bluuebunny/crossref_metadata_2025_split huggingface dataset:
Metachromatic leukodystrophy: Molecular genetics and an animal model
Authors: Gieselmann V. , Matzner U. , Hess B. , Lüllmann‐Rauch R. , Coenen R. , Hartmann D. , D'Hooge R. , Dedeyn P. , Nagels G. 
Published: December 2002

AbstractMetachromatic leukodystrophy (MLD) is a lysosomal storage disorder caused by the deficiency of arylsulphatase A (ASA; EC 3.1.6.8). Deficiency of this enzyme causes intralysosomal storage of the sphingolipid cerebroside sulphate. This lipid is abundant in myelin and it may thus not be surprising that storage mainly affects oligodendrocytes. Patients suffer from a progressive demyelination causing various neurological symptoms. The disease is fatal and treatment is not available. The human ASA gene has been cloned and more than 40 mutations have been analysed that cause metachromatic leukodystrophy. Few of these alleles are frequent among patients, whereas most mutant alleles have only been found in single families. Since MLD has only been described in humans and no naturally occurring animal model has been described, ASA‐deficient mice have been generated by homologous recombination. The ASA knockout mice are unable to degrade sulphatide and store the lipid intralysosomally. The pattern of lipid storage in neuronal and nonneuronal tissues resembles that described for patients. In the nervous system, lipid storage is found in oligodendrocytes, astrocytes and some neurons. Animals display an astrogliosis and a decreased average axonal diameter. Purkinje cells and Bergmann glia of the cerebellum are morphologically aberrant. Demyelination is seen in the acoustic ganglion and occurs between the ages of 6 and 12 months. The animals are deaf at this age and display various neuromotor abnormalities. However, compared to humans the mice have a surprisingly mild phenotype, since they have a normal life span and do not develop widespread demyelination. ASA‐deficient mice have been transplanted with bone marrow, which was transduced with a retroviral vector expressing arylsulphatase A. The majority of transplanted animals display sustained expression of arylsulphatase A from the retroviral construct up to 5 months after transplantation. However, preliminary data suggest that this therapeutic approach does not reduce storage material.
The spectrum of mutations of the aspartoacylase gene in Canavan disease in non‐Jewish patients
Authors: Elpeleg O. N. , Shaag A. 
Published: December 2002

AbstractCanavan disease is an infantile neurodegenerative disease that is caused by mutations in the gene encoding the enzyme aspartoacylase. It has mainly been reported in Jewish families. Genotyping of newly diagnosed patients is essential for the carrier identification and prenatal diagnosis. The sequence of the coding region was determined in 15 non‐Jewish patients and 9 new mutations were identified: Y109X, P183H, V186F, M195R, P280L, P280S, A287T, 245insA, and a tentative missplicing mutation which leads to skipping of exon 5. The common pan‐European mutation, A305E, was identified in 40% of the alleles and the overall detection rate was 93%.
Nutritional deficiencies in a patient with glycogen storage disease type Ib
Authors: Kishnani P. S. , Boney A. , Chen Y.‐T. 
Published: December 2002

AbstractThe current mainstay of treatment in glycogen storage disease type I (GSD I) is dietary management that includes providing a frequent source of glucose to prevent hypoglycaemia. To ensure compliance, routine follow‐up by a health care team, including a dietitian, experienced in the treatment of GSD is necessary. We describe an adolescent patient with GSD Ib in good metabolic control who was admitted with a 3‐month history of weakness, depression, vomiting, decreased appetite and a 11.4‐kg weight loss. He had a recent onset of unsteady gait, inability to write, and sore mouth. After an extensive work‐up, the patient was found to have vitamin B12, folate, iron and other nutritional deficiencies, which explained his symptoms. The patient improved within 72h of initiation of total parenteral nutrition and therapeutic doses of deficient micronutrients, with a complete recovery in 2 months. Dietary restrictions, dependence on non‐food products (e.g. cornstarch in GSD I), and social and developmental issues place individuals with metabolic disorders at a high risk for developing an array of nutritional deficiencies. This case highlights the importance of both close follow‐up of the metabolic control and close monitoring of growth and nutritional intake in individuals with inborn errors of metabolism. This case also illustrates the importance of daily supplementation with appropriate multivitamins, calcium and other minerals needed to meet the Recommended Dietary Allowances (RDAs) in these patients.
Defects in activation and transport of fatty acids
Authors: Brivet M. , Boutron A. , Slama A. , Costa C. , Thuillier L. , Demaugre F. , Rabier D. , Saudubray J. M. , Bonnefont J. P. 
Published: December 2002

AbstractThe oxidation of long‐chain fatty acids in mitochondria plays an important role in energy production, especially in skeletal muscle, heart and liver. Long‐chain fatty acids, activated to their CoA esters in the cytosol, are shuttled across the barrier of the inner mitochondrial membrane by the carnitine cycle. This pathway includes four steps, mediated by a plasma membrane carnitine transporter, two carnitine palmitoyltransferases (CPT I and CPT II) and a carnitine‐acylcarnitine translocase. Defects in activation and uptake of fatty acids affect these four steps: CPT II deficiency leads to either exercise‐induced rhabdomyolysis in adults or hepatocardiomuscular symptoms in neonates and children. The three other disorders of the carnitine cycle have an early onset. Hepatic CPT I deficiency is characterized by recurrent episodes of Reye‐like syndrome, whereas severe muscular and cardiac signs are associated with episodes of fasting hypoglycaemia in defects of carnitine transport and translocase. Convenient metabolic investigations for reaching the diagnosis of carnitine cycle disorders are determination of plasma free and total carnitine concentrations, determination of plasma acylcarnitine profile by tandem mass spectrometry and in vitro fatty acid oxidation studies, particularly in fresh lymphocytes. Application of the tools of molecular biology has greatly aided the understanding of the carnitine palmitoyltransferase enzyme system and confirmed the existence of different related genetic diseases. Mutation analysis of CPT II defects has given some clues for correlation of genotype and phenotype. The first molecular analyses of hepatic CPT I and translocase deficiencies were recently reported.
Muscle carnitine acetyltransferase and carnitine deficiency in a case of mitochondrial encephalomyopathy
Authors: Melegh B. , Seress L. , Bedekovics T. , Kispál G. , Sümegi B. , Trombitás K. , Méhes K. 
Published: December 2002

AbstractProfound decrease of the carnitine acetyltransferase activity (0.08 U/g wet weight; 1.67% of control) and carnitine deficiency (total carnitine was 230 nmol/g wet weight in the patient vs 2730 in the controls) was detected in the skeletal muscle of a female paediatric patient. She died of her illness, which included cerebellar symptoms and slight muscle spasticity affecting mainly the lower extremities, at 1 year of age. Histological examination of the autopsy specimens revealed a selective Purkinje cell degeneration in the cerebellum: the cells had abnormal position, were shrunken and decreased in number, and displayed abnormal dendritic trees and fragmented, disorganized axons. Electron microscopy revealed mitochondrial abnormalities in skeletal and cardiac muscle and also in the Purkinje cells. Deletions of the mitochondrial DNA were detected in the muscle in heteroplasmic form (up to 7%). Mainly the ND4‐ND4L region was affected, as evidenced by the PCR; however, other regions of the mitochondrial genome also showed deletions of varying size and extent, suggesting multiple deletions of the mitochondrial DNA.
Neurochemistry and defects of biogenic amine neurotransmitter metabolism
Authors: Hyland K. 
Published: December 2002

AbstractThe purpose of the current review is to present a brief background examining the mechanisms controlling synthesis, storage, release and action of the biogenic amine neurotransmitters and to provide examples of newly defined conditions that expand our awareness of the diversity and complexity of the inherited diseases that affect these important regulators of central and peripheral homeostasis.
Ceramide accumulation is associated with increased apoptotic cell death in cultured fibroblasts of sphingolipid activator protein‐deficient mouse but not in fibroblasts of patients with Farber disease
Authors: Tohyama J. , Oya Y. , Ezoe T. , Vanier M. T. , Nakayasu H. , Fujita N. , Suzuki K. 
Published: December 2002

AbstractCeramide is recognized as an intracellular mediator of cell growth, differentiation and apoptosis. Tumour necrosis factor, anti‐fas antibody, radiation and anticancer drugs such as actinomycin D are known to induce apoptosis in several cell types through generation of ceramide by activation of the sphingomyelinase pathway or ceramide synthetase. In this study, we examined the occurrence of apoptosis in fibroblasts from patients with Farber disease and from sphingolipid activator protein‐deficient (sap−/−) mouse. These cells accumulate ceramide as the result of genetic deficiency of acid ceramidase and the ceramidase activator (sap‐D), respectively. Amounts of ceramide in fibroblasts from Farber patients and in fibroblasts from sap−/− mouse were increased 2.9‐fold and 2.8‐fold, respectively, over the level of controls. Despite the similar degree of ceramide accumulation, cells exhibiting apoptotic features were increased only in fibroblasts from the sap−/− mouse but not those from the Farber patients. Thymidine uptake of Farber fibroblasts was normal while that of sap−/− mouse fibroblasts was twice normal, consistent with the apparently normal growth and the different rates of apoptotic cell death in these two cell lines. These data suggest that intralysosomal accumulation of ceramide due to defective acid ceramidase or its activator may not play an important role as a mediator of apoptosis. The increased apoptosis in the cultured fibroblasts from the sap−/− mouse may be caused by mechanisms other than the ceramide accumulation. Although more frequent than normal, significant apoptotic cell death was not observed in sap−/− mouse brain in vivo.
Successful pregnancy in severe methylmalonic acidaemia
Authors: Wasserstein M. P. , Gaddipati S. , Snyderman S. E. , Eddleman K. , Desnick R. J. , Sansaricq C. 
Published: December 2002

AbstractMethylmalonic acidaemia is an inborn error of metabolism characterized by recurrent episodes of life‐threatening ketoacidosis. With improved and intensive treatment, these patients are living into adulthood, but many experience late‐onset disease complications such as chronic renal failure, chronic pancreatitis and osteopenia. We report the successful delivery of a healthy baby to a 20‐year‐old woman with vitamin B12‐unresponsive methylmalonic acidaemia who has these late‐onset manifestations of the disease and had plasma methylmalonic acid concentrations of 1900μmol/L during the first trimester of pregnancy.
Survival of two patients with severe δ‐aminolaevulinic acid dehydratase deficiency porphyria
Authors: Gross U. , Sassa S. , Arndt T. , Doss M. O. 
Published: December 2002

AbstractThe course of δ‐aminolaevulinic acid dehydratase activity was studied over the 23 years in erythrocytes of two male patients. The enzyme activity was originally 1–2%, which then increased to ∼8% of normal levels several years after clinical manifestation of the acute hepatic porphyria syndrome. Urinary excretions of δ‐aminolaevulinic acid and coproporphyrin III were excessively increased in the two patients with compound‐heterozygous δ‐aminolaevulinic acid dehydratase deficiency porphyria.
Isolation and characterization of the normal canine β‐galactosidase gene and its mutation in a dog model of GM1‐gangliosidosis
Authors: Wang Z. H. , Zeng B. , Shibuya H. , Johnson G. S. , Alroy J. , Pastores G. M. , Raghavan S. , Kolodny E. H. 
Published: December 2002

AbstractThe acid β‐galactosidase cDNA of Portuguese Water dogs was isolated and sequenced. The entire coding region of the gene consists of 2004 nucleotides encoding a protein of 668 amino acids. Its encoding sequence indicates approximately 86.5% identity at the nucleotide level and about 81% identity at the amino acid level with the encoding region of the human acid β‐galactosidase gene. The deduced amino acid sequence contains a 24‐amino‐acid putative signal sequence, six possible glycosylation sites, and seven cysteine residues. A homozygous recessive mutation, causing canine GM1‐gangliosidosis, was identified at nucleotide G200→A in exon 2 resulting in an Arg60→His (mutation R60H) amino acid substitution. The mutation creates a new restriction enzyme site for Pml1. Genotyping 115 dog samples for this acid β‐galactosidase gene alteration readily distinguished affected homozygous recessives (n=5), heterozygous carriers (n=50) and normal homozygotes (n=60). DNA mutation analysis provided a method more specific than enzyme assay of β‐galactosidase for determination of carriers.
Lovastatin does not correct the accumulation of very long‐chain fatty acids in tissues of adrenoleukodystrophy protein‐deficient mice
Authors: Yamada T. , Shinnoh N. , Taniwaki T. , Ohyagi Y. , Asahara H. , Horiuchi I. , Kira J. 
Published: December 2002

AbstractLovastatin, an inhibitor of 3‐hydroxy‐3‐methylglutarylcoenzyme A reductase, normalizes the very long‐chain fatty acids (VLCFA) concentrations in fibroblasts and plasma from patients with X‐linked adrenoleukodystrophy (X‐ALD). The effects of lovastatin on the accumulation of VLCFA in tissues of adrenoleukodystrophy protein (ALDP)‐deficient mice were assessed. ALDP‐deficient mice were fed chow with 0.01–0.1% lovastatin for 4–8 weeks. The VLCFA concentrations in the plasma, brain, spinal cord, liver and kidneys were measured. Treatment with 0.1% lovastatin significantly reduced body weight and total cholesterol in the plasma of ALDP‐deficient mice. Treatment with lovastatin, however, did not correct the accumulation of VLCFA in the plasma or tissues, including the brain and spinal cord. Lovastatin does not affect the accumulation of VLCFA in ALDP‐deficient tissues in mice.
Effect of sodium benzoate in the treatment of atypical nonketotic hyperglycinaemia
Authors: Neuberger J. M. , Schweitzer S. , Rolland M.‐O. , Burghard R. 
Published: December 2002

AbstractA 6‐month‐old girl presented with hypotonia and mild psychomotor retardation. Subsequently, an atypical manifestation of a nonketotic hyperglycinaemia was diagnosed, confirmed by significantly reduced activity of the glycine cleavage system in the liver tissue. After the patient developed hypsarrhythmia and had a single cerebral seizure, treatment with both sodium benzoate and dextromethorphan was started. During the following year, the girl was free of seizures with improvement of the EEG activity and showed retarded but continuously progressing psychomotor development. At the age of 20 months she began to walk freely but had generalized muscular hypotonia and moderate mental retardation. Discontinuation of dextromethorphan medication after one year of treatment did not change the clinical and electroencephalographic status. However, after cessation of sodium benzoate therapy, epileptic activity in the EEG and behavioural changes occurred. These changes disappeared promptly after sodium benzoate therapy was reinstituted. Thus, this case of mild atypical nonketotic hyperglycinaemia with only moderate psychomotor retardation and without epilepsy benefited from treatment with sodium benzoate in terms of electroencephalographic and behavioural changes.
Mitochondrial respiratory chain defects are not accompanied by an increase in the activities of lactate dehydrogenase or manganese superoxide dismutase in paediatric skeletal muscle biopsies
Authors: Hargreaves I. P. , Heales S. J. R. , Land J. M. 
Published: December 2002

AbstractBoth the activity of lactate dehydrogenase (LDH) and the quantity of manganese superoxide dismutase (MnSOD) protein have been reported to be increased in fibroblasts from individuals with mitochondrial electron transport chain defects. To ascertain whether this is a general phenomenon, we have determined the specific activities of these enzymes in skeletal muscle biopsies from control individuals and patients with defined electron transport chain defects. On investigation, both LDH and MnSOD activities were not found to be elevated. These findings suggest a possible fundamental difference between skeletal muscle preparations and fibroblasts with regard to their metabolic response to an electron transport chain defect.
Erythropoietic and hepatic porphyrias
Authors: Gross U. , Hoffmann G. F. , Doss M. O. 
Published: December 2002

AbstractPorphyrias are divided into erythropoietic and hepatic manifestations. Erythropoietic porphyrias are characterized by cutaneous symptoms and appear in early childhood. Erythropoietic protoporphyria is complicated by cholestatic liver cirrhosis and progressive hepatic failure in 10% of patients. Acute hepatic porphyrias (δ‐aminolaevulinic acid dehydratase deficiency porphyria, acute intermittent porphyria, hereditary coproporphyria and variegate porphyria) are characterized by variable extrahepatic gastrointestinal, neurological–psychiatric and cardiovascular manifestations requiring early diagnosis to avoid life‐threatening complications. Acute hepatic porphyrias are pharmacogenetic and molecular regulatory diseases (without porphyrin accumulation) mainly induced by drugs, sex hormones, fasting or alcohol. The disease process depends on the derepression of hepatic δ‐aminolaevulinic acid synthase following haem depletion. In contrast to the acute porphyrias, nonacute, chronic hepatic porphyrias such as porphyria cutanea tarda are porphyrin accumulation disorders leading to cutaneous symptoms associated with liver disease, especially caused by alcohol or viral hepatitis. Alcohol, oestrogens, haemodialysis, hepatitis C and AIDS are triggering factors. Porphyria cutanea tarda is the most common porphyria, followed by acute intermittent porphyria and erythropoietic protoporphyria. The molecular genetics of the porphyrias is very heterogenous. Nearly every family has its own mutation. The mutations identified account for the corresponding enzymatic deficiencies, which may remain clinically silent throughout life. Thus, the recognition of the overt disorder with extrahepatic manifestations depends on the demonstration of biochemical abnormalities due to these primary defects and compensatory hepatic overexpression of hepatic δ‐aminolaevulinic acid synthase in the acute porphyrias. Consequently, haem precursors are synthesized in excess. The increased metabolites upstream of the enzymatic defect are excreted into urine and faeces. The diagnosis is based on their evaluation. Primary enzymatic or molecular analyses are noncontributary and may be misleading. Acute polysymptomatic exacerbations accompany a high excretory constellation of porphyrin precursors δ‐aminolaevulinic acid and porphobilinogen. Homozygous or compound heterozygous variants of acute hepatic porphyrias may already manifest in childhood.
The natural course of Gaucher disease in The Netherlands: Implications for monitoring of disease manifestations
Authors: Maaswinkel‐Mooij P. , Hollak C. , Van Eysden‐Plaisier M. , Prins M. , Aerts H. , Pöll R. 
Published: December 2002

AbstractThis retrospective study in 20 untreated type I Gaucher disease patients shows that in Dutch patients clinical manifestations of Gaucher disease type I are progressive in the majority of patients, children as well as adults. This is in contrast with studies among Jewish patients. Our results emphasize the need for a regular follow‐up to enable timely initiation of enzyme therapy.
Isolated and contiguous glycerol kinase gene disorders: A review
Authors: Sjarif D. R. , Ploos van Amstel J. K. , Duran M. , Beemer F. A. , Poll‐The B. T. 
Published: December 2002

AbstractGlycerol kinase deficiency (GKD) is an X‐linked recessive disorder. There are two types, an isolated form and a complex form. We review the clinical, biochemical and molecular genetic features of GKD. The clinical and biochemical phenotype of isolated GKD may vary from a life‐threatening childhood metabolic crisis to asymptomatic adult ‘pseudohypertriglyceridaemia’, resulting from hyperglycerolaemia. To date 38 patients from 24 families with isolated GKD have been reported. At least 7 of these patients had a metabolic crisis during a catabolic condition. The complex GKD is an Xp21 contiguous gene syndrome involving the glycerol kinase locus together with the adrenal hypoplasia congenita (AHC) or Duchenne muscular dystrophy (DMD) loci or both. Clinical features of a patient with complex GKD depend on the loci that are involved. Approximately 100 patients from 78 families with a complex GKD have been reported. Seventeen patients with complex GKD (AHC‐GKD‐DMD or AHC‐GKD) died in the neonatal period or early childhood because of unrecognized or inappropriate management of adrenal dysfunction. Since the outcome of the crisis in GKD is highly dependent on the physicians' knowledge of the disease, we devised an algorithmic approach to the diagnosis. From molecular genetic investigations of isolated GKD, 7 missense mutations, 2 splice site mutations, 1 nonsense mutation, 1 Alu Sx insertion and 2 small deletions were reported for isolated GKD in 13 unrelated families. In 4 families consisting of more than one patient with the same biochemical and genetic defect, the phenotypic, variability, of, the, isolated GKD was remarkable. The clinical variability, in, isolated, GKD, cannot, be, explained, by, biochemical, or, by molecular heterogeneity. Isolated GKD patients showed a tendency towards hypoglycaemia with hyperketonaemia; whether the clinical symptoms of GKD are caused by dysfunction of gluconeogenesis and/or ketolysis needs to be investigated further.
Tripeptidyl‐peptidase I deficiency in classical late‐infantile neuronal ceroid lipofuscinosis brain tissue. Evidence for defective peptidase rather than proteinase activity
Authors: Warburton M. J. , Bernardini F. 
Published: December 2002

AbstractBrain tissue from patients with classical late‐infantile neuronal ceroid lipofuscinosis (LINCL, an infantile form of Batten disease) is deficient in the lysosomal enzyme tripeptidyl‐peptidase I (EC 3.4.14.9). The activities of other lysosomal enzymes are either increased or decreased. Tripeptidyl‐peptidase I is a pepstatin‐insensitive exo‐tripeptidase, with little or no endo‐proteolytic activity, that is active on small peptides but not on large proteins. Using haemoglobin and casein as substrates for proteolytic activity, we were unable to demonstrate any significant defect in pepstatin‐sensitive or pepstatin‐insensitive proteinase activity in brain tissue or cultured skin fibroblasts of LINCL patients. These observations suggest that the lysosomal storage of undegraded, small peptides in LINCL results from the absence of peptidase rather than proteinase activity.