bluuebunny/crossref_metadata_2025 huggingface dataset:
Gene mapping of mineral metabolic disorders
Authors: Thakker R. V. , Davies K. E. , O'Riordan J. L. H.
Published: June 2005

Recent advances in the techniques of molecular biology and cytogenetics have enabled the localization of several mutant genes which result in disorders of phosphate, calcium, magnesium and water homeostasis. Thus, the genes causing X‐linked hypophosphataemic rickets, Lowe's syndrome, Di George syndrome, X‐linked recessive hypoparathyroidism, multiple endocrine neoplasia Type I, primary hypomagnesaemia and X‐linked nephrogenic diabetes insipidus have been mapped. The molecular and genetic studies which localized these disease genes are described and the implications of this gene mapping in genetic counselling and in further elucidation of the mineral metabolic defects are discussed.
A new case of dihydropyrimidine dehydrogenase deficiency
Authors: Brockstedt M. , Jakobs C. , Smit L. M. E. , van Gennip A. H. , Berger R.
Published: June 2005

We present the clinical and biochemical features of a boy with dihydropyrimidine dehydrogenase deficiency, which seem to underline a disease entity of developmental retardation, epilepsy and muscular hypertonia.
PAH deficiency in Italy: correlation of genotype with phenotype in the Sicilian population
Authors: Romano V. , Guldberg P. , Güttler F. , Meli C. , Mollica F. , Pavone L. , Giovannini M. , Riva E. , Biasucci G. , Luotti D. , Palillo L. , Calí F. , Ceratto N. , Anello G. , Bosco P.
Published: June 2005

The results of the neonatal screening for phenylalanine hydroxylase (PAH) deficiency in Sicily show that its incidence is higher than previously reported for mainland Italians and that non‐PKU HPA is in excess of classical and mild PKU. The latter finding suggests that a high number of non‐PKU HPA mutations would occur in the Sicilian population compared to populations with an inverted PKU/non‐PKU HPA ratio. Previous studies have identified 40 mutations accounting for the majority (98%) of mutant alleles underlying PAH deficiency in Sicily. In order to study the molecular basis of the distribution of PAH deficiency phenotypes in the Sicilian population, we have correlated 31 of those mutations with clinical and metabolic phenotypes in 12 mentally retarded patients, 14 treated patients with classic or mild PKU, and 13 subjects presenting the non‐PKU HPA phenotype. The present study proposes a tentative classification for a large number (26) of PAH gene mutations which may represent an additional tool for establishing a differential diagnosis for PAH deficiency in the Sicilian population.
Congenital non‐progressive encephalopathy and deafness with intermittent episodes of coma and hyperkynureninuria
Authors: Cheminal R. , Echenne B. , Bellet H. , Duran M.
Published: June 2005

Six of nine children born from first‐cousin parents presented with the same clinical picture: non‐progressive congenital encephalopathy with marked hypertonia resembling the stiff‐baby syndrome, delayed milestones, mental deficiency and congenital deafness. Rare, usually reversible, episodes of sudden worsening of the neurological status, with progressive loss of consciousness and increase of hypertonia, occurred spontaneously or during febrile illnesses. During these periods, and sometimes on other occasions, transitory renal dysfunction was observed (nephrotic syndrome and/or tubular abnormalities). Death occurred before age 2 years in 4 patients; 2 are still alive (10 and 13 years old). Electrophysiological, biological and enzymatic investigations remained negative, particularly those concerning mitochondrial and peroxisomal metabolism. The only biochemical anomaly was a massive hyperkynureninuria, seen only during the periods of coma (up to 213 µmol/mmol creatinine; normal < 10) and after an intravenous protein loading test. This suggests an anomaly of tryptophan metabolism which has not been reported up to now.
Clinical polymorphism of cystinosis encephalopathy. Results of treatment with cysteamine
Authors: Broyer M. , Tête M. J. , Guest G. , Berthélémé J. P. , Labrousse F. , Poisson M.
Published: June 2005

Of the 26 cystinotic patients over 19 years of age followed in our institution, 7 developed CNS complications at a mean age of 23 years. Two forms were observed. The first, associating cerebellar and pyramidal signs, mental deterioration and finally pseudo‐bulbar palsy, may be called cystinosis encephalopathy. The other form resembled a stroke‐like episode with coma and hemiplegia or milder symptoms. Hydrocephalus was rare and not associated with clinical symptoms in this series. Cysteamine was administered for longer than 6 months to 4 of the patients with encephalopathy. Two had an almost complete disappearance of their symptoms including the gross abnormalities of MR imaging in one; one improved partially and remained stable, and one continued to deteriorate but was suspected of noncompliance. These results suggest that cysteamine may be an effective treatment of cystinosis encephalopathy and encourage prescription of this drug in cystinosis in order to prevent this complication
Colorimetric determination of sulphatide in cultured fibroblasts from patients with various types of metachromatic leukodystrophy after sulphatide loading test
Authors: Wiesmann U. N. , Burkhart T. , von Känel J. , Toennesen T. , Ghidoni R.
Published: June 2005

Conclusion

Intracellular determination of sulphatide by the two methods gave very good correlation. The detection limit for the colorimetric methods was in the low nanomolar range per mg protein, providing enough specificity and sensitivity for the determination of sulphatide in fibroblasts after a loading test. While the determination of radiolabelled 3‐OH‐sulphatide is quite time‐consuming and requires special techniques, the colorimetric assay is relatively simple and can be performed in any laboratory equipped for biochemical analyses. The colorimetric test can be used to develop more sensitive sulphatide loading tests which will be better able to discriminate between the various forms of typical and atypical MLD.
Maternal phenylketonuria pregnancy outcome: a preliminary report of facial dysmorphology and major malformations
Authors: Rouse B. , Lockhart L. , Matalon R. , Azen C. , Koch R. , Hanley W. , Levy H. , dela Cruz F. , Friedman E.
Published: June 2005

Conclusion

It is clear from the preliminary data that major malformations, i.e. intrauterine growth retardation, microcephaly and cardiac defects, tend to decrease in frequency as the blood phenylalanine level drops, but not enough to suggest that phenylalanine levels of 600µmol/L are safe levels. The facial dysmorphic features may be used as a sensitive indicator that blood phenylalanine levels should be below 360µmol/L. It is hoped that at the end of the collaborative study more data will be available to suggest blood phenylalanine levels which will prevent the deleterious effects of maternal PKU syndrome.
X‐linked cardioskeletal myopathy and neutropenia (Barth syndrome): Respiratory‐chain abnormalities in cultured fibroblasts
Authors: Barth P. G. , Van den Bogert C. , Bolhuis P. A. , Scholte H. R. , van Gennip A. H. , Schutgens R. B. H. , Ketel A. G.
Published: June 2005

Conclusions

The ATP production from glutamate + malate, pyruvate + malate, or succinate (+ rotenone was lower than the mean values found in control fibroblasts in patient 1 and in the low‐normal range in patient 2. Decreased activities of complex III (±30% of controls) and complex IV (±60% of controls) are in agreement with the previous studies in muscle. These findings provide evidence that respiratory‐chain dysfunction is an essential component of Barth syndrome. Results further indicate that the gene product is essential for the function, formation or stability of both complex III and complex IV. Both complex III and complex IV contain subunits that are encoded by mtDNA. The results of emetine labelling make it unlikely that the gene is involved in the expression of mtDNA. We furthermore suspect that 3‐methylglutaconic aciduria in this syndrome represents an epiphenomenon which is as yet unexplained but has been described so far in patients with separate mitochondrial disorders (Gibson et al 1995).
The mutational spectrum in very long‐chain acyl‐CoA dehydrogenase deficiency
Authors: Andresen B. S. , Vianey‐Saban C. , Bross P. , Divry P. , Roe C. R. , Nada M. A. , Knudsen I. , Gregersen N.
Published: June 2005

Conclusion

We have shown that all of seven unrelated patients with defective palmitoyl‐CoA dehydrogenation have mutations in VLCAD, indicating that they suffer from VLCAD deficiency.

Our study illustrations that there is a large mutational heterogeneity in VLCAD deficiency. It is not at present possible to judge whether or to what extent this large mutational heterogeneity may explain the varying clinical picture observed in this disease.
Improved selectivity of urinary oligosaccharide screening using two one‐dimensional TLC systems
Authors: Abeling N. G. G. M. , Rusch H. , van Gennip A. H.
Published: June 2005

Conclusions

Combination of two one‐dimensional TLC systems provides additional discriminative power with respect to pathology. Breast‐feeding patterns can be distinguished from the α‐mannosidase patterns in the new TLC system using isopropanol.

We prefer the combination of the regular system with the isopropanol system.
The role of steroid metabolic profiling as an aid in the diagnosis of familial precocious puberty, a subgroup of true precocious puberty
Authors: Pike A. W. , Klein J. L. , Gotlin R. W. , Fennessey P. V.
Published: June 2005

We report the results of a study of a rare form of true precocious puberty in a family with a history of the condition. Only the male members manifest the trait, whereas it appears to be carried by both males and females. Routine urinary steroid analysis rapidly eliminated most of the classical enzyme defects associated with premature sexual maturation. Further investigation of urinary steroid extracts using gas chromatography and gas chromatography‐mass spectrometry revealed essentially normal prepubertal androgen values for the proband A at 4 years of age, and for his affected and carrier relatives when compared with healthy age‐matched individuals. While his plasma gonadotropin levels were in the prepubertal range, his plasma testosterone value was significantly elevated with values just below the normal range for an adult male.

This is the fourteenth reported family with a vertical pattern of familial sexual precocity, but the first to have a steroid profile. Analysis suggests sex‐limited autosomal dominance with a greater than 90% penetrance. The elevated plasma testosterone concentration, prepubertal plasma gonadotropin concentration, minimal histopathologic evidence of gametogenesis and only moderate increase in testicular volume over the five‐year course of follow‐up support a diagnosis of the recently described condition of familial gonadotropin independent sexual precocity. The gas chromatography‐mass spectrometry urinary profiling shows elevated cortisol output but otherwise normal adrenal function.
Infantile Refsum's disease: Biochemical findings suggesting multiple peroxisomal dysfunction
Authors: Poll‐The B. T. , Saudubray J. M. , Ogier H. , Schutgens R. B. H. , Wanders R. J. A. , Schrakamp G. , van den Bosch H. , Trijbels J. M. F. , Poulos A. , Moser H. W. , van Eldere J. , Eyssen H. J.
Published: June 2005

Infantile Refsum's disease was diagnosed in three male patients, presenting with facial dysmorphia, retinitis pigmentosa, neurosensory hearing loss, hepatomegaly, osteopenia and delayed growth and psychomotor development.

An elevated plasma phytanic acid concentration and a deficient phytanic acid oxidase activity in fibroblasts were found with an accumulation of very long chain fatty acids in plasma and fibroblasts. There were elevated pipecolic acid levels in plasma, urine and CSF, and abnormal bile acid metabolites in plasma.

Deficient activity of acylCoA: dihydroxyacetone phosphate acyl transferase was found in thrombocytes and fibroblasts of these patients as well as an impairedde novo plasmalogen biosynthesis in fibroblasts. These biochemical abnormalities, previously described in the Zellweger syndrome, suggest multiple peroxisomal dysfunction in our patients.
Lymphoid cell lines as a model system for the study of Wolman's disease: Enzymatic, metabolic and ultrastructural investigations
Authors: Nègre A. , Salvayre R. , Maret A. , Vieu C. , Bes J. C. , Borrone C. , Durand P. , Douste‐Blazy L.
Published: June 2005

Epstein‐Barr virus (EBV) transformed lymphoid cell lines (LCL) were established from blood lymphocytes of a patient affected with Wolman's disease (WD) and from her parents. These LCL showed a severe deficiency in acid lipase activity using every substrate in comparison to LCL from normal subjects, in which acid lipase activity was similar to that in blood lymphocytes. In the LCL from Wolman's disease a major accumulation of neutral lipids was observed, mainly cholesteryl esters, CE (amount around 7 times higher than in normal cells and ratio of esterified/free cholesterol increased by 10 times) and to a lesser extent triglycerides, TG (amount increased by 1.5 times). Electron microscopy showed the storage vacuoles of neutral lipids quite characteristic of this lysosomal disease. The reported data demonstrated the validity of transformed LCL as a cellular model system in culture for experimental studies of Wolman's disease and for investigating the lysosomal metabolism of neutral lipids.
Direct identification of propionylcarnitine in propionic acidaemia: Biochemical and clinical results of oral carnitine supplementation
Authors: Duran M. , Ketting D. , Beckeringh T. E. , Leupold D. , Wadman S. K.
Published: June 2005

Urinary short‐chain acylcarnitine in a patient with propionic acidaemia and low levels of free carnitine was found to consist mainly of propionylcarnitine. The compound was isolated by sequential paper and thin layer chromatography and identified by ammonia desorption chemical ionization mass spectrometry. Treatment of the patient with oral carnitine supplements led to a near‐normalization of the plasma free carnitine concentrations and an increase in his muscle tone. The propionylcarnitine excretion rose and there was a simultaneous decrease in the methylcitrate output. Carnitine treatment did not prevent the occurrence of an episode of metabolic decompensation.
Liver transplantation in a 23‐year‐old tyrosinaemia patient: Effects on the renal tubular dysfunction
Authors: Kvittingen E. A. , Jellum E. , Stokke O. , Flatmark A. , Bergan A. , Sødal G. , Halvorsen S. , Schrumpf E. , Gjone E.
Published: June 2005

Orthotopic liver transplantation was performed on a 23‐year‐old female with hereditary tyrosinaemia. The disorder was diagnosed at 7 years of age due to severe rickets, and the patient was treated with a diet restricted in phenylalanine and tyrosine. Nineteen months before the transplantation she had an acute episode of diffuse gastrointestinal bleeding due to portal hypertension. Three subsequent bleeding episodes with accompanying ascites and signs of encephalopathy were considered life‐threatening.

Nine months after the liver transplantation the patient is well, but serum transaminases are slightly elevated. Without dietary restrictions serum tyrosine and inorganic phosphate are normalized, no succinylacetone can be detected in serum, and urinary excretion ofp‐hydroxyphenyllactate andp‐hydroxyphenylpyruvate is normal.

Excretion of amino acids, glucose andβ2‐microglobulin decreased significantly after the transplantation but is still elevated. The succinylacetone concentration in urine is about 20% of the preoperative level. After an oral tyrosine load, succinylacetone excretion increased sevenfold but no deterioration of the renal tubular function was observed and no tyrosine metabolites were detectable in serum. The findings indicate that the defective tyrosine metabolism occurs in the kidneys, but does not produce tubular dysfunction. The residual tubular dysfunction of the patient is probably due to irreversible damage of the tubular epithelium.
Multiple implantation of normal amnion into cattle with generalized glycogenosis type II
Authors: McC. Howell J. , Dorling P. R. , Dimarco P. N. , Taylor E. G.
Published: June 2005

One normal and two carrier calves, and two calves affected by generalized glycogenosis type II were given multiple transplants of normal bovine amnion inserted below the external oblique abdominal muscle in the flank. The interval between transplants was approximately 5 months. The amniotic tissue was not acutely rejected but a host versus graft reaction did occur. The level of acid α‐glucosidase activity in the amniotic tissue fell rapidly but was still present 2 months after transplantation. Enzyme levels in blood or other tissues did not rise. Excess glycogen deposition and muscle damage occurred in the affected calves and appeared to progress at a rate similar to that in untreated affected animals. One of the affected animals died aged 16 months, which was the same age as the longest surviving non‐treated animal in our herd. The other treated animal died aged 24 months.
Pompe's disease in Chinese and prenatal diagnosis by determination of α‐glucosidase activity
Authors: Lin C. ‐Y. , Hwang B. , Hsiao K. ‐J. , Jin Y. ‐R.
Published: June 2005

We measured the activities of two major forms of α‐glucosidase in lymphocytes and cultured fibroblasts from normal healthy controls and patients with Pompe's disease by using 4‐methylumbelliferyl‐α‐d‐glucoside as substrate. We found (1) enzyme activity of the pH4 and pH6 forms varied with age, and (2) patients with Pompe's disease showed very low activity of the pH4 form and a low ratio of pH4 to pH6 forms. We established a reference range and were also able to diagnose prenatally the homozygote and heterozygote forms of Pompe's disease which occurred in families of southern Chinese and aborigines in Taiwan. This enzyme biochemical study may be useful in anthropology.
Biochemical study of sialidosis type I in a Russian family
Authors: Tsvetkova I. V. , Petushkova N. A. , Zolotuchina T. V. , Kucharenko V. I. , Rosenfeld E. L.
Published: June 2005

A 7‐year‐old boy from a Russian family with decreased vision and a cherry‐red spot but without any somatic and mental abnormalities is described in this paper. The decreased neuraminidase activity in the child's leukocytes and cultured skin fibroblasts and his 10‐fold increase in urinary sialyloligosaccharides allowed us to conclude that he was affected by type I sialidosis. Some other results of the biochemical study of this child and his parents are presented. It is the first case of sialidosis in the Russian population.
Normal dolichol concentration in urine sediments from four patients with neuronal ceroid lipofuscinosis (Batten's disease)
Authors: Paton B. C. , Poulos A.
Published: June 2005

The dolichol contents of urine sediments from a patient with infantile (Santavuori), a patient with late infantile (Jansky‐Bielschowsky) and two patients with juvenile (Spielmeyer‐Vogt) neuronal ceroid lipofuscinosis (Batten's disease) were not elevated when compared to those from healthy controls.
Purification and characterization of sialic acid containing materials accumulated in cultured skin fibroblasts from a patient with type II sialidosis
Authors: Scocca J. R. , Thomas G. H. , Miller C. , Reynolds L.
Published: June 2005

Sialyl conjugates which accumulate in sialidase deficient fibroblasts were made radioactive in the sialic acid moiety by culturing the cells in the presence of [3H]N‐acetylmannosamine. The accumulated radioactive compounds were fractionated by anion exchange chromatography and gel filtration. At least nine chromatographically distinct sialyl conjugates were obtained. Neutral and amino sugar analysis of these compounds indicated that all were sialyloligosaccharides of the type which could be derived from glycoproteins containing complex,N‐asparagine‐linked carbohydrate groups.
Arylsulphatase C activity in leukocytes of patients and carriers of X‐linked ichthyosis
Authors: Herrmann F. H. , Grimm U. , Hadlich J.
Published: June 2005

In Triton X‐100 solubilized leukocytes of 17 patients and 8 obligate carriers of X‐linked recessive ichthyosis (XLI) the activity of arylsulphatase C (ASC) was determined and expressed as the ratio to β‐galactosidase activity. The ASC/β‐gal ratio of XLI patients is markedly decreased (range 0.07–0.48) in comparison to the corresponding control group of males (range 1.3–2.7). The enzyme ratios of 8 obligate carriers of XLI are decreased (range 0.90–1.9) in comparison to the normal females (2.13–5.52). These results indicate that the determination of the enzyme ratio of ASC/β‐gal in Triton X‐100 solubilized leukocytes is a sensitive test for biochemical identification of patients and probably of carriers of XLI.
Mechanisms of blood glucose homeostasis
Authors: Hers H. ‐G.
Published: June 2005

The mechanisms by which glycogen metabolism, glycolysis and gluconeogenesis are controlled in the liver both by hormones and by the concentration of glucose are reviewed. The control of glycogen metabolism occurs by phosphorylation and dephosphorylation of both glycogen phosphorylase and glycogen synthase catalysed by various protein kinases and protein phosphatases. The hormonal effect is to stimulate glycogenolysis by the intermediary of cyclic AMP, which activates directly or indirectly the protein kinases. The glucose effect is to activate the protein phosphatase system; this occurs by the direct binding of glucose to glycogen phosphorylase which is then a better substrate for phosphorylase phosphatase and is inactivated. Since phosphorylasea is a strong inhibitor of synthase phosphatase, its disappearance allows the activation of glycogen synthase and the initiation of glycogen synthesis. When glycogen synthesis is intense, the concentrations of UDPG and of glucose 6‐phosphate in the liver decrease, allowing a net glucose uptake by the liver. Glucose uptake is indeed the difference between the activities of glucokinase and glucose 6‐phosphatase. Since the Km of the latter enzyme is far above the physiological concentration of its substrate, the decrease in glucose 6‐phosphate concentration proportionally reduces its activity.

The control of glycolysis and of gluconeogenesis occurs mostly at the level of the interconversion of fructose 6‐phosphate and fructose 1,6‐bisphosphate under the action of phosphofructokinase 1 and fructose 1,6‐bisphosphatase. Fructose 2,6‐bisphosphate is a potent stimulator of the first of these two enzymes and an inhibitor of the second. It is formed from fructose 6‐phosphate and ATP by phosphofructokinase 2 and hydrolysed by a fructose 2,6‐bisphosphatase. These two enzymes are part of a single bifunctional protein which is a substrate for cyclic AMP‐dependent protein kinase. Its phosphorylation causes the inactivation of phosphofructokinase 2 and the activation of fructose 2,6‐bisphosphatase, resulting in the disappearance of fructose 2,6‐bisphosphate. The other major effector of these two enzymes is fructose 6‐phosphate, which is the substrate of phosphofructokinase 2 and a potent inhibitor of fructose 2,6‐bisphosphatase; these properties allow the formation of fructose 2,6‐bisphosphate when the level of glycaemia and secondarily that of fructose 6‐phosphate is high.
Diagnosis of glycogen storage disease
Authors: Shin Y. S.
Published: June 2005

Glycogen storage diseases are associated with more than 15 different enzyme deficiencies and can be clinically divided mainly into two groups, those that affect primarily the liver and those that affect principally the muscle. In this report each glycogenosis has been clinically and biochemically documented and possibilities for an accurate and prompt diagnosis of the various types have been summarized. Most of the patients suffering from type II, type III, type IV and type VIa can easily be diagnosed by analysis of peripheral blood cells without the need for tissue biopsies. First trimester diagnosis using chorionic villi is feasible for severe forms of the glycogenoses, type IIa, type IIIa and type IV.
Galactose disorders: An overview
Authors: Holton J. B.
Published: June 2005

There are three separate disorders of galactose metabolism of clinical importance. Galactokinase deficiency mainly causes cataracts which regress without complications providing a galactose‐free diet is started early enough. UDPgalactose‐4‐epimerase deficiency seems extremely rare. A common feature of the two reported cases is nerve deafness. Galactose‐1‐phosphate uridyl transferase deficiency poses the greatest problems because of the poor long‐term outcome in spite of a galactose‐restricted diet, and with no clear indications of how and when the underlying damage occurs. Recent evidence of low erythrocyte and tissue UDPgal levels, associated with ovarian dysfunction, may indicate impaired galactoside synthesis. Administration of uridine corrects the UDPgal depletion and trials in which it is added to the galactose‐restricted diet have begun.
Regulation of galactose metabolism: Implications for therapy
Authors: Segal S. , Rogers S.
Published: June 2005

In view of evidence that dietary therapy of galactose‐1‐phosphate uridyltransferase deficiency has failed to prevent complications of the disorder, there is a need for new strategies in treatment. The enhancement of residual enzyme activity in tissues of galactosaemic patients should provide such an approach. This possibility is derived from knowledge of the regulation of transferase activity in normal animal tissues. The pertinent observations summarized herein are: (1) that hepatic transferase activity is modulated by various cellular metabolites, uridine nucleotides being of particular significance; (2) that transferase activity in the young rat liver is subject to developmental programming with a several‐fold increase after birth; (3) that transferase activity in pregnant rat liver is significantly increased which may be related to hormonal effects of progesterone; and (4) that pharmacological doses of folic acid may increase transferase activity. The basis of such regulation can give insight into sufficient augmentation of the residual activity to increase galactose utilization and thereby better the long‐term outcome.
The mechanisms of cataract formation
Authors: Schmitt C. , Hockwin O.
Published: June 2005

This review summarizes current knowledge concerning cataract formation. Metabolically induced forms of cataract are discussed, but mainly aspects of cataract formation in older patients are described, especially with respect to lens protein modifications and epidemiological results. In most cases, cataract in older people is a multifactorial process and therefore cataracts appear in a multitude of different morphological types. Only accurate documentation of lens disturbances and the use of reproducible methods can provide more detailed information about the complexity of the disease cataract.
Cataract and metabolic disease
Authors: Endres W. , Shin Y. S.
Published: June 2005

In addition to the already recognized metabolic diseases which have been associated with cataract formation, e.g. galactosaemia, galactokinase deficiency, Lowe's syndrome and diabetes, several other disorders can also lead to the development of cataracts. They are sorbitol dehydrogenase deficiency, uridine diphosphate galactose‐4‐epimerase deficiency, marginal maternal transferase and galactokinase deficiency, galactitol and sorbitol accumulation of unknown origin, heterozygosity for galactosaemia and galactokinase deficiency as well as the carrier state for Lowe's syndrome. In this review these metabolic disorders have been divided into five groups according to the age at the first appearance of lens clouding and the possible means of treatment have been discussed.
Plasma polyol levels in patients with cataract
Authors: Jakobs C. , Douwes A. C. , Brockstedt M. , Stellaard F. , Endres W. , Shin Y. S.
Published: June 2005

Galactitol and sorbitol concentrations in plasma were determined in patients (with or without cataract) in whom homo‐ or heterozygosity for galactokinase, galactose‐1‐phosphate uridyltransferase, systemic or peripheral UDP‐galactose epimerase and sorbitol dehydrogenase deficiency was confirmed. For the above disorders it can be concluded that elevation of plasma polyols is not always related to the presence or absence of cataract. In all cases with cataract, however, the plasma galactitol or sorbitol levels were elevated. In another group of patients with unexplained congenital or infantile cataracts, but without apparent enzyme defects, mild to moderately elevated concentrations of plasma galactitol or sorbitol were found in about 45%. In 8% of this group the cataract and the elevated plasma galactitol concentration could possibly have been related to partial maternal enzyme deficiency. In all the other cases the elevated plasma polyol concentration remains unexplained but could indicate a further cause of cataract formation due to a hitherto unknown galactose or glucose metabolic aberration.
Schindler disease: An inherited neuroaxonal dystrophy due to α‐N‐acetylgalactosaminidase deficiency
Authors: Desnick R. J. , Wang A. M.
Published: June 2005

The clinical, pathological and biochemical features of a neuroaxonal dystrophy resulting from the deficient activity of lysosomal α‐N‐acetylgalactosaminidase are described. This neurodegenerative disorder was recognized in two brothers who had the typical clinical manifestations and neuropathological lesions observed in patients with Seitelberger disease, the infantile form of neuroaxonal dystrophy. Axonal ‘spheroids’ were observed histologically in the grey matter, and ultrastructural examination revealed the characteristic formations in dystrophic axons in the myenteric plexus and neocortex. Using a newly synthesized fluorogenic substrate, 4‐methylumbelliferyl‐α‐N‐acetylgalactosaminide, the markedly deficient activity ofα‐N‐acetylgalactosaminidase was demonstrated in the affected brothers while their consanguineous parents had intermediate activities, consistent with the autosomal recessive transmission of this disease. No detectableα‐N‐acetylgalactosaminidase was seen in immunoblots using monospecific rabbit antihumanα‐N‐acetylgalactosaminidase antibodies. Abnormally increased amounts of urinary glycopeptides were observed by high resolution thin layer chromatography. Analytical studies identified four of the accumulating urinary compounds, the blood group A trisaccharide GalNAcα1 → 3(Fucα1 → 2)Gal and threeO‐linked glycopeptides, GalNAcα1 →O‐serine and ‐threonine, NeuNAcα2 → 3Galβ1 → 3(NeuNAcα2 → 6)GalNAcα1 →O‐serine and ‐threonine, and NeuNAcα2 → 3Galβ1 → 4GlcNAcβ1 → 6(NeuNAcα2 → 3Galβ1 → 3)GalNAcα1 →O‐serine and ‐threonine. Of eight unrelated patients diagnosed as having infantile neuraxonal dystrophy by pathological studies, none had deficientα‐N‐acetylgalactosaminidase activity, emphasizing the biochemical heterogeneity underlying this diagnostic entity. These findings document the first delineation of a metabolic defect in an inherited neuroaxonal dystrophy and suggest that the axonal pathology in this disorder, and perhaps in the other neuroaxonal dystrophies, results from abnormal glycoprotein metabolism involvingO‐linked glycopeptides.
Advances in the molecular genetics of metachromatic leukodystrophy
Authors: Gieselmann V. , von Figura K.
Published: June 2005

Metachromatic leukodystrophy is a lysosomal storage disorder caused by the deficiency of arylsulphatase A (EC 3.1.6.1). This results in the intralysosomal storage of cerebroside sulphate, which leads to a progressive demyelination of the nervous system. The patients usually die within a few years from the onset of symptoms. Clinically, there are different forms of the disease and the molecular basis for this heterogeneity is unknown. The gene for arylsulphatase A has recently been cloned and provides a necessary tool for the exact description of the molecular defects occurring in the different forms of metachromatic leukodystrophy. Metachromatic leukodystrophy can also be caused by the deficiency of an arylsulphatase A activator protein (sphingolipid activator protein B). The cDNA for the precursor of this protein has been isolated and a mutant cDNA of one patient has been analysed. A substantial arylsulphatase A deficiency can also occur in healthy individuals, a phenotype termed pseudodeficiency. Two concurrent mutations have been identified in this low arylsulphatase A activity allele. This permitted the development of a rapid assay which allows the detection of the pseudodeficiency allele. Bone marrow transplantation has been tried in several metachromatic leukodystrophy patients and there is evidence that this treatment might slow or even halt the progression of the disease. A final conclusion as to whether bone marrow transplantation is a suitable therapy for metachromatic leukodystrophy cannot be drawn yet.
The effects of high phenylalanine concentration on chick embryonic development
Authors: Kirby M. L. , Miyagawa S. T.
Published: June 2005

Cells from a particular portion of the cranial neural crest (cardiac neural crest) migrate from the neural fold into pharyngeal arches 3, 4 and 6, where they provide the support for the endothelium of the aortic arch arteries, and by migration into the outflow tract become involved in septation of the truncus arteriosus. Ablation of the premigratory cardiac neural crest results in persistent truncus arteriosus and other defects reminiscent of the DiGeorge syndrome in man. Removal of a small area of the cardiac neural crest causes a spectrum of heart defects classified together as dextraposed aorta including changes like that of Fallot's tetralogy in man. Some inflow tract anomalies have also been found. Pilot studies injecting phenylalanine into developing chick embryos at a very early stage had little effect on embryo viability or on the incidence of congenital heart defects. However, sham‐treated animals produced predominantly small simple ventricular septal defects but phenylalanine‐treated embryos had more serious and complex heart anomalies. It is not possible to say yet that congenital heart disease in the offspring of mothers with untreated phenylketonuria is due to phenylalanine‐induced damage to the neural crest, but the pilot studies in chick suggest that this idea is worth pursuing.
Clinical aspects of mitochondrial disorders
Authors: Munnich A. , Rustin P. , Rötig A. , Chretien D. , Bonnefont J.‐P. , Nuttin C. , Cormier V. , Vassault A. , Parvy P. , Bardet J. , Charpentier C. , Rabier D. , Saudubray J.‐M.
Published: June 2005

Mitochondrial disorders have long been regarded as neuromuscular diseases only. In fact, owing to the ubiquitous nature of the oxidative phosphorylation, a broad spectrum of clinical features should be expected in mitochondrial disorders. Here, we present eight puzzling observations which give support to the view that a disorder of oxidative phosphorylation can give rise to any symptom in any organ or tissue with any apparent mode of inheritance. Consequently, we suggest giving consideration to the diagnosis of a mitochondrial disorder when dealing with an unexplained association of symptoms, with an early onset and a rapidly progressive course involving seemingly unrelated organs. Determination of lactate/pyruvate and ketone body molar ratios in plasma can help to select patients at risk for this condition.
Nucleus‐driven mutations of human mitochondrial DNA
Authors: Zeviani M.
Published: June 2005

Neuromuscular disorders due to abnormalities of mitochondrial energy supply have become an important area of human pathology. In particular, lesions of the mitochondrial genome (mtDNA), a small extra‐nuclear chromosome which encodes 13 subunits of the respiratory chain complexes, are responsible for a steadily increasing number of neuromuscular syndromes. In addition to sporadic or maternally‐inherited mutations, either qualitative or quantitative abnormalities of mtDNA can be transmitted as Mendelian traits, leading to well‐defined mitochondrial encephalomyopathies. The latter are presumably caused by mutations in still unknown nucleus‐encoded genes which deleteriously interact with the mitochondrial genome. These observations are of importance from both clinical and theoretical points of view, because they are the first examples of diseases produced by abnormalities of the nuclear control over mitochondrial biogenesis.
Molecular detection of altered X‐inactivation patterns in the diagnosis of genetic disease
Authors: Malcolm S.
Published: June 2005

It is widely assumed that when a female carrier of a genetic disorder exhibits clinical signs of the disorder it is due to chance non‐random X‐inactivation in particular tissues. Recently molecular methods have become available for the analysis of X‐chromosome inactivation status. These are based either on the methylation patterns of DNA from the active and inactive chromosomes or on the rescue of active X chromosomes in somatic cell hybrids. As a consequence of the molecular studies, it has become obvious that there are some special cases of non‐random X‐inactivation patterns. These include females carrying X‐linked immunodeficiencies and, sometimes, one of a pair of identical female twins.
Molecular analysis of the fragile X syndrome
Authors: Hirst M. C. , Knight S. M. , Nakahori Y. , Roche A. , Davies K. E.
Published: June 2005

The molecular analysis of human X‐linked disease has progressed rapidly over the last few years owing to advances in power of mapping techniques. Physical DNA maps covering more than 5 million base pairs have been constructed for several chromosomal regions. Many of these regions have now also been cloned into overlapping cosmid and YAC contigs facilitating the search for disease genes. The recent identification of the mutation in the fragile X syndrome is such an example of the power of YAC technology in the characterization of human genetic disease mutations.
Molecular genetics of mineral metabolic disorders
Authors: Thakker R. V.
Published: June 2005

The recent advances in molecular biology and cytogenetics have made it possible to localize, clone and characterize some of the genetic abnormalities which result in disorders of phosphate and calcium homeostasis. Thus, the genes causing X‐linked hypophosphataemic rickets, Lowe syndrome, X‐linked recessive hypoparathyroidism, Di George syndrome, multiple endocrine neoplasia type 1, multiple endocrine neoplasia type 2 and vitamin D‐dependent rickets type I have been mapped. In addition the genes involved in the pathogenesis of the humoral hypercalcaemia of malignancy, vitamin D‐dependent rickets type II, pseudohypoparathyroidism, and some of the autosomal forms of hypoparathyroidism have been cloned and the mutations characterized. The molecular and genetic studies which have mapped and identified these disease genes are described and the implications of these developments in clinical practice and in further elucidation of the mineral metabolic defects are discussed.
X‐linked hypophosphataemia: A homologous phenotype in humans and mice with unusual organ‐specific gene dosage
Authors: Scriver C. R. , Tenenhouse H. S.
Published: June 2005

XLH (X‐linked hypophosphataemia, gene symbolHYP, McKusick 307800, 307810) and its murine counterparts (Hyp andGy) map to a conserved segment on the X‐chromosome (Xp 22.31‐p.21.3, human; distal X, mouse). Gene dosage has received relatively little attention in the long history of research on this disease, which began over 50 years ago. Bone and teeth are sites of the principal disease manifestations in XLH (rickets, osteomalacia, interglobular dentin). Newer measures of quantitative XLH phenotypes reveal gene dose effects in bone and teeth with heterozygous values distributed between those in mutant hemizygotes and normal homozygotes. On the other hand, serum phosphate concentrations (which are low in the mutant phenotype and thereby contribute to bone and tooth phenotypes) do not show gene dosage. InHyp mice serum values in mutant hemizygotes, mutant homozygotes and heterozygotes are similar. Phosphate homeostasis reflects its renal conservation. Renal absorption of phosphate on a high‐affinity, Na+ ion‐gradient coupled system in renal brush border membrane is impaired and gene dosage is absent at this level; the mutant phenotype is fully dominant. Synthesis and degradation of 1,25(OH)2D are also abnormal in XLH (andHyp), but gene dosage in these parameters has not yet been measured. An (unidentified) inhibitory trans‐acting product of the X‐linked locus, affecting phosphate transport and vitamin D metabolism, acting perhaps through cytosolic protein kinase C, could explain the renal phenotype. But why would it have a normal gene dose effect in bone and teeth? Since the locus may have duplicated (to formHyp andGy), and shows evidence of variable expression in different organs (inner ear, bone/teeth, kidney), it may have been recruited during evolution to multiple functions.
Mouse models of hypoxanthine phosphoribosyltransferase deficiency
Authors: Williamson D. J. , Hooper M. L. , Melton D. W.
Published: June 2005

Lesch‐Nyhan syndrome is an X‐linked disease caused by the deficiency of hypoxanthine phosphoribosyltransferase, an enzyme involved in the purine salvage pathways. It is characterized by severe gout, choreoathetosis, self‐mutilatory behaviour and mental retardation. The derivation of mice genetically deficient in this enzyme may help to elucidate the pathogenesis of the neurological abnormality where previously models using drug administration to mimic the disorder have had to suffice.
Biochemistry and molecular biology of chronic granulomatous disease
Authors: Segal A. W.
Published: June 2005

The NADPH oxidase of phagocytic cells is an electron transport chain in the wall of the endocytic vacuole that is activated upon engulfment of the microbe, and is important for its efficient killing and digestion. The oxidase consists of a heterodimeric cytochrome b in the membrane, which is the site of the haem and FAD groups, and two cystolic factors p47‐phox and p67‐phox that appear to activate the system. Absence of this oxidase as a result of defects in each of these specialized proteins causes the syndrome of chronic granulomatous disease (CGD), that is characterized by a profound predisposition to pyogenic infection.
DNA‐based presymptomatic diagnosis of Wilson disease
Authors: Gaffney D. , Walker J. L. , O'Donnell J. G. , Fell G. S. , O'Neill K. F. , Park R. H. R. , Russell R. I.
Published: June 2005

Investigation using DNA markers in a family with Wilson disease revealed that an apparently normal child of 10 years of age with non‐diagnostic copper biochemistry had the disease. The procedure used linked restriction fragment length polymorphic markers. Demonstration of increased liver copper concentration from a liver biopsy confirmed the diagnosis and the child was started on chelation therapy. Two other asymptomatic siblings were shown, using the same techniques, not to have the disease. Similar analysis was carried out on another family with just one index case.
Hereditary tyrosinaemia type II in a consanguineous Ashkenazi Jewish family: Intrafamilial variation in phenotype; absence of parental phenotype effects on the fetus
Authors: Chitayat D. , Balbul A. , Hani V. , Mamer O. A. , Clow C. , Scriver C. R.
Published: June 2005

We describe an Ashkenazi Jewish family in which two adults, offspring of consanguineous parents, have persistent hypertyrosinaemia (770–1110 µmol/L; normal < 110 µmol/L). The metabolic disorder in this family is apparently due to hepatic cytosolic tyrosine aminotransferase deficiency (hereditary tyrosinaemia, type II; McKusick, 276600), because it is associated with the oculocutaneous manifestations of Richner‐Hanhart syndrome. The association of this syndrome with hereditary tyrosinaemia type II is presumed to be constant. It is not in this family. The affected female sib (age 41 years) has hypertyrosinaemia and oculocutaneous signs; the brother (age 39 years) has hypertyrosinaemia but no oculocutaneous disease. Both sibs have two children; none has signs of a metabolic fetopathy. Maternal hypertyrosinaemia and maternal hyperphenylalaninaemia evidently constitute different risk factors for the fetus. Paternal hypertyrosinaemia is apparently not a risk to male infertility.
Tris discriminates between the different α‐glucosidase activities from extracts of human neutrophils
Authors: Ortiz de Apodaca M. Asunción , Fernandez E. , de la Fuente G.
Published: June 2005

In an attempt to detect acid maltase deficiency in neutrophils from patients with type II glycogenosis, without interference from the ‘renal’ α‐glucosidase activity present in these cells, we have evaluated the contribution of the renal component in the total activity measured at pH 4.0 in extracts of human neutrophils. The renal contribution is about 13–25% and renal glucosidase appears to be closely related to the enzyme present on the epithelium of small intestine, which is known to be inhibited by Tris. We have used this compound as a selective inhibitor of the renal component of α‐glucosidase activity measured at pH 4.0 in total extracts of neutrophils. Our results demonstrate that 0.1 mol/L Tris is an inhibitor of the renal α‐glucosidase present in neutrophils and can be used to reduce the interference from this enzyme in assays of acid maltase.
Thiamine transport by erythrocytes and ghosts in thiamine‐responsive megaloblastic anaemia
Authors: Rindi G. , Casirola D. , Poggi V. , De Vizia B. , Patrini C. , Laforenza U.
Published: June 2005

A 9‐year study of thiamine metabolism and cellular transport was performed in two patients with thiamine‐responsive megaloblastic anaemia associated with diabetes mellitus and sensorineural deafness, in their relatives, and in age‐matched controls from the same area. The ratios between the content of thiamine and that of its phosphoesters in erythrocytes were within the normal range, whereas the absolute values of thiamine and thiamine compounds were reduced by about 40% as compared to controls. Thiamine pyrophosphokinase activity was about 30% lower than in controls. Thiamine treatment restored the levels of thiamine and thiamine compounds to normal values, whereas kinase was unaffected. Both the saturable (specific, predominant at low, < 2 µmol/L, physiological concentrations of thiamine) and the non‐saturable component of thiamine transport were investigated. Erythrocytes and ghosts from patients exhibited no saturable component, this abnormality being specific for the patients and not shared by their parents. It is concluded that the cells from thiamine‐responsive megaloblastic anaemia patients contain low levels of thiamine compounds, probably due to their inability to take up and retain physiological concentrations of thiamine, as a result of the lack of the saturable, specific component of transport and reduced thiamine pyrophosphokinase.
Decreased selenium intake and low plasma selenium concentrations leading to clinical symptoms in a child with propionic acidaemia
Authors: Yannicelli S. , Hambidge K. M. , Picciano M. F.
Published: June 2005

A child with biotin‐non‐responsive propionic acidaemia treated with a propiogenic amino acid‐restricted diet presented with an elevated blood mean corpuscular volume (MCV) of 93.1 fl, indicative of macrocytosis, and unusual hair texture with hypopigmentation. Plasma selenium concentration at this time was subnormal (45.9 µg/L), and calculated dietary selenium intake was 4.7 µg/day. After 4 months of selenium supplementation (50 µg/day) plasma selenium concentration normalized (97.7 µg/L) in conjunction with a reduced MCV (84.0 fl) and a dramatic improvement in hair growth, colour and length. Two additional periods off and on selenium supplementation, of varying time intervals, resulted in similar clinical changes. We conclude that these clinical changes were due to a deficient intake of dietary selenium.