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Biomedical subjects

J Jaeken

Publications and source records attributed to J Jaeken.

At least 19 recordsLinked to original sources
PubMed2006

Borderline mental development in a congenital disorder of glycosylation (CDG) type Ia patient with multisystemic involvement (intermediate phenotype).

CDG Ia (phosphomannomutase deficiency) has a wide clinical spectrum with the most severe affected patients having multisystemic disease in addition to severe nervous system involvement. We report a patient with CDG Ia and an intermediate phenotype due to mild neurological impairment and borderline cognitive abilities despite the occurrence of typical extraneurological symptoms. These included liver involvement, coagulopathy and failure to thrive with enteropathy. Genotype analyses showed that he was compound heterozygous for T237R/C241S mutations. This observation underlines that the CDG Ia clinical spectrum may include intraindividual variability that might reflect different degrees of glycosylation abnormalities among distinct body compartments. CDG Ia should be considered in cases of unexplained liver involvement and/or enteropathy in patients with mild developmental delay and subtle neurological signs.

Carbohydrate Metabolism, Inborn Errors↗
PubMed2006

Normal pregnancy outcome in L-2-hydroxyglutaric aciduria.

L-2-Hydroxyglutaric aciduria (L-2-HGA) is a rare progressive neurometabolic disease, defined as a characteristic clinical and radiological entity, mainly including mental retardation, cerebellar dysfunction and involvement of the subcortical white matter, cerebellum and basal ganglia on brain MRI. The biochemical hallmark is an increased urinary excretion of L-2-hydroxyglutaric acid. Management is only supportive. A child born to a Turkish mother in whom L-2-HGA was previously diagnosed is reported. Although pregnancy was repeatedly advised against because of the important degree of mental retardation and the potential risk of a toxic effect on the embryo and/or fetus (at that time no reports of maternal L-2-HGA were available), she became pregnant at 30 years of age and the pregnancy passed uneventfully. On amniocentesis, performed at 5 months of gestational age, elevated 2-hydroxyglutarate, previously shown to be almost exclusively the L-2-stereoisomer, was present in the amniotic fluid: 27.5mu mol/L (controls <1.3; n=5). The child, not affected by the disease as shown by a normal urinary excretion of 2-hydroxyglutaric acid, was normal at birth. When last examined at the age of 3 years, both somatic and mental development were excellent. As the pathogenesis of the extensive brain damage in affected persons remains largely unknown, notwithstanding the recent identification of the mutated gene and the deficient enzyme, one can only speculate on the mechanism by which embryo and fetus from a L-2-HGA mother are spared, at least in this case.

Adult↗
PubMed2005

Clinical and biochemical presentation of siblings with COG-7 deficiency, a lethal multiple O- and N-glycosylation disorder.

Congenital disorders of glycosylation (CDG) represent a group of inherited multiorgan diseases caused by defects in the biosynthesis of glycoproteins. We report on two dysmorphic siblings with severe liver disease who died at the age of a few weeks. Increased activities of lysosomal enzymes in plasma were found, though total sialic acid in plasma was strongly decreased. Isoelectric focusing of serum sialotransferrins showed a type 2-like CDG pattern. Some of the known CDG subtypes were excluded. O-Glycosylation was investigated by isoelectric focusing of apolipoprotein C-III, which showed increased fractions of hyposialylated isoforms. In a consecutive study a defect in the conserved oligomeric Golgi complex was established at the level of subunit COG-7, leading to disruption of multiple glycosylation functions of the Golgi. This report on patients with a new variant of CDG, due to a multiple Golgi defect, emphasizes in addition to sialotransferrins the importance of analysis of a serum O-linked glycoprotein, e.g. apolipoprotein C-III, in unclassified CDG-X cases.

Apolipoprotein C-III↗
PubMed2005

Benzoate treatment and the glycine index in nonketotic hyperglycinaemia.

High-dose benzoate treatment aimed at reducing plasma glycine levels to normal reduces seizures and increases wakefulness in patients with nonketotic hyperglycinaemia (NKH). Since benzoate metabolism is dependent on the available glycine pool, and since the glycine pool is variably affected by the deficiency in the glycine cleavage enzyme system, we examined the importance of interpatient variability in benzoate requirement. To correct for the dietary glycine contribution, the glycine index was introduced as the molar requirement of benzoate dose necessary to normalize plasma glycine levels and subtracting from that the dietary glycine intake, both corrected for weight. The glycine index varied between 3.62 and 4.87 mmol/kg per day in five patients with a poor neurodevelopmental outcome and between 0.92 and 1.90 mmol/kg per day in four patients with a better neurodevelopmental outcome, and was 2.54 mmol/kg per day in a single patient with an intermediate outcome. The glycine index was stable over time within each patient. Exceeding the balance by either increasing food glycine intake or decreasing the benzoate dose resulted in increased glycine levels. Exceeding the glycine tolerance by increasing benzoate resulted in elevated and toxic levels of benzoate. The glycine index is a stable, individually specific parameter in patients with NKH. It has clinical consequences for the dose of benzoate required and the role of dietary management. Through its correlation with neurodevelopmental outcome, the glycine index points to potential genetic factors that could contribute to the psychomotor retardation in NKH.

Adolescent↗
PubMed2005

Tissue distribution of the murine phosphomannomutases Pmm1 and Pmm2 during brain development.

The most common type of the congenital disorders of glycosylation, CDG-Ia, is caused by mutations in the human PMM2 gene, reducing phosphomannomutase (PMM) activity. The PMM2 mutations mainly lead to neurological symptoms, while other tissues are only variably affected. Another phosphomannomutase, PMM1, is present at high levels in the brain. This raises the question why PMM1 does not compensate for the reduced PMM2 activity during CDG-Ia pathogenesis. We compared the expression profile of the murine Pmm1 and Pmm2 mRNA and protein in prenatal and postnatal mouse brain at the histological level. We observed a considerable expression of both Pmms in different regions of the embryonic and adult mouse brain. Surprisingly, the expression patterns were largely overlapping. This data indicates that expression differences on the cellular and tissue level are an unlikely explanation for the absence of functional compensation. These results suggest that Pmm1 in vivo does not exert the phosphomannomutase-like activity seen in biochemical assays, but either acts on as yet unidentified specific substrates or fulfils entirely different functions.

Animals↗
PubMed2004

CDG IIx with unusual phenotype.

Congenital disorders of glycosylation (CDG) are a group of genetic diseases characterized by defective protein glycosylation. N-glycosylation defects are divided into two groups (I and II). CDG group II (types IIa to IIe) refers to defects in the Golgi processing of protein-bound glycans. We report a patient with CDG IIx and an unusual phenotype.

Anemia, Hemolytic↗
PubMed2004

Congenital disorders of glycosylation (CDG): update and new developments.

After a brief overview on CDG, this workshop concentrated on the experience with (mostly) known CDG in a European country (the Czech Republic) and on the Australasian experience, on recent developments regarding congenital muscular dystrophies due to O-mannoslyglycan assembly defects, and on new presentations of CDG. It was concluded that we are still at the beginning of 'explosive' research on CDG and that we need to apply new and known technologies to the diagnosis, understanding of pathophysiology, and treatment of CDG.

Carbohydrate Metabolism, Inborn Errors↗
PubMed2003

Abnormal lysosomal inclusions in liver hepatocytes but not in fibroblasts in congenital disorders of glycosylation (CDG).

We report a retrospective electron-microscopical study of liver biopsies and fibroblast cultures of 19 patients with congenital disorders of glycosylation (CDG) of different subtypes. A constant finding in liver biopsies of all CDG-I cases was that of abnormal lysosomal lamellar inclusions in the hepatocytes, which were not found in CDG-II. None of the patients showed significant abnormalities in their fibroblasts.

Bile Canaliculi↗
PubMed2003

Komrower Lecture. Congenital disorders of glycosylation (CDG): it's all in it!

Congenital disorders of glycosylation (CDGs) are due to defects in the synthesis of the glycan moiety of glycoproteins or other glycoconjugates. This review is devoted mainly to the clinical aspects of protein glycosylation defects. There are two main types of protein glycosylation: N-glycosylation and O-glycosylation. N-glycosylation generally consists of an assembly pathway (in cytosol and endoplasmic reticulum) and a processing pathway (in endoplasmic reticulum and Golgi). O-glycosylation lacks a processing pathway but is otherwise more complex. Sixteen disease-causing defects are known in protein glycosylation: 12 in N-glycosylation and four in O-glycosylation. The N-glycosylation defects comprise eight assembly defects (CDG-I) designated CDG-Ia to CDG-Ih, and four processing defects (CDG-II) designated CDG-IIa to CDG-IId. By far the most frequent is CDG-Ia (phosphomannomutase-2 deficiency). It affects the nervous system and many other organs. Its clinical expression varies from extremely severe to very mild (and thus probably underdiagnosed). The most interesting disease in this group is CDG-Ib (phosphomannose isomerase deficiency) because it is so far the only efficiently treatable CDG (mannose treatment). It has a hepatic-intestinal presentation. The O-glycosylation defects comprise two O-xylosylglycan defects (a progeroid variant of Ehlers-Danlos syndrome and the multiple exostoses syndrome) and two O-mannosylglycan defects (Walker-Warburg syndrome and muscle-eye-brain disease). All known CDGs have a recessive inheritance except for multiple exostoses syndrome, which is dominantly inherited. There is a rapidly growing group of putative CDGs with a large spectrum of clinical presentations (CDG-x). Serum transferrin iso-electrofocusing remains the cornerstone of the screening for N-glycosylation defects associated with sialic acid deficiency. Abnormal patterns can be grouped in to type 1 and type 2. However, a normal pattern does not exclude these defects. Screening for the other CDGs is much more difficult, particularly when the defect is organ- or system-restricted. The latter group promises to become an important new chapter in CDG. It is concluded that CDGs will eventually cover the whole clinical spectrum of paediatric and adult disease manifestations.

Bacterial Proteins↗
PubMed2002

Congenital microcephaly and seizures due to 3-phosphoglycerate dehydrogenase deficiency: outcome of treatment with amino acids.

Congenital microcephaly, intractable seizures and severe psychomotor retardation characterize 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency, a disorder of L-serine biosynthesis. The enzyme defect results in low concentrations of serine and to a variable degree of glycine in plasma and cerebrospinal fluid. Short-term beneficial effects have been reported of oral treatment with the deficient amino acids. In this paper, we report the first follow-up data of amino acid therapy in five patients treated for 3-7.5 years. Different treatment regimes were used, but a favourable response to amino acids was observed in all patients. A major reduction in seizure frequency occurred in all patients; two patients became free of seizures. Amino acids were well tolerated and no adverse effects were documented. A progress of psychomotor development was only observed in one patient, diagnosed early and treated with a high dosage of L-serine. A favourable outcome of 3-PGDH deficiency depends on early diagnosis and treatment.

Carbohydrate Dehydrogenases↗
PubMed2002

Biochemical and molecular studies in 26 Spanish patients with congenital disorder of glycosylation type Ia.

We present our experience with the diagnosis of 26 patients (19 families) with congenital disorders of glycosylation classified as type Ia due to PMM deficiency. In all but one of these CDG Ia families the patients are compound heterozygous for mutations in PMM2. Eighteen different mutations were detected. In contrast to other series in which R141H represents 43-50% of the alleles, only 9/36 (25%) alleles have this mutation. Two mutations (R123Q and T237M) have been found on three disease chromosomes, four (V44A, Y64C, P113L and F207S) on two disease chromosomes and 12 mutations (D65Y, Y76C, IVS3+2C>T, E93A, R123X, V129M, I153T, F157S, E197A, N216I, T226S, C241S) only on one disease chromosome. V44A and D65Y probably originated in the Iberian peninsula, as they have only been reported in Portuguese and Latin-American patients; Y64C, Y76C, R123X and F207S have not been detected in other patients. R123X is the only stop codon mutation so far described in PMM2. The common European F119L mutation has not been found in our patients, although it is very frequent in other populations (43% allele frequency in Danish patients). Probably because of this genetic heterogeneity, Spanish patients show very diverse phenotypes that are, in general, milder than in other series. This points to the necessity of widening the criteria for CDG in the routine screening for inborn metabolic diseases.

Carbohydrate Metabolism, Inborn Errors↗
PubMed2002

Aromatic L-amino acid decarboxylase deficiency with hyperdopaminuria. Clinical and laboratory findings in response to different therapies.

Aromatic L-amino acid decarboxylase (AADC - E.C. 4.1.1.28) converts L-dopa to dopamine and 5-hydroxytryptophan to serotonin. Inherited deficiency of this enzyme leads to decreased brain levels of these neurotransmitters. Clinically this results in the development of a progressive neurometabolic disorder characterized by severe hypotonia, dystonic and choreoathetoid movements, oculogyric crises, and hypothermia from infancy. Here we describe the clinical, biochemical and molecular details of two affected brothers, one of whom, despite the lack of AADC, presented with hyperdopaminuria. In addition, we detail his reactions to treatment with dopaminergic agonists, monoamine oxidase inhibitors and pyridoxine.

Aromatic-L-Amino-Acid Decarboxylases↗
PubMed2001

Increased alpha3-fucosylation of alpha(1)-acid glycoprotein in patients with congenital disorder of glycosylation type IA (CDG-Ia).

Increased fucosylation of the type (sialyl) Lewis(x) was detected on the acute-phase plasma protein alpha(1)-acid glycoprotein (AGP) in patients with the congenital disorder of glycosylation type IA. This is remarkable, because in these patients the biosynthesis of guanosine 5'-diphosphate (GDP)-D-mannose is strongly decreased, and GDP-D-mannose is the direct precursor for GDP-L-fucose, the substrate for fucosyltransferases. The concomitantly occurring increased branching of the glycans of AGP and the increased fucosyltransferase activity in plasma suggest that a chronic hepatic inflammatory reaction has induced the increase in fucosylation.

Amidohydrolases↗
PubMed2001

High residual activity of PMM2 in patients' fibroblasts: possible pitfall in the diagnosis of CDG-Ia (phosphomannomutase deficiency).

Congenital disorders of glycosylation (CDGs) are a rapidly enlarging group of inherited diseases with abnormal N-glycosylation of glycoconjugates. Most patients have CDG-Ia, which is due to a phosphomannomutase (PMM) deficiency. In this article, we report that a significant portion (9 of 54) of patients with CDG-Ia had a rather high residual PMM activity in fibroblasts included in the normal range (means of the controls +/- 2 SD) and amounting to 35%-70% of the mean control value. The clinical diagnosis of CDG-Ia was made difficult by the fact that most (6 of 9) of these patients belong to a subgroup characterized by a phenotype that is milder than classical CDG-Ia. These patients lack some of the symptoms that are suggestive for the diagnosis, such as inverted nipples and abnormal fat deposition, and, as a mean, had higher residual PMM activities in fibroblasts (2.05+/-0.61 mU/mg protein, n=9; vs. controls 5.34+/-1.74 mU/mg protein, n=22), compared with patients with moderate (1.32+/-0.86 mU/mg protein, n=18) or severe (0.63+/-0.56 mU/mg protein, n=27, P<.001) cases. Yet they all showed mild mental retardation, hypotonia, cerebellar hypoplasia, and strabismus. All of them had an abnormal serum transferrin pattern and a significantly reduced PMM activity in leukocytes. Six of the nine patients with mild presentations were compound heterozygotes for the C241S mutation, which is known to reduce PMM activity by only approximately 2-fold. Our results indicate that intermediate PMM values in fibroblasts may mask the diagnosis of CDG-Ia, which is better accomplished by measurement of PMM activity in leukocytes and mutation search in the PMM2 gene. They also indicate that there is some degree of correlation between the residual activity in fibroblasts and the clinical phenotype.

Amino Acid Sequence↗
PubMed2001

Band 3 glycoprotein and glycophorin A from erythrocytes of children with congenital disorder of glycosylation type-Ia are underglycosylated.

Band 3 and PAS-1 (a dimer of glycophorin A) from erythrocyte membranes of three children with congenital disorder of glycosylation, type Ia (CDG-Ia), aged 1 month, 3 years and 10 years respectively, were examined by a new technique that allowed determination of carbohydrate molar composition of glycoproteins separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis. In CDG children a single N-glycan of band 3 glycoprotein was hypoglycosylated and its mannose content was normal or elevated. Glycophorin A which is the major carrier of erythrocyte sialic acid, was deficient in N-acetylgalactosamine, and sialic acid residues. This finding indicated a partial unglycosylation of O-glycans in glycophorin A. In keeping with the results of PAS-1 analysis, total sialic acid in erythrocyte membranes from CDG children was reduced to 40-56% of normal values. A possible molecular mechanism of hypo- and unglycosylation of band 3 and glycophorin A, respectively, in CDG is discussed.

Anion Exchange Protein 1, Erythrocyte↗
PubMed2001

Congenital disorders of glycosylation type Ia and IIa are associated with different primary haemostatic complications.

Congenital disorders of glycosylation (CDG) type I are mostly due to a deficient phosphomannomutase activity, called CDG Ia. CDG IIa (mutations in the MGAT2 gene) results from a deficient activity of the Golgi enzyme N-acetylglucosaminyltransferase II. CDG Ia patients predominantly have a thrombotic tendency, whereas our CDG IIa patient has an increased bleeding tendency, despite similar coagulation factor abnormalities in both types. We have investigated whether abnormally glycosylated platelet membrane glycoproteins are involved in the haemostatic complications of both CDG groups. In flow cytometry, the binding of Ricinus communis lectin (reactive with beta-galactose primarily) to control platelets increased after neuraminidase treatment: this increase was smaller (p < 0.01) in CDG Ia patients (3.1 +/- 0.08 times) than in control platelets (8.5 +/- 1.8 times) and did not occur in the CDG IIa patient. Platelet-rich plasma from CDG Ia patients, but not a CDG IIa patient. aggregated spontaneously and gel-filtered platelets from CDG Ia patients agglutinated at very low concentrations of ristocetin, independently of von Willebrand factor (vWF). Accordingly, in stirred whole blood, the rate of single platelet disappearance of CDG Ia patients was twice that of control platelets. In contrast, perfusion of whole anticoagulated blood of the CDG IIa patient over collagen yielded markedly decreased platelet adherence to collagen at shear rates involving glycoprotein (GP) Ib-vWF interactions. Thus, abnormal glycosylation of platelet glycoproteins in CDG Ia enhances nonspecific platelet interactions, in agreement with a thrombotic tendency. The reduced GP Ib-mediated platelet reactivity with vessel wall components in the CDG IIa patient under flow conditions provides a basis for his bleeding tendency.

Blood Platelets↗