We have calculated the relative frequency and the birth prevalence of lysosomal storage diseases (LSDs) in The Netherlands based on all 963 enzymatically confirmed cases diagnosed during the period 1970-1996. The combined birth prevalence for all LSDs is 14 per 100,000 live births. Glycogenosis type II is the most frequent LSD with a birth prevalence of 2.0 per 100,000 live births, representing 17% of all diagnosed cases. Within the group of lipidoses, metachromatic leukodystrophy (MLD) is the most frequent LSD. MLD was diagnosed in 24% of lipidoses and the calculated birth prevalence was 1.42 per 100,000 for all types combined. Krabbe disease, diagnosed in 17% of cases, also belongs to the more frequent lipid storage diseases in The Netherlands with a birth prevalence of 1.35 per 100,000. The birth prevalence of Gaucher disease, commonly regarded as the most frequent lipid storage disease is 1.16 per 100,000 for all types combined. The combined birth prevalence for all lipid storage diseases is 6.2 per 100,000 live births. Within the group of mucopolysaccharidoses (MPSs), MPS I has the highest calculated birth prevalence of 1.19 per 100,000 (25% of all cases of MPS diagnosed), which is slightly more frequent than MPS IIIA with an estimated birth prevalence of 1.16 per 100,000. As a group, MPS III comprises 47% of all MPS cases diagnosed and the combined birth prevalence is 1.89 per 100,000 live births. The birth prevalence of MPS II is 0.67 per 100,000 (1.30 per 100,000 male live births). All other MPSs are rare. The combined birth prevalence for all MPSs is 4.5 per 100,000 live births. Mucolipidoses and oligosaccharidoses are very rare with birth prevalences between 0.04 and 0.20 for individual diseases. Only 49 cases were diagnosed between 1970 and 1996. Their combined birth prevalence is 1.0 per 100,000 live births.
Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disease characterised by thymine-uraciluria in homozygous deficient patients and has been associated with a variable clinical phenotype. In order to understand the genetic and phenotypic basis for DPD deficiency, we have reviewed 17 families presenting 22 patients with complete deficiency of DPD. In this group of patients, 7 different mutations have been identified, including 2 deletions [295-298delTCAT, 1897delC], 1 splice-site mutation [IVS14+1G>A)] and 4 missense mutations (85T>C, 703C>T, 2658G>A, 2983G>T). Analysis of the prevalence of the various mutations among DPD patients has shown that the G-->A point mutation in the invariant splice donor site is by far the most common (52%), whereas the other six mutations are less frequently observed. A large phenotypic variability has been observed, with convulsive disorders, motor retardation and mental retardation being the most abundant manifestations. A clear correlation between the genotype and phenotype has not been established. An altered beta-alanine, uracil and thymine homeostasis might underlie the various clinical abnormalities encountered in patients with DPD deficiency.
SCADD is far more common than assumed previously, and clinical symptoms in SCADD are nonspecific, generally uncomplicated, often transient, and not correlated with specific ACADS genotypes. Because SCADD does not meet major newborn screening criteria, including a lack of clinical significance in many patients and that it is not possible to differentiate diseased and nondiseased individuals, it is not suited for inclusion in newborn screening programs at the present time.
MTHFR deficiency is a severe disease primarily affecting the central nervous system. Age at presentation and clinical pattern are correlated with residual enzyme activity. Treatment alleviates biochemical abnormalities and clinical symptoms partially.
Enhanced hemopexin activity may be associated with normal pregnancy, but not with preeclampsia. Decreased hemopexin in pre-eclamptic patients may be due to enhanced plasma ATP, which is possibly promoted by diminished activity of vascular ecto-apyrase.
Absolute measurements of protein abundance are important in the understanding of biological processes and the precise computational modeling of biological pathways. We developed targeted LC-MS/MS assays in the selected reaction monitoring (SRM) mode to quantify over 50 mitochondrial proteins in a single run. The targeted proteins cover the tricarboxylic acid cycle, fatty acid β-oxidation, oxidative phosphorylation, and the detoxification of reactive oxygen species. Assays used isotopically labeled concatemers as internal standards designed to target murine mitochondrial proteins and their human orthologues. Most assays were also suitable to quantify the corresponding protein orthologues in rats. After exclusion of peptides that did not pass the selection criteria, we arrived at SRM assays for 55 mouse, 52 human, and 51 rat proteins. These assays were optimized in isolated mitochondrial fractions from mouse and rat liver and cultured human fibroblasts and in total liver extracts from mouse, rat, and human. The developed proteomics approach is suitable for the quantification of proteins in the mitochondrial energy metabolic pathways in mice, rats, and humans as a basis for translational research. Initial data show that the assays have great potential for elucidating the adaptive response of human patients to mutations in mitochondrial proteins in a clinical setting.
and early adulthood, the symptoms seem to regress and norType III glycogen storage disease (GSD) is a disorder mal adulthood appears possible in most patients. 3 With reof carbohydrate metabolism caused by a deficiency of spect to the liver it has been noticed that the hepatomegaly debranching enzyme. Different subtypes with different gradually resolves concurrent with decreases in elevated clinical pictures have been recognized. During childtransaminase levels. 3 Histologically, besides glycogen storhood and early adulthood, the symptoms generally reage, the development of more or less fibrosis seems to be the gress, and normal adulthood appears possible in most rule. Few reports present data on the development of cirrhopatients without symptoms or signs of cirrhosis. We resis with or without the sequelae of portal hypertension. 3-9 port on an adult patient with GSD who developed endDeath caused by end-stage cirrhosis is unusual. In Japan one stage cirrhosis and a small hepatocellular carcinoma.adult patient has been reported with the combination GSD She had GSD subtype IIIb, i.e., there were no signs of III, cirrhosis, and hepatocellular carcinoma. 9 cardiomyopathy, myopathy, or neuropathy. She under-We report on an adult patient with GSD IIIb who received went a successful transplantation, representing the first a transplant because of end-stage cirrhosis and a small hepacase treated this way for this indication to our knowltocellular carcinoma. To our knowledge, this is the first paedge, and she is doing well after 1 year. Debranching tient to receive a transplant for GSD IIIb cirrhosis. enzyme activity was absent both in the liver and in the leukocytes before transplantation. The debranching en- PATIENTS AND METHODS zyme activity remained absent in the leukocytes after transplantation. We conclude that patients with GSDWe describe the case of a woman with GSD IIIb up to 1 year after orthotopic liver transplantation. sponsible deficient debranching enzyme system was identihomogenates were prepared according to standard laboratory pracfied by Illingworth et al. 2 The debranching enzyme complex tice. A post-concanavalin A fraction from a leukocyte and liver hocomprises two different activities: oligo-1,4-1,4 glucan trans-mogenate was prepared according to the method of Van Diggelen et ferase (EC 2.4.1.25), which transfers three glucose residues al. 10 Limit dextrin was prepared from rabbit liver (type III; Sigma, as a unit from a side chain to the main glycogen chain, and Bornem, Belgium), essentially as described 11 using phosphorylase b amylo-1,6-a glucosidase (EC 3.2.1.33), which hydrolyzes the from rabbit liver (Boehringer Mannheim, Almere, The Netherlands). glucose at the a-1,6 position. 3 Different subtypes with differEnzyme Assay. Debranching enzyme was determined by mixing 25 mL of post-concanavalin A supernatant with 25 mL of potassium ent clinical pictures have been recognized. Approximately buffer (10 mmol/L, pH 6.5) and 50 mL of substrate solution (15 mg 80% of patients have subtype GSD IIIa, and ...
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