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Biomedical subjects

J Jaeken

Publications and source records attributed to J Jaeken.

At least 109 records · Page 6Linked to original sources
PubMed1996

Inhibition of phosphomannose isomerase by fructose 1-phosphate: an explanation for defective N-glycosylation in hereditary fructose intolerance.

Isoelectrofocusing of serum sialotransferrins from patients with untreated hereditary fructose intolerance (HFI) shows a cathodal shift similar to that in carbohydrate-deficient glycoprotein (CDG) syndrome type I and in untreated galactosemia. This report is on serum lysosomal enzyme abnormalities in untreated HFI that are identical to those found in CDG syndrome type I but different from those in untreated galactosemia. CDG syndrome type I is due to phosphomannomutase deficiency, a defect in the early glycosylation pathway. It was found that fructose 1-phosphate is a potent competitive inhibitor (Ki congruent to 40 microM) of phosphomannose isomerase (EC 5.3.1.8), the first enzyme of the N-glycosylation pathway thus explaining the N-glycosylation disturbances in HFI.

Animals↗
PubMed1996

Mutations in the MGAT2 gene controlling complex N-glycan synthesis cause carbohydrate-deficient glycoprotein syndrome type II, an autosomal recessive disease with defective brain development.

Carbohydrate-deficient glycoprotein syndrome (CDGS) type II is a multisystemic congenital disease with severe involvement of the nervous system. Two unrelated CDGS type II patients are shown to have point mutations (one patient having Ser-->Phe and the other having His-->Arg) in the catalytic domain of the gene MGAT2, encoding UDP-GlcNAc:alpha-6-D-mannoside beta-1,2-N- acetylglucosaminyltransferase II (GnT II), an enzyme essential for biosynthesis of complex Asn-linked glycans. Both mutations caused both decreased expression of enzyme protein in a baculovirus/insect cell system and inactivation of enzyme activity. Restriction-endonuclease analysis of DNA from 23 blood relatives of one of these patients showed that 13 donors were heterozygotes; the other relatives and 21 unrelated donors were normal homozygotes. All heterozygotes showed a significant reduction (33%-68%) in mononuclear-cell GnT II activity. The data indicate that CDGS type II is an autosomal recessive disease and that complex Asn-linked glycans are essential for normal neurological development.

Blotting, Northern↗
PubMed1996

Haemostatic studies in carbohydrate-deficient glycoprotein syndrome type I.

CDG syndrome (CDGS) type I is the most frequent form of a group of metabolic disorders characterised by a defect of the carbohydrate moiety of glycoproteins. A large number of plasma glycoproteins, including clotting factors and inhibitors, are decreased and stroke-like episodes have been described in about half of the reported patients. We studied blood coagulation factors, inhibitors and D-dimer plasma levels in four subjects, aged 12-23 years, with CDGS type I. Factors VIII, XI, antithrombin III activity, antigen plasma levels of antithrombin III, free protein S and protein C were decreased whereas protein C as activity was normal. In addition two patients had reduction of factors II, V, VII, IX, X reflecting the phenotypic heterogeneity associated with CDGS type I. D-dimer plasma concentrations were elevated in all subjects. The hypercoagulable state as consequence of the combined deficiencies of coagulation inhibitors could contribute to the stroke-like phenomena in CDGS type I.

Adolescent↗
PubMed1995

Phosphomannomutase deficiency is a cause of carbohydrate-deficient glycoprotein syndrome type I.

Carbohydrate-deficient glycoprotein (CDG) syndromes are genetic multisystemic disorders characterized by defective N-glycosylation of serum and cellular proteins. The activity of phosphomannomutase was markedly deficient (< or = 10% of the control activity) in fibroblasts, liver and/or leucocytes of 6 patients with CDG syndrome type I. Other enzymes involved in the conversion of glucose to mannose 1-phosphate, as well as phosphoglucomutase, had normal activities. Phosphomannomutase activity was normal in fibroblasts of 2 patients with CDG syndrome type II. Since this enzyme provides the mannose 1-phosphate required for the initial steps of protein glycosylation, it is concluded that phosphomannomutase deficiency, which is first reported here for higher organisms, is a cause, and most likely the major one, of CDG syndrome type I.

Adult↗
PubMed1995

Carbohydrate-deficient glycoprotein syndrome type II. An autosomal recessive N-acetylglucosaminyltransferase II deficiency different from typical hereditary erythroblastic multinuclearity, with a positive acidified-serum lysis test (HEMPAS).

Carbohydrate-deficient glycoprotein syndromes (CDGS) are a family of multisystemic congenital diseases resulting in underglycosylated glycoproteins, suggesting defective N-glycan assembly. Fibroblast extracts from two patients with a recently described variant of this disease (CDGS type II) have previously been shown to have over 98% reduced activity of UDP-GlcNAc:alpha-6-D-mannoside beta-1,2-N-acetylglucosaminyltransferase II [GlcNAc-TII; Jaeken, J., Schachter, H., Carchon, H., De Cock, P., Coddeville, B. & Spik, G. (1994) Arch. Dis. Childhood 71, 123-127]. We show in this paper that mononuclear cell extracts from one of these CDGS type-II patients have no detectable GlcNAc-TII activity and that similar extracts from 12 blood relatives of the patient, including his father, mother and brother, have GlcNAc-TII levels 32-67% that of normal levels (average 50.1% +/- 10.7% SD), consistent with an autosomal recessive disease. The poly(N-acetyllactosamine) content of erythrocyte membrane glycoproteins bands 3 and 4.5 of this CDGS patient were estimated, by tomato lectin blotting, to be reduced by 50% relative to samples obtained from blood relatives and normal controls. Similar to patients with hereditary erythroblastic multinuclearity with a positive acidified-serum lysis test (HEMPAS), erythrocyte membrane glycoproteins in the CDGS patient have increased reactivities with concanavalin A, demonstrating the presence of hybrid or oligomannose carbohydrate structures. However, bands 3 and 4.5 in HEMPAS erythrocytes have almost complete lack of poly(N-acetyllactosamine). Furthermore, CDGS type-II patients have a totally different clinical presentation and their erythrocytes do not show the serology typical of HEMPAS, suggesting that the genetic lesions responsible for these two diseases are possibly different.

Adolescent↗
PubMed1995

Endocrinology of the carbohydrate-deficient glycoprotein syndrome type 1 from birth through adolescence.

The carbohydrate-deficient glycoprotein (CDG) syndrome type 1 is a genetic multisystem disorder, characterized by hypoglycosylation of glycoproteins and presenting with neurologic impairment. In 12 girls and 14 boys, we confirmed the diagnosis of CDG syndrome type 1 by immune-isoelectric focusing of serum sialotransferrins, and we examined the endocrine status singly or sequentially, including a 16-y follow-up of the index cases, a pair of monozygotic girls. Serum FSH levels were normal in newborns and prepubertal children, but elevated in female toddlers and teenagers, as well as in adolescent males. Serum LH concentrations displayed an analogous age-dependent pattern. In adolescent girls, serum estradiol remained low. FSH bioactivity was low normal, as was the bioactive/immunoreactive FSH ratio. However, exogenous gonadotropins evoked an estradiol response and induced ovarian follicular growth. Male patients virilized at puberty; however, testicular volume was subnormal. The thyroid axis was hallmarked by thyroid-binding globin deficiency and, during infancy, increased serum TSH concentrations. A subgroup of female patients presented hypersomatotropism and/or hyperprolactinemia. During adolescence, the index cases responded to glucagon with normal glycemic, but exaggerated insulin and paradoxically augmented growth hormone responses. The hypothalamo-pituitary area appeared intact on magnetic resonance imaging. Circulating IGF-1 levels were in the lower normal range and transcortin concentrations decreased. In conclusion, a study of endocrine aspects of a major glycosylation disorder revealed an age-dependent constellation, including hypergonadotropic hypogonadism with deficient FSH rather than LH action; transient hyperthyrotropinemia; inconsistent hyperprolactinemia; hyperglycemia-induced growth hormone release; deficiencies of hormone-binding glycoproteins and possibly decreased insulin sensitivity, thus pointing to the importance of glycoprotein glycosylation for pediatric endocrinology.

Adolescent↗
PubMed1995

Thyroid function tests and characterization of thyroxine-binding globulin in the carbohydrate-deficient glycoprotein syndrome type I.

Carbohydrate-deficient glycoprotein (CDG) syndrome is a newly recognized hereditary disorder that presents with psychomotor retardation, cerebellar ataxia, peripheral sensorimotor neuropathy, and, variably, skeletal abnormalities, lipodystrophy, and retinitis pigmentosa. These abnormalities appear to be produced by a defect that causes reduced carbohydrate content in glycoproteins. We studied seven patients with CDG type I belonging to five unrelated families. The concentration of serum TBG, a glycoprotein of hepatic origin, was measured by RIA and T4 saturation and was found to be below the normal range in three of the seven patients and normal in four of them. More than half of the total serum TBG had reduced sialic acid content and localized on isoelectric focusing (IEF) as two prominent bands cathodal to the three major bands of normal TBG. The latter two bands are responsible for the characteristic IEF pattern or CDG syndrome. TBG in patients with CDG had immunoreactivity indistinguishable from that of normal TBG and had normal affinity for T4, T3, and rT3. Serum total T4, T3, and rT3 were below the normal range in seven, five, and seven patients, respectively. The free T4 index was also below normal in four patients, but the free T4 concentration, measured by equilibrium dialysis at low dilution, and serum TSH were in the midnormal range. The serum total T4 and rT3 levels were disproportionately reduced relative to the serum TBG concentration and compared to the concentrations of these iodothyronines in matched subjects with inherited partial TBG deficiency. Chronic illness cannot explain these changes, because, contrary to patients with nonthyroidal illness, those with CDG had significantly higher serum total T3/T4 and lower rT3/T4 ratios. It is concluded that IEF of TBG is a rapid and simple method for the diagnosis of CDG type I and that the abnormal pattern can be detected as early as 5 days postpartum. Patients with CDG are chemically euthyroid, and it is postulated that the reduction in serum iodothyronine concentrations beyond that explained on the basis of low TBG levels may be due to the interference with binding to TBG by an unidentified substance.

Adolescent↗
PubMed1994

Intractable asphyxia at birth: analysis of the underlying conditions.

A review of clinical and pathological data on 10,000 consecutive deliveries revealed that the incidence of unexpected and intractable asphyxia at birth despite adequate resuscitation was 0.24%. Lung hypoplasia appeared to be the underlying non-viable condition in 22 out of 24 infants. Attention is drawn to congenital neuromuscular disorders which were found to be the cause of lung hypoplasia in at least 4 out of 22 infants. Some helpful hints for diagnosis are given which may contribute to the final decision making.

Asphyxia Neonatorum↗
PubMed1994

Localized brain proton NMR spectroscopy in young adult phenylketonuria patients.

Localized proton magnetic resonance spectroscopy with short echo time (TE = 20 ms) was used to investigate biochemical changes in the cerebral white matter of 20 young adult patients (median 19 years) with phenylketonuria (PKU). Results were compared with those of a group of 12 age-matched healthy volunteers (median 25 years). Concentrations of N-acetyl-aspartate (NAA) and choline (Cho) relative to creatine (Cr) were unchanged. However, concentrations of inositol (Ins) relative to creatine were found to be significantly lower (P < 0.001) in the PKU patients (0.30 +/- 0.09 versus 0.57 +/- 0.17). Individual inositol concentrations did not correlate with age, diet, serum phenylalanine (Phe) levels or extent of pathological regions in the T2-weighted images. The lack of correlation with individual data suggests that the decreased inositol concentration could be related to a metabolic deficiency during fetal development. No signal from the phenyl ring protons of phenylalanine was detected in the PKU patients (phenylalanine serum concentration < or = 1.27 mM), which suggests that concentration of phenylalanine may be lower in brain than in serum.

Adolescent↗
PubMed1994

Cerebrospinal fluid as a tool in the diagnosis of neurometabolic diseases: amino acid analysis before and after acid hydrolysis.

We perform systematically amino acid analysis of the CSF before and after strong acid hydrolysis in children with unexplained neurological disease. By comparing the amino acid pattern before and after hydrolysis, defects can be traced in the metabolism not only of amino acids but also of purines, peptides, N-acetylated amino acids and peptides, and probably other compounds. This method has yielded important information such as the identification of two "new" diseases, GABA transaminase deficiency and adenylosuccinase deficiency, and the discovery of a peculiar, acid-labile double peak in the CSF of patients with the transient neonatal hyperammonaemia syndrome and with urea cycle defects. This substance was subsequently identified by others as gamma-glutamylglutamine. As a consequence, we strongly recommend incorporating of this approach in the investigation of all children with unclear neurological disease.

Adolescent↗
PubMed1994

Possible involvement of a gamma-hydroxybutyric acid receptor in startle disease.

Startle disease or hyperreflexia is an autosomal dominant neurological disorder, with a neonatal onset, characterized by muscular hypertonia and myoclonic jerks, exaggerated by the slightest stimulus. Low concentrations of free gamma-aminobutyric acid (GABA) have been found in the cerebrospinal fluid of two affected infants. The involvement of GABA or its receptors has been raised and the use of GABA-agonist drugs has been suggested. We report a newborn with startle disease who also had a low concentration of GABA in the cerebrospinal fluid. No clinical improvement was observed with progabide, a GABA agonist. Furthermore, a high dose (100 mg/kg) of gamma-hydroxybutyrate (GHB) did not improve muscular stiffness and failed to induce general anesthesia. GHB, currently used as an effective general anaesthetic, is a structural analogue of GABA. It is present naturally at low concentrations in the brain and is regarded as an inhibitory neurotransmitter. Two specific GHB receptors, distinct from the GABA receptors, have been identified in rat brain. Failure to induce general anesthesia with a high dose of GHB suggests that one of these receptors could be involved in startle disease.

Anesthetics↗
PubMed1994

Carbohydrate-deficient glycoprotein syndrome with previously unreported features.

A boy with carbohydrate-deficient glycoprotein syndrome died at five months of age in status epilepticus. Postmortem examination failed to show the classically observed olivopontocerebellar atrophy. Two previously unreported features were present: cataracts from the first week of life and lysosomal storage affecting mainly the anterior horn neurons of the spinal cord.

Brain↗
PubMed1994

Carbohydrate deficient glycoprotein syndrome type II: a deficiency in Golgi localised N-acetyl-glucosaminyltransferase II.

The carbohydrate deficient glycoprotein (CDG) syndromes are a family of genetic multisystemic disorders with severe nervous system involvement. This report is on a child with a CDG syndrome that differs from the classical picture but is very similar to a patient reported in 1991. Both these patients are therefore designated CDG syndrome type II. Compared with type I patients they have a more severe psychomotor retardation but no peripheral neuropathy nor cerebellar hypoplasia. The serum transferrin isoform pattern obtained by isoelectric focusing showed disialotransferrin as the major fraction. The serum disialotransferrin, studied in the present patient, contained two moles of truncated monoantennary Sialyl-Gal-GlcNAc-Man(alpha 1-->3)[Man(alpha 1-->6)]Man(beta 1-->4)GlcNAc (beta 1-->4)GlcNAc-Asn per mole of transferrin. A profoundly deficient activity of the Golgi enzyme N-acetylglucosaminyltransferase II (EC 2.4.1.143) was demonstrated in fibroblasts.

Carbohydrate Metabolism, Inborn Errors↗