Biomedical subjects
Publications and source records attributed to J Jaeken.
A boy with a new type of adrenoleukodystrophy is described. This was characterised by fetal and neonatal adrenal insufficiency, a neurological picture as seen in neonatal adrenoleukodystrophy, but with a normal number of peroxisomes in the liver and a peroxisomal dysfunction limited to the very long chain fatty acids and pristanic acid.
Carbohydrate-deficient glycoprotein syndrome type I is a multisystem disease with early severe nervous system involvement. The disease, which is inherited as an autosomal recessive trait, is biochemically characterized by complex defects in the terminal carbohydrate residues of a number of serum glycoproteins. This can be most readily detected in transferrin. A whole genome scan was initiated in order to localize the gene (CDG1) with linkage techniques. We analyzed individuals from 25 CDG1 pedigrees with several highly polymorphic microsatellite markers and after exclusion of about 30% of the genome linkage was detected with markers located in chromosome region 16p. The lod score (Zmax) was above 8 (theta max = 0.00) for several markers in this region. In order to further localize the CDG1 gene, recombination and linkage disequilibrium analyses were performed. Recombination events in some pedigrees indicated that the CDG1 gene is located in a 13 cM interval between microsatellite markers D16S406 and D16S500. Furthermore, allelic association was shown for marker D16S406 indicating that the CDG1 gene is located close to this. No heterogeneity could be detected in the European family material tested by us. The positions of cytogenetically localized flanking markers suggest that the location of the CDG1 gene is in chromosome region 16p13.3-p13.12.
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Adenylosuccinase (ASase) catalyses both the conversion of succinyl-aminoimidazole carboxamide ribotide (succinyl-AICAR) into AICAR and that of adenylosuccinate into AMP in the synthesis of purine nucleotides. Its deficiency results in the accumulation in body fluids of the nucleosides corresponding to both substrates, succinyl-AICAriboside and succinyladenosine. Two main subtypes of the defect are type I with severe mental retardation and succinyladenosine/succinyl-AICAriboside ratios around 1, and type II with slight mental delay and succinyladenosine/succinyl-AICAriboside ratios around 4. We report that in fibroblasts of type I patients, the activity of ASase with both adenylosuccinate and succinyl-AICAR is about 30% of normal. In contrast, in type II fibroblasts, the activity with adenylosuccinate is only 3% of normal, whereas that with succinyl-AICAR is also 30% of normal. If also present in other tissues, this non-parallel deficiency provides an explanation for the higher concentration of succinyladenosine in type II. In type I fibroblasts, ASase is further characterized mainly by a 3-fold to 4-fold increase in Km for succinyl-AICAR, and by retarded elution from an anion exchanger. In type II fibroblasts, ASase is characterized by a similar increase in Km for succinyl-AICAR but by a potent inhibition by KCl and nucleoside triphosphates, and by a normal elution profile. These results suggest a modification of the surface charge of ASase in type I, and the addition of one or more positively charged residues in the active site in type II.
In fibroblasts of severely retarded (type I) adenylosuccinase (ASase)-deficient children, activities with the two substrates of the enzyme, succinylaminoimidazole carboxamide ribotide (succinyl-AICAR) and adenylosuccinate are decreased in parallel, to about 30% of normal. In a markedly less retarded (type II) patient, ASase activity with adenylosuccinate reaches only 3% of normal, whereas activity with succinyl-AICAR is also about 30% of normal. To assess the functional significance of a partial versus a profound deficiency of ASase, precursor incorporation studies were performed in intact fibroblasts. In cells from controls and from type I patients, incorporation of 0.2 mmol/L [14C]formate into adenine and guanine nucleotides was not accompanied by accumulation of either [14C]succinyl-AICAR or [14C]adenylosuccinate. Similarly, incorporation of 20 mumol/L [14C]hypoxanthine was not accompanied by accumulation of [14C]adenylosuccinate. In contrast, in fibroblasts of the type II patient, in accordance with the profound deficiency of ASase with adenylosuccinate, and with the inhibitory effect of Cl- and nucleotides on the activity with succinyl-AICAR, incorporation of [14C]formate resulted in accumulation of [14C]succinyl-AICAR and [14C]adenylosuccinate, and incorporation of [14C]hypoxanthine in a marked build-up of [14C]adenylosuccinate. That both precursors were still incorporated into the adenine nucleotides of the fibroblasts of the type II patient indicates that adenylate synthesis remains possible even with 3% residual ASase activity, as also shown by their grossly normal ATP concentrations. The results suggest that the pathophysiology of ASase deficiency may be mediated at least in part by accumulation of succinyladenosine and succinyl-AICAriboside.
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Gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian central nervous system, is produced from glutamic acid in a reaction catalysed by glutamic acid decarboxylase. The sequential actions of GABA-transaminase (converting GABA to succinic semialdehyde) and succinic semialdehyde dehydrogenase (oxidizing succinic semialdehyde to succinic acid) allow oxidative metabolism of GABA through the tricarboxylic acid cycle. The inherited disorders of GABA metabolism include: (1) pyridoxine-dependent seizures (?glutamic acid decarboxylase deficiency) (> 50 patients); (2) GABA-transaminase deficiency (2 patients/1 family); (3) succinic semialdehyde dehydrogenase deficiency (32 patients/21 families); and (4) homocarnosinosis associated with serum carnosinase deficiency (3 patients/1 family). Homocarnosine is a brain-specific dipeptide of GABA and L-histidine. Of these four defects, definitive enzymatic diagnoses have been made only for GABA-transaminase and succinic semialdehyde dehydrogenase deficiencies. The presumptive mode of inheritance for all disorders is autosomal recessive, and all are associated with central nervous system dysfunction. Only succinic semialdehyde dehydrogenase deficiency manifests organic aciduria, which may account for the higher number of patients identified with this disorder; identification of additional patients with some of the other disorders will require increased request for analysis of cerebrospinal fluid metabolites by paediatricians and neurometabolic specialists.
L-2-Hydroxyglutaric acidaemia represents a newly defined inborn error of metabolism, with increased levels of L-2-hydroxyglutaric acid in urine, plasma and cerebrospinal fluid. The concentration in cerebrospinal fluid is higher than in plasma. The other consistent biochemical finding is an increase of lysine in blood and cerebrospinal fluid, but lysine loading does not increase L-2-hydroxyglutaric acid concentration in plasma. This autosomal recessively inherited disease is expressed as progressive ataxia, mental deficiency with subcortical leukoencephalopathy and cerebellar atrophy on magnetic resonance imaging. Since these features were described in 8 patients by Barth and co-workers in 1992, 4 more patients with similar findings have been diagnosed and added to the present series. L-2-Hydroxyglutaric acid is found in only trace amounts on routine gas chromatographic screening in normal persons, and its origin, its fate and even its relevance to normal metabolism are unknown. Therefore its catabolism was studied in normal liver. Incubation of rat liver with L-2-hydroxyglutaric acid did not produce H2O2, which excluded (peroxisomal) L-2-hydroxyacid oxidase as the main route of catabolism. However, L-2-hydroxyglutaric acid is rapidly dehydrogenated if NAD+ is added as a co-factor to the standard reaction medium. This could also be demonstrated in human liver. The preliminary evidence for this enzyme activity in rats and humans, L-2-hydroxyglutaric acid dehydrogenase, is given. Further investigations are required to clarify the possible relevance to the metabolic defect in L-2-hydroxyglutaric acidaemia.
The carbohydrate-deficient glycoprotein (CDG) syndromes are a newly recognized family of diseases with autosomal recessive inheritance. The basic defects are probably in the glycosylation pathway (endoplasmic reticulum, Golgi apparatus or post-Golgi). In the present state of our knowledge the central nervous system is always severely affected but nearly all other organs are involved to a variable degree. Like the peroxisomal disorders they also comprise dysmorphic features, the most typical being an abnormal distribution of subcutaneous adipose tissue. A reliable diagnostic test is isoelectric focusing of serum transferrin showing a cathodal shift as a consequence of the partial sialic acid deficiency. Prenatal diagnosis and heterozygote detection are not yet available. These diseases should be differentiated from secondary CDG syndromes such as classical galactosaemia.
The nutrient requirements of most (pre) term newborns receiving intensive care appear to be relatively fixed. The range of optimal fluid load however, is perceived as being quite narrow and highly variable in time. We designed four amino acid-dextrose mixtures for a standardized neonatal parenteral nutrition, delivering a fixed amount of nutrients in four dilutions with water and corresponding to a fluid load of 90, 110, 130 or 170 ml/kg per day. The addition of a lipid emulsion completes the TPN. In a pilot study, we followed the weight of 30 very low birthweight infants on this parenteral nutrition. After a stabilisation period, the weight gain was found to be similar to the normal fetal weight accretion in utero. We have now infused these solutions in to more than 1000 infants, without significant complications. These formulations proved to have substantial advantages compared to the individualized prescription in terms of availability, safety and time- and cost-effectiveness.
The carbohydrate-deficient glycoprotein syndromes are a recently delineated group of genetic, multisystemic diseases with major nervous system involvement. Three distinct variants have been recognized and there are probably many more. They are characterized by a deficiency of the carbohydrate moiety of secretory glycoproteins, lysosomal enzymes and probably also membranous glycoproteins. The biochemical changes are most readily observed in serum transferrin and the diagnosis is usually made by isoelectric focusing of this glycoprotein. The deficiency of sialic acid, in particular, results in a cathodal shift and hence the presence of abnormal isoforms of transferrin with higher isoelectric points than normal. The basic defects are probably in the processing and synthesis of the carbohydrate moiety of glycoproteins; there is indirect evidence for a deficiency of asparagine-N-linked oligosaccharide transfer in type I (endoplasmic reticulum defect) and for a deficiency of N-acetylglucosaminyltransferase II in type II (Golgi defect). From the large number of patients detected in only a few years, it is expected that these diseases will become as important as, for example, the lysosomal, peroxisomal or mitochondrial disorders. Their study will undoubtedly yield a wealth of new information on the function of glycoproteins and of their carbohydrate moiety.
The carbohydrate-deficient glycoprotein syndromes are a recently individualized group of genetic multisystemic disorders. A predominant feature is a severe involvement of the central and peripheral nervous system resulting in psychomotor retardation, seizures, ataxia, and, mostly after infancy, stroke-like episodes. The hallmark biochemical feature is a carbohydrate deficiency in a large number of serum glycoproteins. Because coagulation factors and inhibitors are also glycoproteins, we performed a systematic study of these factors and inhibitors in nine patients with carbohydrate-deficient glycoprotein syndrome. All showed a decreased activity of factor XI and of the coagulation inhibitors antithrombin III and protein C. In five of seven patients more than 1 y old, there was also a (less pronounced) decrease of protein S and of heparin cofactor II. This combined coagulation inhibitor deficiency could explain the stroke-like episodes occurring in these children.
Xeroderma pigmentosum (XP) and Cockayne syndrome (CS) are two rare inherited disorders with a clinical and cellular hypersensitivity to the UV component of the sunlight spectrum. Although the two traits are generally considered as clinically and genetically distinct entities, on the biochemical level a defect in the nucleotide excision-repair (NER) pathway is involved in both. Classical CS patients are primarily deficient in the preferential repair of DNA damage in actively transcribed genes, whereas in most XP patients the genetic defect affects both "preferential" and "overall" NER modalities. Here we report a genetic study of two unrelated, severely affected patients with the clinical characteristics of CS but with a biochemical defect typical of XP. By complementation analysis, using somatic cell fusion and nuclear microinjection of cloned repair genes, we assign these two patients to XP complementation group G, which previously was not associated with CS. This observation extends the earlier identification of two patients with a rare combined XP/CS phenotype within XP complementation groups B and D, respectively. It indicates that some mutations in at least three of the seven genes known to be involved in XP also can result in a picture of partial or even full-blown CS. We conclude that the syndromes XP and CS are biochemically closely related and may be part of a broader clinical disease spectrum. We suggest, as a possible molecular mechanism underlying this relation, that the XPGC repair gene has an additional vital function, as shown for some other NER genes.
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The pathophysiology of startle disease (hyperekplexia) is unknown. Hyperactivity of the brainstem reticular formation has been suggested as a cause. We report a newborn infant with classic features of startle disease in whom cerebrospinal fluid (CSF) concentrations of gamma-aminobutyric acid (GABA) were substantially lower than normal during the first weeks of life. She improved greatly on clonazepam treatment. We suggest that the signs of this disorder may be due to a genetic defect or to delayed maturation resulting in low CSF GABA.
Routine screening for organic acids revealed increased and isolated urinary excretion of L-2-hydroxyglutaric acid in 8 mentally retarded patients from five unrelated families, including three pairs of siblings. L-2-Hydroxyglutaric acid concentration was also found to be increased in the cerebrospinal fluid (CSF) and to a lesser extent in plasma. The only other biochemical abnormality was an increased concentration of lysine, both in plasma and in CSF. No organic acid abnormality was found on screening of asymptomatic family members. Patients were of either sex, and became symptomatic during childhood, with moderate to severe mental deficiency in all and definite cerebellar dysfunction in 7. Magnetic resonance imaging revealed an identical abnormal pattern with subcortical leukoencephalopathy, cerebellar atrophy, and signal changes in the putamina and dentate nuclei, in all patients. No specific biochemical function or catabolic pathway involving L-2-hydroxyglutaric acid is known in mammals, including humans. Preliminary loading and dietary studies failed to reveal the origin of the compound. The elevated CSF/plasma ratio suggests that it is in part generated within the central nervous system. This report describes a novel inherited neurometabolic disease, probably autosomal recessive, with distinct clinical, biochemical, and neuroimaging features.
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