several patients affected by one of the three hereditary disorders of copper metabolism: Menkes disease, occipital horn syndrome and Wilson disease. In this review we discuss mainly Menkes disease and the impact of the recent findings on the diagnosis of this disorder.
Identification of new medium‐chain acylcarnitines present in urine of a patient with medium‐chain acyl‐CoA dehydrogenase deficiency
Authors: Libert R. , Van Hoof F. , Thillaye M. , Vincent M.‐F. , Nassogne M.‐C. , Stroobant V. , de Hoffmann E. , Schanck A. 
Published: December 2002

AbstractPreviously undescribed medium‐chain acylcarnitines were identified in a urine sample from a patient with medium‐chain acyl‐CoA dehydrogenase deficiency. These are the 4‐methylvaleryl, 4‐ and 5‐methylhexanoyl, 6‐methyl‐heptanoyl‐, 6‐methyloctanoyl‐, 4,5‐dimethylhexanoyl‐ and 4,7‐decadienoyl‐carnitines. Their chemical structures were obtained by gas chromatography–mass spectrometry analysis of their fatty acid moieties as picolinyl esters.
Generalized peroxisomal disorder in male twins: Fatty acid composition of serum lipids and response to n−3 fatty acids
Authors: Søvik O. , Månsson J.‐E. , Bjørke Monsen A.‐L. , Jellum E. , Berge R. K. 
Published: December 2002

AbstractMale, identical twins presented with hypotonia, hypoglycaemia, dysmorphic facies, feeding problems, discoloured stools, hepatomegaly, and nephrolithiasis. Elevated blood levels of very long‐chain fatty acids and bile acids suggested a peroxisomal disorder. Plasmalogen biosynthesis in cultured fibroblasts was reduced. Morphologically distinct peroxisomes were undetectable in liver. Twin 1 suffered from nephrocalcinosis and severe infection, and died at 18 months of age. Twin 2 was blind and physically severely retarded with epilepsy, but survived up to the age of 5 years. Studies of the fatty acid composition of serum lipids showed barely detectable values of eicosapentaenoic (EPA) and docosahexaenoic acid (DHA). During long‐term treatment with these n−3 fatty acids, started at age 10 months, the fatty acid profile of the serum lipids was improved or normalized. Since n−3 fatty acids are essential elements in normal development, notably of the nervous system, we suggest that treatment with EPA and DHA should be started as early as possible in general peroxisomal disorders.
Medium‐chain triglyceride loading test in carnitine–acylcarnitine translocase deficiency: Insights on treatment
Authors: Parini R. , Invernizzi F. , Menni F. , Garavaglia B. , Melotti D. , Rimoldi M. , Salera S. , Tosetto C. , Taroni F. 
Published: December 2002

AbstractThe results of a medium‐chain triglyceride loading test in a patient with severe carnitine–acylcarnitine translocase deficiency clearly demonstrated impaired in vivo utilization of medium‐chain triglycerides. The loading test was performed at the ages of 7 and 36 months. The diet was adjusted accordingly. The clinical course has been favourable and the child is now in very good condition at age 4 years. We conclude that the utilization of medium‐chain triglycerides is only partial in carnitine–acylcarnitine translocase deficiency and cannot reasonably be considered an optimal source of energy for these patients. Careful adjustment of dietetic treatment may help to improve prognosis.
Molecular characterization of methylmalonate semialdehyde dehydrogenase deficiency
Authors: Chambliss K. L. , Gray R. G. F. , Rylance G. , Pollitt R. J. , Gibson K. M. 
Published: December 2002

AbstractThree patients have been reported with (putative) methylmalonic semialdehyde dehydrogenase (MMSDH) deficiency. The urine metabolic pattern was strikingly different in all, including β‐alanine, 3‐hydroxypropionic acid, both isomers of 3‐amino‐ and 3‐hydroxyisobutyric acids in one and 3‐hydroxyisobutyric and lactic acids in a second, and mild methylmalonic aciduria in a third patient. In an effort to clarify these disparate metabolite patterns, we completed the cDNA structure, and characterized the genomic structure of human MMSDH gene in order to undertake molecular analysis. Only the first patient had alterations in the MMSDH coding region, revealing homozygosity for a 1336G>A transversion, which leads to substitution of arginine for highly conserved glycine at amino acid 446. No abnormalities of the MMSDH cDNA were detected in the other patients. These data provide the first molecular characterization of an inborn error of metabolism specific to the L‐valine catabolic pathway.
Effects of ethanol and of alcohol dehydrogenase inhibitors on the reduction of N‐acetylaspartate levels of brain in mice in vivo: a search for substances that may have therapeutic value in the treatment of Canavan disease
Authors: Baslow M. H. , Suckow R. F. , Hungund B. 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 3000–2800cm−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.
Clinical significance of brain phenylalanine concentration assessed by in vivo proton magnetic resonance spectroscopy in phenylketonuria
Authors: Leuzzi V. , Bianchi M. C. , Tosetti M. , Carducci Cl. , Carducci Ca. , Antonozzi I. 
Published: December 2002

AbstractRecent studies using in vivo proton magnetic resonance spectroscopy (1H MRS) have suggested that plasma phenylalanine (Phe) may not be a reliable indicator of brain Phe level in subjects with phenylketonuria (PKU). Interindividual variation in cerebral Phe can contribute to the phenotypic variability of the disease. We report the results of the direct assessment of brain Phe by 1H MRS in 10 off‐diet PKU patients (aged 15.5–30.5 years), 4 detected and treated early, 6 late. In a single patient, brain Phe was evaluated before and 15 days after diet discontinuation. FLAIR MRI and 1H MRS were performed in the same setting by a 1.5 T clinical MR scanner. MR images were scored according to the extent of the lobar white‐matter hyperintensity. Brain 1H MRS Phe signal (resonating at 7.36 ppm) was evaluated as a ratio to the creatine+phosphocreatine signal. Brain Phe was correlated with clinical, biochemical and MRI findings. Results were as follows. (1) An abnormal concentration of brain Phe was detected in all 10 PKU subjects (ranging from 0.030 to 0.074), associated with a wide interindividual variability of concurrent plasma Phe (ranging from 724 to 2800 μmol/L). (2) In late‐detected subjects, brain Phe concentration correlated with clinical phenotype better than did plasma Phe. The discrepancy between brain and plasma Phe was relevant from a clinical point of view in two cases: in one, a late‐detected patient with normal mental development, a high level of plasma Phe was associated with a relatively low concentration of brain Phe; in the other, a late‐detected subject with severe neurological impairment, a very high level of brain Phe was associated with plasma Phe compatible with the diagnosis of mild PKU. (3) White‐matter alterations were detected in all patients. FLAIR MRI sequences disclosed an involvement of optic chiasma and tracts in 7 subjects. No correlation was found between white‐matter alterations and concurrent brain Phe concentrations. (4) In the only case assessed under different intake of Phe, the relevant increase of brain Phe paralleled the concurrent increase of plasma Phe, showing that 1H MRS can be a useful tool in evaluating the individual vulnerability of PKU patients to different values of plasma Phe.
Malonic aciduria in Maltese dogs: Normal methylmalonic acid concentrations and malonyl‐CoA decarboxylase activity in fibroblasts
Authors: O'Brien D. P. , Barshop B. A. , Faunt K. K. , Johnson G. C. , Gibson K. M. , Shelton G. D. 
Published: December 2002

AbstractA family of Maltese dogs with malonic aciduria is reported. The propositus presented at 3 years of age with episodes of seizures and stupor with hypoglycaemia, acidosis, and ketonuria. Urinary organic acid assays showed elevated malonic acid without elevation of methylmalonic acid. Cultured fibroblasts had normal malonyl‐CoA decarboxylase activity. Treatment with frequent feedings of a low‐fat diet high in medium‐chain triglycerides resulted in normalization of clinical signs and a resolution of the malonic aciduria. Two full siblings of the propositus had died at a young age of undiagnosed metabolic and neurological disease. Urine organic acid assays were performed on other family members. A half‐sister showed mild malonic aciduria and other organic acid changes similar to the propositus, while the mother and half‐brother showed mildly elevated ketone bodies. This family suggests further genetic and clinical heterogeneity in the malonic acidurias.
Regulation of cholesterol biosynthetic pathway in patients with the Smith–Lemli–Opitz syndrome
Authors: Honda M. , Tint G. S. , Honda A. , Salen G. , Shefer S. , Batta A. K. , Matsuzaki Y. , Tanaka N. 
Published: December 2002

AbstractThe Smith–Lemli–Opitz syndrome (SLOS) is a recessively inherited birth disorder caused by a defect in 7‐dehydrocholesterol (3β‐hydroxysteroid) Δ7‐reductase, the final enzyme in cholesterol biosynthesis. To investigate in vivo regulation of the cholesterol biosynthetic pathway in SLOS, we measured hepatic microsomal sterol concentrations and activities of several key enzymes in the pathway, including HMG‐CoA synthase, HMG‐CoA reductase, squalene synthase and 7‐dehydrocholesterol Δ7‐reductase in liver specimens from a patient with SLOS and 11 controls. Hepatic microsomal 7‐dehydrocholesterol Δ7‐reductase activity in the patient was less than 1% of the control mean, and decreased cholesterol concentration and markedly increased 7‐ and 8‐dehydrocholesterol concentrations were observed in the patient's microsomes. HMG‐CoA synthase and squalene synthase activities in the patient were upregulated to 149% and 532%, respectively, while the activity of HMG‐CoA reductase, the rate‐limiting enzyme in the pathway, was reduced to 39% of the control mean. Downregulation of HMG‐CoA reductase activity in SLOS was supported by measuring plasma levels of mevalonic acid, the immediate product of HMG‐CoA reductase. The levels in SLOS patients (n=9) were significantly low compared with age‐matched controls (n=8) (12±2 vs 28±6 nmol/L, p<0.05). These results suggest that in most SLOS patients in vivo HMG‐CoA reductase is not stimulated in spite of blocked cholesterol biosynthetic pathway and reduced plasma and hepatic cholesterol concentrations.
Defective folding and rapid degradation of mutant proteins is a common disease mechanism in genetic disorders
Authors: Gregersen N. , Bross P. , Jørgensen M. M. , Corydon T. J. , Andresen B. S. 
Published: December 2002

AbstractMany disease‐causing point mutations do not seriously compromise synthesis of the affected polypeptide but rather exert their effects by impairing subsequent protein folding or stability of the folded protein. This often results in rapid degradation of the affected protein. The concepts of such ‘conformational disease’ are illustrated by reference to cystic fibrosis, phenylketonuria and short‐chain acyl‐CoA dehydrogenase deficiency. Other cellular components such as chaperones and proteases, as well as environmental factors, may combine to modulate the phenotype of such disorders and this may open up new therapeutic approaches.
Ornithine carbamoyltransferase deficiency: Improved sensitivity of testing for protein tolerance in the diagnosis of heterozygotes
Authors: Potter M. , Hammond J. W. , Sim K.‐G. , Green A. K. , Wilcken B. 
Published: December 2002

AbstractThe most direct test of functional capacity of the liver in nitrogen disposal is to stress the urea cycle with a high protein load. This has been used in the diagnosis of heterozygosity for ornithine carbamoyltransferase deficiency for many years by measuring the subsequent excretion of orotic acid in urine. Reports have shown some ambiguity in both this and the more recent allopurinol test. We investigated the effects of different foods as the protein load and of different analytical methods. A standardized protocol was developed, giving 35 g protein per m2 surface area as steamed fat‐free chicken breast to be eaten within 30 min. Urine was collected at zero time and over 0–2, 2–4 and 4–6 h. Compliance was checked by assessing excretion of amino acids. Diagnostic sensitivity was improved by reference to the change in excretion, i.e. the ratio of excretions 2–4 h/0–2 h. Extension of the test to 6 h gave no diagnostic advantage over a 4 h test. Comparison of the analysis of total orotic acids by the photometric method of Harris and Oberholtzer, the reference method for this study, with that by the method of Goldstein and colleagues showed that the latter gave erratic results with some false positives. However, comparison of the method of Harris and Oberholtzer with specific orotic acid analysis by a modification of the stable‐isotope internal standard method of Rimoldi and colleagues yielded the same diagnoses. The improved protein load test gave a clearly positive result in all 16 obligate heterozygotes and 2 possible heterozygotes tested from 14 kindred, and a clearly negative result in all 18 control subjects and all 6 of the possible heterozygotes who were later shown by DNA studies not to carry the family mutation. The test appears at least as sensitive and specific as the allopurinol test, and is more convenient because of the short period of sample collection.
Why Have We Been More Successful in Reducing Tobacco Use Than Violent Crime?
Authors: Biglan Anthony , Taylor Ted K. 
Published: December 2002

AbstractTobacco control efforts have been associated with a significant reduction in the prevalence of tobacco use in the United States. Efforts to reduce the incidence of violent crime have been much less successful. This paper argues that progress on tobacco control stems from the existence of a clear, empirically based, and widely understood analysis of the tobacco problem that articulates (a) the harms associated with its use, (b) the causes of tobacco use, and (c) the programs and policies that could reduce tobacco use. This analysis has guided the development of a network of social organizations that have been advocating for policies and programs that are reducing tobacco use. In contrast, there is not a widely shared, cogent, and empirically based analysis of the problem of violent crime. As a result, efforts to combat violent crime are fragmented and it has proven difficult to generate support for preventive programs and policies. Substantial empirical progress has been made, however, on how violent crime could be prevented. That evidence is reviewed. It is argued that the articulation of this evidence is a critical first step for achieving widespread reduction in the incidence of violent crime. Communication of that evidence to audiences that matter will require that behavioral scientists become better organized to advocate for the adoption of empirically supported practices.